CA2097892A1 - Prevention and control of cancer - Google Patents

Abstract

ABSTRACT
A method of conditioning the immune system in humans to resist the formation of one or more cancerous tissue types, comprising administering a non-toxic dosage amount of a composition comprising pharmaceutical excipients suitable for administration to a human, a therapeutically effective non-toxic dosage amount of a non-steroidal anti-inflamatory agent (NSAID),an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid and optionally vitamin C, which together are effective when the composition is administered to condition the immune system in humans to resist the formation of one or more cancerous tissue types.

Description

t~78~2 TITLE OF INVENTION
PREVENTION OF CONTROL OF CANCER.
FIELD OF INVENTION
This invention relates to the augmentation of body defences to prevent cancer, the prevention of cancer and the control of cancer.
BACKGROUND OF THE INVENTION
In an article entitled "Solid cores of tumors keeping out best drugs" by Sandra Blakeslee published in the July 8, 1989 edition of the Globe and Mail, Toronto, Ontario, Ms.
Blakeslee submitted that a growing number of researchers believe that a basic misunderstanding of the structure of solid tumors has led researchers into designing cancer drugs that are doomed to fail in many patients.
15She relates that, Dr. Herberman, Director of the Pittsburgh Cancer Center, said that for decades, cancer researchers have simply developed drugs, put them in the ~; bloodstream and assumed they would be carried to the tumor giving almost no consideration to how uniformly the drug is distributed once it reaches the tumor.
Her article also provided that according to Dr. Judah Folkman, a leading researcher on blood growth factors at the Harvard Medical School, for a long time, physicians have been taught that tumors outgrow their blood supply. According to the article that statement is not true. Tumors compress their blood supply. This compression makes it harder to administer drugs.
The article provides further that most people think a tumor is nothing but a collection of cancer cells. According to Dr. Jain, another researcher, in reality the tumor is only 50 - 2 - 2G97~92 per cent cells. The other half is blood vessels and interstitial space. Interstitial space in a tumor, he said, can be likened to the space between marbles packed in a box.
The article further provides that no matter how S biological agents are mixed and administered, they must cross a blood-vessel wall and then cross the interstitium to reach their targets, cancer cells. The article continues that every tumor is different and there are different regions within each. Moreover, tumors change daily as they grow and rearrange parts. Most blood vessels inside tumors are highly disorganized as they take tortuous turns and grow peculiar attachments to nearby vessels.
In general, Dr. Jain said, as a tumor grows, its outer region recruits new blood vessels from surrounding normal tissue. It also forms several abnormal blood vessels of its own. As the tumor grows in a confined space, many of the twisted blood vessels near its center are crushed. In turn, the tumor cells near them appear to die, although they grow into active cancer if transplanted in other animals. High pressures build up in these necrotic regions. Both blood vessels and liquid plasma in the interstitial spaces are squeezed. The pressure, therefore, prevents blood-borne molecules, including oxygen, from entering the central tumor areas.
Pressure is not uniform in normal tissue, Dr. Jain said, so a large molecule such as an antibody would reach its target through convection induced by pressure differences. But in the center of a tumor, pressure is uniformly high, blocking convection.
Molecules also migrate by diffusion Dr. Jain said, which is similar to the way a drop of ink spreads in water.
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- 3 - 2~97892 sut he indicated that he measured antibody diffusion in tumors and found that it can take days, weeks or months for such large molecules to reach uniform concentration by diffusion in tumors. By then, it may be too late for treatments to do any good.

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Finally, the fluid that builds up in the interstitium ., :~ :, ::: . .
slowly leaks out of the tumor, he said, washing away molecules trying to reach its center.
In the publication Ontario Medicine, Volume 8, No. 16 dated August 21, 1989 the article "Toxic drug tamed but still potent" describes how an experimental liposomal drug delivery system, is used to encapsulate a highly toxic but highly effective anti-fungal agent, demonstrating that noxious drugs can be transformed into non-toxic agents without compromising lS clinical efficacy.
The article concluded as follows~
"It was initially hoped that liposomes would offer considerable potential as a drug delivery system for almost all pharmaceutical agents. However, research into the drug delivery system over the past two decades has shown that the artificial, cell-sized spheres form spontaneously with only a small subset of drugs available today thus limiting their use."
Hoffer in a study explored the effects of ascorbic acid (Vitamin C) in respect of the health of patients. In the article he discussed the effects of Vitamin C with respect to cancer treatmert. He also discussed the findings of Cameron and Pauling of the use of ascorbic acid in 10 gram doses to treat cancer patients and which administration of the ascorbic acid increased the survival of terminally ill cancer patients. He ~ - 4 - 2 0 3 7 ~ ~ 2 :. ~ -, .
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also discussed the safety of the use of ascorbic acid and the safety in very high doses. He stated at page 11 of his study that the ascorbic acid was water soluble, was bulky but had no ~;;
LD-50. Hoffer states that - -~
S " When the vitamin cannot be absorbed completely from the gastrointestinal system, it will remain water in the bowel leading to diarrhea, which is watery but not dangerous unless it causes ~ ~-dehydration; it quickly forces patients to decrease the doses. It has and is being used by millions of ~-people in these doses. Patients I have known have taken 30 grams per day for 30 years. It is safer than common table salt, gram for gram. It does not cause kidney stones, does not cause pernicious IS anemia, does not make women infertile, does not cause cancer."
Hyaluronic acid is a naturally occurring glycosaminoglucan. Its molecular weight may vary from 50,000 ;,~
;~ dalton upwards, and it forms highly viscous solutions. As -~ `
regards the actual molecular weight of hyaluronic acid in natural biological contexts, this is still a matter of much uncertainty: When the molecular weight of hyaluronic acid is to be determined, different values are obtained depending on the assay method employed, and on the source, the isolation method 25 etc. The acid occurs in animal tissue, e.g. spinal fluid, ocular ~-,: :: .
fluid, synovial fluid, cockscombs, skln, and also in some ~ -streptococci. Various grades of hyaluronic acid have been ~-obtained. A preparation with an allegedly high degree of purity and alleged to be entirely free from side effects, is a non-~ `

'~` ~ ; '' ' 5 ~ 2 ~ 3 7 ~ 9 2 inflammatory form described in U.S. Patent No.4,141,973; this preparation is said to have a molecular weight exceeding 750,000 dalton, preferably exceeding 1,200,000 dalton and is suggested for therapeutic use in various articular conditions. -The Merck Index Specifies that Hyaluronic Acid has a .: ,:.: .: :,-.
Molecular Weight within the range pf 50,000 to 8 X 106 depending on source, methods of preparation and methods of determination. : ~
The Merck Publication teaches hyaluronic acid as a surgical aid ~ --(ophthalmological). -~ ~ -United States Patent 4,725,585 relates to a method of enhancing or regulating the host defence of a mammal, said method comprising administering to a mammal a therapeutically effective amount of hyaluronic acid.
At column 1 lines 43 - 46, the patent provides that the invention was based on the unexpected discovery that administration of hyaluronic acid to mammals results in a considerable increase in the defence.
The hyaluronic acid employed in the Patent was Healon ~ ~;
(T.M.) provided by Pharmacia AB, Uppsala, Sweden (Pharmacia AB
is also entitled to the benPfit of United States Patent 4,141,973). The patent provides at column 4, line 19 that because a patient's infections had been hard to treat, instead of just hyaluronic acid being administered to the patient to increase the patient's defence, the patient was given hyaluronic 25 acid and an antibiotic. While the patent states that the -~
antibiotic was given in combination with hyaluronic acid, in fact because the hyaluronic acid was administered subcutaneously and because the patient was a heart patient, one skilled in the art would understand that any antibiotic administered, while ~ . :. ,:-:::

- 6 - 2a37g92 : ~ ~

possibly administered simultaneously was definitely administered separately intravenously (probably) or intramuscularly (less probably). Thus, (most probably) the hyaluronic acid administered according to the teachings of this patent was administered in order to prevent possible development of infections (increase the host's defence) and not for any other reason.
There have been extensive studies to determine the defect in immune function that allows a tumor cell to develop.
It was postulated initially by Jerne, and subsequently by Burnett that the immune system's major role was that of immunological surveillance to destroy abnormal cells. The concept of surveillance, while somewhat simplistic, remains an accepted concept for the elaborate mechanism of immune recognition and function that is present in the higher species -mammals.
It has then been postulated that tumors develop because of local or generalized immune suppression. However, as pointed out by Moller, if general immune suppression occurs, it is only certain types of neoplastic disorders that develop, mainly those of the lympho-reticular system. This observation is correct and represents a major challenge to the immune surveillance theory unless a specific reason can be shown as to why the individual cancer cell can develop plus individually evade the immune system.
It was demonstrated experimentally in 1974 that defects of macrophage function may exist in neoplastic disease.
The initial experiments found suppressor cells to be part of the immune system; these were either of the T-cell type . :- .

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- 7 ~ 20~7~32 of the macrophage cell system. There was presence demonstrated in neoplasia, chronic bacterial infection, recovery from massive injury and chronic fungal infection.
- There has been repeated demonstration in experimental animals, that the macrophage cell function is altered in neoplastic disease. The macrophages in the animal's systems appeared "blocked" in their function. Generally when removed from the in vivo situation, washed in saline and cultured, they could perform normally. This block has been shown to be related to the excessive production of prostaglandin by neoplastic tissue or by the macrophage itself.
~ In the basic research efforts in the latter '70s and ^. the early 80's, there existed considerable confusion as to what role immunotherapy should take in cancer. Activation or "hyping" of macrophages was thought to be important. However, in an examination by Romans and Falk of peritoneal macrophages obtained from patients with neoplastic disease, there was ~ definite evidence that these macrophages were already activated ,~,1 yet were co-existing with cancer cells and not causing their ~! 20 destruction.
In the early part of 1989 it has been shown by several independent investigators that the malfunction of macrophages or the putitive block is due to excessive prostaglandin and that this can be altered in tissue culture by corticosteroids, ASA, ~,, and the non-steroidal anti-inflammatory drugs, i.e.
`~ indomethacin, and naproxen (Naprosyn~). Again, in animal tumors it was repeatedly demonstrated that these substances could alter the response to neoplastic cells and that various combinations of these substances employed with immune enhancing - 8 - 2037832 ~
.
agents could produce very credible success in eliminating experimental tumors. Lala and co-workers combined Indomethacin therapy with Interleukin 2 and showed that this could effect a cure with experiment neoplasm.
S There were continued problems with the use of any of these agents in the actual human in vivo experience. All of the non-steroidal anti-inflammatory agents (NSAID) produced major toxicity in terms of gastro-intestinal, neurological, and other areas. Thus, the basis of the present approach is that under general circumstances the use of these agents in human disease, in sufficient amounts, the drug will penetrate to any pathological tissue to alter therapeutically local prostaglandin production. While intravenous preparations exist of Indomethacin and now of other agents, the data is overwhelming, as is our own experience, that using these drugs alone produces prohibitive side effects in human subjects. Therefore only insufficient amounts can be brought into the body to effect more than occasional responses in neoplasm.
However the majority of the evidence is present to indicate and therefore it can be postulated that the basis for neoplastic development and how the initial cell "sneaks by" the immune surveillance mechanism relates to its production of ; prostaglandin. One need postulate only one mutation to alter the amount of prostaglandin synthesis produced by cells when they become "malignant" to establish a mechanism of blocking out the initial ceIl in any immune reaction, i.e. the macrophage.
It therefore became essential to develop a combination of NSAIDS
for clinical use to produce a major improvement in response in neoplastic disease and other conditions where excessive 9- 2~37~92 .. ~.
prostaglandin synthesis represents the basis of the pathogenesis of this disease state, i.e. arthritis, and various others of the so-called connective tissue inflammatory disorders and/or auto- ~;~
aggressive diseases. ; ~ -; 5 In the Article entitled "Aspirin Use and Risk of Fatal Cancer~ by Michael J. Thun et al., reported reduced risk of 7 ~ fatal colon cancer among persons who used aspirin in a large ;~. ;
prospective study and reported on other fatal cancers in ~ , relation to aspirin among 635,031 adults in that study. ` "~
This analysis examines other fatal cancers in relation -to aspirin among 635,031 adults in that study who provided - `
information in 1982 on the frequency and duration of their ~ :
-. . , ~ .
aspirin use and did not report cancer. Death rates were measured through 1988. Death rates decreased with more frequent aspirin use for cancers of the esophagas, stomach, colon, and ~ rectum but not generally for other cancers. For each digestive ~-,i~ tract cancer death rates were approximately 40% lower among persons who used aspirin 16 times/month or more for at least 1 year compared to those who used no aspirin. The trend of decreasing risk with more frequent aspirin use was strongest among persons who had used aspirin for 10 years or more; it remained statistically significant, except for esophageal ~ cancer, in multivariate analyses that adjusted for other known ;~ risk factors. Biases such as early detection or aspirin avoidance among casts do not appear to explain the results. Our data suggest that regular, prolonged use of aspirin may reduce the risk of fatal cancer of the eyophagus, stomach, colon, and rectum. Future epidemiological and basic research should i~
-~ examine all digestive tract cancers in considering the ~-.'.,.~ i:~ .. " ~

lo - 2 ~ 9 7 8 9 2 chemopreventive or therapeutic potential of non-steroidal anti-inflammatory drugs.
In "Could Aspirin Really Prevent Colon Cancer" The New -~
En~land Journal of Medicine, Volume 325, No. 23 at 1644, -successful use of nonsteroidal antiinflammatory drugs are used to prevent carcinogen-induced intestinal cancer in animals stating~
Indomethacin and piroxicam consistently prevent ~
carcinogen-induced intestinal cancer in animals. In rodents ~-these drugs are effective against agents acting either directly or indirectly, and they are active when given several weeks after the administration of a carcinogen, as well as earlier, during the early-promotion or late-initiation phases of .,: ~
carcinogenesis. The anti-cancer effect is reversible; the `~
incidence of tumors increases shortly after the agent is discontinued. Experimental data in humans are scanty; in ~;;
:., :: .
~ studies of patients with Gardner's syndrome, the administration , :: :
of sulindac appears to cause the regression of large-bowel ~ polyps. ~ ;

20 How might aspirin prevent colon cancer? Despite . :. ~ ~.. ::
having different chemical structures, aspirin and other NSAIDs inhibit cyclooxygenase and thereby block the production of prostaglandins. The effects of prostaglandins in carcinogenesis ~-~
are not clear; in mouse skin and colon, however, NSAIDs inhibit ,,i : .
25 tumor-promoter-induced increases in ornithine decarboxylase ~ -activity and cellular proliferation, both of which may be a;
mediated by prostaglandin E2. Beneficial effects on immune responses have also been proposed. 10 Interestingly, NSAIDs by ;- -~
themselves seem to have little or no effect on cellular ;~

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2~97892 proliferation; they may even increase proliferation in the mucosa of the large bowel, which in itself would seem to -? ~
increase, rather than diminish, the risk of cancer.
NSAIDs, including aspirin, may be particularly desirable agents for preventing colon cancer. A pill, even one that requires regular administration, would probably be more acceptable to the public than an overhaul of lifestyle or diet.
Despite the promise of these agents, however, current information is clearly inadequate to support their widespread use for cancer prevention.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to have anticancer activity in cancer patients ,~ (Panje, 1981; Hirsch et al, 1983) and in animals (Plescia et al, ~ 1975; Fulton, 1984; Rubio, 1986), this effect may be : -~
15 attributable to NSAID-mediated inhibition of the cyclooxygenase `

pathway, and specifically to reduced prostaglandin E2 (PGE2) .~ .
~ synthesis PGE2 is known to attenuate cell-mediated immunity; in "~ particular, this prostaglandin inhibits natural killer (NK) cell cytotoxicity (Hrunda et al, 1980), mitogen-induced lymphocyte ; 20 proliferation (Tilden and Balch, 1982) and macrophage (M0) proliteration and antitumor cytotoxicity (Elliott et al, 1988).
The antitumor activity of NSAIDs is synergistic with ~..- :.::
, that of interferon-gamma (IFN-g) (Kim and Warnaka, 1989).

Hannigan and Williams (1991) have postulated that the anticancer 25 activity of IFN-g is mediated through inhibition of PGE2 ~ ~-synthesis; IFN g promotes rapid hydrolysis of the prostaglandin precursor and major cyclooxygenase pathway substrate arachidonic ; ~-acid. This lymphokine has been used to treat cutaneous basal ;~
and squamous carcinomas in clinical trials. Unfortunately, the .~ , -.

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~: 2~978~2 anticancer efficacy of IFN-g demonstrated in these trials has been offset by adverse effects.
Topical NSAID preparations have been used in the treatment of minor, superficial musculoskeletal disorders in ;~
Europe and Asia (Russell, 1991; Kroll et al, 1989).
SUMMARY OF THE INVENTION
When applied in a hyaluronic acid (HA)-based vehicle (eg. sodium hyaluronate), NSAID biodistribution appears to be confined to the epidermis and superficial dermis (Wagener and Chlud, 1992); this vehicle allows drug to be delivered specifically to the skin with little or no systemic absorption.
We report the results of a prospective study of anticancer efficacy of topical application of the NSAID, diclofenac, administered in a HA vehicle, in patients with .
nonmelanoma skin can_er.
One hundred patients with biopsy-proven basal cell carcinoma of the skin were entered into this study by five participating physicians between July, 1991 and December, 1992.
~ , ; The majority of patients had multiple superficial lesions on the hands and face, these were either primary and persistent in .
nature or represented recurrent disease. Papular, nodular, ulcerative and cystic variants of basal cell carcinoma were excluded from the study. Except for one instance periorbital basal cell carcinomas were excluded to minimize the risk of 25 ocular irritation. `~
~Patients were supplied with the gel formulation and ; advised to apply 0.5 gm twice daily to the skin lesions under : . . :.
study. One of the five physicians directed a selected patient -~

to apply the gel only once per week, keeping the area covered ~q ~ .. :

"~ - 13 ~ 20~7~92 with an occlusive dressing between applications. Clinical assessments were made at intervals of 4 weeks. Treatment duration ranged from 6 to 20 weeks. By visual clinical observation, all patients' tumors responded within 4 weeks of starting treatment, most tumors underwent complete regression by week 8.
There were a number of interesting observations made in the course of this trial. In one patient with multiple basal cell cancers over the arms, hands and right ear, all lesions except the ear tumor underwent rapid and complete regression.
When ~uestioned, he admitted that the ear had not been treated because of concerns about getting the gel in his hair. The ear lesion was briefly treated and then excised; histology showed an intense mononuclear inflammatory response with a few residual tumor cells remaining.
Four weeks of treatment with the gel formulation containing 2.5% sodium hyaluronate and 3% Diclofenac in 50 gram tubes resulted in disappearance of the lesion, and treatment continued for a further six weeks. The patient remains free of disease at 20 months follow-up.
In patients whose tumors had been completely eradicated by the HA/diclofenac gel, there arose the question of what further treatment or precautions should be taken above and beyond close surveillance. These patients were advised to avoid sun exposure or sue high SPF sunscreen formulations. After any prolonged sun exposure irrespective of the use of sunscreen, they were directed to apply the HA/diclofenac gel to the lesion site. With this regimen, there has been no recurrence of tumor in any patient to date (follow-up 12 to 20 months).

2097892 ~ ~ ~
The a~ueous sodium hyaluronate diclofenac gel was tested in an initial Phase I trial of 24 patients. It was established that the gel could be applied as often as 12 times daily to the same skin site without adverse consequence (unpublished data). There was one patient with a past history of gastrointestinal sensitivity to oral NSAIDs who developed heartburn during treatment with the topical preparation; there ::- :. .:: ~
were otherwise no systemic effects related to the therapy.
In six of the 100 patients, a persistent erythematous inflammatory reaction was noted following disappearance of the basal cell carcinoma. The HA/diclofenac gel was replaced with plain 2.5% HA gel, and the inflammation resolved. When the HA/diclofenac was restarted, the erythema did not recur.
The results herein demonstrate that percutaneous administration of the NSAID diclofenac in a HA gel vehicle is highly efficacious in treating superficial basal cell carcinoma.
The method of treatment is simple, the formulation well tolerated, and patient compliance high. In addition, ongoing experience with HA/diclofenac suggests that intermittent application of the gel appears to prevent the development of new basal cell cancers and should be used as prophylaxis in patients at high risk because of extensive previous sun exposure.
The erythematous reaction noted in six patients was : -.
initially thought to be a hypersensitivity phenomenon; the formulation was withdrawn and then re-administered to test this impression. Failure of the reaction to recur on the second challenge with the HA/diclofenac suggests that this is not the cause. We postulate that the skin in which basal cell cancers develop harbors nonmalignant and premalignant W radiation-- :.: ~:..~, '' ;, ;'''~'.'''..'`' ~ 2~7$~ :

damaged cells. With NSAID-mediated inhibition of local prostaglandin production, resident cutaneous immune cells such as the cells of Langerhans become cytotoxic to these elements as well as to the cancer, resulting in a classical cell-mediated delayed hypersensitivity reaction which proceeds over the course of 3 to 14 days. Rechallenge with HA/diclofenac after subsidence of the reaction does not provoke further response as these abnormal but nonneoplastic cells may already have been destroyed.
HA/diclofenac topical therapy is conceptually attractive as compared to conventional treatment such as surgery, cryotherapy, fulguration, Mohs' chemosurgery, radiotherapy or topical 5-fluorouracil. It is a simple, well tolerated and cost-effective treatment for the most common group lS of neoplasms seen in North America today.
Further, four years ago we began our studies with a group of drugs known as non-steroidal anti-inflammatory drugs abbreviated in the literature as NSAIDs. These drugs have been used in medicine for 30 years and are know to effect prostaglandin synthesis and thus reduce pain and inflammation.
~here are many experimental animal tumour systems where these drugs have been shown to inhibit tumour growth to a major extend. Several different clinical studies were initiated with ~ these drugs; however, they could never achieve their potential i~ 25 in cancer therapy because of the major toxicity to the gastrointestinal tract ie. the development of ulcers.
We had begun to use a carrier molecular, a form of hyaluronic acid (HA) (for example, sodium hyaluronate), because it helped transport drugs to penetrate into tumour tissue.

2B~7$~

Thus, with HA we could use cytotoxic drugs and produce more tumour cell destruction. With improved tumour cell destruction we became aware that further therapeutic measures were required ~ -;
to help the body scavenge and eliminate dead tumour cells. We identified the NSAID drugs which can enhance NK cell +
macrophage (scavenger cell) function. We were aware of the prohibitive toxicity of these drugs at parenteral doses. We asked the question in animal experiments whether the HA would alter the targeting of the NSAID series of drugs and this proved to be the case. It not only altered the targeting of drugs but also produced a 'sustained release' effect. Through these two phenomena it allowed us to increase the dose of these drugs and give them intravenously safely at three to four times the -previous doses. Also, we could administer these drugs repeatedly on a daily basis for a month or more. Not only did this allow us to eliminate the terrible pain suffered by cancer victims but through the inhibition of prostaglandin production we improved the macrophage/natural killer cell function and observed significant improvement in the clinical course of metastatic tumours.
We then combined these drugs (NSAIDS and HA) with sodium ascorbate (Vitamin C). This classical anti-oxidant drug ~i (Vitamin C) has been at the centre of a major controversy for years. Vitamin C has excellent anti-oxidant effects; given in combination with the NSAIDS and HA it helps reduce excessive prostaglandin production and enhances the production of -~
prostacycline. Using this combination with standard cyto-destructive therapy we improved our results in cancer treatment. -The reason for the improved results is two-fold we ~

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- 17 - 2~37892 believe. First, the NSAIDS inhibit without decreasing the immune response as do the corticosteroids. This inhibition of prostaglandin production allows for improved function of the body's natural killer and scavenger cells.
This allows for enhanced tumour destruction and improved elimination of the dead tumour tissue. This, however, by itself would not explain why in a number of cases the NSAIDS, sodium ascorbate, HA produced inhibition of tumour growth over an extended period of time. A group of investigators working with our pharmaceutical division then gave us the clue as to why there was this effect. The growth and metastases of tumour cells depends on the phenomena of new, abnormal blood vessel development (neoangiogenesis). These investigators showed that NSAIDS/HA could prevent neoangiogenesis in an experimental situation. This was of very major significance; the pursuit of drugs to block tumour neoangiogensis has been ongoing on for 30 years at considerable expense with minimal success. The drug combinations that we have developed can block this phenomena and ~, . .
' through it and the inhibition of prostaglandin produce control -~
20 of cancer growth by an entirely non-toxic combination of ;
therapy. ;
One of the most well known anti-inflammatory drugs i used routinely is aspirin a non-steroidal antiinflammatory drug. ~-To a major extend aspirin functions in a similar fashion to the ; - `
~-~ 25 NSAID series of drugs. Recently, there have been four articles ~ in the scientific literature indicatlng that the routine ù~ consumption of one aspirin a day (two of which articles are j~
'' referred to herein), decreases the incidence of the development ~ .
of at least four different types of cancer. These articles : . . .
, .

- 18 - 2 ~ ~ 7 8 9 2 . ~

discuss why aspirin should have this effect. In summary, the authors are uncertain as to why this benefit should be produced -,. . - :-by one aspirin tablet per day.
The answer to these questions are available through our studies. Aspirin reduces prostaglandin production and alsodecreases the coagulative properties that normal blood has by reducing the production of a substances called Thromboxine.
Through this mechanism aspirin has been shown to be beneficial in decreasing the incidence of first and second heart attacks, strokes and improving the vascular circulation throughout the human body. The demonstration that aspirin can prevent the development of cancer to a significant extent, is not at all mysterious. It is related to the phemonena that I have described. The future of aspirin and the NSAID series of drugs in terms of the prevention of cancer and circulatory disease is at hand.
Our work with the NSAID series of drugs provides the .: :,. .: .
answer for why the observed phenomena occured. It is highly !.'''.:'.'`,"'''',''' ~. :: ::- ' : :'..
significant that such a relatively simple drug as aspirin without prohibitive side effects, can impact on three of the major causes of death; heart disease, cerebral vascular disease : ` ': . - ' ", ' and cancer.
In our therapeutic models we have used NSAIDs, sodium ascorbate in HA intravenously in conjunction with cytotoxic therapy. Once the therapy is underway, the patient can maintain the inhibition of prostaglandin production and prevent tumour neoangiogenesis by simply using oral NSAIDS (motrin, diclofenac, ;~ or aspirin).
In our studies we have produced a major impact on all , ~ ~

- 19 - 2037~92 basal cell carcinomas as discussed. This is possible due to the tremendous usefulness of the topical gel NSAIDS, (diclofenac in HA) .
The next step is conclusive to use the same type of drugs in a different fashion to l) prevent cancer and 2) control established cancer. This is of critical importance in the present climate with the emphasis on controlling health care costs. Not only can these agents be utilized to prevent disease ~ -but they can control existing disease phenomena at a very low 10 cost. -~
It is therefore as will be appreciated by a person skilled in the art, an object of the invention to provide a regimen, prophylaxis and method to argument the body defences to prevent the development of cancer into a raging disease.
It is as will be appreciated by a person skilled in . .:: .: ,.,::::
the art a further object of the invention to provide a regimen, prophylaxis and method to prevent cancer for example basal cell carcinoma.
It is as will be appreciated by a person skilled in : - - ;
20 the art still a further object of the invention to provide a ~ -regimen, and method to control cancer.
It is still a further object of the invention to provide a regimen and method to augment the body defences in the control of cancer.
It is as will be appreciated by a person skilled in ;.-~
the art still a further object of the invention to provide formulations and compositions suitable for use with such regimens, methods and prophylaxis.
Further and other objects of the inventions will be ~::

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~ ' ~: : . : ' ' - 20 - 2~97892 realized by those persons skilled in the art from the disclosure herein. -According to one aspect of the invention there is provided a method of preventing cancer for example by conditioning the immune system in humans to resist the formation of one or more cancerous tissue types, comprising administering a non-toxic dosage amount of a composition comprising i~
pharmaceutical excipients suitable for administration to a ;-human, a therapeutically effective non-toxic dosage amount of a non-steroidal anti-inflammatory agent (NSAID),an effective non~
toxic dosage amount of hyaluronic acid and/or salts thereof -and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid and optionally an ~ -effective amount vitamin C, which together are effective when : 15 the composition is administered to prevent cancer in a human In one embodiment the form of hyaluronic acid is ;
hyaluronic acid and salts thereof. ~ ;
In one embodiment wherein the amount of the hyaluronic `~
acid exceeds about 5mg. ; - i;;``
In one embodiment wherein the pharmaceutical- ~ ;~
composition is for topical application to the skin and/or --exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg/cm2 of skin and/or exposed tissue to which it is applied.
In one embodiment the amount of the form of hyaluronic acid exceeds about 10 mg. per 70 kg person.
In one embodiment pharmaceutical composition is for ~-~
systemic administration and the amount of the form of hyaluronic acid exceeds about 200 mg/70kg person. ~
' ' In one embodiment the pharmaceutical composition is for systemic administration, and wherein the composition comprises vitamin C and the amount of the form of hyaluronic acid exceeds about 200 mg/70kg person.
5In one embodiment the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.
In one embodiment the non-steroidal anti-inflammatory drug ~NSAID) is selected from Diclofenac in an amount selected i-from between about 35 mg and about 500 mg/70 kg. person.
lOIn one embodiment the NSAID is selected from ;~
diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of ketorolac), ibuprofen, piroxicam, propionic Acid derivatives, aceytylsalicylic acid and Flunixin. ;~
In one embodiment the development of the cancerous tissue is attributable to prostaglandin synthesis.
In one embodiment a dosage amount of the composition is administered after any prolonged sun exposure.
In one embodiment the composition is administered intermittently in humans at high risk for the development of 20 skin cancer due to extensive sun exposure. ;
According to another aspect of the invention there is ~ provided a method of preventing the spread and/or metastasis of ,l one or more cancer tissue types in humans, comprising :
administering a non-toxic dosage amount of a composition ; 25 comprising pharmaceutical excipients suitable for administration ;~ --to a human, a therapeutically effective non-toxic dosage amount of a non-steroidal anti-inflammatory agent (NSAID), an effective '~
~ ; non-toxic dosage amount of hyaluronic acid and/or salts thereof ;~ and/or homologues, analogues, derivatives, complexes, esters, - `

- 22 - 2~37~92 ::
-~
fragments, and/or sub-units of hyaluronic acid and optionally an ~ -effective dosage amount of vitamin C, which together are effective when the composition is administered to prevent the spread of metastasis of one or more cancerous tissues in a -;
human.
In one embodiment the form of hyaluronic acid is hyaluronic acid and salts thereof.
In one embodiment the amount of the hyaluronic acid i~
exceeds about 5mg. -In one embodiment the pharmaceutical composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg/cm2 ~-~
of skin and/or exposed tissue to which it is applied.
In one embodiment the amount of the form of hyaluronic ~ -~
15 acid exceeds 10 mg. per 70 kg person. - ~P
In one embodiment the pharmaceutical composition is - -for systemic administration and the amount of the form of hyaluronic acid exceeds about 200 mg/70kg person.
In one embodiment the pharmaceutical composition is 20 for systemic administration, and the composition comprises ~ -vitamin C and the amount of the form of hyaluronic acid exceeds about 200 mg/70kg person.
In one embodiment the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.
In one embodiment the non-steroidal anti-inflammatory drug (NSAID) is selected from Diclofenac in an amount selected . - . , .
from between about 35 mg and about 500 mg/70 kg. person.
In one embodiment the NSAID is selected from diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of - 23 - 2~37~92 ketorolac, ibuprofen, piroxicam, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin. -In one embodiment the treatment is administered - .-daily for a number of weeks.
In one embodiment the treatment comprises administering effective dosage amounts of the composition, a number of times daily for a period of weeks.
According to another aspect of the invention there is provided a sunscreen composition including a plurality of effective non-toxic dosage amounts of a composition for administration to humans to prevent cancer, for example condition the human immune system to resist formation of one or more types of skin cancer tissues each such dosage amount comprising a therapeutically effective non-toxic (to the patient) dosage amount of a non-steroidal anti-inflammatory drug, optionally an effective dosage amount of vitamin C and an effective non-toxic dosage amount of hyaluronic acid and/or . . .
salts thereof and/or homologues, analogues, derivatives, ,~ complexes, esters, fragments, and/or sub-units of hyaluronic acid to condition the human immune system to resist formation of one or more types of cancer.
In one embodiment of the sunscreen composition also comprises an amount of a composition which provides SPF (Sun Protection Factor) which is acceptable - for example greater than Number/5 and preferably about 29.
In one embodiment each of the plurality of effective non-toxic dosage amounts of the composition making up the pharmaceutical composition comprises at least about 5 mg of the form of hyaluronic acid.

l ~ ~ ' : $ - ;: ` . ~ ~

- 24 - 20378~2 :;

In one embodiment the pharmaceutical composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg.
In one embodiment the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid is hyaluronic acid and/or a salt thereof.
In one embodiment the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.
In one embodiment the non-steroidal anti-inflammatory drug (NSAID) is Diclofenac.
In one embodiment the NSAID is selected from diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of ketorolac, IBUPROFEN, PIROXICAM, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin.
According to another aspect of the invention there is provided a pharmaceutical composition from which dosage amounts may be taken and administered to inhibit the formation of basal cell carcinoma in humans the pharmaceutical composition comprising~
(1) a non-steroidal anti-inflammatory agent; and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, in a form suitable for administration to humans; characterized in that an effective dosage amount comprising effective non-toxic dosage amounts of components (1) and (2) taken and administered from said composition (i) are in a form available to inhibit the formation of basal cell carcinoma.

~ ' ~ ` ' , '`, ' . "~

- 25 - 2037892 ;::
.

In one embodiment the composition comprises a sunscreen agent having a acceptable SPF (Sun Protection Factor) number for example of at least about 15 and an effective amount of Vitamin C. ,-~ `
In one embodiment the effective non-toxic dosage amount of component (2) comprises an effective non-toxic dosage ~ ;
amount of at least about 5 mg in the dosage amounts taken from -the pharmaceutical composition to be administered. ~
In one embodiment the pharmaceutical composition is ~ - -10 for topical application to the skin and/or exposed tissue and ~- ?
the effective amount of the form of hyaluronic acid taken from -the composition exceeds about 5 mg/cm2 of skin to which it is to be applied.
In one embodiment the pharmaceutical composition is for systemic administration and the amount of the form of hyaluronic acid exceeds about 10 mg/70 kg person and preferably :~: .: .
200 mg/70 person. ` ~
:
In one embodiment the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and/or sub-units of hyaluronic acid is hyaluronic acid and/or a salt thereof.
In one embodiment the molecular weight of the form of hyaluronic acid is less that about 750,00 daltons.
In one embodiment the non-steroidal anti-inflammatory drug (NSAID) is Diclofenac.
According to another aspect of the invention a ~ ;
sunscreen composition including a plurality of effective non- ~ -toxic dosage amounts of a composition for preventing the spread and/or metastasis of one or more cancer tissue types in humans, -~ `, - 26 ~ 7`89~

is provided each such dosage amount comprising ingredients including sun-screen agents having an acceptable SPF number (Sun Protection Factor) preferably greater than 15, constituting an effective sunscreen composition, a therapeutically effective non-toxic (to the patient) dosage amount of an non-steroidal - , anti-inflammatory drug, optionally vitamin C and optionally an effective non-toxic dosage amount of hyaluronic acid and/or :" .,, salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic ~;~
:.: -.~: -:.- .
acid to condition the human immune system to prevent the spread and/or metastasis of one or more cancer tissue types in humans.
.
According to another aspect of the invention the sun screen composition may be used to prevent skin cancer for example basal cell carcinoma, the said composition comprising sun screen agents having a acceptable SPF number (Sun Protection Factor) preferably greater than 15, suitable excipients for the sun screen composition and a non-steroidal anti-inflammatory for example diclofenac, in suitable dosage amounts. The sun screen composition may also comprises optionally Vitamin C and optionally a form of hyaluronic acid (for example hyaluronic acid and/or salts thereof (sodium hyaluronate)) to transport the Vitamin C, the sun screen agent, and NSAID as the case may be to protect the skin. The composition is such to contain a plurality of dosage amounts which can be taken from the composition and applied (for example each dosage amount . ~

; containing in eXcess of about 5 mg/cm2 of skin to which it will be applied. ~-~
According to one aspect of the invention there is provided the use of~
~'.'':.'.',.^.~....

- 27 _ 2 ~ 3 7 8 9 ~

(a) a non-steroidal anti-inflammatory agent, and (b) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, and optionally an effective dosage amount of Vitamin C in the manufacture of a pharmaceutical composition for inhibiting the formation of cancer in a therapy wherein dosage amounts taken from the composition each comprise~
(l) a therapeutically effective amount of component (a); and (2) a therapeutically effective amount of the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub~
units of hyaluronic acid, and an effective dosage amount of Vitamin C where present the pharmaceutical composition being characterized in that for each dosage amount taken from the pharmaceutical composition, the amount of components (a) and (b) and Vitamin C (where present) prevent cancer.
In one embodiment the component (b) is hyaluronic acid and/or salts thereof having a molecular weight less than about 750,000 daltons.
In one embodiment the dosage amount of component (b) in an amount of the composition taken from the composition (to be taken from the composition) and administered is present in a , ;, dose amount greater than about 5 mg. `
n one embodiment the pharmacéutical composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg.

- 28 - 2 0 ~ 7 ~ 9 2 In one embodiment the pharmaceutical composition is i~
for systemic administration and the amount of the form of hyaluronic acid exceeds about 10 mg. per 70 kg person and , ~
preferably exceeds about 200 mg/70kg person. - - -In one embodiment the component (a) the non-steroidal anti-inflammatory drug (NSAID), is selected from diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of ketorolac, IBUPROFEN, PIROXICAM, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin.
According to another aspect of the invention there is provided the use of~
(1) a non-steroidal anti-inflammatory agent (NSAID), and ~-~
';: ~. .
(2) hyaluronic acid and/or salts thereof, (3) a composition having an SPF factor and (4) optionally Vitamin C
in the manufacture of a pharmaceutical composition for topical application for preventing the development of basal cell i~ carcinoma in humans in a therapy wherein a dosage amount comprises a therapeutically effective amount of said agent (1) ` and a therapeutically effective amount of the hyaluronic acid ' and/or salts thereof having a molecular weight less than about , 750,000 daltons, an effective amount of (3) and if present an ;-~
effective amount of (4) the use being characterized in that the amount of components (1) and (2) and (4) if present are immediately available upon administration. ~-`
~ In one embodiment the dosage amount of component (2) f'' iS present in a dose greater than about 10 mg. ~-In one embodiment the composition comprises ~ ~

- 29 - ~
--~ 2~78~2 :~
pharmaceutically compatible excipients to provide a form for ease of administration.
According to another aspect of the invention there is provided a container containing a composition for administration S to a human for the prevention of cancer in humans, the composition comprising a plurality of dosage amounts of each of (a) an NSAID and (b) hyaluronic acid and/or sodium hyaluronate and optionally Vitamin C, each dosage amount comprising an effective non-toxic dosage amount of each of the NSAID and hyaluronic acid and/or sodium hyaluronate and where present Vitamin C to prevent cancer in a human.
In one embodiment the pharmaceutical composition comprises a sunscreen having an acceptable SPF (Sun Protection Factor) number (for example exceeding about 15) and is for topical application.
In one embodiment the hyaluronic acid and/or sodium hyaluronate has a molecular weight less than about 750,000 daltons.
In one embodiment the effective dosage amount of the hyaluronic acid and/or sodium hyaluronate is in a dosage amount exceeding 5 mg of the hyaluronic acid and/or sodium hyaluronate in the dosage amount administered.
In one embodiment the pharmaceutical composition is for topical application to the skin and/or exposed tissue and the dosage amount of the form of hyaluronic acid exceeds about ~; 5gm.
In one embodiment the pharmacéutical composition is for systemic administration and the amount of the form of hyaluronlc acid exceeds about 10 mg/70 kg person and preferably .. . : ~

~ 30 - 2 ~ 3 7 8 ~ 2 200 mg/70kg person.
According to another aspect of the invention there is provided the use of an effective dosage amount of a composition comprising an effective dosage amount of an NSAID and an -effective non-toxic amount of hyaluronic acid and/or salt thereof and optionally an effective dosage amount of Vitamin C
sufficient upon administration to augment body defences to prevent cancer in a human.
In one embodiment the amount of hyaluronic acid and/or salts thereof exceeds at least about 5mg.
In one embodiment the amount of the hyaluronic acid and/or salts thereof exceeds 10 mg. ;
In one embodiment the pharmaceutical composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg/cm of skin and/or exposed tissue.
In one embodiment the pharmaceutical composition is for systemic administration and the amount of the form of hyaluronic acid exceeds about 200 mg/70kg person. ;-In one embodiment the molecular weight of the ; ;
hyaluronic acid and/or salts is less than about 750,000 daltons.
According to another aspect of the invention there is provided the use of a pharmaceutical composition to control cancer in patient by the administration of the composition administered comprising together with pharmaceutical excipients suitable for the route of administration, a therapeutically effective non-toxic (to a human) amount of a non-steroidal anti-inflammatory and an effective non-toxic dosage amount of at least about 5 mg of hyaluronic acid and/or salts thereof having - 31 - 2 G 3 7 ~ 3 2 : ~ ~

a molecular weight less than about 750,000 daltons and optionally a therapeutically effective dosage amount of vitamin C.
A composition from which dosage amounts may be taken and administered to a human may also be provided, the composition comprising a plurality of dosage amounts which may be taken and administered, each dosage amount comprising an effective non-toxic dosage amount of an NSAID and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid exceeding 5 mg.
and optionally a therapeutically effective dosage amount of Vitamin C.
In one embodiment the form of hyaluronic acid is hyaluronic acid and/or a salt thereof.
In one embodiment molecular weight of the form of ~ hyaluronic acid is less than about 750,000 daltons.
;;~ In one embodiment the NSAID is Diclofenac and the effective dosage amount of Diclofenac in each of the plurality of dosage amounts of the composition comprises in excess of about 35 mg.
Where systemic administration is involved the hyaluronic acid and salts thereof may be utilized at varying doses - 10 to 1000 mg/70 kg person with the optimal doses tending to range between 50 and 350 mg/70 kg individual. As ~ there is no toxicity, the hyaluronic acid can obviously be ^~ administered in a dose excess (for example 3000 mg/70 kg ~ individual) without any adverse effects.

~ ~ ,' ,' '' ''~

2~37~2 Applicants postulate that the hyaluronic acid and/or salts thereof and/or the homologues, analogues, derivatives, complexes, esters, fragments, and/or sub units of hyaluronic acid facilitate the transport of the agent to the site to be S treated and to penetrate the tissue (including scar tissue) through all membranes in the individual cells to be treated.
By way of example and to illustrate the facilitation of the delivery or transport of a chemical to a site in a mammal, when ethyl alcohol is injected directly into a tumor, and sonographic (ultrasound) assessment is made, it is not dispersed throughout the tumor. When the ethyl alcohol to be administered into a tumor is carried by hyaluronic acid and/or salts thereof, sonographic assessment of the tumor, demonstrates the dispersion of the ethyl alcohol throughout the tumor.
While Applicants postulate that the hyaluronic acid facilitates the transport and delivery, Applicants' invention may be used as described irrespective of the actual method of operation of the hyaluronic acid and/or salts thereof and/or the homologues, analogues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid.

We have treated in excess of 3000 patients on an experimental basis who have been diagnosed as terminally ill , , , whose life expectancy was only several months to half a year.
Of these we randomlv selected 100 of such patients. 90% of the 100 patients o~ 90 of the patients, expected to live no more than 6 months, have survived more than 3 1/2 years. We have concluded that the reason for their longevity has been our manner of treatment with our formulations and combinations.

~ '~

- 2037892 : ~
. .. ~ :, . . ....
~, ~ . ..~. .
The following examples are offered. In substantially -~
all, if not all cancer cases, the patient had been unresponsive -~
to conventional treatment. The hyaluronic acid referred to herein also includes other forms - for example sodium hyaluronate.

CASE I~
- - :
A 59 year old male with a laryngeal epidermoid (squamous type tumor) treated in its primary state with a :. -,;, - . .
combination of surgery and radiation developed metastatic disease in the liver some seven years later. Two major tumors were noted at a size of 12 cm and 6 cm diameter. These were treated with combination therapy using systemic chemotherapy ~ 15 with added DMSO to enhance penetration, phloretin -~ solubilized by N methyl glucamine with added DMSO to enhance penetration and the direct administration of adriamycin, carboplatinum and methotrexate into the tumor by systemic and intratumor injection therapy but in this case but with added hyaluronic acid at a dose of 10 to 60 mgs for the different drugs. This was achieved without any adverse effects and the patient was reassessed four weeks later. At that point in time the smaller tumor had disappeared entirely. The larger tumor was apparent only as a necrotic focus measuring now 5 cm in diameter but no apparent surviving tumor could be detected by examination an-d needle biopsy. This case illustrates the ~; superior effect of hyaluronic acid on penetration of drug ~hus i~ allowing better tumor destruction.
~ Follow-U~

~:

: :

~ 34 ~ 2~37~2 Subsequently patient was given treatment of ndomethacin 300mg and 300mg Hyaluronic Acid daily; patient was in remission, however patient died of infection at a later date.

"~ ' ~; -S CASE II~

A 42 year old female developed malignant melanoma with - ~`
:
tumor present in the left upper thigh and inguinal nodes, the~--abdominal cavity and liver, lungs, and the base of the brain affecting involvement of various cranial nerves. Her primary~ ~
10 tumor had been excised and she had developed recurrent disease -- ;
which was deemed untreatable as there is no cytotoxic or cytostatic chemotherapy that has major effects on this tumor -.: . . . ,,~ . ~:
when it is as widespread as observed in this patient. The patient was treated with a combination of phloretin solubilized in N methyl glucamine with added hyaluronic acid at a dose of 10 to 50 mg/2 to 4 grams administered intravenously and this agent was given for five days over 4-24 hours/day. She also received ,~hyperthermia to the various areas of the tumor and concomitant ?~systemic therapy with carboplatinum with added hyaluronic acid at a dose of 250 mg carboplatinum total plus methyl CCNU
administered at a total dose of 120 mg over 5 days orally while the patient received hyaluronic acid systemically. Methotrexate mixed with hyaluronic acld was injected into the tumor which could be palpated in the left thigh or inguinal region at a dose of 37.5mg with 60 mg of hyaluronic being added, the doses being divided equally at two different days by injection. The patient responded over the next 10 to 20 days with dramatic and total regression of the upper thigh and inguinal tumors, dramatic improvement in liver function with the tumors in the liver - 35 - 2~37~92 becoming cystic (generally regarded as a sign of tumor break down) and disappearance of the lung tumors. The tumor at the base of the brain regressed as manifested by improvement of her cranial nerve function and a decrease of pain and headaches. In this patient a tumor which is unresponsive to the majority of agents at this phase of development was made markedly responsive when the same agents were used with hyaluronic acid as a penetrating agent.

Follow-U~
The patient was subsequently given treatments of phloretin, indomethacin (NSAID) and hyaluronic acid. This patient is now in complete remission.

CASE III~
A 55 year old female patient with cancer of the gallbladder occupying the entire right lobe of the liver. This patient had been treated on three previous occasions with a combination of heat, systemic chemotherapy with added DMSO, phloretin with added DNSO and direct injection of cytotoxic drugs with added DMSO. Beginning May 1989 she was treated with the comparable drugs with added hyaluronic acid as a carrier or dispersing molecule administered both systemically and by direct injection :, into the tumor. The tumor which had shrunk marginally by -approximately 20% prior to this now reduced in size dramatically by over 50% and continues to diminish in size. This tumor is judged unresponsive to these drugs alone when administered by the normal routes.

Follow-U~
Unfortunately the patient relapsed, became depressed and died.

CASE IV:
A 55 year old female with cancer of the colon metastatic to the liver with one major large tumor mass occupying the entire right lobe of the liver and medial segment of the left lobe extending into the 1 left lobe and judged unresectable by a hepatic surgeon two months earlier was treated with systemic chemotherapy and injection of chemotherapeutic agents directly into the tumor plus phloretin solubilized with N methyl glucamine with hyaluronic acid and hyperthermia. The patient had a three day course of therapy and was injected on one -~ 15 occasion directly into the tumor with cytotoxic drugs and hyaluronic acid and reassessed three weeks later. Sonographic examination showed total liquafaction of the tumor leaving only ~,~a small rim of apparently viable tissue; 500 ccs of amber colored fluid with necrotic tumor tissue present was drained from the now cystic lesion. This is an unusual and dramatic :~ . ::
response for an adenocarcinoma which generally responds extremely slowly. It is judged that less than 30% of these patients achieved any significant disease regression utilizing standard cytotoxic or cytostatic chemotherapy. The enhanced 25 destruction here occurring over three weeks and is judged as due ~ ~ ;
to the use of the carrier penetrating molecule, hyaluronic ;~
acid.
,` ' '"'''~''-'.`' ~ Follow-U~ ~ ~

2 ~ ~ 7 ~ 3 : : ~

From the examinations, there was total tumor necrosis.
The patient however died some time later of liver failure and pulmonary embolism.
CASE V:
A 53 year old man with transitional cell cancer of the bladder in a very advanced state of his disease with metastases involving the entire left pelvis, extending to the periaortic and parapancreatic and supraclavicular nodes having recurred after previous surgical excision, radiation and having not responded by major regression to standard chemotherapy was treated using phloretin solubilized in N-methyl glucamine with added hyaluronic acid with a direct injection of carboplatinum and methotrexate into the tumor tissue. Hyperthermia to the areas of the tumor was also applied. The patient developed a dramatic response and developed a febrile reaction due to tumor break down and release of bacteria. This reaction was controlled by antibiotics and appropriate hydration and as the patient was observed through this phase a dramatic decrease in the size of the tumor was observed on an almost daily basis with an over 50% reduction in tumor size having occurred by 7 days after therapy. This is a remarkable and dramatic response of a tumor which at this phase had been judged as unresponsive to all therapy and it is thought to be due to the use of the drug which blocks glucose transport employed here with a carrier and penetrating molecule, hyaluronic acid and chemotherapy administered di~ectly into the tumor with the same agent.

Follow-U~
There was, as a result, total tumor necrosis. However - 38 - 2~7~92 ~:

at a later date, the patient died of an infection.

CASE VI~
This patient had a right upper lobe lesion diagnosed, ~ `
;5 confirmed by biopsy and deemed not surgically resectable. This tumor, according to documentation utilizing chemotherapy or radiotherapy has a zero response rate. He was treated with ;~
systemic chemotherapy in hyaluronic acid as follows~

10 DATE DRUG DOSE ~ -05/10 vinblastine 3 mg 05/10 mitomycin 3 mg 05/10 calcium leukovorin40 mg 15 05/10 5fluorouracil250 mg 05/10 5fluorouracil250 mg 05/10 Oncostatin IV 3 mg Hyaluronic Acid III 10 mg 05/11 carboplatin 250 mg ~; 20 05/11 vinblastine 5 mg 05/11 mitomycin 4 mg 05/11 calcium leukovorin40 mg ; 05/11 5fluorouracil250 mg 05/11 5fluorouracil250 mg 25 05/12 carboplatin 100 mg 05/12 vinblastine 2 mg 05/12 5fluorouracil250 mg 05/12 5fluorouracil250 mg ;
05/12 calcium leukovorin40 mg 30 05/12 Oncostatin IV 2 mg Hyaluronic Acid20 mg ; 06/19 mitomycin 5 mg Hyaluronic Acid10 mg 06/19 vinblastine 5 mg --~ 35 Hyaluronic Acid IV10 mg -~ 06/19 5fluorouracil250 mg - ", 20~7892 Hyaluronic Acid IV 10 mg 06/19 5fluorouracil250 mg Hyaluronic Acid IV 10 mg 06/19 calcium leukovorin 40 mg S 06/19 Oncostatin IV 3 mg Hyaluronic Acid50 mg 06/20 5fluorouracil250 mg Hyaluronic Acid IV 10 mg 06/20 5fluorouracil250 mg Hyaluronic Acid IV 10 mg 06/20 calcium leukovorin 40 mg 06/20 mitomycin 5 mg Hyaluronic Acid IV 10 mg 06/20 vinblastine 5 mg IS Hyaluronic Acid IV 10 mg 06/20 Oncostatin IV 3 m Hyaluronic Acid IV 50 mg 06/21 Carboplatin 20 mg Hyaluronic Acid IT 10 mg 20 06/21 methotrexate12.5 mg 06/21 carboplatin 150 mg Hyaluronic Acid IV 50 mg Oncostatin IV 3 mg Hyaluronic Acid IV 50 mg 25 06/22 carboplatin 100 mg Hyaluronic Acid IV 10 mg 06/22 Oncostatin IV 3 g Hyaluronic Acid IV 50 mg 06/23 Oncostatin IV 3 g Hya`luronic Acid IV 50 mg 08/16 calcium leukovorin 40 mg 08/16 5fluorouracil500 mg Hyaluronic Acid IV 50 mg 08/16 carboplatin 250 mg Hyaluronic Acid IV 100 mg Oncostatin IV 3 g Hyaluronic Acid IV 100 mg . :, :~ .:
08/17 carboplatin 200 mg :~
:::: ::: . .
: ,~, ~ ,.'::: .::

, .- -.

2 ~ , 9 2 Hyaluronic Acid IV 150 mg 08/17 carboplatin 30 mg ~
Hyaluronic Acid IV 50 mg -08/17 adriamycin 2.5 mg ~ ~ `
Hyaluronic Acid10 mg Oncostatin 3 g Hyaluronic Acid100 mg 08/18 5fluorouracil500 mg Hyaluronic Acid100 mg 08/18 calcium leukovorin 40 mg Oncostatin IV 2 g Hyaluronic Acid200 mg He was also treated with phloretin in hyaluronic acid.
His tumor was injected with the following chemotherapeutic agents in hyaluronic acid~

DATE DRUG DOSE
05/11 methotrexate12.5 mg hyaluronic acid50 mg -~
adriamycin 1 mg 06/21 methotrexate12.5 mg carboplatin20 mg hyaluronic acid 10 mg 08/18 carboplatin30 mg hyaluronic acid 50 mg ` ;~

,30 08/18 adriamycin25.5 mg --hyaluronic acid 10 mg '~
He has had regression of his disease by 50 per cent in a situation that is otherwise not treatable. This therefore ~
35 documents that unresponsive tumors can respond to chemotherapy ;-~ `
when administered in hyaluronic acid and/or salts thereof.
.".......
.',~ ~-....,.

- 41 - 2037~2 ~.

CASE VII~
Female patient, aged 58, had a massive cancer of the -~
breast with supraclavicular and auxillary lymph nodes palpable.
This has been confirmed by a biopsy. She was treated with combination systemic therapy and hyperthermia and did not improve significantly. She then received radiation from ;;~
December, 1988 to January, 1989. She was subsequently seen again by Dr. Falk on May 17, 1989 and had not had a response to 10 therapy to date. She then developed a plural effusion. She was -treated by Dr. Falk by a combination of chemotherapeutic agents as follows~
(Hyaluronic Acid may be Sodium Hyaluronate) 05/16 methotrexate25 mg -~
Hyaluronic Acid IT 10 mg ~ ;
05/16 methotrexate25 mg ; Hyaluronic Acid axilla IT 10 mg 05/16 methotrexate25 mg Hyaluronic Acid SC node IT 10 mg 05/16 Oncostatin IV 3 g -~
Hyaluronic Acid20 mg ;
05/17 5fluorouracil250 mg 05/17 5fluorouracil250 mg 05/17 vinblastine 5 mg '~ 05/17 mitomycin 5 mg ~ 30 05/17 Oncostatin IV3 mg `` Hyaluronic Acid30 mg 06/02 methotrexate25 mg ~ -Hyaluronic Acid IT 30 mg -~
06/02 vinblastine 5 mg - 42 - ~ ~37~92 Hyaluronic Acid IV 10 mg 06/02 Oncostatin IV 3 g Hyaluronic Acid 30 mg 06/05 5fluorouracil 250 mg S Hyaluronic Acid IV 10 mg 06/05 5fluorouracil 250 mg Hyaluronic Acid IV 10 mg 06/05 calcium leukovorin 35 mg 06/05 vinblastine 5 mg Hyaluronic Acid IV 10 mg 06/05 Oncostatin IV .3 g Hyaluronic Acid 30 mg 06/21 carboplatin 20 mg Hyaluronic Acid IT 10 mg lS 06/21 methotrexate 12.5 mg 06/21 vinblastine 5 mg Hyaluronic Acid IV 10 mg 06/21 mitomycin 5 mg Hyaluronic Acid IV 10 mg 20 06/21 Oncostatin IV 3 mg Hyaluronic Acid 50 mg 07/10 carboplatin 25 mg Hyaluronic Acid IT 20 mg 07/10 methotrexate 12.5 mg Hyaluronic Acid IT 20 mg : 07/10 Oncostatin IV 3 g Hyaluronic Acid 50 mg 07/12 Oncostatin IV 2 g Hyaluronic Acid . 50 mg 30 08/14 vinblastine 5 mg , Hyaluronic Acid IV 50 mg 08/14 5fluorouracil 50 mg Hyaluronic Acid IV 50 mg 08/14 calcium leukovorin 30 mg 35 08/14 Oncostatin IV 3 g Hyaluronic Acid 100 mg 08/16 Oncostatin IV 3 g Hyaluronic Acid 100 mg , . .: ~ ' . ..

~ 3 ~ 2 0 3 7 8 9 2 She had also had a thoracentesis with subsequent instillation of 5fluorouracil, mitomycin C and hyaluronic acid into the chest cavity. Her pleural effusion is totally resolved. The lesions in her breast continue to recede and her supraclavicular and axillary lymph adenopathy is totally gone. ; ~- -This patient represents a response with relatively low : ::: .::, doses of hyaluronic acid and/or salts thereof added to conventional chemotherapy used systemically by injection into tO the tumor and by intra-pleural cavity instillation. The response has been further enhanced by the use of phloretin in synacid T.M. (hyaluronic acid and/or salts thereof) at the same time.

Follow-U~
At a much later date this patient is in remission and doing very well.

CASE VIII:
This is a 62 year old female treated previously with systemic chemotherapy, two different drug combinations without any response. She was referred for treatment including hyperthermia, and direct chemotherapy injections to which she responded initially, beginning September.
She was noted in April-May, to have an increase in the tumour in the right upper lobe of her lung. This tumour was an anaplastic small cell carcinoma. The tumour was treated by injecting into the lesion bleomycin with hyaluronic acid and indomethacin with hyaluronic acid. She also received ~ ~0~7892 systemically indomethacin 300 mg daily with 300 mg hyaluronic acid. The patient was followed radiologically and improved very dramatically over the next 2 to 4 weeks. The last film report shows that the left hemi-thorax is clear. On the right side S there is no evidence of pleural reaction. There is a prominent right upper lobe volume loss with elevation of the right hilum.
The area of increased lucency in the right apex may represent a region of cavitation within the collapsed lobe or elevation of the superior segment of the right lower lobe. Comparison with previous films shows that the mass has decreased significantly in size and cannot now be distinctly identified on this examination.
The applicants believe that this response is a direct result of the carrier molecule - hyaluronic acid - injected with a chemotherapeutic agent and with a non-steriodal anti-inflammatory drug to assist in clearance of the necrotic tumour.

:":"';,'''',' CASE IX:
This patient was diagnosed as having a gastric cancer July, 1988 and it was deemed unresectable. A gastroenterostomy-type of bypass was performed. Saw the patient initially in August and treatment was initiated in September, 1988. At that ; time he was heated and received phloretin with very low dose chemotherapy employing 5-FU plus immune augmenting agents.
This therapy essentially was continued until February, 1989 when Dr. Falk began to use DMSO as a carrier/penetrating agent in addition to MSN. He did receive increasing amounts of chemotherapy employing 5FU leukovorin, mitomycin C and methotrexate and subsequently in July and early August, as there -" 2 ~ 3 7 8 ~ 2 . "

was tumor progression, he also received novantrone.
As of May he began to receive these drugs in hyaluronic acid but the initial amounts of hyaluronic acid were small, employing 10-30 mg per average dose with the original 5 drug i.e. phloretin, or the chemotherapeutic agent. There was ;~
some initial improvement in his status but then in mid August he -~
progressed to a situation where there was increasing evidence of gastric obstruction, and also obstruction of the biliary tree with jaundice and elevation of the bilirubin. Dr. Falk then treated with higher doses of hyaluronic acid to a total dose of 500-600 mg of hyaluronic acid divided among the different drugs. `- , The patient continued to receive the same types of drugs.
While his condition initially deteriorated, an upper gastro~intestinal series performed on September the 7th shows his gastric bypass to be totally open whereas prior to this the patient had been vomiting all oral intake. His status has now steadily improved. ;
On the basis that the patient received identical drugs earlier, the improvement must be attributed to the higher doses of the carrier molecule, allowing for better penetration of drug into what is always a scarred, fibrotic tumor and generally fatal at this stage. -- ,,-;.. ;

Follow-U~
Unfortunately at a subsequent date, patient died as a consequence of tumor necrosis and scar tissue developing - not ~ --from cancer.
: .::~':, ~, CASE X~

- 46 - 2 0 3 7 ~ 9 2 Patient was diagnosed as having a hepatoma now over 2 years age. The tumor had been stable or with minimal growth over the past 18 months. Since treatment with low dose , chemotherapy and the carrier/penetrating molecule, hyaluronic acid, she appears to have had a complete response. Her alkaline phosphatase is now at 150 international units and the remainder ~, ''' of her liver function tests are essentially normal. Her ultrasound show no distinct tumors anymore in the liver. Dr. '~
Falk is now treating her once every 2-3 months. '~"
1 0 , ,Follow-U~
This patient is still doing well. '~

CASE XI~
15 This patient was infused on June 15, 1989 with ,''' ',-,,',',~
chemotherapy with added hyaluronic acid on one occasion. She ,''~,- '',' then received hyperthermia. Previously with multiple hepatic ;';'"''"'', metastases from cancer of the breast she had been stable on '',' '' ~ tamoxifen, the estrogen-blocking substance. '' ";'', ,!~ 20 After one course of infusion of only 8 hours she has ',~
had what would appear to be a complete response. Her ultrasound ',. ;,""',~
now shows no tumor present in the liver and her liver function ',",~
, , tests are all normal. , ~'''''''"'''''""'"' For the present no further treatment necessary are "',`,:~,,"",,,ij`',' following her and continuing her on tamoxifen to block the ~-~'; estrogen receptor. ~,''~,',-"

Follow-U~ ' --'' This patient relapsed after another doctor gave ~ .. ..

- 47 - 2~37 ~2 vaginal estrogen cream (tamoxifen) to her for vaginal irritation. In response, patient was given treatments of 300mg of indomethacin in 300mg of hyaluronic acid daily. She is now in remission.

CASE XIA ~
This patient had a massive leomyosarcoma of the uterus resected on March 26, 1989. There was residual tumor present as demonstrated by a CAT scan. Dr. Falk has treated her with a .: ~
combination of hyperthermia, very low dose methotrexate using this intraperitonealy with a carrier/penetrating molecule -hyaluronic acid and then using the agent that blocks glucose transport protein - phloretin, also with hyaluronic acid and alpha II interferon intraperitonealy again combined with hyaluronic acid.
On sequential CT scan this patient shows significant improvement in size of the residual mass. As soft tissue :: ... i .
sarcomas are so very resistant to all forms of therapy this ~ ~ ~
:: :- . ~
could be described as an unusual response and is in all likelihood related to the use of the carrier/penetrating molecule - hyaluronic acid. Dr. Falk is now treating this ~ : .: :- . . : .~
patient approximately every 6-8 weeks for 2 days and hopefully her regression of tumor will continue. If that is the case, ~i than one could consider closing her colostomy in about 6 month's time.

Follow-U~
Some tumor grew back. Patient was given treatments of Vitamin C (50mg daily), indomethacin (300mg daily) in 300mg of ;
'' ' - 48 - 20378~2 .
hyaluronic acid. This patient is feeling much better.
'~' ''~ '' ~'''' CASE XIB~
This patient has received relatively low doses initially of methyl CCNU and carboplatin with methotrexate injected into the inguinal recurrent melanoma. All of these molecules were given in the carrier/penetrating agent hyaluronic acid. In addition she received the agent that blocks glucose transport which Dr. Falk has developed. This is a molecule called phloretin which was used many years ago. It has been solubilized in a special solution and is also given with hyaluronic acid as it will also enhance the penetration of this molecule into the tumor. Dr. Falk then treated her with hyperthermia using both capacitive and inductive radio frequency hyperthermia and microwave hyperthermia. In addition she has received immune stimulating agents which Dr. Falk believes will produce benefit but only in conjunction with other agents.
In the last 2 courses of treatment she has received only carboplatin with added hyaluronic acid, phloretin with added hyaluronic acid and methotrexate administered now by intra-peritoneal route at a low dose - 25-35 mg in hyaluronic acid again.
Dr. Falk saw her this week and he will treat her for 2 days. She is clinically in excellent condition. She has the .
one complaint of right-sided back pain. On examination one does have the impression that this could be tenderness over the right kidney. The ultrasounds of her kidneys have suggested a solid ~ ~ `
mass in the right kidney which was interpreted as being either a ~ ~
hamartoma or even an angiomyolipoma. ~ ~-~37g32 - :
In view of the patient's rather dramatic response Dr. Falk thinks it would be worth while to get a CAT scan done of the --abdomen. There is still the question of a small cystic lesion in the right lobe of the liver but her liver function in now normal.
,''','''~''','~'"

Follow-U~ ;~
This patient is now in complete remission.

CASE XVI~
A dentist with melanoma, age 51, developed acute -~
herpes zoster in the 9th thorasic dermital on the left side of hls body. He was in excruclating pain, not relieved by classical medications. Dr. Falk asked him to take orally ~-`
l5 cyclofur as an antiviral but he did not begin this immediately. - ,~
However, Dr. Falk also indicated that he should take "Delfen~" '.' ''!'',~
and "LifeCore~" hyaluronic acid, mix equal portions and then apply this topically. He did this and had immediate relief of , ,- , ~: .. :
i~pain within 5 minutes. The pain has remained absent for the next 4 days. In addition, the lesions of herpes zoster immediately began to disappear within the first 24 hours and now, 5 days later, none are apparent. This is a dramatic response suggesting a major antiviral affect of this combination, with the hyaluronic acid obviously enhancing penetration.
" I . .
~ : .,:
CASE XVII:
This man developed stomach cancer which metastasized to his liver. He was treated for seven months with low dose -- 50 - 20373~2 - ; :.. ::, chemotherapy (5 FU), low doses of mitomycin and novantrone with various amounts of hyaluronic acid, and Vitamin C (50gm daily).
There was no detectable tumor. He is now in remission and all ~ -tumors are calcified.
S '~
' ::', '' " ..::
CASE XVIII~
This male patient had a serious car accident, shortly `
thereafter he developed colon cancer which was resected with multiple liver metastases. He came to Dr. Falk in June, 1989. -lO He was treated with chemotherapy (phloretin) and hyaluronic acid ~
with heat. He remained stable for approximately one year, then -his alkaline phosphatase began "creeping up". Consequently, Dr.
Falk treated him with Vitamin C (50gm daily for three days), -hyaluronic acid (up to 300mg daily), indomethacin in ~-methyl ' i glucamine (300mg daily in the 300mg of hyaluronic acid), and i ~, i, ".., . ~ ....
Toradol~ (60mg) once or twice daily with hyaluronic acid (50mg). Since that time he has shown improvement. His alkaline phosphatase decreased, and therefore his liver is functioning better.

: .: ~
;~

CASE XIX:

This man, age 46, was diagnosed in the last three months with a difficult to treat broncheolar alveolar carcinoma . . .
of the lung. Appropriately, neither chemotherapy nor major amounts of radiation were used, although spot radiation was given to two areas; one on either side of the chest where there apparently was some indication of skeletal involvement.
Subsequent to that, the patient visited a cardio- -~
pulmonary transplant unit in London who thought that a ~ ' ~'' , ~: ~ ... ... .

~ 2~37892 : ~
transplant might be appropriate but there was a waiting list of about one year.
After this the patient went to Dr. Frederick Douwe's clinic in Germany and was placed on a variety of regimens, the .
main direction of which includes; (a) immune enhancement at the T-cell level; and (b) free radical scavenging and detoxification.
He has improved somewhat since this treatment was ~ ~
initiated with episodes when he is very short of breath, having - -had one of those 24 hours ago.
On examination he has very severely diminished air entry on both sides with bilateral rales and ronchi. There is no evidence of supraclavicular adenopathy. There is no evidence of skeletal tenderness at this point or of hepatic enlargement.
tS He then came to Dr. Falk and he treated him with ~ `
Vitamin C (50gms), non-steroidal indomethacin (NSAID)(100 mg -reduced from initial amount of 300mg because of heartburn) dissolved in hyaluronic acid (300mg). He improved dramatically after the first 5 days of therapy with reference to lung 20 capacity and radialogical appearance on the X-ray. -~
Dr. Falk then prescribed daily injections of hyaluronic acid (300mg) with Toradol~ (60mg) to be taken at home ("home" being outside of Canada).
Comparison has been made to the previous examination.
Since that previous examination, there has been resolution of some of the increased interstitial markings so that the lungs -;
now look clearer than they did on the previous exam.
Nonetheless, increased interstitial markings are still present within both lung fields. . ;~
: '"""' " ;'~ ,',~''' ::::::::: : .

~ :`` 2 0 3 7 ~ 9 2 , ~ .
....- ....
.... ~ ~ ...~ ... i ~ . ~.. . . ~ .
CASE XX~
A female patient, age 74, was diagnosed with cancer of the colon and was resected. The cancer had however mestastasized to the liver (right lobe). Over a one month period, she was treated twice with methotrexate (25mg) in hyaluronic acid (400mg) intraperitoneally, five times with - -oncostatin (2 gm) in hyaluronic acid (300 - 500mg), Vitamin C
(50gm) in hyaluronic acid (300mg), and indomethacin (NSAID) ` -~
given twice, 100mg of indomethacin in 300mg hyaluronic acid and 250mg of indomethacin in 500mg of hyaluronic acid.
The patient is now doing very well, feeling better, and the liver tumor is regressing (shrinking). -~

CASE XXI~
This female patient, age 51, was diagnosed with cancer of the uterus which had spread to the lungs (leiomyosarcoma).
Dr. Falk treated her with various doses of oncostatin (low doses of 0.5gm to 3gm) with hyaluronic acid (300-500mg), Vitamin C
(50gm) in hyaluronic acid (300mg), and indomethacin in hyaluronic acid (intraperltoneally and intravenously).
The pelvic mass is presently regressing and the lungs ~ ;
are now stable.

CASE XXII:

This man, age 52, has a history of Crohn's Disease and .
: .
chronic infection in the bowel from Crone's disease. He eventually developed a tumor in the peritoneum (adenocarcinoma).
The patient was treated with doses of 2gm and 3gm of .:

~ 53 ~ 2 ~ 3 7 8 9 2 ~ ,. .. `~
OncostatinTM (phloretin) each in hyaluronic acid (500mg) and DMSO (total of 2000). Doses of indomethacin ranging from 75mg to 450mg in 200 to 700mg of hyaluronic acid were given. Patient was also treated with Vitamin C (50gm) in hyaluronic acid 5 (300mg), and naproxen (lgm) in hyaluronic acid (400mg). These treatments were given to the patient via several routes intraperitoneally, intravenously, rectally (for detoxification) (insertion of catheter and administered rectally). The pain is now gone.
Patient was given CT Scan of the abdomen and pelvis.
There is moderate hepatic steatosis without evidence of metastatic disease. The spleen, pancreas, adrenals and right kidney appear normal. There is a left nephrostomy tube in place with no evidence of residual hydronephrosis. There is a large and necrotic tumor mass occupying most of the deep pelvis with anterior displacement of the urinary bladder and likely some invasion of the prostate gland. There is no evidence of sacral destruction although the rectal tumor is closely apposed to its anterior surface.
,, :
Thus there appears to be a large and necrotic pelvic tumor mass without evidence of sacral destruction, para-aortic ;~
lymphadenopathy or distal visceral metastases. A left percutaneous transrenal ureteral stent is in place.
The patient was seen August 1, 1990, in the clinic and ~ 25 he has been feeling very well. He is doing extremely well; the `
;~ ; necrotic tumor mass is slowly reducing in size.

CASE XXIII~

This female patient, age 47, was diagnosed in January, ...,.'..".

~ 54 ~ 2 0 3 7 8 ~ 2 1990. A gastric resection and colonic replacement of oesophagus (for swallowing) was performed. She had also developed an intraperitoneal tumor. She was given chemotherapy and lost her hair. (Dr. Falk gave her minoxidil and hyaluronic acid to apply to her scalp and her hair grew back). Dr. Falk saw this patient on June 6, 1990, and gave her lower doses of phloretin together with heat and hyaluronic acid, indomethacin in hyaluronic acid, and Vitamin C in hyaluronic acid.
Since the time of treatment, the patient has made good improvement. She has gained weight, and is no longer feeling any pain. The carcinoembryonic antigen is down to 26 nonograms/ml and steadily falIing.

CASE XXIV~
This man (age 45) first seen by Dr. Falk on March 1, 1988, he was diagnosed with carcinoma of the pancreas. He was treated with DMSO and heat together with low doses of chemotherapy. Dr. Falk injected the DMSO and the other drugs into the tumor. More than one year later, this patient was given treatments with Vitamin C, and other agents in hyaluronic acid. This patient is now in complete remission. He has not been treated in more than six months.

"' ' ~

CASE XXV:
Dr. Falk saw this female patient (age 62) in August, 1989. This woman was diagnosed with carcinoma of the pancreas.
She was treated with low doses of chemotherapy (5-FU and mitomycin) together with 300mg of hyaluronic acid and heat. She - 2 ~ ~ 7 8 ~ 2 - ~
was having trouble with her bile ducts. She was operated on, but a tumor was not found and the bile ducts were bypassed. The patient was then treated with indomethacin and Vitamin C in ~ ~, hyaluronic acid, and the heating treatments were stopped. Since ~-her treatment she has experienced a gain in weight and there is : . . ~
no evidence of a significant tumor. --~

CASE XXVII: ~-This woman (age 65) patient illustrates important ~-points. Her previous chemotherapists did not recognize they had killed most of her tumor. She had been taking chemotherapy ~
-:
- previously. However as the tumor was breaking up, as Dr. Falk has now concluded, there was a retention of water fluid in the area of the tumor (they should have looked at the ultrasound for `
assistance). Dr. Falk saw her and treated her with heat, phloretin, Vitamin C, indomethacin and some 5-FU, all in hyaluronic acid. (According to her previous doctors, she had an enlarged tumor after taking 5-FU. Therefore, they stopped ~:, :: -;~ chemotherapy). The patient is now looking better and feeling ~`

better and there is no edema.
-', ,~, ;~ CASE XXVIII: ~ -This female -patient had carcinoma of the ovary with ~ -intermittent to complete bowel obstruction with encasement of , ~ "
the bowel with tumor and also significant amounts of pleural fluid. The most striking example of the effect of Lasix . .; ~ ,. .. .
(furosemide) occurred under the following circumstances. On ~ ~
April 28th and 29th, 1990, the patient excreted a total volume of 2,450ml of urine over 48 hours despite the administration "` ' 2 G 3 7 8 9 2 ~ ., ;", .
of.33 per cent sodium chloride solution with added potassium chloride at 40 mEq/l administered at the rate of 100-125ml per hour. The patient's body weight was 40kg. During this period of time the patient received 120-200mg of Lasix administered intravenously.
On April 30th, she received 40mg of Lasix with added 350mg of hyaluronic acid administered over half of an hour. She produced a diuresis within the following 5 hours of 2,500ml of urine. During the evening hours with no additional Lasix being given, urine output fell dramatically and she excreted only 400ml of urine from 7:00 p.m. April 30th to 7:00 a.m. May 1st.
At 7:30 a.m. she received 40mg of Lasix in 300mg of hyaluronic acid administered intravenously. Over the next 8 hours, this patient produced 2,600ml of urine. This case demonstrates the ., . ~ . ~,, .
fact that even a relative insensitivity to furosemide (Lasix) can be overcome with the addition of hyaluronic acid to enhance drug penetration to the appropriate area.
The similar type of phenomena has been observed by us in patients where there is a so called "hepatorenal syndrome"

., ~ :,.
and where the kidney stops excreting urine due to the failure of the liver to function adequately. Under these circumstances, urine output may decrease to essentially zero levels. This can ~ ;
be dramatically effected by furosemide (Lasix~) administered intravenously in hyaluronic acid, even though furosemide (Lasix~) administered by itself produced no effect.

CASE XXIX:

In normal healthy individuals, it was observed that adding hyaluronic acid to furosemide (Lasix~) administered at a ~ ..::

5/ - 2 0 3 7 ~ 9 2 dose of 20mg intravenously with 300mg of hyaluronic acid, there was an increase of urine excretion by 3 to 5 fold as compared to that observed with furosemide (Lasix~) alone. This is cited as evidence that hyaluronic acid increases penetration/permeation of the drug and thus facilitates its function.

CASE XXXI~
This female patient (age 32) was diagnosed as having an epitheloid sarcoma on the basis of a Mayo Clinic review.
Her history of the disease dates back to December 12, 1978, when she developed nodularity in the left ring finger which was excised. She has had recurrent episodes of this type of problem since then and has had an amputation of the left 4th finger. She has been extensively staged and investigated as she was found to have nodules of the same type of disease up her arm and a left axillary lymph node biopsy was positive in March, 1990 for an epitheloid sarcoma.
At the Mayo Clinic she received three courses of ` chemotherapy with mitomycin C, adriamycin, cisplatinum in high ; 20 doses without any response. She was scheduled for a fore~
guarter amputation for the sarcoma of the left arm and forearm.
This patient was first seen by Dr. Falk on June 25, 1990, and was treated for three days with heat, phloretin-hyaluronic acid, vitamin C-hyaluronic acid, methotrexate-hyaluronic acid, and also received solu-medrol. She did not have a clear response at that point in time and the lesions remained the same.
She returned on July 23 and was treated for three consecutive days with a reduced dose of phloretin, same dose of ~- - 58 - 2 ~ 3 7 8 3 2 vitamin C-hyaluronic acid and received both naproxen and indomethacin with hyaluronic acid both subcutaneously and intravenously. She returned home and received Toredol~ (Syntex - non-steroidal anti-inflammatory druy) intra-muscularly on a S daily basis at a dose of 30-120mg administered once or twice per day with lOOmg of Hyal Pharmaceutical type hyaluronic acid.
She was reassessed on August 20 and has had a dramatic decrease in size of all measurable disease by greater than 50%.
In fact, at this point, biopsy would have to be done to ascertain if there is any viable tumor present. The treatment plan is to continue on the Toredol~ and hyaluronic acid.
While the patient had some minimum response with heat, phloretin, conventional chemotherapy with the addition of hyaluronic acid with these drugs, she did have an excellent response with the non-steroidal anti-inflammatory drugs using all three types; Indocid~, naproxen and Toredol~ when combined with hyaluronic acid as a carrier/penetrating vehicle to facilitate target ng to pathological tissue. She has had few if any of the standard side-effects that occur with the non-steroidal anti-inflammatory drugs.

; CASE XXXII~
This male was diagnosed as having gastric cancer in 1988. The tumor was in the distal third of the oesophagus at 2S the gastro-oesopageal junction. A Celestine tube was placed by an intraoperative abdominal procedure and sutured to the lesser curvature of the stomach.
The patient was treated from January, 1990 up until 3 months ago (June, 1990). Repeated CAT scans have shown no . ,.

:- . "' ~ 59 ~ 2037~92 change in any situation; symptomatically he had been completely well. Most recent CAT scan was June 26, 1990. This raised questions in respect of some areas in the liver; however, sonographic examination suggested that these were in fact homogenous.
On July 4th he had some "hot dogs" at a picnic.
During the night he woke up with acute left upper quadrant pain which was not associated with nausea or vomiting. Subsequent to this he had episodes of pain essentially every time he consumed any food. The pain was always the same, felt in the back and the front of the abdomen and tended to ~'spread" to both flanks.
It has never been associated with any direct peritoneal tenderness, vomiting, diarrhea or fever and chills.
Investigation included the previous CAT scan done just eight days prior to the onset of this pain, and an upper GI series with follow-through. Further CAT scan now could not be done because he was still full of barium.
It is important to recognize that a significant dose of Demerol just barely relieved his pain. Further examination is unremarkable. There were no abdominal, thoracic or lymph node findings to suggest any spread of the disease.
Dr. Falk reviewed the X-rays with a Professor at the Department of Radiology, Toronto General Hospital, University of Toronto. He suggested that the upper GI series was a classical picture of "tethering" of the small bowel. He said, this could be either from fibrous adhesions or from neoplastic disease, or indeed, a combination of both, as is very common with adenocarcinoma of the stomach. However, the neoplastic seedings :~ would necessarily be very minimal, as nothing shows on the ~ ''-, '~': ~

- 60 - 2~37~92 ~ ~

previous CAT scan.
Dr. Falk treated the patient with a combination of non-steroidal anti-inflammatories administered intravenously with hyaluronic acid in conjunction with hyperthermia and oncostatin, which is a combination of phloretin and hyaluronic acid and achieved almost immediate relief of pain. He can now eat without having symptoms (had lobster soup recently at one of the local restaurants).
Dr. Falk has also given him a supply of probanthine 10 which he could use, as the type of pain that occurs with these ~ ~
type of adhesions is usually relieved by one of the anti- ~ ;
cholinergic drugs. Dr. Falk has also suggested to him to come back for further therapy and continue when he goes home on a combination of felden lOmg b.i.d. and naprosyn 500mg directly as l5 suppository once per day and take zantac 150mg twice a day. -~
In addition Dr. Falk placed him on Vibramycin (Doxycyline) 200mg for one day and a lOOmg daily dosage for fourteen days. This is an antibacterial agent and also blocks intracellular and anerobic glycolosis. -~
~ -Follow-U~ ~
, .
Recent biopsies showed chronic inflammation of the lower one third of the oesophagus (tube in oesophagus recently removed); however, there were no malignancies found. - -~ ' . ~ . , .
; 25 ; CASE XXXIII:
This man has had major tumor breakdown and this has -~ ~
occurred only after chemotherapy was omitted from the treatment ~ ;-regimen. This initially made him significantly more ill; this - 61 - 20~78~2 ~ ~
, was reflected only to a minor extent in terms of his hepatic function tests. The alkaline phosphatase did become elevated. ;~
He had profound malaise, weakness, excessive fatigue and loss of appetite. This has been corrected by intensive use of indomethacin in hyaluronic acid and detoxification programs.
He was reassessed and was significantly better. Under ultrasound, the tumor shows virtually total necrosis. There is ~;
now increased normal liver tissue present. ;~-~

10 CASE XXXIV~ c,~
This man had a chronic abscess cavity in his pelvis with a bowel obstruction which necessitated an operation on January 5, 1990. At that time the cavity was irrigated out and drained through the perineum. He had an uneventful post- `-operative course and was discharged from hospital on January 18, 1990 . " ''~
However, subsequently he developed a fever and because this had been a large cavity in the pelvis, it now drained through the lower anterior part of his abdominal incision. This occurred two weeks prior to the present visit.
Dr. Falk assessed him. This is a large cavity and he thought that this would take 4 to 6 weeks to close. Dr. Falk ~ .;~
instituted daily irrigations during the 5 day working week with ~ ~-ampicillin, flagyl and hyaluronic acid using 500mg of ampicillin and 500mg of flagyl. This is a very benign form of treatment in contrast to what Dr. Falk would usually use which would consist of irrigation and packing the area open.
When seen later, the abscess cavity had closed over.
The patient advised that the visiting nurse on the weekends had - 62 - 2~3'~8~2 difficulty putting a catheter into this cavity over Saturday and -Sunday and in fact could not gain entrance of the catheter. Dr.
Falk concluded that the cavity had granulated in from the "bottom up" but has done so much more rapidly than he would have S anticipated. In view of the fact that this is a chronic cavity ~`~
. . .. . .
in a patient who has had a chronic and ongoing problem in the pelvis, this is clearly an unanticipated result with a much more rapid and better resolution of a chronic abscess cavity than anticipated.
Dr. Falk has instructed the patient to call if he develops any temperature subsequent to this. He has had a mild itching sensation over his skin which Dr. Falk believes is probably a reaction to cold and for which he gave him an ointment to be applied daily.
IS - ~
CASE XXXV: ~-Woman had a 9th and 12th nerve lesion, which was thought was located just lateral to the base of the skull. It ~
was also thought that she may have had metastases in the region ~ ~;
of the dentoid process, and an MRI scan was undertaken to try and demonstrate this. It showed somewhat abnormalities in the appropriate area. A CT scan of the region was unhelpful. ;;
The patient then attended The Ontario Cancer Treatment ~C~
and Research Foundation and was found to have very advanced malignant melanoma, and was discharged from the hospital with a hopeless prognois.
Much later the people of Ontario Cancer Treatment and ; ~-~
Research Foundation were surprised and delighted to find that ~ ~ -she had responded unbelievably well to both positive mental ~ ~

- 63 - 2~37892 . ~
imaging and to Dr. Falk's treatment. This involved hyperthermia ~;
and chemotherapy in hyaluronic acid. Dr. Falk used usual doses of Carboplastin and low doses of Methotrexate in the hyaluronic acid. -Her chest now appears clear, and she has some -;~
persistent lesions in kidney and liver, but these may well be under control. During the summer, her tongue got better, and no longer deviated to the left. However, during the last three or ~`
four weeks, things have deteriorated from that point of view. `~
On recent examination, the neurological examination was entirely normal, except for a deficit (incomplete) ingag on the left side of the pharynx, and a problem with some fasciculations and atrophy of the left side of her tongue.
This patient has done remarkably well.

Follow-U~
More recently this woman has been administered hyaluronic acid (300mg daily), NSAID and Vitamin C (50gm daily).
The patient appears now to be clear of tumour. ;~
' ~;
CASE XXXVI:
This man has a mesothelioma following surgical resection and then adjuvant treatment. It is now seven years since the initial diagnosis. In the spring of this year he developed a recurrence while in Florida. Although Dr. Falk has biopsied this three times, Dr. Falk has never obtained cells diagnostic of malignancy. However, clinically the situation is -:
very clear from the CAT scan, liver function test and ~ - -ultrasound.
: : . :.~
..... ~,.. - ':

- 64 - 20378~2 :::

This patient has been treated with phloretin in hyaluronic acid, and heat to the area. Initially, he did not show a major response. However, on the last occasion he received no chemotherapy and only phloretin in hyaluronic acid S with a higher dose of hyaluronic acid. He has had a major response and has had major problems with accumulation of fluid, Dr. Falk believes, secondary to tumor breakdown. The tumor breakdown is clearly apparent on the sonographic assessment;
here there is actual liquification of the tumor.
During his present stay, he was treated one day with hyperthermia and received phloridzin in hyaluronic acid.
However, he required an additional two days of treatment with Vitamin C in hyaluronic acid to assist in detoxification. He also received additional diuretics LasixTM (furosemide) with -hyaluronic acid.
His creatinine which was 400m mols/l has decreased to 155y mols/l (kidney function tests - went from high to almost normal). Dr. Falk has instructed him regarding further management. Dr. Falk does not think the patient will require major further therapy as Dr. Falk thinks the majority of this tumor has been destroyed, through his own immune response, the antibody and the soluble mediators being allowed to enter into the tumor by hyaluronic acid.
In July, l990 moderate ascites (fluid in body) occurred. The patient was given furosemide (LasixTM) and hyaluronic acid, indomethacin and hyaluronic acid. The patient's urine output increased substantially and the problem cleared.

- 65 - . : : .
0 ~ 7 8 ~ 2 :: :
CASE XXXVI I ~
,' '~ '.~''`" " ''""`
A 37 year old female had a carcinoma of the cervix which was a class IIIB at the time of diagnosis. She was treated by radiation at the Cross Cancer Centre, unsuccessfully, and developed further growth of the tumor which was diagnosed approximately 1 to 2 months after the radiotherapy. She was then seen by Dr. Walde at the Sault Ste. Marie hospital. He administered epirubicin, cisplatinum at high doses and did : -produce regression of the tumor as assessed by intravaginalassessment and biopsy, but apparently there was regrowth and worsening of the pain with partial ureteric obstruction demonstrated as shown by a CT scan of the abdomen and pelvis - :
done June 28, 1990.
At laparotomy, the patient had extensive tumor with ~ ~
major areas of necrosis but tumor extending to and involving the ; ~ ;
left common iliac artery and vein producing obstruction of the vein, the tumor was considered not resectable for surgical cure because of its extent in the lateral true and false pelvis to ~ ~;
20 the pelvic wall. This was assessed by a urological and two -general oncological surgeons.
For this reason and because of imminent rectal .
obstruction, a colostomy was performed. In addition, the urological surgeon established an ileal conduit.
This patient was in excruciating pain continuously for several weeks prior to and after the surgical procedure. This ~-~ ,.,,~-: ,-necessitated high doses of intravenous morphine with only -partial control of the pain. On July 8th she was noted to have -~

~. : ~., :-~ a major febrile reaction and a CAT scan that day showed an : :;: :: . ::: - -2~37~92 ~: `
abscess in the left pelvis. This was drained under CAT scan localization and the patient was placed on systemic antibiotics with only slight improvement in her infectious symptoms.
She was brought to Dr. Falk on Wednesday, July 11th.
S She received lgm of ampicillin through the draining catheter for ;~
the abscess with 500mg of hyaluronic acid. In addition, she received lmg of ampicillin intravenously and ancef and flagyl systemically in 500mg "LifeCoreTM" hyaluronic acid. She also received 100mg of indomethacin with 500mg LifeCoreTM hyaluronic ~:: . : :: :::
acid intravenously. Within 12 hours her pain had dramatically :: : ::-: ~:::
decreased, all infective symptoms were eliminated and the drainage from the abscess cavity had almost stopped. Her massively enlarged left leg due to venous and lymphatic obstruction improved to almost normal size within a 12 hour ~ -:. . .::
period of time.
The patient was subsequently treated further with the same regimen for the next 3 days resulting in total relief of pain and continued improvement in her status, to the point where she could be discharged from the hospital on July 18th without anti-biotic therapy. Her systemic analgesia with .
morphine agents had been eliminated. There was no hyperthermia and no cytosis chemotherapy and/or Oncostatin (phloretin) utilized in this patient. She received anti-oxidant therapy with hyaluronic acid concomitently with the indomethacin-hyaluronic acid. This patient has demonstrated a very dramaticimprovement emphasizing that the indomethacin-hyaluronic acid is targeting specifically to pathological tissue improving macrophage function at this site and allowing the body's immune system to perform appropriate tumor destruction.

-:: ~, :-:.; ~ ,' ';' .~ ' ~

. :. .: . ::

We have also developed formulations and compositions suitable for topical application for percutaneous penetration (best targeting the epidermis) S systemic independent acting (not acting essentially through the blood, the pharmaceutical compositions comprising:

comprising a plurality of dosage amounts each comprising, together with pharmaceutical excipients suitable for topical application, a therapeutically effective (to treat and to assist to resolve diseases and conditions of the skin and exposed tissue (for example basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, "liver" spots and like lesions (found for the most part in the epidermis), squamous cell tumours, metastatic cancer of the breast to the skin, malignancies and/or tumours in the skin primary and metastatic melanoma in the skin, genital warts (condyloma acuminata), cervical cancer, and HPV (Human Papilloma ~: ..:, ,. .:
Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis), corns on the feet and hair loss on the head of pregnant women), non-toxic (to the patient) dosage amount of a drug for example which inhibits prostaglandin synthesis, preferably a non-steroidal anti-inflammatory drug (NSAID), for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol~) and an effective non-toxic amount of hyaluronic acid ; - :
and/or salts thereof (for example, thé sodium salt) and/or homologues, analogues, derivatives, complexes, esters, : fragments, and/or sub-units of hyaluronic acid (preferably .:~
. '-"`" '"'' - 68 - 2~78~2 ::~

hyaluronic acid and salts thereof) to transport (facilitate or cause the transport of) the drug (for example NSAID's) rapidly to the site in the skin (for example epidermis) and/or exposed tissue of the disease or condition into the tissue to remain S there for a prolonged period of time to assist to treat and assist to resolve the disease or condition for example by blocking prostaglandin synthesis.
Effective dosage amounts of the form of hyaluronic acid to facilitate or cause the transport of the drug into the lO skin and/or exposed tissue by the form of hyaluronic acid, - ~-exceeds about 5 mg. - 10 mg. in the dosage amount administered (applied and rubbed in) for each 1 cm2 of skin and/or exposed tissue area of the disease or condition (for example basal cell carcinoma) to which the dosage amount is applied. The dosage amount applicable will depend upon the surface area of the skin and/or exposed tissue in which the condition or disease exists.

:- . ~
Thus if the disease or condition occupies about .5 cm2, in excess of about 2l/2 mg of the form of hyaluronic acid would be used (applied and rubbed in). In the same way if the area is 2 cm2, the amount of the form of hyaluronic acid preferably exceeds about 10-20 mg of the dosage amount of the formulation or composition applied. Preferred forms of the hyaluronic acid (for example hyaluronic acid and the sodium salt thereof) have molecular weights less than about 750,000 daltons (for example about 150,000 to about 225,000 daltons) to transport the , ~, ,: - -~ :.,:
~ medicine in the skin and/or exposed tissue. While higher . . -.
- molecular weights of the hyaluronic acid and forms thereof may be used to penetrate the skin and/or exposed tissue and ~` transport the medicines or drugs, where the molecular weight of ~ `

.- " -." ''.' ~ . .: :: ~" :.

-` 2~97~92 , the hyaluronic acid chosen for use is very large, it is preferred that the form of hyaluronic acid is autoclaved, to break down the hyaluronic acid to fragments of lesser molecular weight or if feasible diluted to permit administration and S ensure no coagulation on or in the skin. Where the molecular weight of the form of hyaluronic acid being employed is large, the concentration of the form of the hyaluronic acid in the composition may for example be reduced (for example to less than about 3~) dependent on the molecular weight.
The blockage of prostaglandin synthesis by the ;~
transported drug (for example NSAIDS) then unblocks the macrophages and permits the macrophages of the patient proximate the lesion (for example, the basal cell carcinoma) to destroy the lesion or condition. Treatment by dosage amounts of the `~
composition (formulation and/or combination) eliminates the condition without recurrence, even where the lesion has recurred a number of times after unsuccessful treatments according to the prior art. ;
Other non-steroidal anti-inflammatory drugs (NSAIDS) may be used such as other propionic acid derivatives, Ibuprofen, acetylsalicylic acid, piroxicam and flunixin. ~;
When dosage amounts of such compositions, combinations and formulations are applied to the site of the disease or condition for example the basal cell carcinoma of the patient - -~
25 suffering from the basal cell carcinoma, over a period of time ; ~
(for example, for a period of 2-4 weeks 3 times daily) the basal - -cell carcinoma is completely resolved and disappears. -Thus according to another aspect of the invention `~
there is provided a pharmaceutical composition from which dosage '.,.''..','' `.'. `'~''`".

- 70 - ~ ~

amounts may be taken for application to the skin and/or exposed tissue, the pharmaceutical composition comprising in a form for application to a human a plurality of dosage amounts of medicine and/or therapeutic agent to treat a disease or condition in a human and a plurality of dosage amounts of hyaluronic acid and/or salts and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid such that when dosage amounts of the pharmaceutical composition are taken from the composition, the amount of the medicine and/or therapeutic agent comprises an effective non-toxic dosage amount of the medicine to treat the disease or condition in the skin and/or exposed tissue in a human and the amount of the form of hyaluronic acid in the dosage amount is present in an effective amount to transport (facilitate or cause lS the transport of) the medicine and/or therapeutic agent intradermally (percutaneously, intercutaneously, ': ~.'~ ,.; .
intracutaneously) into the skin (preferably to the epidermis and dermis) and/or exposed tissue of a human to the site of a pathology and/or trauma. The effective amount of the form of hyaluronic acid has a molecular weight and concentration to transport the medicine (drug) and/or therapeutic agent to the site of trauma and/or pathology in the skin and/or exposed tissue. In this regard the preferred amount of the form o hyaluronic acid in each dosage amount exceeds 5 mg./cm2 and preferably the molecular weight is less than about 750,000 daltons, (in ane embodiment about 150,000 to about 225,000 daltons) in some embodiments with a concentration of between about 1 and 3%, preferably concentrations of between about 2 to about 3% by weight. Where forms of hyaluronic acid are used ` ~97~9~- ~
having greater molecular weights, they are preferably cleaved and/or diluted to smaller concentrations, to facilitate or cause the transport of the medicine and/or therapeutic agent.
According to another aspect of the invention there is .:
provided a pharmaceutical composition (for example a gel or cream) from which dosage amounts may be taken and applied to the :~
skin to treat a disease or condition in humans, for example as discussed above, the pharmaceutical composition comprising~
(1) a medicinal and/or therapeutic agent suitable lO for treating a disease or condition in the skin and/or exposed . `~
tissue in humans, for example a drug which inhibits .
prostaglandin synthesis (for example an NSAID); and .
(2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, :.::~
: lS fragments, and sub-units of hyaluronic acid, in a form suitable for administration to the skin and/or exposed tissue in humans; .~.
characterized in that an effective non-toxic dosage amount comprising components (1) and (2) taken and administered from ;.. ~.
said composition (i) is available in the skin and/or exposed .. ~
. . : ~
'~ 20 tissue upon administration to treat said disease or condition in humans by penetration at the site to be treated to the site of trauma and/or pathology, and (ii) comprises an effective non-toxic dosage amount of component (2) effective to transport (facilitate or cause the transport of) component (1) immediately upon administration percutaneously into the skin (preferably the epidermis) to~the site to be treated for example the site of ~: trauma and/or pathology where it remains for a prolonged time, accumulating there and from which it is discharged via the ~; lymphatic system.

.

~- 2~378~2 The pharmaceutical composition will normally include pharmaceutically compatible excipients to provide a form for ease of administration to the skin and/or exposed tissue for transport into the epidermis. For example a suitable dosage amount of a gel may be squeezed from a tube as a ribbon of gel ~X~ cm long (which dosage amount (in the form of the ribbon ~x~
cm long) contains the effective non-toxic dosage amounts of the drug and form of hyaluronic acid. Or a dosage amount of cream packaged in a jar may be scooped from the jar by a measuring device or by "two fingers" in a suitable amount (for example in a spoon containing a premeasured volume or an amount about half the "length of the fingers"). Each of the dosage amounts selected comprises the effective amounts of drug (for example NSAID) and effective amount of the form of hyaluronic acid (for example hyaluronic acid and/or salts thereof). In this way the patient may "squeeze" or "scoop" or "what have you" the appropriate dosage amount and apply (rub in) the dosage amount onto the skin and/or exposed tissue for transport into the epidermis.
Thus, according to another aspect of the invention, a method of treating a disease and/or condition of the skin or exposed tissue, for example basal cell carcinoma, the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, "liver" spots and like lesions (found for the most part in the epidermis), squamous cell tumours, metastatic cancer of the breast to the skin, primary and metastatic melanoma in the skin, malignancies and/or tumours in the skin, genital warts (condyloma acuminata), cervical cancer, HPV (Human Papilloma - 73 - .
2~7~2 Virus) including HPV of the cervix, psoriasis (both plaque-tYPe psoriasis and nail bed psoriasis), corns on the feet and hair loss on the head of pregnant women, in a human is provided comprising administering topically to human skin and/or exposed S tissue an effective non-toxic dosage amount of a composition comprising, together with pharmaceutical excipients suitable for topical application to the skin and/or exposed tissue, for example in the form of a gel or cream (to give the composition definition and form so that specific dosage amounts are easily selected or taken for administration (for example squeezed from a tube or scooped from a jar and rubbed into the skin or exposed tissue?, a therapeutically effective (to treat and to assist to resolve the disease or condition for example basal cell ~: carcinoma or other lesion), non-toxic (to the patient) dosage ~: 15 amount of a drug for example which inhibits prostaglandin synthesis, for example a non-steroidal anti-inflammatory drug NSAID), for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark ` ToradolTM) and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof (for example, the sodium salt) and/or homologues, analogues, derivatives, complexes, ~ esters, fragments, and/or sub-units of hyaluronic acid ; (preferably hyaluronic acid and salts thereof) to transport (facilitate or cause the transport of) the drug (for example NSAID) into the skin or exposed tissue to the site of the ~ disease or condition to be treated percutaneously, (to the site i~ of trauma and/or pathology), for example into the epidermis, where the form of hyaluronic acid and medicine accumulates and remains for a prolonged period of time thereby for example blocking prostaglandin synthesis in the skin or exposed tissue.
The form of hyaluronic acid is then cleared through the ~-lymphatics (lymphatics system).
Thus, according to another aspect of the invention, -S the treatment may employ the use of the composition, formulation -- -;
or combination for the treatment of the diseases and conditions -aforesaid as for example by applying dosage amounts of the -composition, formulation or combination a number of times daily ~; ;
(for example, 3 times daily) for a period of time, for example, 2-4 weeks to clear the disease, lesion or condition. Each dosage amount applied will depend upon the size of the lesion or -~
condition on the skin or exposed tissue. For example, a `
suitable dosage amount may include 5-10 mg. of the form of -~
hyaluronic acid per 1 cm2 skin area or exposed tissue area.

ISOne such formulation may comprise 3% (by weight) diclofenac in a 2l/2% (by weightt hyaluronic acid (sodium ` `
hyaluronate - molecular weight 661,600) gel formulation, with .::,. .. ;~ ,~,;
the excipients being glycerine (5~), benzyl alcohol (3%) (acting in part as a solubilizer and preservative), and sterile water (the balance) in a 50 gm. tube of the composition (a plurality of dosage amounts) whose tube O.D. (outer diameter) of the opening through which the gel formulation is discharged from the tube is 8 mm and whose I.D. (inner diameter) of the opening is 4 mm. Therefore a ribbon 2-3 cm in length, squeezed from a tube gives about 5 mg-7l/2 mg of hyaluronic acid for application to a skin or exposed tissue surface area of l-ll/2cm2 with an effective dosage amount of diclofenac. While greater amounts squeezed from the tube, may be applied, the application of substantial excessive dosage amounts to the skin and/or exposed - 75 ~ 2~37832 tissue may saturate the skin or exposed tissue and thus the . ::
epidermis. (There is therefore no more room for the composition to pass between the cells and therefore further applications at that time will not provide additional benefit). Where pain S relief is also required additional dosage amounts, for example in excess of about 10 mg. of the hyaluronic acid taken from the same pharmaceutical composition applied per/cm2 of surface area of the skin or exposed tissue may be required to be applied. -, :,.: , --.:; ::
Another formulation may comprise 3% (by weight) tO diclofenac in a 2l/2% (by weight) hyaluronic acid (sodium hyaluronate - molecular weight 679,000) gel formulation (also in a tube) with excipients being benzyl alcohol (1%) (a preservative), methoxypolyethylene glycol 350 (20% by weight) (a solubilizer), and sterile water (the balance).
IS While the above compositions, combinations and formulations are proposed, provided there is sufficient amounts of the form of the hyaluronic acid (for example, sodium hyaluronate) in the dosage amounts applied to the skin and/or exposed tissue to facilitate or cause the percutaneous (intracutaneous) transport of the drug for example which inhibits prostaglandin synthesis, preferably an NSAID (for example, diclofenac) to block prostaglandin synthesis, then the formulations may be of any suitable form, for example, a 1%
lotion of hyaluronic acid with NSAID, or a cream or gel or any other suitable form.
Therefore according to another aspect of the invention, there is provided containers (for example tubes and jars) containing compositions comprising a plurality of dosage amounts of the drug and form of hyaluronic acid, each dosage '''~:

2~378~2 amount comprising an effective non-toxic dosage amount of the drug and an effective non-toxic dosage amount of the form of hyaluronic acid (preferably sodium hyaluronate having molecular weight less than about 750,000 daltons) to transport the drug into the skin and/or exposed tissue. In some embodiments, means are provided to assist the removal from the container of an effective dosage amount of the composition in the container for use to apply to the skin or exposed tissue at the site of trauma and/or pathology to treat the disease and/or condition (for example mouth opening of a tube to control the amount discharged from the tube).
Furthermore, because there is little concern with respect to the toxicity or adverse effects of the use of, for example, the NSAIDs with the hyaluronic acid in the compositions 15 of this invention the NSAID may be combined as needed (after solubilizing (if required) of the NSAID in a suitable solubilizer) with the form of the hyaluronic acid.

:, ,: - ~.
According to another aspect of the invention, a method of accumulating a drug and a form of hyaluronic acid in skin and/or exposed tissue is provided comprising topically ;~ administering a therapeutically effective non-toxic dosage amount of a composition comprising pharmaceutical excipients suitable for topical applications, an effective non-toxic (to i . . . ..
the patient) dosage amount of a drug for example which inhibits prostaglandin synthesis, preferably a non-steroidal anti-,,. ~ , .
~ inflammatory- drug (NSAID), for example, diclofenac, ,, : . ~
indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac ~ -~ (sold under the trademark Toradol~) (to treat and to assist to ~~ resolve the disease and conditions of the skin and exposed 2 ~ 3 7 8 9 2 ~
tissue (for example basal cell carcinoma, the precancerOUs, often recurrent, actinic keratoses lesions, fungal lesions, "liver" spots and like lesions (found for the most part in the epidermis), squamous cell tumours, metastatic cancer of the breast to the skin, malignancies and/or tumours of the skin, primary and metastatic melanoma in the skin, genital warts cervical cancer, and HPV (Human Papilloma virus) including HPV
of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis), corns on the feet and hair loss on the head of pregnant women), and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof (for example, the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid (preferably hyaluronic acid and salts thereof) effective to . :: - -: .. - ;. .
transport (to facilitate or cause the transport of) the drug (for example NSAID) percutaneously to the site in the skin (for example epidermis) or exposed tissue of the disease or condition to accumulate and remain there for a prolonged period of time for example to block prostaglandin synthesis.
According to another aspect of the invention, a method of quickly delivering a drug to the skin or exposed tissue, particularly the epidermis, and maintaining the drug therein for a prolonged period of time is provided, the method comprising topically administering (for example rubbing in) an effective non-toxic dosage amount of a composition comprising pharmaceutical. excipients suitable for topical application, a therapeutically effective (to treat and assist to resolve the disease and/or condition of the skin and exposed tissue (for example basal cell carcinoma, the precancerous, often recurrent, , 2 ~ ~ 7 8 3 2 actinic keratoses lesions, fungal lesions, "liver~ spots and like leslons (found for the most part in the epidermis), squamous cell tumours, metastatic cancer of the breast to the skin, primary and metastatic melanoma in the skin, malignancies and/or tumours of the skin, ~enital warts, cervical cancer, and HPV (Human Papilloma Virus) including HPV of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis), corns on the feet and hair loss on the head of pregnant women)), non-toxic (to the patient) dosage amount of a drug for example which inhibits prostaglandin synthesis, preferably a non~
steroidal anti-inflammatory drug (NSAID), for example, diclofenac, indomethacin, naproxen, and (+/-) tromethamine salt of ketorolac (sold under the trademark Toradol~) and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof (for example, the sodium salt) and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid (preferably hyaluronic acid and salts thereof) sufficient to transport (to facilitate or cause the transport of) the drug for example the NSAID percutaneously to the site of the trauma and!or pathology in the skin (for example epidermis) or exposed tissue, for remaining there for a prolonged period of time (for example in the epidermis and dermis) to for example block prostaglandin synthesis. Suitable amounts of the form of hyaluronic acid may comprise in excess of :~ 25 5 mg. per cm2 in a form which transports the drug (for example : molecular weights of the form of hyaluronic acid being less than about 750,000 Daltons or if at substantially greater molecular weights, diluted (to reduce) the concentration or autoclaved or cleaved if required to reduce the size of the molecules.

.;, ' .:: -:, : `
- 2 ~ ~ 7g 9 2 "~
According to another aspect of the invention, a method of controlling the unloading of a drug from the skin or exposed tissue into the lymphatic system comprises delivering (transporting) an amount of drug into the skin or exposed tissue by an effective non-toxic dosage amount of a form of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid to the skin (epidermis) or exposed tissue to control the unloading of the drug into the lymphatic system (for example by the application of greater than 5 mg./cm2) of the form of hyaluronic acid.
Thus according to another aspect of the invention a composition is provided which when administered to a human by preferably administration to the skin and/or exposed tissue of a human, unloads its contents into the lymphatic system, the composition comprising an effective non-toxic dosage amount of a drug (for example an NSAID or an anti-cancer drug (Novantrone) and an effective non-toxic amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and/or sub-units of hyaluronic acid (for example at least about 5-lO mg/cm2 of skin or exposed tissue). Thus the composition is made up of a plurality of such dosage forms (for example a cream or lotion or gel).
Thus according to another aspect of the invention, a new composition for treating diseases via the lymphatic system is provided comprising a plurality of effective non-toxic dosage ~ amounts of the composition, each dosage amount comprising : hyaluronic acid and/or salts thereof and/or homologues, ~ analogues, derivatives, complexes, esters, fragments and/or sub-:

- 80 - 2 0 3 ~ 8 ~ 2 units of hyaluronic acid for passing into the lymphatic system ~ ~ -and a therapeutic effective amount of medicine for treatment of ~ `
a disease (which disease may be in the lymphatic system).
According to another aspect of the invention, the 5 composition may be for application to the skin or exposed `
tlssue .
According to another aspect of the invention, a composition is provided from which effective dosage amounts may be taken and administered, each effective dosage amount of the ;
10 composition comprising an effective non-toxic dosage amount of `~
hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments and/or sub-.-units for transporting a therapeutically effective non-toxic dosage amount of a medicine and/or therapeutic agent (for example an NSAID) in the composition into the skin and/or exposed tissue when applied thereto to an area of pathology and/or trauma then into the lymphatic system, the dosage amount being essentially systemic independent such that substantial amounts do not enter the blood system prior to clearing ~passing) into the lymphatic system. Preferably the amount of the form of hyaluronic acid in each dosage amount administered is greater than about 5-10 mg./cm2 and the molecular weight is less than about 750,000 daltons.
We have compared the penetration and retention of one of our combinations (formulations) with a control and Voltarol Emulgel in the skin as follows~

: ~

- 81 - 2037~92 (A) OUR FORMULATION ~ ~

:: . . : . .
1% DICLOFENAC IN 3.0% HA GEL 50~/tube , ~-LOT XPB 044 Quantity 150Oml FORMULA Su~lier Lot Amount Percent -~
Sterile Water Baxter AW45F1 1397ml Glycerin Life 1043 45g(36ml) 3%
l0 Benzyl Alcohol Caledon 02517 22.5g(22ml) 1.5%
Liquid Wax DICDD Brooks 191-175 45g 3%
Diclofenac Sodium Prosintex 9113003 15g 1%
Sodium Hyaluronate Skymart HG-1103 45g 3%
Mol. Wt. 661,600 PROCEDURE -- Set up stirring apparatus using a 3 liter stainless steel beaker -`
- Add Water, Glycerin, Benzyl Alcohol and Liquid Wax DICDD, stir and mix for 10 minutes .
- Add Diclofenac Sodium and stir for 30 minutes to dissolve - Add Sodium Hyaluronate and stir for 90 minutes 30 In a 50 ml aluminum collapsible tube, :~
inside of tube lacquered with a phanolic resin, outside of tube white regular enamel coating;
9 mm white polypropylene screw on cap with pierce tip Gels Batch No.s 35 (B) Voltarol Emulgel 060400 10 93 (C) 1~ Diclofenac Gel XPBO49 (Control) :; '~' '- . '"`, - 82 - 2 ~ ~ 7 8 9 2 (C) CONTROL
1% DICLOFENAC IN CARAPOL GEL, 50a Jar :~
LOT XPB 049 Quantity 100ml 5 FORNULA Supplier Lot Amount Percent Sterile Water Baxter AW45N5 93ml Glycerin BDH 2579 3g 3%
Benzyl Alcohol BDH 23797 1.5g 1.5% :
Liquid Wax DICDD Brooks L-1424 3g 3%
l0 Diclofenac Sodium Prosintex 9113003 lg 1% :~
Carbopol 934 A~C Chemicals 910304 lg 1% :;
PROCEDURE
- Set up stirring apparatus using a 400ml stainless steel .
beaker .~
,:
- Add Water, Glycerin, Benzyl Alcohol, Liquid Wax DICDD, and ~ . ~
stir to mix thoroughly for 10 minutes ~; :
~: - Add Diclofenac Sodium and stir for 20 minutes to dissolve ~:
- Very slowly add Carbopol 934, avoid getting lumps `;~
Samples Cell Sample Quantity of gel applied (mg) :~

; B 060400 10 93 192 ' ~.
C EPDICLOl* 192 D EPDICLOl* 192 * - Our Formulation - .':
Skin Tvoe -: ~ .::
One piece of skin (Female, 3i years, smoker, breast ;skin) was used for one sample from each batch. A second piece 35 of skin (no further details available) was used for the second :~

- 83 ~
~ ~ 3 7 8 9 2 .~ . ..... ~ - . ` , sample from each batch. The skin was stored deep frozen (<- ;
20C) until thawed for this experiment. FUll thickness skin was used for this experiment. .
Ex~erimental Conditions Skin permeation cells were prepared containing an exposed skin surface area of 9.6 cm2 and a constantly stirred receptor fluid beneath the skin consisting of 135 ml of ethanol:phosphate buffered saline (25:75 v/v).
Each cell was allowed to equilibrate for l hour at 37C after which the gel was spread evenly over the skin surface at a concentration of 20 mg/cm2). See table above.
The cell was then maintained at 37C with an air temperature above the skin of 35C.
24 hours after application of the gel the experiment was stopped and a portion of the receptor fluid removed. The skin was removed from the cell and any gel remaining on the surface carefully wiped off with dry paper towel followed by paper towel moistened with water. The skin was cut with a scalpel to obtain thin top and thicker lower sections of skin. ~ ;

This was done in order to obtain layers of skin which approximated the epidermal and dermal layers. Each skin section was weighed and the residual diclofenac extracted with lOml of fresh receptor fluid using an ultra turrax homogeniser. The homogenates were centrifuged and a portion of the resultant supernatant solutions removed.
The receptor fluid and skin éxtracts from each cell were assayed for diclofenac content by using a validated reverse phase high performance liquid chromatography (HPLC) method.
',' ~.~

: : :

Results Distribution of Diclofenac 24 hours after a~lication of Diclofenac Gel 8amDl- R-c-~tor TOD 8~1n oort~ On Bottom ~1n DOrtiOn ~g 8~in ~ ~ 8kin ~ ~g/~
_____________ _________ W ~ht ._____ ______ Wei~ht ____ ________ .

(Volt~rol l) 060400 10 93 447 0.1363 101 742 1.2449 217 174 15 060400 10 93 764 0.2445 141 577 1.2351 202 164 ' ,~
M-an 606 660 169 ~Our 20 For~ul~tion) ~4 ~PDSC~O1 2470.1535 133 867 1.4663 148 101 ~PDIC 01 2920.1647 145 879 1.0022 86 86 ~~ -M-an 269 873 93 ~ (Control) ~ .j",~.
"~ XP~O~9 184 0.127535 272 1.1324 58 51 !~
~ XP~O49 147 0.206882 396 1.0893 68 63 ; 30 M-an 165 _ _ 334 L 57 ____________ _______ ______ ____ ______ _______ ___ __--------Thus having regard to the above and Figures 1', 2' and 3', it is clear that the sodium hyaluronate takes the diclofenac :-::~
into the skin to the epidermis level (See Figure 1') more :.
rapidly than the Voltarol Emugel or non-hyaluronic acid diclofenac containing control formulation, accumulates it there and retains it there longer. The other formulations permit the -~
NSAID, diclofenac, to pass through the bottom skin portion - 85 - 2G37~92 - ~ ~

(dermis) quicker, thereby clearing it from the epidermis and dermis, quicker. Furthermore, more of Applicants' formulation is in the epidermis and in the dermis even after 12 hours.
It is also clear that Applicants' formulations clear into the lymphatic system not through the blood system. Yet the prior art topical formulations have always tried "to drive" the formulations through the skin into the blood for treatment of the disease or condition in the area (i.e. systemic action).
Thus, our composition, formulation and combination, (and dosage amounts thereof) penetrate quickly and rapidly at the site of treatment through the upper skin into the epidermis, where the paccinian bundles are located and the NSAID and the form of hyaluronic acid are accumulated and are retained longer, where needed (for example for the treatment of basal cell carcinoma).
Further, the NSAIDs are retained in the area to be treated with the form of hyaluronic acid. In doing so, they preclude prostaglandin synthesis , in effect, deactivating the synthesis or inhibiting the synthesis, of prostaglandins, permitting the macrophages' scavenger cell activity to eliminate the tumour and lesion. Additionally, a rapid onset of pain relief (analgesic effect) is provided (depending on the amount of NSAID and form of hyaluronic acid) usually where in excess of about 10 mg of the form of hyaluronic acid (preferably hyaluronic acid and salts thereof) is administered per cm2 of ., . .. . ~ ..
surface area co~prises the dosage amount administered. However, -~
there are no blood levels of the NSAID in the immediate area of treatment. The forms of hyaluronic acid are thus cleared via the lymphatic system. Then the lymphatics pass the forms of :- ,, : . ' ' - ': , ' :: '' ::' - 86 - 2037~2 hyaluronic acid, Applicants believe, to the blood system. Thus, the NSAIDs and forms of hyaluronic acid stay at the site to be treated for well in excess of 12 - 24 hours, a protracted stay.
Thus, over the period of treatment (for example, applications of effective non-toxic dosage amounts of compositions containing for example effective non-toxic dosage amounts of the NSAIDS and effective non-toxic dosage amounts of the sodium hyaluronate, 3 times a day for 2-4 weeks, transport the NSAIDS to to the epidermis to inhibit prostaglandin synthesis to enable the macrophages to "scavenge" the tumour cells and eliminate them. The end result is the successful treatment of the disease or condition at the site of trauma and/or pathology of the skin or exposed tissue, for example, the ~;resolution of, the basal cell carcinomaj the precancerous, often recurrent, actinic keratoses lesions, fungal lesions, "liver"
spots and like lesions (found for the most part in the epidermis), squamous cell tumours, metastatic cancer of the breast to the skin, malignancies and/or tumours in the skin, primary and metastatic melanoma in the skin, genital warts cervical cancer, and HPV (Human Papilloma Virus) including HPV
of the cervix, psoriasis (both plaque-type psoriasis and nail bed psoriasis), corns on the feet and hair loss on the head of pregnant women, with complete disappearance of the disease or condition as the case may be, by topical therapy without - .~
2S resorting to surgery.

One of the formulations whlch we have employed -~

~;successfully is a gel formulation comprising 3% diclofenac in 2.5~ sodium hyaluronate formulated as follows:

:
. : :

- 87 - 2~97892 - `
Formulation 1 (3000 ml.) Formula Su~lier (LOT) Amount Percent ,~ ~
Glycerine Life 1043150 g (119 ml) 5 Benzyl Alcohol Caledon 02517 90 g (86 ml) 3 Diclofenac Sodium Prosintex 9113003 90 grams 3 -Sodium Hyaluronate SkymarkHG1003 75 grams 2.5 (MW 661,660) Sterile water Baxter AW44552795 ml.
balance Procedure - set up stirring apparatus using a 4 litre stainless steel beaker - add water, Glycerine, and Benzyl Alcohol; stir to mix - add Diclofenac Sodium and stir for 30 minutes -- then add the Sodium Hyaluronate and stir for 90 minutes .. ~
- initially, stir at a high torque but avoid splashing; as the gel thickens, stir at a lower torque.
The gel is then packaged in a tube or jar or other suitable container for use. Identification of suitable dosage amounts and how they are taken from the container may be provided with the container - for example squeeze "X" cm. of ribbon from the tube; fill spoon or spatula accompanying jar;
(the spoon or spatula containing a predetermined dosage amount) then apply and rub into site of trauma and/or pathology (the dosage amount indicated will be such amount of the composition which comprises in excess of about 5 mg. of sodium hyaluronate per cm2 (square centimeter) of skin or exposed tissue to which the dosage amo~nt is to be applied. The amount of Diclofenac Sodium was determined in the same manner (having regard to the dosage amount required).
Another such formulation is~

:: ~:

- 88 - 20~7,3~2 - ~

Formulation 2 Formula Su~lier lLOT) Amount Percent 5 Methoxypolyethylene Sigma 34F-0266 300 g. 20 Glycol 350 Benzyl Alcohol BDH 23797 15 g.
Diclofenac Sodium Prosintex 9123012 45 g. 3 Sodium Hyaluronate Skymart HG 1004 37.5 g. 2.5 (MW 679,000) ~
Sterile Water Baxter AW45R6 1200 ml. ,;''`-t.~'.`:~,'~,'',.', ' balance `` ` ~
' ' ' " ' - `~
"--¢ ,,~, Procedure - set up stirring apparatus using a 3 litre stainless steel beaker - add water, Methoxypolyethylene Glycol 350, and Benzyl Alcohol and stir for 20 minutes to mix - add Diclofenac Sodium and stir for 30 minutes to dissolve - add Hyaluronate Sodium slowly and stir initially at a high speed, but avoid splashing - after addition, stir at a slower speed for 90 minutes; the slower speed reduces the formation of air bubbles :,::: . : . ~::
- the result is a clear, transparent, viscous gel which is put into a container. Once again instructions are given for administration and if applicable measuring devices (to provide a premeasured dosage amount) accompany the -container.
Still other formulations ar~:
.:

, ~: ::, :~-- 89 - 20~7~2 Formulation 3 3% Diclofenac in 2.5% HA Gel Formula Su~lier LOT Amount Percent Sterile Water Baxter AW45K6 1200 ml Methoxypolyethylene Sigma 34F-0266 300G (273 ml) 20%
Glycol 350 Benzyl Alcohol BDH 23797 15G (14 ml) 1% ~ -Diclofenac Sodium Prosintex 9123012 45 g 3% -Sodium Hyaluronate Skymart HG 1004 37.5 g 2.5% ~ -~
10 MW 679,000 Procedure ~ ~

15 - Set up stirring apparatus using a 2 liter stainless steel ~-beaker, -- Add water, Methoxypolyethylene Glycol 350, and Benzyl Alcohol and stir for 20 minutes to mix, - Add Diclofenoc Sodium and stir for 30 minutes to disolve, 20 - Add Hyularonate Sodium slowly and stir initially at a high speed, but avoid splashing, - After addition, stir at a slower speed for 90 minutes,the slower speed reduces the formation of air bubbles, - The result is a clear transparent, viscous gel which is poured into jars and tubes. Once again instructions accompany the container and where applicable appropriate devices for providing a premeasured amount of the composition aocompany ~he container.

" ':

.'''-' ~ ~"' 2~7~2 Formulation 4 5% IBUPROFEN IN 3.0% HA GEL, 50 ml JAR
Formula Su~lier LOT Amount Percent ;~
5 Sterile Water Baxter AW45R6 196 ml Meglumine Falk 15684 11 g 5.5%
Ibuprofen BDH 19/241 10 g 5%
Benzy Alcohol BDH 23797 2 g 1%
Glycerin BDH 2579 2 g 1% .
10 Hyaluronate Sodium Skymart HG 1003 6 g 3% ` ~ ~ :
Mol Wt 661,600 - Set up stirring apparatus using a 300 ml stainless steel beaker, - Add Sterile Water and Meglumine, and stir for 10 minutes, - Add Ibuprofen and stir for 15 minutes, - Add Benzyl Alcohol, followed by Glycerin and stir for 15 .: ~
minutes, - Finally, add Hyaluronate Sodium slowly and stir initially at a high torque to mix, but avoid splashing, - As the gel thickens, stir at a slow speed for 90 minutes. :

-,:~ - :.:: :. . ::
: :,:..:::
~ ,' ':" ', : , ~.. :

- 91 ~
~ 20~7892 : -Formulation 5 2% PIROXICAM IN 2.5% HA GEL
Formula Su~lier LOT Amount Percent Sterile Water Baxter AW45R6 200 ml --5 Meglumine Falk 15684 8 g 4%
Piroxicam AMSA 1-010 4 g 2% - : :
Hyaluronate Sodium Skymart HG 1003 5 g 2.5%
MW 661,600 PROCEDURE

- Set up stirring apparatus using a 300 ml stainless steel -: :- :
beaker, ; ;
- Add 200 ml of sterile water, ; ~ .
- Add 8 grams of Meglumine and dissolve, - Very slowly add 4 grams of Piroxicam and stir for 20 :~
minutes, - Slowly add 5 grams of Hyaluronate Sodium and stir at high speed, - Stir for 90 minutes at a slower speed COMMENTS -- A clear yellowish transparent gel '~' ~.'`;;

- 92 - 20~7~92 Formulation 6 5% IBUPROFEN CREAM, 50 ml JAR .

OILY PHASE
Formula Su~lier LOT Amount Percent Liauid wax DICDD Brooks L-1424 450 g 15%
Brookswax D Brooks P-490 480 g 16% :~
0 Glvcerin BDH 109109/2578 150 ~(119 ml) 5%
AQUEOVS PHASE
Sterile Water Baxter AW45F1 1950 ml -- : ~-Neglumine Falk 15684 150 g 5%
Ibuprofen BKH 19/241 150 g 5%
MW 200,00 : -Sodium Hyaluronate Skvmart O01 45 a 1.5%
Preservative Suttocide A Sutton SH-107 9 a 0.3%

PROCEDURE
20 A - Add all the ingredients of the oily phase A into a 4 liter stainless steel beaker, melt at 55c, finally heat to 75% ~ ~
when Aqueous Phase B is ready ~ :
B - Into a 3 liter stainless steel beaker, add 1950 ml water, set up, the stirring apparatus, add the Meglumine, stir to ;~
dissolve for 10 minutes, - Slowly add Ibuprofen, stir to dissolve for 20 minutes, - Very slowly add Sodium Hyaluronate and stir for one hour to dissolve all the Sodium Hyaluronate, - Finally, heat to 75C,with stirring for a total time of 30 .
minutes.

: ~ - .. ~.
: i..:

~ .'' ~... '.':' 2037~2 POUR B INTO A, both at a temperature of 75C, slowly - Remove the heat source and stir with a strong vortex for one hour, - . . . -, - When the temperature has cooled down to 45C add S preservative Suttocide A, - Continue stirring at a slower speed until the temperature ~ -is 35C, - At 35C remove the propeller, pour into 50 ml jars.
Formulation 7 . ,. . :- . : : . ..:
1~ DICLOFENAC IN 3% HA Gel, 50 ml iar Quantity 3000ml Formula Su~lier LOT Amount Percent Sterile Water Baxter AW45R6 2796ml -% ;
15 Glycerin BDH 2579 50g(71ml) 3%
Benzyl Alcohol BDH 23797 45g(43ml) 1.5%
Liquid wax DICDD Brooks 191-175 90 g 3 Diclofenac Sodium Prosintex 9113003 30 g 1%
Hyaluronate Sodium Skymout HG 1004 90 g 3% ;
; 20 MW 679,000 PROCEDURE
.- . . .
- Set up stirring apparatus using a 4 liter stainless steel ;~
beaker.
- Add water, Glycerin, Benzyl Alcohol and Liquid wax DICDD
: ~ : ; ,-and stir to mix thoroughly for 10 minutes - Add Diclofenac Sodium and stir for 30 minutes to dissolve. ~ `
- Slowly add Hyaluronate Sodium, stirring at a high torque ~
initially during addition. ~ -- After addition stir at a slower speed for 90 minutes.
~ : .. :. :.,, :.
~; 30 - A white opaque viscous gel is formed. ~ ~ -: ~' '' '''`.':
'~.~ ' ' '`,`"`

~: ~ :: .::- :~
: -:, :- .: : ..

~::
- 94 - 2037~92 .. . ~ ~
Formulation 8 ~ ~
:
1% DICLOFENAC IN 3.0% HA Gel, 50 ml tube ;~ -Quantity 1500 ml 5 Formula Supplier LOT Amount Percent Sterile Water Baxter AW45F1 1397 ml -%
Glycerin Life 1043 45g(36 ml) 3% ~~
Benzyl Alcohol Caledon 02517 22.5g(22ml) 1.5%
10 Liquid wax DICDD Brooks 191-175 45 g 3%
Diclofenac Sodium Prosintex 9113003 15 g 1% ~ :
Sodium Hyaluronate Skymart HG 1003 45 g 3%
Mol. Wt. 661,600 ~ :'.. ';
PROCEDURE
- Set up stirring apparatus using a 3 liter stainless steel b ker ea - Add water, Glycerin, Benzyl Alcohol and Liquiwax DICDD, stir to mix for 10 minutes. ~ `
- Add Diclofenac Sodium and stir for 30 minutes to dissolve.
: -: :: :.::::
- Add Sodium Hyaluronate and stir for 90 minutes. - ~ ~
' '~ ~' ;~' ,',"
:~ , ',:' ' . ,.. '.,:'.' ; ~ . ., '.' ', . !

- 95 ~
2037~92 :~
Formulation 9 HYANALGESE CREAM (B) 50 ml tube ;- -~
Quantity 3000 ml 5 FORMULA :~
A Oilv Phase SUPPLIER LOT AMOUNT PERCENT
Liquid Wax DICDD Brooks/Amisol 450g 15.0% . ;~
Brookswax D Brooks/Amisol 480g 16.0%
1O Glycerine Amisol 150g 5.0% ;~
B. A~ueous Phase Sterile Water Baxter AW4YA8 1950ml -% : :
Neglumine Falk 150g 5.0%
Sodium Hyaluronate Skymart PO1 45g 1.5%
5 MW 207,000 Ibuprofen BDH 150g 5.0% : :~
Suttocide A Sutton 9.0g 0.3%

PROCEDURE
A. - Add all the ingredients of the oily phase into a 4 liter stainless steel beaker, melt at 55C, finally heat to 75C -~
when aqueous phase is ready (at 75C) to pour in.
B. - Into another 4 liter stainless steel beaker, add 1950 ml :~
25water.
: - Set up the stirring apparatus and add the Meglumine ' ;
- Stir to dissolve with high torque, then slowly add ;~
Ibuprofen - When the Ibuprofen is dissolved, slowly add Sodium Hyaluronate - Stir cold for one hour to dissolve all the ingredients - Finally heat to 75C and stir thoroughly throughout a 30 minute period . :, . : .' -'~ ~ .. ' .:.', ' ;: ',' ~ ' --~ 2~7~92 MIX B INTO A ::~
- Slowly pour B into A (both at 75C) with stirring - Immediately remove the hot plate (heat) and stlr ;~
- Stir with a strong vortex for one hour 5 - When the temperature is 45C, add the preservative -~
Suttocide A -- Stir for about an hour to cool to 35C ~ ;
- At 35C remove the propeller and pour into 50 ml tubes - Pour 50 grams of the cream into each tube 1% BANAMINE IN 2.5% HA GEL
(L) XPB 041 Quantity 3000 ml FORMULA
SUPPLIER LOT AMOUNT PERCENT
Sterile Water Boxter AW4SA2 2400 ml --% ;.;:~
Sodium Hyaluronite Skymart HE1003 75g 2.5% :~
MW 661 600 .~.::.:.:.. :i::
*Banamine, 100 ml vial Scheing O CNXB13 300 ml 1% : ~ ',,!~,,'',' 20 Banamine,. 100 ml vial Scheina O CNXB12 300 ml 1%
3000 ml -; ~.. :: .~;
(50 mg/ml) 600 = 30,000mg :~
= 30 grams Flunixin in 600 ml :.
*Banamine contains Flunixin Meglumine ~50 mg Flunixin per ml) 25or 83 mg Flunixin Meglumine .

PROCEDURE ` '~
- Set up stirring apparatus using a 4 liter stainless steel beaker - i.
- Add water, stir with a strong vortex, then add sodium Hyoluronate slowly - Then immediately add the Banamine, stir the mixture .. - -`~ for 4-hours. .
One form of hyaluronic acid and/or salts thereof (for ;..... .. .~ `
example sodium salt) and homologues, analogues, derivatives, complexee, esters, fragments, and sub-units of hyaluronic acid, : ~:: .. ~. .:

2 0 ~ 7 ~ 9 2 preferably hyaluronic acid and salts and thereof, suitable for use with Applicant's invention is a fraction supplied by Hyal Pharmaceuticals Limited. One such fraction is a 15 ml vial of Sodium hyaluronate 20mg/ml (300mg/vial - Lot 2F3). The sodium hyaluronate fraction is a 2% solution with a mean average molecular weight of about 225,000. The fraction also contains water q.s. which is triple distilled and sterile in accordance with the U.S.P. for injection formulations. The vials of hyaluronic acid and/or salts thereof may be carried in a Type 1 .
borosilicate glass vial closed by a butyl stopper which does not react with the contents of the vial. -~
The fraction of hyaluronic acid and/or salts thereof ~ ~for example sodium salt) and homologues, analogues, ;~ derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, preferably hyaluronic acid and salts thereof, may comprise hyaluronic acid and/or salts thereof having the following characteristics~
a purified, substantially pyrogen-free fraction of -.. . ".
~ hyaluronic acid obtained from a natural source having at least ;~ ~
,: , ~ . . ~ - . . ~.
one characteristic selected from the group (and preferably all characteristics) consisting of the following:
i) a molecular weight within the range of . -. . .; .
150,000-225,000; ~ ~ ~
.. .....
ii) less than about 1.25% sulphated mucopoly~
~ 25 saccharides on a total weight basis;
iii) less than about 0.6% protein on a total weight basis;
iv) less than about 150 ppm iron on a total weight basis;

.

}, ~ . ' " . . . ` . ~ ` ' ` ` : - ~ ' .

f,~':: ` :' .~

:~ 2~37892 - ~
v) less than about 15 ppm lead on a total ;
weight basis; : ~.
vi) less than 0.0025% glucosamine;
vii) less than 0.025% glucuronic acid; :
S viii) less than 0.025~ N-acetylglucosamine;
ix) less than 0.0025% amino acids;
~ ~ :
x) a W extinction coefficient at 257 nm of less than about 0.275;
xi) a W extinction coefficient at 280 nm of less than about 0.25; and xii) a pH within the range of 7.3-7.9.
Preferably, the hyaluronic acid is mixed with water and the ; ~-fraction of hyaluronic acid has a mean average molecular weight ;
: within the range of 150,000-225,000. More preferably, the fraction of hyaluronic acid comprises at least one characteristic selected from the group (and preferably all :~ characteristics) consisting of the following characteristics: -;
i) less than about 1% sulphated ,.
mucopolysaccharides on a total weight basis; - .
ii) less than about 0.4% protein on a total .. -~
weight basis; : -:.
iii) less than about 100 ppm iron on a total ;:::
weight basis; .. ~. , iv) less than about 10 ppm lead on a total 25 weight basis; . `;-v) less than 0.00166% glucosamine; :` -vi) less than 0.0166% glucuronic acid;
~ vii) less than 0.0166% N-acetylglucosamine;
-~ viii) less than 0.00166% amino acids;

- 9 9 - : ~
- " 2 0 ~ 7 8 9 ~
x) a UV extinction coefficient at 257 nm of less than about 0.23; ;
xi) a UV extinction coefficient at 280 nm of -less than 0.19; and xii) a pH within the range of 7.5-7.7 Applicants also propose to use sodium hyaluronate ; ~-~
produced and supplied by LifeCore~ Biomedical, Inc., having the following specifications~
Characteristics S~ecification Appearance White to cream colored particles Odor No perceptible odor Viscosity Average < 750,000 Daltons Molecular Weight ; ;;- -W /Vis Scan, 190-820nm Matches reference scan OD, 260nm < 0.25 OD units ~-Hyaluronidase Sensitivity Positive responseIR Scan Matches reference ;~
pH, 10mg/g solution 6.2 - 7.8 Water 8% maximum Protein < 0.3 mcg/mg NaHy Acetate < 10.0 mcg/mg NaHy Heavy Metals, maximum ppm As Cd Cr Co Cu Fe Pb Hg Ni 2.0 ~.0 5.0 10.0 10.0 25.0 10.0 10.0 5.0 - ``
Microbial Bioburden None observed Endotoxin < 0.07EU/mg NaHy Biological Safety Testing Passes Rabbit Ocular Toxicity Test :
- :

r,. ~' ~ , ., , , : ' . :

- 2~7892 : : :
Another form of sodium hyaluronate is sold under the name Hyaluronan HA-M5070 by Skymart Enterprises, Inc. having the following specifications:
Specifications' Test Results Lot No. HG1004 pH 6.12 -Condroitin Sulfate not detected Protein 0.05%
Heavy Metals Not more than 20 ppm Arsenic Not more than 2 ppm Loss on Drying 2.07% -Residue on Ignition 16.69%
Intrinsic Viscosity 12.75 dl/s (XW: 679,000)', ' '' ~.` '!,-',~",~
Nitrogen 3.14%
Assay 104.1% - ~;
Microbiological Counts 80/g ~, ' E. coli Negative ,"', "','' ",:."''! ,."
Mold and Yeast Not more than 50/g -~

, ~., :~ :::.

,, ,- ~. ~"

'`' ' ~ '., .

- 101 - .
2~7392 ~: ~
Other forms of hyaluronic acid and/or its salts, and homologues, derivatives, complexes, esters, fragments and sub units of hyaluronic acid may be chosen from other suppliers, for -~
example those described in prior art documents provided the form S of hyaluronic acid chosen is suitable for transport of the medicine.
The following references teach hyaluronic acid, -sources thereof, and processes for the manufacture and recovery thereof which may be suitable. -United States Patent 4,141,973 teaches hyaluronic ` ~ -~
acid fractions (including sodium salts) having: - -"(a) an average molecular weight greater than ~-~
about 750,000, preferably greater than about ~-1,200,000 - that is, a limiting viscosity number lS greater than about 1400 cm3/g., and preferably greater than about 2000 cm3/g.; - -(b) a protein content of less than 0.5% by; ~ ;;
weight;
(c) ultraviolet light absorbance of a 1% solution of sodium hyaluronate of less than 3.0 at 257 ;
nanometers wavelength and less than 2.0 at 280 nanometers wavelength;
(d) a kinematic viscosity of a 1% solution of sodium hyaluronate in physiological buffer greater than about 1000 centistokes, preferably greater than 10,000 centistokes;
(e) a molar optical rotation of a 0.1 - 0.2%
sodium hyaluronate solution in physiological buffer of less than -11 X 103 degree - cm2/mole :~ . ': :

--` 2~37832 :: ~
(of disaccharide) measured at 220 nanometers;
(f) no significant cellular infiltration of the -~
vitreous and anterior chamber, no flare in the -aqueous humour, no haze or flare in the vitreous, and no pathological changes to the cornea, lens, iris, retina, and choroid of the owl monkey eye ~ -, when one milliliter of a 1% solution of sodium hyaluronate dissolved in physiological buffer is -~
implanted in the vitreous replacing approximately ~ `
one-half the existing liquid vitreous, said HUA '~
being (g) sterile and pyrogen free and (h) non-antigenic."
Canadian Letters Patent 1,205,031 (which refers to lS United States Patent 4,141 973 as prior art) refers to hyaluronic acid fractions having average molecular weights of ,i from 50,000 to 100,000; 250,000 to 350,000; and 500,000 to -730,000 and discusses processes of their manufacture.
In order to determine the blood levels in patients j::,: :. ~.:~, :.
using formulations made according to embodiments of the invention, a study of the pharmacokinetic profiles of two topical diclofenac formulations after repeat dosing were ~: : :.: ~, .
undertaken. ;
:, One such product was the product Voltarol Emulgel marketed in the United Kingdom by Geigy. The other was a : - : . :,-- .:
Diclofenac preparation in Hyaluronic Acid. -This was an open, repeat dose, crossover comparison using a randomized balanced block in six healthy volunteers.

The study consisted of administration with one, two ;.':
; ' ,''. ,~
':, : :' ~ ` 2 ~ 3 7 ~ ~ 2 week period in between periods, each period lasting fourteen days. The test articles applied were for the first six days of each period and the seventh day was study day during which the final application is made and blood samples taken.
S The approximate duration of the study including pre ~-and post study screening was six weeks. -Dose~

Diclofenac (3.0%) with Hyaluronic Acid (2.5%) Dose: Approximately 2 g, three times daily ;~
Route: Topical (Wl)Voltarol Emulgel, Diclofenac diethylammonium salt 1.16g aqueous gel (Geigy) Dose: Approximately 2 g, three times daily Route: Topical (Wl) ADMINISTRATION: to suitablo Datients Subjects applied one of the desianated test articles -topically to the calves and massaged into the skin, in a dose of 20 approximately 2 g per application three times a day for six -consecutive days. The size of a 2g dose was prepared by comparison with a silicone example given to each subject.
On the seventh day, the cream was applied once, in the same manner as before, under the supervision of the staff of the Clinical Investigation Unit.
After a washout period of one week the procedure was repeated with the alternate test article.
The following were the results of the tests:
(H = hyaluronic acid formulation) (V = Voltarol Emulgel) - 2 0 3 7 ~ '~ 2 PERIOD 1 .
All concentrations ng ml - 1 SUBJECT TIME POINT (hours) -0 0.25 0.5 1 2 3 4 5 6 8 10 12 H-l 10.3 7.1 6.4 ND ND 5.4 6.5 5.1 ND ND ND ND - - -H-2 ND 5.1 ND 5.1 ND ND ND ND ND 5.1 ND ND
ND ND ND 5.5 5.2 ND ND ND ND ND ND ND V-3 - -~

ND ND ND ND ND ND ND 8.4 ND ND ND ND V-6 ND = NONE DETECTED (> 5.0 ng ml-l) :::i PERIOD II -All concentrations ng ml ~
~ ~' SUBJECT TIME POINT (hours) 0 0.25 0.51 2 3 4 5 6 8 10 12 v-l ND ND ND ND ND ND ND ND ND ND ND ND

H-3 ND ND ND ND ND ND ND ND ND ND ND ND ~ 5 ND = NONE DETECTED (>5.0 ng ml-l) Other tests were undertaken to determine blood levels comparing Proflex (a formulation containing Ibuprofen) and the ~. .`
following formulation containing hyaluronic acid and Ibuprofen.
HYANALGESE CREAM (L) X PB 022 - 50 ml tube Quantity 3000 ml FORMULA . :
40 A. Oilv Phase SUPPLIER LOT AMOUNT PERCENT
~-Liquid Wax DICDD Brooks/Amisol 450g 15.0 Brookswax D Brooks/Amisol 480g 16.0%
Glycerine Amisol 150g 5.0%
: 45 B. Aaueous Phase Sterile Water . Baxter AW4YA8 1950ml -%
Meglumine Falk 150g 5.0% ~ ~
Sodium Hyaluronate Skymart POl 45g 1.5~ `
MW 207,000 50 Ibuprofen BDH 150g 5.0% '~
Suttocide A Sutton 9.0g 0.3%
::

:
: :
- 105 - ~ ~
- " 2 0 9 7 8 ~ 2 . ,........ ~
The following were the results ... ~. ,-~
(A) PROFLEX
. ~: . -. -.
S SUBJECT Time after administration (Hours) ..
Number PD O 0.25 0.5 1 2 3 4 5 6 8 10 12 . .`.. ~
1 ND 0.41 0.37 0.37 0.32 0.30 0.27 0.27 0.24 0.37 0.31 0.31 0.16 , ~ , 0 2 ND 0.12 0.12 0.08 0.11 0.12 0.12 0.07 0.08 0.09 0.08 ND 0.06 3 ND 0.09 0.08 0.07 ND ND ND ND ND ND ND ND ND i 4 ND 0.12 0.14 0.16 0.11 0.11 0.25 0.24 0.17 0.13 0.16 0.11 0.13 '~
ND 0.14 0.19 0.19 0.15 0.16 0.16 0.14 0.12 0.11 0.13 O.10 0.07 6 ND 0.11 0.09 0.09 0.06 0.07 0.05 0.05 0.05 ND ND ND ND
15 Nean 0.00 0.17 0.17 0.16 0.13 0.13 0.14 0.13 0.11 0.12 0.11 0.09 0.07 S.D. 0.00 0.12 0.10 0.11 0.10 0.10 0.10 0.10 0.08 0.13 0.11 0.12 0.06 (B) HYALURONIC ACID AND IBUPROFEN
SUBJECT Time after administration (Hours) :~
Number PD O 0.25 0.5 1 2 3 4 5 6 8 10 12 ::
;,: . -::: .: -::
1 ND 0.11 0.11 0.12 0.08 0.08 0.09 0.11 0.12 0.08 0.11 0.16 0.14 2 ND 0.22 0.21 0.26 0.17 0.24 0.24 0.25 0.23 0.19 0.19 0.20 0.14 , 3 ND 0.17 0.10 0.12 0.09 0.08 0.07 0.06 ND 0.06 0.26 0.09 0.05 5 ND 0.17 0.16 0.16 0.12 0.09 0.10 0.11 0.10 0.09 0.10 0.07 ND
6 Nl~ _Q,07 0.07 _ 0.09 ND ND ND ND ND ND ND ND ND
Mean 0.00 0.12 0.11 0.13 0.08 0.08 0.08 0.09 0.08 0.07 0.11 0.09 0.06 S.D. 0.00 0.08 0.07 0.08 0.06 0.08 0.08 0.09 0.09 0.07 0.10 0.08 0.07 ' ND None detected <0.05 ~g/ml ~ ;
The above clearly indicates that the blood levels are much less using hyaluronic acid to administer the NSAID.
PRELIMINARY REPORT

A trial was conducted using a gel composition (Number 109) comprising 3% Diclofenac in 2.5% Hylauronic Acid as ; previously described and a composition containing Diclofenac ~, . .
,~, .
sodium salt 3% but not including any form of hyaluronic acid.
(Number 112) The trial was conducted with 60 patients who were randomly assigned to test preparations number 109 or 112. The ~' 45 trial has not been completed as yet but so far 31 patients have ` -`
finished the protocol. Patients were diagnosed: ~

- 106 - 20~7892 4 Rheumatoid arthritis of the knee ~;
8 Myofascial trigger points in the M. trapezius area 12 Periarthropathies of knee without effusion 7 Periarthropathies with effusion in the knee joint ;~
The 31 patients were aged 22-75 years (27 females, 4 -males). All patients were hospitalized. Patients entering the -trial were thoroughly examined and type of extraarticular or <
articular rheumatism assessed.
'..... -: ,: . ',',.
On day 1 baseline pain was assessed on the 10 cm 10 visual analogue scale (VAS) and pain measurement of the `~
quantititative pain sensitivity using a pressure tolerance meter (PTM) were performed. Then test gel - approximately 2.g - was massaged on to the skin of maximum pain. Gels were applied 3 times daily.
0.5, 1, 1.5, and 2 hours after morning application measurements of pain sensitivity were carried out and values recorded.
This procedure was countinued on day 2, 3 and 4;
measurements (VAS and PTM) of pain severity were done on day 1, 2 and 4.
Prior of the beginning of the study and at the end on day 4, physician's global assessment, assessment of swelling, tenderness and limitation of movement were recorded.

: '' ' , 2 0 3 7 ~ ~ 2 .
. .. ~..
AS the study is ongoing statistical evaluation is not yet available. For further details see Table 1.

TAsLE 1 Composition Composition - `

Reaction 109, n = 16 112, n - 15 ~ -~
Good Alleviation 13 8 of pain Moderate Alleviation 2 2 ;~
10 of pain No Alleviation 1 5 of pain From the data recorded we have concluded that the patients to whom composition 109 was administered did better in terms of earlier and longer lasting analgesic effect (up to 4 hours) than the 112 composition especially in patients with myofascial trigger points and with periarthropathies of the knee -~
joints without effusions. Neither composition 109 nor composition 112 treated patients showed any effect on swelling if any swelling exist at all. Systemic side effects have not been observed; one patient to whom composition 112 was administered showed reddening of the skin on the site of application.
Any intake of system NSAIDS,corticosteroids and other analgesics was not allowed one week before and during the trial.

- 108 ~
- ` 2 ~ ~ 7 8 ~ 2 EX~MPLES
The following examples are offered to illustrate uses ~-:
of Applicants' invention.
.. . ....
S Exam~le 1 A male patient had a number of lesions (basal cell carcinoma), including one on his forehead which was a combination of major "horny epithelium" and some degree of ulceration. After continuous treatment with Formulation 1 (several times per day for several weeks of dosage amounts squeezed from tubes as ribbons of composition), the lesions showed epithelialization, no hemorrhagic areas, and no initiated areas (as they were in the past without our treatment). The "horny epithelium" and ulceration of the forehead lesion were also gone. The patient had a complete successful response with :~ ~ :,, the formulation. All basal cell carcinoma lesions had been ~ .

resolved and disappeared. There has been no recurrence.

: ~:: , .
Exam~le 2 - ;
60 year old male tennis player had sore elbow and basal cell carcinoma on forearm proximate sore elbow. Patient -. ,~,, ~ . .
tried Formulation 1 to abate pain in tennis elbow. (Dr. Falk was not treating this patient for anything at the time, did not know of the basal cell proximate the elbow and merely offered the formulation for pain relief of the elbow instucting the patient to squeeze a ribbon of the composition and apply and rub into the sore elbow). However, the formulation "spilled" over ~-onto the Patient's basal cell carcinoma. Patient was planning ;~
to have basal cell carcinoma removed surgically by another ~ ~
, : ~ ~ ~ ., .;

log - 2 ~ 9 7 8 ~ 2 doctor, but when the patient returned to see the doctor, the basal cell carcinoma was disappearing (because of spill-over of Formulation 1). Dr. Falk was then advised and treatment was now undertaken by Dr. Falk with direct application of Formulation 1 to the lesion 3 times a day for two additional weeks. After two weeks, the basal cell carcinoma disappeared. There has been no recurrence.

Exam~le 3 Male, mid to late 40's had severe basal cell carcinoma on left temple. Doctors recommended its removal by surgery.
However, the surgery would have been risky because of the lesion~s proximity to facial nerves.
Patient saw Dr. Falk who gave him Formulation 2 to be applied in dosage amounts 3 times daily.
After 14 days, 75% of the lesion was gone. Surgery was postponed and the treatment was continued. Application of dosage amounts of Formulation 2 was continued for an additional two weeks. At the end of the 2- week period, the lesion was completely resolved and disappeared without any surgery being required. There has been no recurrence.
'~ '''"', Exam~le 4 Male, early 40's, had recurrent actinic keratoses lesion on his right temple. Early attempts at removal by third parties involved the application of liquid nitrogen (twice) without final resolution. The lesion kept recurring. The patient was sent to Dr. Falk who treated the lesion with Formulation 1 with applications of dosage amounts 3 times daily -- 110 - 2 ~ '~ 7 8 ''~

for 7 days. After 7 days, the lesion was completely resolved with no subsequent recurrence.

Exam~le 5 A male patient with basal cell carcinoma was first treated by an oncologist who attempted to surgically excise the lesion (without success) and then irradiated the lesion again without success. The patient then attended before Dr. Falk who ~ -applied Applicant's formulation (diclofenac with sodium hyaluronate and excipients). Application was made three times daily for about a month and the lesion disappeared. Some excoriation anterior and slightly superior developed over the last two weeks but was cleared by the application of hyaluronic acid by itself. ;-~ ~;
~ . :
This resolution clearly indicates that even with prior applications of unsuccessful therapies (surgery and irradiation), Applicant's formulations can be used successfully.

Exam~le 6 A patient with dermal (skin) metastases in a fibratic :; .
scar form and metastatic cancer in the form of musculoskeletal ;~
involvement in her thorax.
On topical application of our formulation comprising diclofenac (Voltaren) in hyaluronic acid (sodium hyaluronate), ;~
25 her pain decreased dramatically and her skin and boney ~ ~;
involvements steadily improved.

, , ~
TOPICAL DICLOFENAC ACID 3% IN HYALURONIC -~
ACID GEL (2.5%) BASE
,:

::: : .,:.: .

2 a ~ 7 3 ~ 2 A practitioner reviewed the effectiveness of topical Diclofenac Acid 3% in hyaluronic acid gel (2.5%) base in acute traumatic injuries of no longer than 3 days duration. The cases were all in the spectrum of ages between 18 and 65. Normal S exclusion criteria were followed regarding exclusion of pregnancy, aspirin or N.S .A. I.D., allergies or active peptic ulceration. ;~
As an overall, the following impressions were gained from 30 cases~
1. The topical H.D.(composition comprising sodium hyaluronate and diclofenac) had an obvious analgesic action with onset occurring rapidly within one hour;
this is a phenomenon not obviously seen with other non-steroidals that we have used. ~-2. There was a very definite patient acceptance of the gel as a form of treatment, being logical, easy to apply, without local or systemic side effects, rapid ;, /~, absorption with no staining of clothing. i 3. The anti-inflammatory action was equivalent on a "guestimate" based on experience of similar ;`
injuries to oral N.S.A.I.D.s, without the threat or -~
risk of side effects.
In summary, compared with other topical N.S.A.I.D.s the analgesic effect is distinct, the anti-inflammatory is equal to oral N.S.A.I.D.s and the patients' acceptance is far superior to any other diclofenac or piroxicam topical that the " practitioner evaluated. ;~
`-~ Following the practitioner's basic preamble regarding the parallelism of topical N.S.A.I.D.s and topical steroids,the -- 112 - 2037392 ::

practitioner has used the former in contact dermatitis, insect bites and U.V. erothema, all with very positive effects, again pointing direction to trials of a double blind nature in these fields. ~. .

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CHRONIC CONDITIONS - EVA~UATIONS ` :
2.5% HYALURONIC ACID WITH 3% DICLOFENIC ACID (HD) :
S Positive (P) .~ -Patients Date Negative (N) Initials Of Fil Unable to (M) or (F) Birth No. Diaanosis Comments on Outcome Comment (U) .
LA (M) 11.04.56 Hypcr- Severe discomfort following P
aesthesia extensive surgery to dorsal spine with insertion of Example of ~: :
rods in 1989. Even contact peripheral with clothes produced sig- action on nificant discomfort. super-Initially treated with EML~ sensitiza-with only transient anaes tion of :
thetic results, however nerve :~
even after 3 days treatment ending with Hyal diclofenac acid queried.
noticed marked decrease in supersensitivity which has .~
continued for at least 4 :.. :.: :-weeks while still using gel. .
XB (F) 08.06.58 Chronic Treated right knee which was P :~
chondro- worse initially and was .
malacia amazed at the response, then perhaps started to treat left knee dating back that was not so painful, : to 1976. again with positive response. .~..... ,-Here we have a built-in con- .

35 DB (F) Chronic Initially felt some improve- N
neurogenic ment which was not continued pain in although initially quite :: :
ankle with positive - query placebo associated reaction.
dysae~thesia DC (F) 07,11,51 Chronic back N
pain - query I
due to facet syndrome or points, ~.
really diag-uncertain. ;~
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- 114 - 2~78~2 ~ :

CHRONIC CONDITIONS - EVALUATIONS
HYALURONIC ACID WITH 3% DICLOF~NAC ACID (HD) ~:
Positive (P) 5 Patients Date Negative (N) ~: :
Initials Of Eil Unable to ' (M) or (F) Birth No. DiaanosisComments on Outcome Comment (U) CC 18.01.25 Chronic cap- Definite effect over knee p sulitis where application to tar-right hip get distance short. No .
right knee obvious effect over hip. .
AG (F) 07.11.58 Myositis in Initially given placebo in P
rhomboids error, only marginal or muscles minimal effect, if any.
following Found active to be effect-motor vehicl tive while being used, did accident not cure condition which needed trigger point therapy. ~ -CH (F) 22.08.61 Chronic No significant effect, nor N
relapsing has aggressive therapy since tendonitis including injection with right elbow cortisone and numerous - ~ -opinions.
SH (F) 16.07.55 Tendonitis Control of tendonitis while ~ `
and myositis using preparation. Is now back at work. ~ :
DM (M) 17.06.47 Neuronitis This patient has a very U
unusual pain in his left - ~-groin following nerve -injury, with the use of preparation noticed de-crease in pain sensation while on medication.
Hyperaesthesia altered -although pain (which may be phantom) still present.
PJ 15.06.45 Capsulitis Symptoms improved 50% while U
of right using Hyal diclofenac acid, wrist however, on discontinuation pain reappeared. Exact etiology uncertain. ;~
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- 115 - 2~97~2 CHRONIC CONDITIONS - EVALUATIONS - :
HYALURONIC ACID WITH 3% DICLOFENAC ACID IHD) Positive (P) 5 Patients Date Negative (N) Initials of Fil Unable to (M) or (F) Birth No. Diaanosis Comments on OutcomeComment (U) DJ (F) Dorsal Control while using gel myositis equal and with less side ;.
effects than tiger balm.
Controlled symptoms while ~ ~ ~
using medication. Exact -diagnosis as to cause of - ::
myositis uncertain. , DK (F) 27.08.38 Severe This patient has had capsu-capsulitis litis left shoulder for many left shoulde years and treated with only Extremely transient relief with corti- rewarding sone injections, poor relief case with topical piroxicam. Was started on topical diclo-fenac acid and noticed relief of pain in 20 minutes -~
continuing for 4 - 6 hours.
See letter March 11/92. At - -present is using H.D. regu- :~
larly, has found it to be useful in other areas of chronic pain. Is President - ~ !
North American Chronic ~ -Pain Association, has good insight into medication and placebos etc. Has two D.C.S. ~ :
implants.

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2~7892 :
CHRONIC CONDITIONS - EVA~UATIONS ~ :
~YALURONIC ACID WITH 3% DICLOFENAC ACID (HD) : :
Positive (P) 5 Patients Date Negative (N) Initials Of Fil Unable to (M) or (F) Bixth No. Diaqnosis Comments on Outcome Comment (U) .~ ~
JL (M) 10.12.45 Chronic Pain has failed to respond N ~-.
myositis to many aggressive treat- :.
secondary to ments.
query facet syndrome ~ ~ .
15 RMC(F) 13.06.57 Neuronitis It is a difficult case with U
following considerable overlay, she facet obtained some relief with .
rhizotomy H.D., would estimate 30-40~ ~ ~
with result- Interestingly hyper- :~:
ing pain in anaesthesia was decreased.
her back RM (F) 20.08.52 Chronic Using H.D. significant p --~
capsulitis improvement in pain while . .~
used, on stopping treatment ~- . :.
recurrence of pain, needed . ::
intra-articular cortisone. ;-~
GM ~F) Sub-acute Rapid resolution of pain - -tendonitis within one day and positive :~
right ankle return of function. - .: --:'.'~. ~: ~ ""'''''~
PM (F) 20.09.46 Acute on Rapid analgesic response : :-:. ' chronic with rapid settlement.
osteo- f arthritis of first meta- ~ : -tarsal :;: :'::- ::
phalyngeal :. : :. :
joints : ~ :
DN (F) 10.03.44 Chronic Excellent response to appli- P - : :
fasciaitis Cation of H.D. with occlu-of feet sion. Had failed to respond , :~
to oral N.S.A.I.D.s and ~- .
physiotherapy. Query posi-tive result due to short application target distance ~ :~
in a vascular tissue. : : :

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- 117 - 2~37~92 CHRONIC CONDITIONS - EVALUATIONS
HYALURONIC ACID WITH 3% DICLOFENIC ACID (HD) Positive (P) :~
S Patients Date Negative (N) Initials Of Fil Unable to :~
~M) or (F) Birth No. Diaanosis Comments on Outcome Comment (U) BP (F) 04.03.20 Severe Initially one knee treated 0 chronic with such good results that arthritis of both knees treated, see Side the knee. letter. Not only did pain effects~
Unable to decrease but marked swell- non/Inci-take oral ing around knees. Signifi- dental ~n~
]5 N.S.A.I.D.s cant relief of pain and resolution increase in movement as a of area of result of this and perhaps thrombo- :. ;
reduction of swelling. phlebitis Intrestinalv has severe below area suDerfiaial varicose veins. of treat ~ :
develo~ed thrombo~hlebitis ment around riaht knee and the ~ -area treated bv chance showed far less redness and tenderness than the throm-bo~hlebitis below this area.
SP (M) 06.11.48 Idio- Has had similar episodes U
pathic with poor response to many diffuse treatments including capsulitis N.S.A.I.D.s per os of hands WS 04.06.45 Chronic Has been exposed to number- U
neuronitis ous treatments including due to tow attempts of surgery injury to without effect. There is lateral decrease in hyperaesthesia cutaneous but no change in pain.
nerve of thigh MS (P) 04.06.28 Chronic Pailed to respond to number P
capsulitis of treatments, good back-ground resolution of pain, however, still had acute pain with certain movements. ~
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- 118 - 20~7~32 -. .

CHRONIC CONDITIONS - EVALUATIONS .: .
HYALURONIC ACID WITH 3% DICLOFENAC ACID (HD) :
Positive (P) Patients Date Negative (N) nitials of Fil Unable to (M) or (F) Birth No. DiaonosisComments on Outcome Comment (y) IS (F) 15.01.48 Chronic Had failed to respond to P
capsulitis numerous treatments -~
including oral and topical N.S.A.I.D.s Using H.D ~
there was equivalent control --lS of pain as with other ~-therapies which lasted while -;
medication was used.
Referred for surgical opinion.
GS (F) 26.03.47 Chronic oral diclofenac acid dis- P
tendo- continued due to gastritis -sinovitis and also history of ulcera- ~ ;
tion. tion. Control using H.D.
equal to or better than oral N.S.A.I.D.s.
VK (F) 01.01.39 Chronic Good relief of pain and p tendonitis tenderness while using H.D. for pain however on discontinuation N c.
of gel symptoms returned, for treated with intramuscular resolution steroids.
GH (N) 03.11.21 Acute onIn view of age and general P ~ ~ `
chronic parous medical condition, Commented ,~
osteo- ideal for topical. Had on better ~ -arthritis been previously on topical absorption left hand piroxicam for left shoulder compared capsulitis. to topical piroxicam : :
:. :.:
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:,:: ~:: ' - 119 - 2 ~ ~ 7 ~ ~ 2 ' ' '. ~

CHRONIC CONDITIONS - EVALUATIONS
HYALURONIC ACID WITH 3% DICLOFENAC ACID (HD) Positive (P) ~' 5 Patients Date Negative (N) ~ - :
Initials Of Fil Unable to ~ ;
~M) or (F) Birth No. Diaanosis Comments on Outcome Comment (U) ~A (M) 06.02.58 Severe post- Produced good superficial traumatic analgesia especially where and surgical staples were irritating sub-osteo- cutaneolls tissue, little arthritis of effect on deeper, severe left leg osteoarthritic pain of knee. -with staples This pain was of consider-Poor result able severity, needing nar-to oral cotics.
N.S.A.I.D.s also gastric irritation.
IM (M) 30.11.51 Chronic Severe rhomboid inflammation P
superficial right side, treated with myositis H.D., very definite improve-ment in pain and tenderness.
TK (P) 23.04.70 Acute on Excellent rapid analgesic chronic followed by anti-inflammator :
capsulitis response in young women who :.
due to could not take oral N.S.A.D.
sports due to past gastritis. .
injury right hand AD (F) 03.01.49 Chronic Poor response to H.D. After N
diffuse pain intensive investigation and thought to numerous consultations and be myositis treatment, pain still un-diagnosed and unresponsive.
NH (F) 25.03.25 Subacute Excellent response analgesic P
capsulitis and anti-inflammatory-wise ;
right ankle wlthin a few days. Marked clinical improvement. In s view of this patient's parous general medical con-dition and hypertension, not suitable for oral NSAIDs.

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.:~
CHRONIC CONDITIONS - EVALUATIONS
HYALURONIC ACID WITH 3% DICLOFENAC ACID (~D) Positive (P) 5 Patients Date Negative (N) Initials Of Fil Unable to (M) or (F) _ Birth No. Diacnosis Comments on Outcome Co~ment (U) ~ ~ -MD 18.04.34 Subacute Had failed to respond to N ~ :
rheumatoid oral N.S.A.I.D.s, which arthritis caused gastritis, tried on topical piroxicam with nega- -tive effects. Negative response to H.D.
MW (F) 07.05.46 Heberden's Very slow positive outcome, P
nodes, pain- initially improvement in ful, swollen pain followed by reduction causing in swelling. Etiology of - ~
difficulty this condition is unknown, - ~ :
20 in movement partly genetic. Would have -been interesting to treat alternate digits, plus or minus thermographic confir-mation.
: . ;:::
LP (F) 20.07.23 Acute on Initially treated with p ~ i sub-acute Idarac, poor response over-osteo- all, some improvement in arthritis of generalised arthritis of the hands hands but none on Heberden's - i with nodes. Pain flared on stop-Heberden's piny Idarac due to gastritis. -~
nodes Started on H.D., especially - -favourable results with sub-sidence of tenderness of nodes and settling of arthritis. Interestingly enough, no flare up on dis- .
continuation after one month .''~
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- 121 - 20~7892 ~:

CHRONIC CONDITIONS - EVALUATIONS
HYALURONIC ACID WITH 3% DICLOFENAC ACID (HD) Patients Date Positive (P) Initials Of Fil Unable to (M) or ~F) ~3irth No. Diaanosis Comments on OutcomeComment (U) JG (F) 24.11.50 Post facet Had failed to respond to Urhizotomy oral N.S.A.I.D.s and --hyper- E.N.L.A. Application of : .
aesthesia, H.D. improved the surface with marked pain significantly but had pain and no effect on the deeper hyper- pain. My impression was ~ S
aesthesia that the deeper pain was between due to section of the facet -;: -scapulae nerve and beyond the reach ~ :.
of the topical medication. :~
There is little doubt that .
the skin sensitivity was ~ ~
decreased. . ~ .
SW (F) 10.09.39 Rnee pain Upset in past due to oral Pdue to N.S.A.I.D.s., also hyper- (Effec- : ~-~
chondro tension made one loa~he to tive while malacia use this medication with being serum levels. Good anal- used) ;:~:
gesic and anti-inflammatory Condition action, however on discon- only cured tinuation pain flared. Seen by surgery :. .
for arthroscopic surgery --:-.
with relief of pain.
* Two types of pain-response in only one 1. Interestingly in the whole series, there was not one ~-~ case of local side effects and as expected from past studies, no general or systemic. Since this report was prepared we have had 40 one case of mild folliculitis which responded to discontinuation ;;~
of treatment, will rechallenge.
2. A number of patients commented that they felt the gel ;
improved the texture and softness of their skin, and commented ; that it was messy or stained their clothes.
45 3. In one case of topical thrombophlebitis where the ~ `;
inflamed vein crossed the area of treatment, the vein in the ~ ~
area of treatment improved while that outside at a distance did ;~:
~;~ not. Again, similar to using oral N.S.A.I.D.s. ***.
,r.~

'~ 2 ~ 3 i ~ 9 2 Photographs were taken of patients with basal cell carcinoma Figures 1-6 photographs, and of mice with tumors induced in the skin of the hind legs (Figure 7 photographs).
The patients were treated by using combinations of NSAIDS, (non-steroidal anti-inflammatory drugs) and hyaluronic acid (including sodium hyaluronate) according to the invention (3 diclofenac in 2.5% sodium hyaluronate gel base). Each of the six sets of Figures made up of photographs of the different persons should include a legend describing or explaining each picture as follows~
Legend for Figures lA and lB should read: - -~
Patient : W.D., male, 82 years Diagnosis: Basal cell carcinoma Treatment: NSAIDS plus HA gel. 3 times per day Figure lA: June, 1991 Figure lB: December, 1991 Legend for Figures 2A and 2B should read:
Patient : M.F., male, 45 years Diagnosis: Basal cell carcinoma Treatment: NSAIDS plus HA gel. 3 times per day Figure 2A: January, 1992 Figure 2B: April, 1992 Legend for Figures 3A, 3B, 3C and 3D should read~
Patient : H.A., male, 82 years Diagnosis: Basal cell carcinoma Treatment: NSAIDS plus HA gel. 3 times per day -Figure 3A: January 26, 1992 Figure 3B: March 16, 1992 Figure 3C: January 26, 1992 Figure 3D: March 16,1992 ~;
Legend for Figures 4A, 4B, 4C and 4D should read:
Patient : R.F., male, 64 years Diagnosis: Basal cell carcinoma ~ -~ Treatment: NSAIDS plus HA gel. 3 times per day -~ 35 Figure 4A: January 26, 1992 Figure 4B: March 16, 1992 Figure 4C: January 26, 1992 Figure 4D: March 16, 1992 :..'..' ~.. ,: . .

I_ ~A 2~37~32 Legend for Figures 5A, 5B, SC and 5D should read~
Patient : R.W., male, 86 years Diagnosis: Basal cell carcinoma Treatment: NSAIDS plus HA gel. 3 times per day S Figure 5A: January 26, 1992 ` ~
Figure 5B: Narch 16, 1992 ~ -Figure SC: January 26, 1992 untreated Figure SD: March 16, 1992 untreated Legend for Figures 6A, 6B and 6C should read: ', 10 Patient : E.D., female, 70 years Diagnosis: Basal cell carcinoma Treatment: NSAIDS plus HA gel. 3 times per day 1 Figure 6A: April 20, 1992 Figure 6B: May 13, 1992 15 Figure 6C: July 7, 1992 The Legend for Figure 7 (Figures 7A and 7B) relate to:
Mouse Strain: DBA2 Tumour: p815 ` Figure 7A: control, 19 days ;
Figure 7B: Novantrone plus HA gel 19 days '',.,~",'fi;',;
The mice shown in Figures 7A and 7B had tumours ` induced in the skin of their hind legs and dosage amounts i ~ .:.. ........
(2ml) of Novatrone (10 mg. per dosage amount) (MITOXANTRONE
(t.m.) and 2.5~ sodium hyaluronate were applied (rubbed onto) the skin at the site of the pathology. The tumours reduced in size (See Figure 7B) clearly illustrating the percutaneous - `
delivery of the medicine by the hyaluronic acid. (See Figure l ~z ~

/ The following additional comments are made with respect to the patients.
With respect to R.W. and Figure 5, the reader will note in Figures 5a and 5c the patient suffered from basal cell carcinoma on his back (Figure 5c) and his temple (Figure 5a).
Because of the age of the individual (86) the basal cell carcinoma on his back could not be reached by him for application of the medication. Thus the basal cell carcinoma in :.", :...
.: . ::;
5c remained untreated and grew (see Figure 5d). However, the portion indicated in 5a on his temple could be reached and after -application of the basal cell carcinoma formulation to the ., .: ."
temple and forehead the results are as in 5b; the basal cell ' carcinoma is disappearing. Thus, the gentlemen's own method of ":'',' ',..
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treatment acted as a control.
With respect to R.F. and Figures 4, two areas of basal cell carcinoma in need of treatment are shown by the arrows in Figures 4a and 4c and the results are shown in Figures 4b and 4d 5 as indicated by the arrows after treatment with Applicant's ;~
invention.
With respect to H.A., male, and Figures 3, Figure 3a ;~ ~
indicates two areas of basal cell carcinoma by the arrows, ~ `-close-ups of which are shown in Figures 3c and 3e. After lO treatment with the NSAIDS and HA gel three times a day for the ;~
period between January 26, 1992 and March 16, 1992 the basal cell carcinoma is clearing as per Figures 3b, 3d and 3f.
The same is true with respect to male M.F. and Figures ;
2 which appears clear in the photographs (see Figure 2a and the -l5 response shown in Figure 2b). `.
With respect to male, W.D. and Figures 1, the upper lesion in Figure la (indicated by the upper arrow) is gone after ~ - ;
treatment with Applicant's invention (See Figure lb) and the two ' lower lesions in Figure la are well on their way to disappearing ~ -20 (See Figure lb). ~ -With respect to female D and Figure 6, the lesion was ;, ~
left untreated for a long period and gradually encompassed her ~ ` -eye. Surgery could not be undertaken without jeopardizing the eye. By applying Applicant's invention (dosage amounts) over a ; -25 prolonged period, the basal cell carcinoma has constantly -;~decreased in size.
With respect to Figure 7, (7a) shows mice having -. ~:. : -: .
tumors in the skin induced in their hind legs. After continuous applications to the shaved hind legs having the tumors in the ~ --- 124 - 203~2 skin by rubbing in dosage amounts by Applicant's invention, the tumors have decreased in size. ~ `
The effect of Hyaluronic acid as a drug carrier of anti-cancer agent (5-FU) 5-Fluoracil was also studied.
S (Intratumour injection study) . EXPERIMENTAL MODEL (2) 1. Method and Material ; ~;
a. Animal : Fisher 344 rat, male 200-250g b. Tumor model Fisher Bladder Carcinoma Tumor (2mm viable tumor fragment) was lS transplanted subcutaneously on the right frank by trocar `-c. Treatment was started when tumor size is about ~ ~ `
1.5 cm. ~ -(2 weeks after implantation.) 1. These drugs were administrated by intratumor iniection. ~-(right frank) At the same time, iniection into normal skin (left frank) was carried out similarly.
Group A : H-5-FU 5mg/kg + saline /0.3ml (i.t.) B : H-5-FU 5mg/kg + HA 15 mg/kg /0.3ml (s.c.) : :: . ~. -; 3H-FU without or with HA was injected as a single dose (0.3ml) into the center of the tumor (on the right frank) with a ;;
30 gause needle. At the same time, injection into normal skin 35 (on the left frank) was carried out similarly. ~
The tumor and skin was then removed at different times ~ - `
(lh,6hr) for counting radioactivity of the remaining content in the tissue. `~ 5 e~lt i All ~h~ results were eXres~C~ ~ Mean 1 3.F.

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l2 S`' 2~3789~ :
2. Result All the results were expressed as ~ean + S . E. : .
TUI~OR TI8SW~ NORUAL SKIN
cpm~ 5-FU ~group 1CPm ~ 5~U ~H~9roup 5-FU group l~> ~ I~l 5-FU group ~ooo p~Ql~S JOOO

1hr 6hr lhr 6hr 3. Conclusion ... ~
1. In 5-FU HA arou~ radioactivity was accumulated -h.~
20 and retained in the tumor tissue for a long period, whereas .. -.
rapid clearance was demonstrated in normal tissue. (skin) 2. In 5-FU aroup, radioactivity immediately disappeared from the tumor or the normal tissue by diffusion, primarily into blood capillaries. :. ~`, ``
---- 5FU can traverse freely between the interstitial .. .;; ~
space and blood capillary. ;' ,.:., h~ ~ffes~ of ~y~lu~onic A~id a~ a ~rug ~ er in Tarqet ~_Yu3 ~ n~ ~ ~ o~~

A. EXPEFI~oU.Ir~L MODYL (l? Intrf~eno~ ~Gt~cu~L~
l____A41Jsod~ ~r~M~teri~l - ~ .`
a._ Animal : PislleL 3~4 1~, mal~
~ lQ-~50g - 126 - 2~978~2 ~ ~

,: , The Effect of Hyaluronic Acid as a Drug Carrier in Target Cancer Chemotherapy A EXPERIMENTAL MODEL (1) Intravenous Injection) 1. Method and Materi~l -S a. Animal : Fisher 344 rat, male 200-250g ~ ~
: ~ :., b. Tumor model Fisher Bladder Carcinoma Tumor (2mm viable tumor fragment) was transplanted subcutaneously on the right frank by trocar -c. Treatment was started when tumor size is about 1.5 cm.
15 (2 weeks after implantation.)... tumor weight:1.0 + 0.3g The drug was administered Intravenouslv (through the -penile vein) ~ ''`'~"`'`~'!'~
,"'"~
Group A : 5-FU 20mg/kg (3H-5-FU30~Ci) + saline -~
B : 5-FU 20mg/kg (3H-5-FU30~Ci) + HA 15mg/kg C : 5-FU 20mg/kg (3H-5-FU30~Ci) + HA 15mg/kg -+ (3H-HA30~Ci) 2. Sample Collection `
., ,: :~ ,..
a. accumulation of ADR, 5-FU in tumor tissue and liver ~ -(1). Tumor was surgically removed (and blood was collected) at *~redeterminated time after drug administration. Tumor weight was measured (and blood was centrifuged to obtain a plasma `
sample.) * 15min, 60 min, 3hr, 4hrs,.... after drug administration Liver was removed for radioactivity counting at the same time.
(2). Radioactivity level in tumor tissue was -counted, using a liquid cintillation counter.

2 ~ i 2 ~ ~ 7 8 9 2 3. Conclusion _ Radioactiv-ty in Tumor Tissue and Liver Tumor Liver 15min 3H-5FU (n=6) 2810+165 18680+625 3H-5FU+HA (n=6) 352+190 23593+1460 .- :~
3H-SFU+3H-HA (n=4) 4087+681 32060+2145 '., ~ ,-';' ,', 60min 3H-SFU (n=3) 1751+149 5451+841 3H-5FU+HA (n=4) 2599+489 8265+1849 1 0 . .~
3hrs 3H-5FU (n=6) 1493+227 2230+449 ---3H-5FU+HA (n=6) 2512+449 2897+340 3H-5FU+3H-HA (n=4) 3606+929 6977+1633 . ., - . .. -.::
lS Shrs 3H-FU (n=3) 853+129 1129+70 - -3H-5FU+HA (n=3) 1981+479 1754+248 3H-SFU+3H-HA (n=3) 2168+163 3018+325 mean+ S.E. , ;~

HA : lS mg/kg (30ilCi/kg) (CPM) RADIOA~:TIVITY IN TUMOR
5000- TISSUE 5 - FU : 2Omg/kg (30ilCi/kg) : .. ~ 5 FU~'HA .. : `
: S FU-HA ;.
4000 ~ - ~ - 'SFU 1. Radioactivity in tumor tissue in 5~
FU + HA group is higher than that in , ~ S-FU group There is signi'icant \ difference 3000~ \ \ (p>0 05, ANOVA) bet~een wi h and i ~ without HA at 3hrs after i.. jection ~ ~ ~ The high intratumor concentracion was \ ~ ~ retained for a orolor.ged time in S-2000~ \ . ~ , FU+HA group (This stention ~as , p<~O5 confirmed by the irtra~umo injectior.
~ 2 These resuits teach hat HA can lOO~ ~ enhance S-FU up~a~e in tumor tiss~e ~- ~
; , - This phenomenon -esul~s from '{A : :~:~ -;., .. `.
dis~ribution (in tu.-or tissue HA may `~
be lost from the ext~aceilular matrix) , . . and the vascular uniqueness of .umor 100 200 300 400 tissue (hyperpermiability of tumor (MiNUTES) vessels to macromolecular drug, HA) I. ~ges can be made to ~-he in departing from the scope of ~ n~ ~r,~ic is intended that all material ~ rein be interpreted as illustrative of ~ ~ ion and not_;~ a limiting sense.

- 127 - ~37~2 3. Conclusion Radioactivitv in Tumor Tissue and Liver Tumor Liver 15min 3H-5FU (n=6) 2810+165 18680+625 3H-5FU+HA (n=6) 352+190 23593+1460 3H-5FU+3H-HA (n=4) 4087+681 32060+2145 60min 3H-5FU (n=3) 1751+149 5451+841 :~
3H-5FU+HA (n=4) 2599+489 8265+1849 3hrs 3H-5FU (n=6) 1493+227 2230+449 3H-5FU+HA (n=6) 2512+449 2897+340 -~
3H-5FU+3H-HA (n=4) 3606+929 6977+1.633 15 5hrs 3H-FU (n=3) 853+129 1129+70 3H-5FU+HA (n=3) 1981+479 1754+248 3H-5FU+3H-HA (n=3) 2168+163 3018+325 mean+ S.E.
HA : 15 mg/kg (30~Ci/kg) - ~c 5-FU : 2Omg/kg (30~Ci/kg) 1. Radioactivity in tumor tissue in 5-FU
+ HA group is higher than that in 5-FU
group. There is significant difference (p>0.05, AWOVA) between with and without HA at 3hrs after injection. The high intratumor concentration was retained for a prolonged time in 5-FU+HA group.
(This retention was confirmed by the intratumor injection study.) 2. These results teach that HA can enhance 5-FU uptake in tumor tissue.
This phenomenon results from HA
distribution (in tumor tissue HA may be lost from the extracellular matrix) and the vascular uniqueness of tumor tissue (hyperpermiability of tumor vessels to macromolecular drug, HA). ~ :~

Where the combinations of the form of hyaluronic acid :;~: :
(for example sodium hyaluronate), NSAID (non-steroidal anti-inflammatory drug) (for example diclofenac) with or without the addition of the optional antioxidant Vitamin C are applied - 128 - 2~7~2 : :~

externally (topically to the skin), they may be applied as a gel (for example as those previously described) as components of a lotion having compatible ingredients, for example in a lotion such as LUBRIDERM (t.m.)[produced by Warner-Lambert Company, Consumer Health Care Division, Scarborough, Ontario, Canada]
which contain the following ingredients if compatible; water, mineral oil, lanolin, soribitol, stearic acid, acetyl alcohol, .,.., .,. :~.
trolamine, parabens, fragrance and sodium chloride.
Another such formulation which may be applied 10 topically (for external application to the skin) may combine the -form of hyaluronic acid (for example sodium hyaluronate), NSAID ~ -and optionally Vitamin C in a cream for topically application ~ - ;
containing compatible ingredients. One such cream may be a cream like Urenol (t.m.) produced by Trans CanaDerm Inc., - -Montreal, Quebec, Canada, H4R 2H4.
This cream is a cream for severe dry itchy skin proposed for the local treatment of xerosis, ichthyosis, . : .: . .:
nummular eczema and occupational dermatitis comprising Urea USP
20% in an emollient cream base.
The combination of the form of hyaluronic acid, NSAID
and optional Vitamin C is preferably put into a sunscreen form for topically application. The sunscreen preferably contains ; compatible ingredients including materials providing high Sun Protection Factor (SPF) (in excess of 15). The following :~
formulations are available for consideration (as are many others) if the components are compatible to incorporate the form of hyaluronic acid, NSAID and optionally Vitamin C. ;~
Additionally Sun Protection Factor (SPF) may be added to the formulations described above (with or without Vitamin C). Some 2 d37~9~

sunscreen formulations which may incorporate the form of hyaluronic acid, NSAID and optionally Vitamin C (provided the ::: . :- :: .~
ingredients are compatible and if not appropriately, then ;~
modified) are set out below.
Sunscreen "Presun 29" Cream Sunscreen WA/UVB Protection - Protection from the harmful burning effects of both W A and W B
Medicinal Ingredients Octyl Methoxycinnamate 7% W/W
Octyl Salicylate 5% W/W
Oxybenzone 6% W/W -Non-Medicinal Ingredients Carbomer 940 Cetyl alcohol .:
DEA Cetyl Phosphate Diazolidiny urea Dimethicone - 225 ::: ;
Isodecyl neopentanoate ~:
Isopropyl myristate . :~
Kathon CG
PG Dioctanoate ::
PVP/Eicosene Copolymer :~
Stearic Acid Triethanolamine Water Produced -Westwood - Squibb Bellville, Ontario, Canada, K8N 5E9 ;Vichy" -- 130 - 2 ~ ~ 7 8 ~ 2 Distributed by Vichy Canada, Montreal, Quebec, Canada, H4T lK5 Filtering Agents~
Octyl Methoxycinnamate 7.5%
Benzophenone-3 2%
S Non-Medicinal Ingredient Vitamin F 0.5%
SOLBAR~ SPF 15 SUNSCREENS OTC - - -SOLBAR~ SPF 15 Sunscreens are specially formulated to provide maximum protection from the sun's burning and tanning rays.
Provides substantial broad spectrum protection from WA and W B
light for sun sensitive and fair skinned persons, Fragrance-free formula. Liberal and regular use of these products over the years may help reduce the chance of premature aging of the skin ~ -and skin cancer. ~ ~-lS SOLBAR~ PF 15 LIQUIDt*+
CONTAINS
Octyl methoxycinnamate 7.5%, Oxybenzone USP 6%, SD alcohol 40, 76%
HOW SUPPLIED
Plastic bottle, 4OZ (NDC 0096-0684-04) WARNING
Keep away from open flame.
SOLBAR~ PF 15 CREAMt*+
:
CONTAINS

Octyl methoxycinnamate 7.5%, Oxybenzone USP 5%.

HOW SUPPLIED

Plastic tube, 2.5OZ (NDC 0096 0682-75) SOLBAR~ PLUS 15 CREAMt*+

CONTAINS

''- ;''~. ~

2 ~ 3 7 8 9 2 : : ~
Oxybenzone USP 4%, Dioxybenzone USP 2%, Octyl dimethyl PABA 6%. :-HOW SUPPLIED
Plastic tube, 4OZ (NDC 0096-0681-04) 5 t Directions: Apply liberally on all exposed skin. To ensure -~
maximum protection, reapply after swimming or exercise.
: - -: :.-,-.
* Caution: If irritation or sensitization occurs, discontinue use and consult a physician. Avoid contact with the eyes.
+ Warning: For external use only. Keep out of the reach of l0 children.
SOLBAR~ PF ULTRA CREAM SPF 50 OTC
Ultra protection sunscreen Broad Spectrum W A and W B protection DIRECTIONS ~ -~
Apply liberally to all exposed areas before sun exposure.
Massage in gently. Reapply to dry skin after prolonged sunning, swimming, excessive perspiration or towel drying. Repeated applications during prolonged sun exposure are recommended. ;~
CONTAINS
Oxybenzone USP, Octyl Methoxycinnamate, Octocrylene ~ : .
INDICATIONS .-~
SOLBAR~ PF 50 Cream is specially formulated for ultra protection from the sun's burning and tanning rays. Oxbenzone enhances protection from UVA and UVB light which is particularly important to photosensitive or photoallergic people. Waterproof formula maintains sunburn protection up to 80 minutes in water.
~iberal and regular use of this product over the years may help ;`
reduce the chance of premature aging of the skin and skin cancer.

::

~ "~ 2 ~ 3 7 ~ 9 2 CAUTION
For external use only, not to be swallowed. If irritation or .~: ~, .. ...
sensitization occurs, discontinue use and consult a physician.
Avoid contact with the eyes. In case of contact, rinse eyes with water. Keep this and all drugs out of reach of children.
.,. . ~ .
HOW SUPPLIED

Plastic bottle, 4OZ (NDC 0096-0686-04) ' ~ ~ ' '~ '"'"

10 SOLBAR~ PF ULTRA LIQUID SPF 30 OTC
Ultra protection sunscreen ~ P`~
Broad Spectrum WA and WB protection DIRECTIONS
Apply liberally by spreading to all exposed areas before sun 15 exposure. To ensure maximum protection, reapply to dry skin -after prolonged sunning, swimming, excessive perspiration or ; ~ -~
towel drying. Repeated applications during prolonged sun ;
exposure are recommended.
CONTAINS ~ , 20 Octocrylene, Octyl Methoxycinnamate, Oxybenzone and SD Alcohol ~ ;~
40.
INDICATIONS ~ -~
:: : .~ :,~
!, ! SOLBAR~ PF 30 LIQUID -is specially formulated for ultra protection from the sun's burning and tanning rays. Oxybenzone ;: : ~
25 enhances the protection from long wave ultraviolet which is -particularly important to photosensitive or protoallergic people.

FRAGRANCE FREE -; Liberal and regular use of this product over the years may help .~ , -- 133 - 2~3 7g9 2 reduce the chance of premature aging of the skin and skin cancer.
CAUTION
For external use only, not to be swallowed. If irritation or S sensitization occurs, discontinue use and consult a physician.
Avoid contact with the eyes. In case of contact, rinse eyes with water. Keep away from open flame. Keep this and all drugs out of reach of children. Use on children under two years of age only with the advice of a physician.
HOW SUPPLIED
Plastic bottle, 3.8OZ (NDC 0096-0685-04) ~ ~ a~iS
OTl~ S/4~,e/~Js~'~S~/' /~7~ VP~3~ ;~
Additionally, Applicants have been responsible for and ~ ;~
been involved in the development of a new method, and new 15 compositions suitable for use, for the inhibition of -~
angiogenesis (the formation and differentiation of blood vessels) which finds two applications, in the treatment of tumours and as an adjuvant to any cancer treatment for the inhibition of metastasis of the cancer.
`} ~ `' ',''.:;'. ,'~ ~ .
'~''''' ~', 2037892 ~ ~
.. --. ~ . .. :

Seotlon Xlll Sun Care- Products SUNSCREEN 8UTTER~OIL8/PETROLATUM/EMOLLIENT/COCOA iBUTTER) RAW MATERIALS ~ By Welqht ,~
I.A~erscreon P U.V. Aosorber 1.50 ^ ~",'"
2.Witconol APEM Surfactant 5 00 '~
3.Ac-tulan Lanolln Alcohol Acetat- 3 00 ~, 4.Am rchol CA13 Emulslfler/Stablllzer ~ 20.00 , ,`' ~ `
5~ ~ ^ 5.Petrolatum 20 00 ' ",~
6.Coco~ Butt-r 10 00 ,~
~; 7.Nodul-n Emolll-ntl0.00 ~"~ B.Nln-ral Oll 10.00 i'-,,~,',' ,,~ 9.Coconut Oil 6.00 ~"'`~'"
011, 6.00 ' ';~
ll.Sesams Oll 4.50 12.0zocorlto Wax 4.00 " ''' h".~ 1OO.OO
FORNULATION NOTE8 ~, s.
~ l.Add perfumo, as de~lrod '~
,z ~ ' 2.To ad~ust cons1stency,, vary ratlos of cocoa butter to ollve ~ 8 'and 8e~ame oll and potrolatum to m1neral oll ~ '5~' ~, 3.Por SPF of 8, use 3.5 to 4.0~ Amerscroen P U.V.Ab~orber ~" i ,~ Hard ~nhydrous butter wlth emolllent propertles ,~x~
Reduced o1llnoss ,',`r SPF s 80URCEsAmerchol Corp.:SUNSCREENSsButter S-1023 ~',,-'';~

, ~: : , . ~ ,; :

r..s~

_~ Cosmetic and Toiletry Formula~ions 2 ~ ~ 7 ~ 9 2 13 ~ 3 SUNSCREEN auTTER(pALMITATEs/wAx/oIL/LANoLIN) RAW MATERIALSa By Weight l.Amerscreen P U.V.Absorber 1.5û
2.Witconol APEM Surfactant 5.00 3.0Hlan Lanolin Derivative 5.û0 4.Microcrystalline Wax5.û0 5.Octyl Palmitate 8.50 - -6.Isopropyl Palmitate10.00 7.Multiwax W-835 Microcrystalline W/-x 15.00 8.Amerchol L 101 Emulsifier/Stabilizer 40.00 9.Mineral Oil 10.00 .
100.00 .:
FORMULATION NOTES -l.Add perfume, as degired 2.To vary consistency, vary ratlo of mineral oil to microcrystalline waxes 3.For reduced oiliness, add Acetulan Iianolin Alcohol Acetate KEY PROPERTIES
Soft butter suitable for tube dispensing Emollient properties and easy spreading SPF: 4 SOURCEJAmerchol Corp.~SUNSCREENS:3utter S-1025 SUNSCREEN BUTTER~PETROLATUM/MOISTURIZER/WAX/lZMOL~IENTI
RAW MATERIALS ~ By Weight ~
l.Mlcrocrystalllne Wax ~ 5.00 ~ m 2.Ganex V-216 Emolllent 5.00 3.Petrolatum ~USP Whltel 76.40 ~ ~ ~
4.Rltachol Emul-lfier 2.00 ~ - i 5.Rltaderm Molsturlzer10.00 ~: ~0 6.Octyl Dimethyl PABA1.50 ; ~- -7.Propylparaben 0.10 `
100.00 ,":,., .,, "
PORMULATION NOTE
Add color and/or perfume, as deslred KEY PROPERTIES ~ :
Bxcellent emolllency, water-re-l-tAnt, protectlve, mol-turlzlng and condltlonlng propertle~
SOURCEtR.I.T.A. Corp.tHANDBOOI~ FOR FORMULATORStFormul~ RF-93 2~37~2 (33c .~.,,,~,,.

SUNSCREEN BUTTER¦PETROLATUM/OILS/EMOLLIENT/COCOA BUTTER~
RAW MATERIALS ,~ By Weight l.Amerscreen P U.V. Absorber 1.50 2.Witconol APEM Surfactant 5.00 3.Acetulan Lanolin Alcohol Acetate 3 00 5.Amerlate P Isopropyl Ester 10 00 7.Sweet Almond Oil 7 00 :
8.Cocoa Butter 10.00 ~ 5 9.Microcrystalllne Wax 3.00 lO.Mineral 011 10.50 ll.Amerchol CAB Emulsifler/Stabilizer 20 00 12.Petrolatum 20 00 ~ ~ `
100.00 FORMULATION NOTES
l.Add perfume, as desired 2.For greater slip, replace microcrystalline wax with cetyl XEY PROPERTIES
Soft butter with s~in treatment properties ~
Reduced oiliness SPF: 4 ~-SOURCE:Amerchol Corp.:SUNSCREENS:BUTTER S-1024 ~;; ~, .
.~';' ' '' ~ Cosm~tic and Toilrnry Formulations 2 G 9 7 8 3 2 .
SUNSCREEN CREAM~COCONU~ OIL/UV ABSORBER/LANO~IN/G~UCOSE~
RAW MATERIALS~ sy Weight l.Amerscreen P U.V.Absorber 3 00 2.Witconol APEM Surfactant 5;00 3.081an Lanolin Derivatlve 3.00 4.Glucate SS Fatty Acid Ester 4.10 5.Amerchol L Emulslfier/Stabilizer 5.00 6.Arlacel 165 Emulsifler 5.00 7.Coconut 011 5 00 8.Glucamate SSE-20 Emulsifler 0 90 9.Glucam E-20 Glucose Derivatlve 2.50 lO.Water 66.50 100.00 : ~:.
FORMULATION NOTES
l.Add perfume and/or preservatlve as required 2.For reduced oiliness, add 1~ AcétulaM Lanolin Alcohol Acetate 3.For 1rmer conslstency, replace coconut oil with cocoa butter 4.Por maximal protection(SPF-8), increase Amer~creen P to 4.5-5.0 KEY PROPERTIES
Soft, nonionlc cream .
Leaves light, nontacky residual emollient film SOURCE:Amerchol Corp.:SUNSCREENS:Cream S-1006 -~
.: ',~ ' ' ~7~9~ ~ 3 ~
~"`.;.:

' ` '": " ' ."~

SUNCREBN CRBAH~BSTER/ALCOHO~/EANOLIN/STEARATE~
RAW MATERIALS t By Weight -2 Amerscreen P U.V. Absorber 4 00 _ 3.Glucate Ss ~atty Acid Ester .
4.Stearamide ~EA-Stearate 3 00 5.Solulan 5 Eanolin Derivative . ~, 6 Glucamate SSE-20 Ethoxylate 82 50 100.00 PORMUI,ATION NOTES
1 Add perfume and/or preservative, as requlred 2 For flrmer consistency, replace myristyl alcohol wlth 3.For increased body, add Glucam E-20 Glucose Derlvatlve to water phase Soft cream, whlch is a good emollient, sultable for tube ~; .
SOURCE:Amerchol Corp.:SUNSCREENS:Cream S--1004 ---, ' ,'~
SUNSCRBÉN CREAM~GLYCERIDBS/PARAFFIN/LIGHT BARRIER) .
RAW MATERIAES
l MlgiYtl G~e80KGEYmUl lf; r 5.00 ~ `
3 Elquld Paraffln 4 N-o-Hellopan Elght Tvarrler 5.Water 100.00 ,~ . . ' ':'" .. ' .: -:
PORMUL.ATION NOSB ~ `
Md perfume and/or preservatlve, as requlred ~:~ KBY PROPERSIES
Improved conslstency Extreme thermal stablllty Qulckly rubs lnto the skln, leavlng no gloss behlnd Skln 18 left soft and supple SOURC~:Kay-Frlel~,Inc.:MIGLYOL-GEL:Suggested Pormula ~ -~:: '. :. :~ :, .' ; , . ,. . !

. r . . ... ~ .

Co~me~c an~ Toil-~ly Fo~mulatlons ~ 9 7 8 ~ 2 SUNSCREEN CREAM(LANOLINS/PALMITATE/AMINE/UV ABSORBER) RAW MATERIALS ~ Sy Weight l.Amerscreen P U.V.Absorber 2.00 2.Solulan PB-2 Lanolin Deriv~tlve 5.00 3.Solulan PB-20 Lanolin Derlvatlve 10.00 4.Isopropyl Palmltate10.00 5.Arlacel 165 Emul8ifler1.00 6.Carbopol 934 Resin 0.7s 7.Water 65.25 ~-8.Sodlum }iydroxide ~10~ in Water~ 2.25 9.Ethomeen C/25 Allphatic Amlne 3.75 100.00 '~'',' E'ORMULATION NOTES
l.Add perfume and/or pre8ervatlve, a8 requlred 8 2.For more lubricity, replace part of isopropyl palmitate `
with Amerlate P Isopropyl Ester 3.Por firmer consistency, add cetyl alcohol to oil phase .
IU~Y PROPISRTIl!S
Soft glossy cream Llquefies on appllcatlon to soothlnq emolllent fllm --~ f Water resistant conditloning film SP~4-5 SOURC15:Amerchol Corp.:SUNSCREEN9:Cream S-1008 . -~::' : - -:
''' ':'~'' . `~ ' ~ .
: '. ~,,, ' ~ "'' ' `;.
` ~ `
.

--` 2 ~ 3 7 g 9 2 ~ ~

SUNSCREEN CREAM(LANOLINS/UV ABSORBER/ESTER/ETHOXYLATE~
RAW MATERIALS 3 By Weight ~ ;
l.Amerscreen P UV Absorber 3.00 2.Glucate SS Fatty Acid Ester 3.00 3.Stearamlde MEA-Stearate 2.00 ; -4.Promulgen G Emulsifier 8 00 5.Solulan 75 Lenolln Derivative1 00 ~
6.Solulan 98 Lanolin Derivative3.00 -7.Amerchol BL Emulsifier/stabllizer 1.00 8.Water 76.00 9.Glucamate SSE-20 Ethoxylate 3.00 ~ `
100.00 PORMULATION NOTES
l.Add perfume and/or pre~ervatlve, as reguired -~
2.For moderate protectlon(SPF-4), use 2~ Amer3creen P
U.V.Absorber 3.For lotion cons~stency, replace Promulgen G Emulsifier -~
with Promulgen D Emulsifler and add 0.5~-1.0~ Acetulan Lanolin Alcohol Acétate KEY PROPERTIES
Very soft nonionic cream Low oil content ~ -Good rub-in, with light residue SW RCE:Amerchol CorpsSUNSCREENSsCream S-1003 : :~
~: ' :.

; ' ~ ' ~' : ~
",'"'-'"""' ,.,.'..

Cosmetic and Toiletry Formulations 2~37~92 ~::
SUNSCREEN CREAM(MYRISTATE/ESTER/STEARATE/GLUCOSE/ALCOHOL~
RAW MATERIALS 8 By Weight l.Amerscreen P U.V.Absorber3.00 2.5tearic Acid 2 70 3.Amerlate P Isopropyl Ester6 00 4.Cetyl Alcohol 3.00 5.Isopropyl Myristate 7 50 6.Glyceryl Stearate 4 00 7.Promulgen G Emul8ifier 5.00 8.Water 64.50 9.Triethanolamine 1.30 lO.Glucam E-20 Glucose Derivative 3.00 100 . 00 FORMULATION NOTES
l.Add perfume and/or preservative, as required 2.For firmer consistency, replace cetyl alcohol with stearyl alcohol 3.~o liquefy, replace Promulgen G with Promuigen D Emulsifier and cetyl alcohol wlth myristyl alcohol 4.For moderate protectlon ~SPF4), use 28 Amerscreen P U.V.
Absorber KEY PROPERTIeS
Soft, moisturi~ing cream with excellent dry rub-in Lubrlcating skin treatment SOURCE:Amerchol Corp.:SUNSCREENS:Cream S-1005 "''" ;~'','' .
-'; ~

20~78~2 :~

..~
, ~ . ..
SUNSCaEEN CREAM(PARAFFIN/GLYCERIDES/LIGKT EARRIERI
RAW MATERIA~S - S By Welght l.Miglyol-Gel Glycerides 15.00 2.Imwitor 780K Emulsifier 5.00 ~ ;
3.Liquid Paraffln 5.00 4.Neo-Heliopan Light Parrier Agent 5 00 5.Water (Distilled) 70 00 ~ ,~ !~, 100 . 00 ' `, FORMULATION NOTE
Add perfume and/or preservative, as required XEY PROPERTIES
Excellent emulsiflcatlon propertles -~
Exceptional stability SoURCE~Kay-Frles,Inc.:IMWITOR 780K:Suggested Pormula SUNSCREEN CREAM~STEARAL/COCONUT OIL/SSEARATES/PALMITATE) RAW MASERIALS ~ By Weight -~
l.Coconut Oll 5 00 2.Solulan PD-20 Lanolin Derivative 3 00 3.Isopropyl Palmitate 5.00 ~-.Myristyl Alcohol 2.00 5.0Hlan Lanolin Derivative1.00 - 6.Glucate SS Fatty Acid Ester3 o0 7.Glucamate SSE-20 Ethoxylate3 00 ~- . 8.Acetulan Lanolin Alcohol Acetate 0.50 9.Amerscr-en P U.V.Absorber3.00 10.Arlacel 165 Pmul~ifler 5.00 12 wmtrchol L lol Emulsifier/Stabillzer 58 00 13.Glucam B G1UCOAe Derivative 1.50 100.00 -PORMULASION NOSES ,.
l.Add perfume and/or preservative, as required 2.Por greater lubricity, replace part of isopropyl palmitate wlth Amerlate P I~opropyl Ester ~ 3.For firmer vlsco~lty, replace myristyl alcohol with cetyl -i alcohol -XEY PROPERSlES
~ ~ , Soft, elegant nonionic cream, emollient-rich, nongreasy ~;
; SOURCE:Amerchol Corp.lSUNSCREENS:Cream S-1002 '''~ ~ '.' ""
..': . ~'. .

."`~". '.'''"'"~

'.'~ "'-`'','` :'' ~ Cosrmticand Toiletry Formulations 1 ~ 3 ~ J
2~37892 ~
SUNSCRBEN CRBAM(STEARATE/COCONUT OIL/UV ABSORBER~
RAW MATBRIALS ~ By Weight l.Coconut oil 7.00 2.Amerchol CAB Emulsifier/Stabilizer 2.00 3.Stearic Aeid 5.00 4.Glyceryl Stearate 8.50 5.Amersereen P U.V.Absorber 5.00 6.Glucate SS Fatty Acid Ester1.00 7.Glueamate SSE-20 Ethoxylate 1.00 8.Water 67.50 9.Glueam B-10 Glucose Derivative2.00 10.Triethanolamine 1.00 100.00 FORMULATION NOTES
l.Add perfume and/or preservative, as requlred 2.For ~extra~ protection (SPP-6), use 3.0-3.5~ Amerscreen P
U.V.Absorber 3.For marketing preference, replace coconut oil with cocoa butter ~EY PROPERTIES
Blegant, nongreasy eream with maximum proteet~on GOGGCEIA_ rchol Co~p.:5U~SCGEEh9~Cr-a- G-IC01 ~ .
~ '~''""',''' ~' ' .., ' '-, " "'.'~

. ~
' -' '~' .:~':
'',"',., ,',.
':-:~ ,, ' -:'-':' ,",,.,". ".........
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SUNSCREEN CREAMISTEARIC ACID/EMOLLIENT/LANOLIN/W AsSORBER) RAW MATERIALS ~ i3y Welght l.Amerscreen e U.V.Absorber 2 00 2.St0aric Acld 4 00 3.Dehydag Wax SX 8ase Compound 1.00 4.Myristyl Alcohol 1.00 5.Modulan Emolllent 2 00 -, 6.Amerchol L 101 Emulslfler/Stabillzer2 00 .,. -.;
7.Acetulan Lanolln Alcohol Acetate 1.50 ~ -~
8.Isopropyl Myrlstate 1.50 -9.Amerlate P I~opropyl Ester 1.50 -~-10.Carbopol 940 Resln ~3~ ln Water) 7.00 ll.Trlethanolamlne 1.00 12.Water 75.50 -loo.oo - ~:

l.Add perfume and/or preser~ative, as requlred 2.For flrmer consistency, replace Amerchol L 101 Emulsifier/
Stabilizer with Amerchol CAB Emulslfler/Stablllzer and myrlstyl alcohol wlth cetyl aleohol ` -~
3.To liguefy, replace s~earlc acld wlth Amerlate LFA
Lanolin Fatty Acld -KEY PROPERTIES -Soft cream W
Excellent emolllent ~ - ^~
Molsturlzlng, lubrlcatlng and dry rub-ln SPF: 4-5 SOURCE:Amerchol Corp.:SUWSCREBNS:Cream S-1007 ::; i: :, ; ., '., ' .'..' '...
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SUNSCREEN CR-EAMls-TEARIc ACID/LANOLINtGLUCOSE/PALMlTATE) RAW MATERIALS ~ By Weight l.Amerscreen P U.V.Absorber1.00 2.0Mlan Lanolln Derlvative0.50 3.Solulan PB-20 Lanolin Derivative 5.00 4.Isopropyl Palmitate 5.00 5.Stearlc Acld 6.50 6.Arlacel 165 Emulsifler 6.00 7.Dow Cornlng 200 Fluld (350 cSt~ 1.00 8.Carbopol 934 Resln 0.30 9.Glucam E-20 Glucose Derivative 5.00 lO.Trlethanolamine 1.00 ll.Water 68.70 lo o . oo FORMULATION NOTE
Add perfume and/or preservatlve, as required ~ -KEY PROPERTIES
Nonionic sunscreen cream, stable in heat and sunlight Does not staln skln or Eabrlcs SOURCEs8.F.Goodrich~PERSONAL CARE PRODUCTS:Formula No.33 ~Amerchol Corp.) 8UNSCREEN CREAM(STEARIC ACID/LANOLINS/GLUCOSE/PALMITATE) RAW MATERIALS~ By Weight l.Amerscreen P U.V.Absorber2.00 2.Acetulan Lanolln Alcohol Acetate 2.00 3.Solulan PS-10 Lanolin Derivatlve 8 20 4.St-aric Acld 22 80 5.Amerlate P Isopropyl Ester ~ 2.50 6.Isopropyl Palmltat- 2.50 7.Gluc-m E-10 Glucose Derlvatlve 4.00 8.Triethanolamine 1.20 -~
9.Water 54.80 100.00 ' PORMULASION NOTES
l.Add perfume nd/or preservative, as requlred 2.For mlnlm-l protection~SPF-2), reduce Amerscreen P U.V.
Absorber to 1.0-1.5~. For extra protection(SPF-6), lncre--- Amer~creen P U.V.Ab-orber to 3.0-3.5 KEY PROPERTIBS
P rle~cent, ~olt vanishing cream, no olllness, lubrlcity.
SOURCEtAmerchol Corp.:SUNSCREENS:Cream S-1009 ;

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SUNSCREEN CREAM(TRIGLYCERIDE/EIG~T BA MIER/PARAFFIN) RAW MATERIA~S 8 By Weight l.Miglyol-Gel Glycerldes 15.00 2.Imwltor 780~ Emulslfier 5 00 ;~
3.LlquLd Paraffin 5 00 4.Neo-~elLopan Llght Barrier Agent 5.00 -5.Water ~Dlstllled) 70.00 -: '~.;:: ., .
100 . 00 ' FORMULATION NOTE .~ -Add perfume and/or preservatlve, as requlred SOURCE~Kay-Frles,Inc.sCOSMETIC FORMULAS:Pormula 4.5 SUNSCREEN AND INSECT REPELLENT CREAMIREPELLENT/ALCO~OL) RAW MATERIALS 8 By Welght l.Amerchol L 101 Emulslfler/Stàbillzer 3.50 2.Modulan Emollient l.OO
3.MGK Intermediate 5734 In~ect Repellent 12.00 4.Escalol 506 Sun-Screen 1 20 5.Tinuvln P U.V.Absorber 0 05 6.Arlacel 165 Emulslfler 5.00 7.Cetyl Alcohol 1.50 ,~``~
8.C~rbopol 940 Resln . 0.21 9.Water ~Dlstllled) 75 34 lO.Trlethanolamlne 0 20 ~ ;
100.00 : ~,' ''".''"
PORMULATION NOTE
Add perfume and/or preservatlve, as requlred -KEY PROPERTIES
Elegant, glossy soft cream sultable for squeeze bottle or tube packaglng Cream spreads and rubs ln easlly wlthout whltenlng Protectlve molsturizlng and emolllence, without ob~ectlonable olllness or tacklness SOURCE:B.F.Goodrlch:PERSONAE CARE PRODUCT:Formula No.34 (Amerchol Corp.) .: ` . ' ~.
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:: :. ~ ,-" ` ' Cosmetic and Toil~try Formulations 2 0 3 7 ~ 9 2 SUNSCREEN FOAMlOILS/STEARIC ACID/LIGHT BARRIER!TRIGLYCERID~S) RAW MATERIALS ~ sy Weight l.Miglyol 840-Gel lû.00 2.Miglyol 812 Neutral Oil 5.00 3.Wool Fat 1 00 4.Softlgen 967 Triglyceride 1 50 5.Softigen 701 Triglyceride 0.50 6.Cetyl Alcohol 1.00 7.Stearic Acid 4.00 8.Triethanolamine 2.00 9.Neo-Heliopan Light Barrier Agent 3.00 10.Water (Distilled) 72.00 100 . 00 FORMULATION NOTES
l.Add perfume, as deslred 2.Aerosol:Active Ingredients 90 00 Propellents 12/114(40/60)10 00 SOURCE:~ay-Frles,Inc.:COSM~TIC FORMULAS:Formula 4.4 SUNSCREEN GEL(ALCOHOL/G~YCO~/UV ABSORi3ER) RAW MATERIALS ~ i3y Weight l.Carbopol 9~0 Resin ~3~ in Water) 25.00 3 Triethanolamlne ~10~ in Water) 227 50 4.Amerscreen P U.V.Ab-orber ~ 5.00 5.Propylene Glycol 20 00 6.8DA-40 Alcohol 20 00 loo.oo FORMU~ATION NOTES
l.M d perfume and/or preservative, as required 2.Por 8PF of 5-6, use 3~ Amerscreen P U.V.Absorber 3.For dry fllm re~ldue, replace part of propylene glycol wlth Glucam P-10 Glucose Derlvative ~FY PROPERTIES
Clear~ tran~parent, hydroalcohollc, moblle gel Plea~ant feel Dry rub-ln SOURCE~Amerchol Corp.:SUNSCREENS:Gel S-1016 . ',,', . '' :.: ::-~:,.'. i : ,',. :' ....
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~ ~ r SUNSCREEN LOTION(ALCO~IOL/EMOLLIENT/SUNSCREEN) RAW MATERIALS ~ By Weight l.Glv-Tan P Sunscreen Agent 2 00 ~-~
2.Wltconol F26-46 Emolllent 25 00 3.SDA Alcohol 73.00 1 0 0 . 0 0 .-, - .: .~, . .
PORMULATION NOTE --Add perfume, as deslred SOURCEsWltcosSURFACSANTS FOR COSMETICS AND TOILeTRIES: ~ o Formula 117C

SUNSCREEN LOTION~ALCOIIOL/GLUCOSE/GLYCOL/UV A8SORBER) RAW MATERIALS ~ By Welght l.Amerscreen P U.V.Ab60rber . 2.00 ' 2.SDA--40 Alcohol 49.00 3.Glucam P-10 Glucose Derivative 10.00 4.Propylene Glycol 10.00 ~;
S.Water . 29.00 loo.oo :: ~
POR~IULATION NOTES .
~ l.Add perfulne, a8 deslred - 2.For hlgh SPF~ lncreas- Amerscreen P U.V.Ab30rber and add `~ Uvlnul MS-40 U.V.Llght Absorber ,~
ItEY PROPICRTIES
Clear, thln hydroalcohollc solution , ~ F
Pl-a-ant, dry fllm SPFs2-4 SOURCEsAm rchol Corp.:SUNSCREENS:Solution S-1017 -'' ~ `~ , ` , ' '.~

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Rl-- Cosmetic and Toilotry Formulations 2 ~ 9 7 ~ 9 2 SUNSCREEN LOTION(ALCOHOL/OIL/SUNSCREEN) RAW MATERIALS~ By Weiqht l.Lipal 20 OA Surfactant/Emulsifier 3.00 2.Lipal 4 CSA Surfactant/Emulsiiier 1.00 3.Neobee 1~-20 Cosmetic Oil 5.00 , ~-4.Carbopol 940 Resln0.50 S . Water 6 0 . 0 0 6.SDA-40 Alcohol 28.00 -1 7.E8CA1O1 506 Sun-Screen 1.50 -~ ~
8.Triethanolamlne 0.50 , ~ s g.eerfume 0.50 100 . 00 .
SOURCE:B.F.Goodrlch:PERSONAL CARE PRODUCTS:Formula No.32 ~

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SUNSCReEN LOTION~ALCOHOLS/OLEYL ETHER/SUNSCREEN) ~ ~, RAW MATeRIALS~ 8y Welght I.Carbopol 940 Resin0.50 2.Water IDelonlzed)5~.50 3 .Liquld Ba~e 4 . 00 4.Novol Distllled Oleyl Alcohol 2.00 ,; ~-5.Volpo 20 Oley~l Ether 3.00 6.Polawax ~atty Alcohol Derlvatlve 1.00 S ~;
7.SDA--40 Alcohol27.70-28.50 -8.Sunscreen ~Alcohol-soluble) 1.00-1.80 9.Trlethanolamlne 0.50 ~ -100 . 00 ~ .. `.' .~ :` .
.:,:....: .. :.-FORMULATlON NOTE ~- -Add perfume, as de~lred ~ -KEY PROPeRTI15S
Opaque alcohollc emulslon greaselesr~ sunscreen vehlcle ~-SOURCBIB.F.Goodrlch:PERSONAL CARE PRODUCTS:Formula No.35 ::.:.: :,.,:
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SUNSCREEN LOTION~ALCOHOL/SUNSCREEN) RAW MATERIALS ~ By Weight l.lsobutyl-para-aminobenzoate 5.00 2.Tween 20 Surfactant 9.0o `~
3.SDA-40 Alcohol 45.00 4.Water 41.00 -~
100 . 00 . .,, `,., `
KEY PROPERTIES ;s ~:
Simple form of clear sunscreen lotlon Has high level of water SOURCE:}CI Amerlcas,Inc.:SOLUBILIZATION:Formula S-3 .,i., , . ,. ,~, "

SUNSCREEN LOTION(ALCOHOL/UV A8SORBER/GLYCOL) RAW MATERIALS ~ By Weight l.Amerchol L 101 Emulslfier/Stabllizer 5.00 . ~U
2.Amerlate P Isopropyl Ester 1.00 3.Carbowax 1540 Polyethylene Glycol 3.00 4.Amerscreen P U.V.Absorber ~ 3.00 -~3~i~
5.Carbopol 934 Resin (3~ in Water) 16.00 ;i~
6.Water 41.50 -, ~`~
7.Trlethanolamine 0.50 :
8.SDA-40 Alcohol 30.00 oo . oo FORMULATION NOTE8 /;
l.Add perfume, a8 deslred -~
2.For flrmer consistency, replace part of Amerchol L 101 ~ :
Emulslfler/Stablllzer wlth Amerchol CAB Emulsifier/
Stabillzer N~;
3.For more nonolly resldual feel, add Glucam P-20 Glucose -~
Derivatlve KEY PROPERTIES
Very soft, hydroalcohollc cream gel ~-Excellent emolllency and suspenslon Pleasant rub-ln and good residual feel SPF:4-6 i SOURCEsAmerchol Corp.:SUNSCREENS:Gel S-1015 d ~-:~ ' ':'~' : :

~_ Cosmetic and Toiletr~/ Formulations 2 0 3 8 9 2 1 3 3 ~

SUNSCREEN LOTION(ALCOHOL/LANOLIN/UV ABSORBER/ESTER) RAw MATERIALS ~ By Weight l.Amerchol L 101 Emulsifier/Stabillzer 5.00 2.Amerlate P Isopropyl Ester1.00 3.Solulan 25 Lanolin Derivative 3.00 ~ -4.C-rbopol 934 Resin o.So 5.Natrosol 250HR HydroxyethylCellulose 0.20 6.Water (Dlstilled~ sa.ao 7.Triethanolamlne 0.5û
8.Amerscreen P U.V.Absorber 2 50 9.Ethyl Alcohol 28 50 100.00 FORMULATION NOTE ?
Add perfume and/or preservaSlve, as required KEY PROPERTY
Hydro~lcoholic sunscreen lotion SOURCEsHercules,Inc.:COMPARATIVE ADVANTAGES OF HERCULES
PRODUCTS:Table XXV(Amerchol Corp.) , '',"-,~,, .~', .' -''.' ~''" '.

SUNSCReEN LOTION~ALCOHOLS/W ABSORBER~ - -RAW MATERIALS 8 By Weight l.Carbopol 940 Resln ~3~ in Water~ 6.50 --~
2.W ter 52.80 1 3 3.ethomeen C/25 Allph-tlc Amlne0.20 4.Amerscreen P U.V.Absorber 5.00 5.I~o-tearyl Alcohol , s.So 6.SDA--40 Alcohol 30.00 ~ ~
100 . 00 `, ~, .-,.
FORMULATION NOTES
l.Add perfu-e, ~8 de~lred 2.For SPF of 6, use 3~ Amerscreen P U.V.Absorber ~-~
KFY PROPERTIES
Unlque, hydro-lcohollc lotlon ~dlU vl~coslty, mull~ifler-~ree mul~lon wlth excellent SOURCFlAmerchol Corp.lSUNSCREENS:Lotlon S-1014 '.':;~

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. . . - . .

SUNSCREEN LOTION(EMOIILIENT/ALCO~OL/W ABSORBER1 RAW MATERIALS ~ By Weight : ..: .:
l.Arlamol E Emolllent/Solvent 8 00 3 Bri~ 72 Emulsifier/Wetting Agent 1 20 4.Stearyl Alcohol IUSP\ 4.00 5.Amerscreen P U.V.Absorber 2.00 6.Carbopol 934 Resln0.20 7.Dowlcll 200 Antlmlcroblal 0 10 8.Water IDelonlzed)81 30 9.Trlethanolamine0.20 10.Pnrfume 0.20 1 00 . O O
XEY PROPERTIES
Oil-ln-water lotion Excellent emolliency SOURCE:ICI Amerlcas,Inc.:ARLAMOL E:Suggested Formula , . , ~

SUNSCREEN LOTION(EMOLLIENT/SUNSCREEN
RAW MATERIALS~ By Welght l.Arlamol B Emolllent/Solvent 95.00 2.Sun~creen Agent5.00 100 . 00 FORMULATION NOTES
Seleet Sunl~eraen Agent from the following:
8Olprot~x IIIt Flrmenlch, Inc.
Escalol 506: Van Dyk ~ Co.,}nc.
Meta homomenthyl sallcylate: Frltzsche Dodge & Olcott,Inc Sunscreen Agent M: Frltzsche Dodge ~ Olcott~ Inc Benzyl Sallcylata~ Frltzsche n~odge & Olcott,Inc.
Cycloform: Armak Uvlnul M: GAF Corp.
E~calol 507: Van Dylc ~ Co.,Inc.
Amerscreen P: Amerchol Corp.
KEY PROPERTIES
Clear product Wlde varlety of active Ingredlents can be used SOURCE:ICI Amerlcas,Inc.:ARLAMOL E:Suggested Formula ::
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Cosmetic and Toil~try Formulations 2 0 ~ 7 8 9 2 SUNSCREEN LOTION~EMOLLIENTS/UV ABSORBER/LANOLIN/GLUCOSE) RAW MATERIALS ~ sy Weight l.Amerchol L 101 Emulsifler/Stabilizer 5.00 2.Modulan Emollient 1.00 3.Amerlate LFA Lanolin Patty Acid 3.00 4.Witconol APEM Surfactant8.00 -. :~
5.Amerscreen P U.V.Absorber3 00 6.Glucate SS Fatty Acid Ester 2 50 7.Myristyl Alcohol 2.00 8.Glucam E-10 Glucose Derivative 3.00 ~-~
9.Trlethanol~mine 1.00 10 Glucamate SSE-20 Ethoxylate 2.50 100.00 "' ~
FORMULATION NOTES
l.Add perfume and~or preservatlve, ~8 required 2.~o opacify, increase Glucate SS Fatty Acid Ester 3.To thicken, replace part of myristyl alcohol with cetyl 4.For more skin ~reatment, increase Modulan Emollient KEY PROPERTIES
Flowing, lightly translucent lotion System that rub- ln dry Drynes- and elegant feel ` i~
SPFs 5-6 `~
SOURCE:Amerchol Corp.:SUNSCREENS:Lotlon S-1010 SUNSCREEN LOTION~GLYCOL/LANOLIN/ALC000L~ W ABSORBER) RAW MATERIALS ~ By Weight l.Amer-croen P U.V.Absorber 2.00 2.Propylene Glycol 20 00 3.Amoroxol OE-20 Alcohol4 70 -4.Solulan 16 Lanolin Derlvative 4.70 ~i 5.Water 68.60 FORMULATiON NOTBS
; l.Add perfume and~or pre-ervative, as required 2.To olubillze more hydrophoblc perfume 0118, replace Ameroxol OE-20 wlth Ameroxol OE-10 Alcohol 3.For mor- re~idual feal and fragranc- retention, add Glucam P-20 Glucose Dorlvatlve Clear, moblle~ ~olublllzed lotlon wlth 8PF of 4 80URCE:Amerchol Corp:8UN8CREEN8:801ution 8-1018 ~ - .

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SUNSCREEN LOTION~POLYHERS/NYRISTATE/PALHITA~E/EMOLLIENT~
RAW HATERIALS ~ Ey Welght l.Water ~Purlfled1 52.55 2.Propylene Glycol 4.70 3.5Odium Lauryl Sulfate 0.05 4.Escalol 506 Sun-Screen 2.00 ~ ;;
5.Isopropyl Myristate 10.00 . , ~, 6.Isopropyl Palmltate 10.00 7.Modulan ~molllent 4.70 a.Carboset 514 Polymer 13.00 9.Carbopol 960 Resin 0.50 . .
10.Tlmlca Pearlwhlte 2.50 100.00 ~-'~',,.,'.. ~.
PORHULATION NOTES
l.Add antlmlcroblal, antloxidant and/or perfume, as requlred ~ H -2.0ther sultable nacreous pigments lnclude Fl~menco Pearl CQ, Tlmlca Pearlwhite, Silkwhite or Sparkle - -SOURCE:The Mearl Corp.:COSHETIC PORMULARY:Suggested Formula ~

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SUNSCREEN_LOTION~STEARATE/_TEARIC ACID/EMOLLIENT/ET~O Y ATE~
RAW HATERIALS ~ Py Welght l.Modulan Emolllent 2.00 2.Glyceryl 8tearat- 4.00 3.Stearlc ACld 2.50 4.Am rscreen P U.V-Absorber1.50 5.Glucate SS Fatty Acld Ester2.00 6.Glucamate SSE-20 Ethoxylate2.00 2.Water 83.50 8.Glucam E-20 Gluco~e Derlvatlve 2.00 ~i 9.Trl~thanolamlne 0-50 ~" 100.00 ' '~ ': '' PORMULATION NOTES
l.Add perfume and/or preservative, a8 requlred . ~;
2.For lubrlclty, add Amerlate P Isopropyl Ester 3.For lmproved spreadlng, add Ameroxol OE-2 Alcohol KEY PROPERTIES
Medlum vlscoslty, flowlng, moisturizing, skln softenlng, ~ -~
humectancy,SPF of 3-4 SOURCE:Am rchol Corp.sSUNSCRE~NSILotlon 5-1013 ' :'~ ':.~.

~4< Cosme~ic and Toiletry Formulations 2 ~ ~ 7 ~ ~ 2 SUNSCREEN LOTION~UV ABSORBER/LANOLINS/MYRISTATE/ESTER) RAW MATERIALS s ~y Weight -~
l.Amerscreen P U.V.Absorber5.00 ~
2.Witconol APEM Surfactant5.00 -M
3.Isopropyl Myrlstate 4.00 4.Glyceryl Stearate 2.00 5.Cetyl Alcohol 2.00 -6.Acetulan Lanolln Alcohol Acetate 2.00 5 7.Glucate SS Fatty Acid Ester2.50 -8.Solulan L-575 Lanolin Derivative 2.50 9.Glucam E-10 Glucose Derlvative 2.00 10 Glucamate SSB-20 Emulsifier2.50 ~ -ll Water 70.50 ~
~.: .:~: .::-PORMULATION NOTES ~ -l.Add perfume and/or preservatlve, as required 2.To reduce viscosity, replace part of cetyl alcohol with myristyl alcohol 3.For moderate protection, reduce Amerscreen P to 2.0-2.5 . . -KEY PROPERTIES
High viscoslty, nonlonlc lotlon for squeeze bottle dispensing Good rub-ln, velvety feel, sllp ~ ;
SPF~ 8-10 SOURCE:Amerchol Corp.~SUNSCREENS~Lotlon S-1011 NscREeN OIL~OIL/ALCO~O~/LANOLIN/GLUCOSE/UV ABSORBER~
RAW MATERIALS i By Weight l.Amerscreen P U.V.Absorber1.20 2.Wltconol APEM Surfactant30.00 3.Acetulan Lanolln Alcohol Acetate 5.00 4.Ameroxol OE-2 Alcohol 5.00 ~
5.Glucam P-10 Gluco-e Derivative 5.00 .m 6.Mineral Oil 53.80 100.00 '~
FORMULASION NOTES
1.Add perfume oll, as requlred 2 For llp, add myrlstyl alcohol 3 To coordlnat- wlth deep-tannlng labellng clalm, add oll-~oluble colors ~EY PROPERTIES
Elegant oll wlth dry rub-ln and good apreadlng SP~ 2 SOURCE~Amerchol Corp.:SUNSCREENS~Oll S-1022 , :.

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SUNSCREEN OIL(OIL/ALCOMOL/LANOLIN/PALMITATE/W AssoRBBR) RAW MATERIALS O By Weight l.Amerscreen P U.V.Absorber 3.00 2.Witconol APEM Surfactant 30.00 3.Acetulan Lanolin Alcohol Acetate 5.00 4.Amerchol L lOl Emulsifier/Stabili2er 5.00 5.Ameroxol OE-2 Alcohol 5 00 6.Dilsopropyl Adipate 1 00 7.0ctyl Palmitate 4.00 8.Isodecyl Oleate 1.00 9.Sesame Oil 46.00 100.00 , ~
FORMULATION NOTES :~
l.Add perfume, as required , .
2.For labeling claims, substltute corn or other oils for -~
~esame oil , I~EY PROPERTIES
Light lotion, pleasant feel, good moisturizer SPF: 4 SOURCE:Amerchol Corp.:SUNSCREENS:Oll S-1020 -' ~ ' SUNSCREEN OILlOIL/EMO~IENS/W ABS~
RAW MATERIALS ~ i3y Welght l.Amerscreen P U.V.Absorber 3 00 2.Wltconol APM Surfactant 30 00 . ~ -3.Modulan Emolllent 5.00 4.Mineral Oll 62.00 -100.00 ~
FORMULASION NOTES i~ `
l.Add perfume, as requlred 2.To reduce olly feel, add Acetulan Lanolln Alcohol Acetate 3.For SPP of 2, use 1.2-1.5~ Amerscreen P U.V.Ab~orber 4.Por better spreAdlng, add Ameroxol OE-2 Alcohol ~EY PROPERTIES . - ~-Cleàr, llght oll wlth some rasldual olly feel and skln treatment beneflts - - -, , SPF: 4 ~
SOURCE:Amerchol Corp.:SUNSCREENS:Oll S-lOl9 : -~.;;

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Cosmetic and Toiletry Formulations 2 0 ~ 7 3 ~ 2 SUNSCREEN 0IL~OIL/MYRISTATE/SALICYLATE/LANOLINS
RAW MATERIALS ~ By Weight l.Isopropyl Myristate 10.00 ~-2.Ritalan Liquid Lanolin 3.00 ~ -3.Rltacetyl Lanolin 1.75 4.Aldo DGDO Acid Ester 5-00 -~
5.Mineral O11 (65/75 Saybolt)72.15 6.Propylparaben 0.10 7.Homo Menthyl Salicylate 8.00 -100.00 ,~
FORHULATION NOTE
Add perfume, as desired Key PROPERTIES
Lubrlcation, emollience, excellent compatibility, reduced ~ ~;
oily after-feel SOURCE:R.I.T.A.Corp.:HANDBOOK FOR COSHETIC AND TOILETRY
FORHULATORS:Formula No. RF-94 ' ~ ',.~ ., ., ,' . .
SUNSCRLEN OIL(OIT/PARAFFIN) ~
RAW HATRRIALS ~ By Weight l.Higlyol 812 Neutral Oil80.00 2.Paraffln Wax (Llquld) 15.00 3.Prosolal S9 5-00 100.0~ ' ~, .:
FORHULATION NOTE :
Add perfume, as desired SOURCE:Kay-Frie-,Inc.:HIGLYOL:Suggested Formula ,~, :

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SUNSCREEN OIL(OIL/UV A8SORBER/ALCOHOL/EMOLLIENT) RAW MATERIALS 0 By Welght ~ -~
l.Amerscreen P U.V.Absorber 2~Witconol APEM Surfactant25.00 3.Modulan Emolllent 3.00 4.Amerchol L 101 Emulslfler/Stablllzer 10.00 5.Ameroxol OE-10 Alcohol 6.Mineral Oll (70 Welght) 56 00 ~ ~
100.00 ' '~'' :' FORMULATION NOTES
l.Add perfume, a~ deslred 2.Por hlgher vlscoslty, use hlgher weight mlneral oll 3.To reduce olly feel, add Acetulan Lanolln Alcohol Acetate 4.To lmpart sllp, add cetyl alcohol -~
KEY PROPERTIES
Emolllent formulatlon deslgned to spread readlly Provldes skln treatment .;,~

SOURCEsAmerchol Corp.:SUNSCREENS:Oll S-1021-~; SUNTAN cREAMlL-ANoLINs/pETRoLATuM/AMINEiguNscREEN~
RAW MATERIA8S ~ 8y Welght l.Amerchol L 101 Emul~lfier/St~blllzer 5.00 2.Modulan Emolllent 3.Solul~n 16 ~nolln Derlvatlve1 00 ~ -5 Penreco Snow Petrolatum 5.00 6.Carbopol 934 Resln 0.75 ,.`,.;~
7.Water 75.25 8.Sodlum Hydroxlde (10~ ln Water) 2 25 ~ -9.Ethomeen C/25 Allphatlc Amlne 3 75 10 0 . 0 0 KEY PROPERTIsES
A whlt; opaque cre m whlch goes on easlly and l-aves a ~llky '',"~,,.,,"~"`?`
SOURCE:PenrecosCOSMETlC FORMULAS:Suggested Pormula 2 ~ 3 7 ~ ~ 2 , ~ :

Experimental and Test Data is set out below.

PROTOCOL FOR TOPICAL AND INTRA-POUCH

IN COMBINATION

Introduction~
The formation of a subcutaneous air pouch in the dorsum of mice allows the formation of a lining which responds to produce a chronic inflammatory lesion in response to various antigens, irritants and foreign bodies. It can also be used for the introduction of drugs and various other treatments into the site of inflammation and the collection of inflammatory exudate. ; :
15A unique and simple technique has been perfected which quantitatively assesses angiogenesis in the developing inflammatory air pouch, by making a vascular cast incorporating carmine which can then be spectrophotometrically assayed.
Method:
20For this experiment female mice (TO, 25-30g, 10 per group) were lightly anesthetized with hypnorm/hypnoval. Air ~ -pouches were formed by the subcutaneous injection of 3 ml of filter-sterilized air, into the dorsum of each mouse. After 24 hours, chronic inflammation was induced in the air pouch lining by the injection of 0.5ml Freund's complete adjuvant (FCA) supplemented with 0.1% croton oil.
Dosln~ Schedule:
Animals were dosed daily from the time of injection of FCA/croton oil, for 6 Days. At which point the analysis was 30 performed. ;

: - :: .:

- 13~ -2&~73~2 : ~

1. Topical: (See Table One: Topical Application) Four groups, - 0.1ml Aqueous Cream * (Thornton & Ross Ltd.) - 0.lml Aqueous Cream + 6mg/kg Diclofenac ;
(HPC lot.9113003) -~
- 0.lml Hyaluronic Acid (HPC lot.OG019) ; -- 0.1ml Hyaluronic Acid (1% solution, M.W.
less than 750,000 daltons) + 6mg/kg Diclofenac Before the topical application the hair on the dorsum was removed using hair clippers and depilatory cream (Louis Narcel). The skin surface was broken in one or two mice in each group, while using the electric clippers. These animals were discarded from the results. ~;, 2. Intra-Pouch:(Injection) -,.. ~ .:
Four groups, - 0.1ml Sterile Saline (0.9%) - 0.lml Sterile Saline + 6mg/kg Diclofenac (HPC lot.9113003) ~ ,'~;~

- 0.lml Hyaluronic Acid (HPC lot.OG019) ;

0.1ml Hyaluronic Acid (1% solution, M.W.

less than 750,000 daltons) + 6mg/kg Diclofenac ''"'.'''.'~

Vascular Castlng:

Mice were anesthetized with hypnorm/hypnoval and placed on a heated operating platform maintained at 37C for 20 minutes. Each mouse was then placed into a water jacketed `~
-:, . ~, . :
incubation chamber at 37C and injected i.v. with lml of 15%
carmine dye in 10% gelatin (in Hanks balanced salt solution) with syringe and solution prewarmed to 40~C. Cadavers were then chilled at 4C for 4 hours.
Analy~

' :.' ~ .'''''' ~7~2 The granulomatous tissue was dissected free and dried in an oven at 56C for 48 hours. The dried granuloma was weighed and then digested in 9ml of papain solution (12-Units/ml in 0.05 M phosphate buffer, pH 7.0, supplemented with 0.33g/1 N- ~ S
5 acetyl cysteine), at 56C for 48 hours. The digests were then made up to lOml with 5.OM NaOH and vortexed, to solubilise the dye and centrifuged. The digests were filtered through 0.2~m cellulose nitrate membranes and 200ml samples aliquoted into 96 well plates and analyzed for dye content by spectrophotometric lO analysis at 490mm using a microplate reader. Vascular volume was calculated as carmine content per mg dry mass of tissue. :
*Commercially available water based cream.

~ '' ' ~',"-,' ",,., ,."",,.

. ., . ! ' ~

~, ~ ''',.'''';. ''''','';' - 137 - ~3~2 Table One: Topical Application ~ ;

~y~luronic ~cid (O.lml) ;~
(1% ~olut~on (10 mg/ml), M.W. ~ -S Aaueoum cro~ ~0 ~ le~s th~n 750 000 d~ltc ~
Animal Dry wt ~mg) Absorbnesc mg s~armine ug/dYe/ms Dry wt(mg) Absorbous ug carmine ug dye mg 174 .0183 65.5 .376 187 0657 246 1.316 2 303 0.848 319 1.053 178 0.528 197 1.107 3 133 0.613 229 1.722 146 0.148 52.2 0.358 10 4. 163 0.769 289 1.773 190 0.433 161 0.847 S
6 221 1.014 382 1.728 181 0.505 188 1.039 ~""' ~`~''' 7 130 0 . 689 258 1 . 985 179 0 . 494 184 1 . 028 ' ~
8 122 0.606 227 1.661 160 0.567 212 1.325 ,.~; ,~ .. ';', ~. ' `',`',~, 5 9 192 0.631 263 1.229 ~'~`~
10 191 0.413 156 0.817 .,"- ,~ . ,',"'~',~: .' ME4N 179 . 6 240 . 7 1 . 389 176 . 62 184 . 5 1 . 031 S.e.m. 21.26 346 0.201 561 31.3 0.111 , . ~
V= NS NS NS ~.; ' ' . ~` ~, ;.~
Hy-luronla cld Aaueou~ cre-m ~ dlclo(6ma/~a) ' : `~
(1% eolutlon) I ~Lclo(6ma/~a~
', ~ ~,.:' ~''`~'' 1 152 0.185 66.2 0.436 1260.528 218 1,730 ' ~' `
2 176 0.125 43.4 0.242 1760.420 156 0.886 3 201 0.441 164 0.816 1400.401 148 1.057 ` ~ ;
4 149 0.461 171 1.148 196 0.578 216 1.102 1240.510 190 1.532 `~
6 167 0.464 1731.035 `~
7 88 0.176 62.8 0.714 8 131 0.195 70.1 0.535 1970.808 304 1.534 9 135 0.109 37.3 ' 0.276 2070.854 231 1.551 ,~ 10 193 0.217 78.2 0.405 Mean 154.6 103.6 0.658 166.3187.3 1.216 S.e.m 13.79 24.3 0.123 11.58 23.6 0.158 2 p= NS 0.0104~ 0.0209~ NS NS NS

n = X
(diclo = Diclofenac) - ~.

: ,:: ~. :.

- 138 ~ 2~97~92 ~

Table Two: Intra - pouch ;

Hyaluronic Ac$d (1% Hyaluronic Acid S ~olution) I d4clo(6ma~ ~a) (1% ~olutio~ l~ :
Animal Dry wt (mg) Absorbness mg carmine ug/dye/m Dry wt(mg) Absorbous ug carmine ug ~ye mg 104 0.323 68 0.654 126 0.607 130 1.032 .; ~
2. 106 0.293 61.5 0.580 128 0.209 43.3 0.337 ~ , 3. 140 0.215 44.6 0.319 142 0.710 152 1.069 0 4. 133 0.305 64.1 0.482 108 0.603 129 1.194 ' ':~
115 0.460 97.7 0.846 118 0.414 87.8 0.747 , 6 90 0.258 53.9 0.602 97 0.293 61.8 0.637 7 262 0.271 56.8 0.217 134 0.190 39.2 0.294 8 72 0,178 36.6 0.509 160 0.494 105 0.654 1 5 9 6 4 0 . 171 3 5 . 1 0 . 5 4 5 14 7 0 . 4 9 5 10 5 0 . 71 6 10 85 0.210 43.5 0.512 130 0.318 66.9 0.517 ' ME~N 117.1 56.2 0.5266 129 91.97 0.7197 S.e.m. 17 8 0 0029~ 0 0260' 5.85 12.24 0 0~57 sali~ ~Lla~. ~ dic lo(6ma/~
211 o.sls 197 0.932 139 0.773 166 1.194 2 98 0.590 126 1.282 158 0.242 50.5 0.320 3 135 0.390 82.6 0.614 99 0.730 156 1.577 ~
~ 25 4 161 0.880 lol 1.184 39 0.400 104 1.050 ~ ;
:~ 5 117 0.482 103 0.880 129 0.409 86.7 0.674 6 134 0.587 125 0.932 124 0.262 54.8 0.442 ~ , 7 138 0.447 94.9 0.686 162 0.402 85.2 0.526 -8 233 0.398 84.3 0.361 135 0.303 63.7 0.471 9 109 0.438 93 0.854 170 0.468 99.5 0.586 lo 168 0.220 45.7 0.272 122 0.292 61.3 0.520 Me~ 150.4 114.3 0.7988 133.7 92.75 0.7363 ~ :
' s.e.m 13.8 15.1 0,1022 7.75 12.77 0.1275 P= NS NS NS ~: . ~:.. .
~.-::- ::
~ 35 N = 10 :::: :

- 139 - 2~78~2 Table Three: ~e 8 U 1 t 8 CArmine av~ (u~ Gr~nulom~ drv wt.(m~) u~.dv~/m~.~r~mulom~
Topical Mean S.e.~l. P= Nean S.e.m. P= ~ean S.e.m. P=
Aq.crea 240.7 34.6 179.6 21.3 1.389 0.201 aq+dicl 187.3 23.6 NS 166.3 11.6 NS 1.216 0.158 NS
HA 184.3 21.3 NS 176.6 5.6 NS 1.031 0.111 NS
HAldicl 103.6 24.3 0.0104 154.6 13.8 NS 0.658 0.123 0.0209~
i-pouch ' . .. .
0 Saline 114.3 15.1 150.4 13.8 0.7988 0.1022 diocnlOol 92.6 12.8 NS 133.7 7.8 NS 0.7363 0.1229 NS
HA 91.9 12,5 NS 129 5.9 NS 0.07197 0.0957 NS
~2~i5~ ~ 56.2 5.85 O.0029~ ' 117.1 17.8 O.0454 O.5266 O.0546 O.0260 lS n = 8 for Topical application n = 10 for Intra -pouch treatment This data supports the notion of HA and Diclofenac, in combination, acting synergistically as an angeistatic agent.
Also, it is important to note that although not significant, the trend is such that HA + diclo ismore angiostatic than HA alone, the latter being more potent than diclo.
All the data has been included for statistical analysis, if however one excludes "obvious" flyers, eg. table two, animal 7, HA + diclo, the results are more significant.
The results of the tests and experiments firmly establish that forms of ~hyaluronic acid (for example sodium hyaluronate having a molecular weight less than 750,000 daltons) and NSAID (for example diclofenac) act on angiogenesis to inhibit angiogenesis, in for example the granuloma resulting in a reduction in granuloma dry weight.
The inhibition of angiogenesis may be used in the treatment and destruction of cancerous tumours. The '' .' - 140 - 20~7892 : ~
. . .
compositions, dosage amounts taken from the compositions, processes and treatments by the invention may be used as an adjuvant to any anti-cancer treatment (for example radiation, chemotherapy using anti-cancer drugs, etc.) The invention may S also be used to prevent metastasis in cancer patients so that while one tumour is being eradicated, no other malignant tumours develop. Thus the development of tumours is inhibited by inhibition of blood vessel growth to a tumour (cutting off the supply of blood vessels to the tumour). In this regard use of the invention counters, opposes, interferes with and inhibits resulting activity by Tumour Angiogenesis Factor (TAF) produced by a cancerous tumour to increase blood vessel growth to such tumour, thereby inhibiting such growth. A composition, for ~ -example comprising sodium hyaluronate and diclofenac ~-~ m~
administered systemically to a human patient inhibits angiogenesis and the tumour is eradicated. The composition may be administered over a short term or a longer term as required (for example a number of weeks or months as required). .
It will also be appreciated by those skilled in the 20 art that the processes, uses, compositions and dosage forms :~
according to aspects of the invention may be applied for example to inhibit prostaglandin synthesis and angiogenesis and thus control, inhibit and prevent cancer. It is therefore clear that many uses can be made of embodiments and aspects of this :::
25 invention without departing from the scope thereof. It is ::~
~: therefore intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
~:": ~

'

Claims (154)

1. A method of conditioning the immune system in humans to resist the formation of one or more cancerous tissue types, comprising administering a non-toxic dosage amount of a composition comprising pharmaceutical excipients suitable for administration to a human, a therapeutically effective non-toxic dosage amount of a non-steroidal anti-inflamatory agent (NSAID),an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or cub-units of hyaluronic acid and optionally vitamin C, which together are effective when the composition is administered to condition the immune system in humans to resist the formation of one or more cancerous tissue types.

2. The method of Claim 1 wherein the form of hyaluronic acid is hyaluronic acid and salts thereof.

3. The method of Claim 2 wherein the pharmaceutical composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg/cm2 of skin and/or exposed tissue to which it is applied.

4. The method of Claim 3 wherein the composition includes ingredients constituting an effective sunscreen having an acceptable SPF number.

5. The method of Claim 2 wherein the amount of hyaluronic acid exceeds about 10 mg.

6. The method of Claim 2 wherein the pharmaceutical composition is for systemic administration and the amount of the form of hyaluronic acid exceeds about 200 mg/70 kg person.

7. The method of Claim 2 wherein the pharmaceutical composition is adapted for intra-venous administration, and wherein the composition comprises vitamin C and the amount of the form of hyaluronic acid exceeds about 200 mg/70 kg person.

8. The method of any one of Claims 1 to 7 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

9. The method of any of the preceding Claims wherein the non-steroidal anti-inflamatory drug (NSAID) is selected from Diclofenac in an amount selected from between about 35 mg and about 500 mg/70 kg person.

10. The method of any one of Claims 1 to 8 wherein the NSAID is selected from diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of ketorolac, ibuprofen, piroxicam, propionic Acid derivatives, aceytylsalicylic acid and flunixin.

11. The method of any of the preceding Claims, wherein the development of the cancerous tissue is attributable to prostaglandin synthesis.

12. The method of any of the preceding Claims wherein a dosage amount of the composition is administered after any sun exposure.

13. The method of any of the preceding Claims wherein the composition is administered intermittently in humans at high risk for the development of skin cancer due to extensive sun exposure.

14. A method of preventing the spread and/or metastasis of one or more cancer tissue types in humans, comprising administering a non-toxic dosage amount of a composition comprising pharmaceutical excipients suitable for administration to a human, a therapeutically effective non-toxic dosage amount of a non-steroidal anti-inflamatory agent (NSAID), an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid and optionally vitamin C, which together are effective when the composition is administered to prevent the spread and/or metastasis of one or more cancerous tissues in a human.

15. The method of Claim 14 wherein the form of hyaluronic acid is hyaluronic acid and/or salts thereof.

16. The method of Claim 15 wherein the pharmaceutical composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg/cm2 of skin and/or exposed tissue to which it is applied.

17. The method of Claim 15 wherein the pharmaceutical composition is for systemic administration and the amount of the form of hyaluronic acid exceeds about 200 mg/70 kg person.

18. The method of Claim 15 wherein the pharmaceutical composition is adapted for intra-venous administration, and wherein the composition comprises vitamin C and the amount of the form of hyaluronic acid exceeds about 200 mg/70 kg person.

19. The method of Claim 16 wherein the composition includes ingredients constituting an effective sunscreen having an acceptable SPF number.

20. The method of Claim 19 wherein a dosage amount is administered after sun exposure.

21. The method of Claim 19 wherein the composition is administered intermittently in humans at high risk for the development of skin cancer due to excessive sun exposure.

22. The method of any one of Claims 15 to 21 inclusive, wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

23. The method of any of the preceding Claims 15 to 22 inclusive, wherein the non-steroidal anti-inflamatory drug (NSAID) is selected from Diclofenac in an amount selected from between about 35 mg and about 500 mg/70 kg. person.

24. The method of any one of Claims 15 to 22 inclusive, wherein the NSAID is selected from diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of ketorolac, ibuprofen, piroxicam, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin.

25. The method of any of the preceding Claims 15 to 24, wherein the treatment is administered daily for a number of weeks.

26. The method of treatment of Claims 15 to 24 inclusive, wherein the treatment comprises administering effective dosage amounts of the composition, a number of times daily for a period of weeks to prevent the spread or metastasis of one or more cancerous tissues types in a human.

27. The method of Claim 20 to 26 inclusive in combination with any method of treating cancer.

28. A sunscreen composition including a plurality of effective non-toxic dosage amounts of a composition for administration to humans to condition the human immune system to resist formation of one or more types of skin cancer tissues, each such dosage amount taken comprising ingredients, including sunscreen agents having an acceptable SPF number, constituting an effective sunscreen composition, a therapeutically effective non-toxic (to the patient) dosage amount of an non-steroidal anti-inflamatory drug, optionally vitamin C and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid to condition the human immune system to resist formation of one or more types of skin cancer tissues.

29. The sunscreen composition of Claim 28 wherein the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid is hyaluronic acid and/or a salt thereof.

30. The sunscreen composition of Claim 28 or 29 wherein each dosage amount of the sunscreen composition comprises at least about 5 mg/cm2 of the form of hyaluronic acid.

31. The sunscreen composition of Claim 28, 29 or 30 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

32. The sunscreen composition of Claim 28, 29 or 30 wherein the non-steroidal anti-inflamatory drug (NSAID) is Diclofenac.

33. The sunscreen composition of Claim 28, 29 or 30 wherein the NSAID is selected from diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of ketorolac, IBUPROFEN, PIROXICAM, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin.

34. A sunscreen composition from which dosage amounts may be taken and administered to condition the human immune system to resist formation of one or more types of skin cancer tissues, the sunscreen composition comprising:
(1) a non-steroidal anti-inflamatory agent (NSAID);
(2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, in a form suitable for administration to humans;
(3) ingredients including sunscreen agents having an acceptable SPF number constituting an effective sunscreen composition; and (4) optionally, Vitamin C;

characterized in that an effective dosage amount comprising effective non-toxic dosage amounts of components (1) and (2) taken and administered from said composition are in a form available to condition the human immune system to resist formation of one or more types of skin cancer tissues.

35. The sunscreen composition of Claim 34 the amount of component (2) is at least about 5 mg per effective dosage of component (1).

36. The sunscreen composition of Claim 34 wherein the amount of the form of hyaluronic acid in each dosage amount of the composition exceeds about 5mg/cm2 of skin and/or exposed tissue.

37. The sunscreen composition of Claim 34, 35 or 36 wherein the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid is hyaluronic acid and/or a salt thereof.

38. The sunscreen composition of Claim 34, 35, 36 or 37 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

39. A sunscreen composition comprising:
(1) a non-steroidal anti-inflamatory; and (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, (3) ingredients including sunscreen agents having an acceptable SPF number constituting an effective sunscreen composition; and (4) optionally vitamin C;
characterized in that said composition (a) is in a dosage form which is suitable for administration to a human; and (b) is in such an amount and in such form that components (1) and (2) are in effective dosage amounts to condition the immune system in humans to resist the formation of one or more skin cancer tissue types.

40. The composition of Claim 39 wherein the form of hyaluronic acid in the composition comprises hyaluronic acid and/or salts thereof.

41. The composition of Claim 39 or 40 wherein the effective amount of the form of hyaluronic acid in the composition exceeds about 5 mg per dose of the composition.

42. The composition of Claim 41 wherein the amount of the form of hyaluronic acid exceeds about 5mg/cm2 of skin and/or exposed tissue.

43. The composition of Claim 39, 40, 41, or 42 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

44. The composition of Claim 39, 40, 41, 42 or 43 wherein the non-steroidal anti-inflamatory (NSAID) is Diclofenac.

45. The composition of Claim 39, 40, 41, 42 or 43 wherein the agent (NSAID) is Diclofenac and the effective dosage amount of Diclofenac is between about 35 mg and about 500 mg/70 kg.
person.

46. A sunscreen composition including a plurality of effective non-toxic dosage amounts of a composition for preventing the spread and/or metastasis of one or more cancer tissue types in humans, each such dosage amount comprising ingredients including sunscreen agents having an acceptable SPF
number constituting an effective sunscreen composition, a therapeutically effective non-toxic (to the patient) dosage amount of an non-steroidal anti-inflamatory drug, optionally vitamin C and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid to condition the human immune system to prevent the spread and/or metastasis of one or more skin cancer tissue types in humans.

47. The sunscreen composition of Claim 46 wherein each dosage amount of the sunscreen composition comprises at least about 5 mg of the form of hyaluronic acid.

48. The sunscreen composition of Claim 47 wherein the amount of the form of hyaluronic acid exceeds about 5mg/cm2 of skin and/or exposed tissue.

49. The sunscreen composition of Claim 46, 47 or 48 wherein the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid is hyaluronic acid and/or a salt thereof.

50. The sunscreen composition of Claim 46, 47, 48 or 49 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

51. The sunscreen composition of Claim 46, 47, 48, 49 or 50 wherein the non-steroidal anti-inflamatory drug (NSAID) is Diclofenac.

52. The sunscreen composition of Claim 46, 47, 48, 49 or 50 wherein the NSAID is selected from diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of ketorolac, IBUPROFEN, PIROXICAM, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin.

53. A sunscreen composition from which dosage amounts may be taken and administered to prevent the spread and/or metastasis of one or more skin cancer tissue types in humans, the sunscreen composition comprising:
(1) a non-steroidal anti-inflamatory agent, (2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, in a form suitable for administration to humans;
(3) ingredients including sunscreen agents having an acceptable SPF number constituting an effective sunscreen composition; and (4) optionally vitamin C;
characterized in that an effective dosage amount comprising effective non-toxic dosage amounts of components (1) and (2) taken and administered from said composition (i) are available to prevent the spread and/or metastasis of one or more skin cancer tissue types in humans.

54. The sunscreen composition of Claim 53 wherein the effective non-toxic dosage amount of component (2) comprises an effective non-toxic dosage amount of at least about 5 mg in the dosage amounts taken from the sunscreen composition to be administered.

55. The sunscreen composition of Claim 54 wherein the sunscreen composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg.

56. The sunscreen composition of Claim 53, 54 or 55 wherein the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid is hyaluronic acid and/or a salt thereof.

57. The sunscreen composition of Claim 53, 54, 55 or 56 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

58. The sunscreen composition of Claim 53, 54, 55, 56 or 57 wherein the non-steroidal anti-inflamatory drug (NSAID) is Diclofenac.

59. A sunscreen composition comprising:
(1) a non-steroidal anti-inflamatory;
(2) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid;
(3) ingredients including sunscreen agents having an acceptable SPF number constituting an effective sunscreen composition; and (4) optionally vitamin C;
characterized in that said composition (a) is in a dosage form which is suitable for administration to a human;
and (b) is in such an amount and in such form that components (1) and (2) are in effective dosage amounts to prevent the spread and/or metastasis of one or more skin cancer tissue types (for example basal cell carcinoma) in humans.

60. The composition of Claim 59 wherein the form of hyaluronic acid in the composition comprises hyaluronic acid and/or salts thereof.

61. The composition of Claim 59 or 60 wherein the effective amount of the form of hyaluronic acid in the composition exceeds about 5 mg.

62. The composition of Claim 61 wherein the sunscreen composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg.

63. The composition of Claim 61 wherein the sunscreen composition is for systemic administration and the amount of the form of hyaluronic acid exceeds about 200 mg/70 kg person.

64. The composition of Claim 59, 60, 61, 62 or 63 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

65. The composition of Claim 59, 60, 61, 62, 63 or 64 wherein the non-steroidal anti-inflamatory (NSAID) is Diclofenac.

66. The composition of Claim 59, 60, 61, 62, 63 or 64 wherein the agent (NSAID) is Diclofenac and the effective dosage amount of Diclofenac is between about 35 mg and about 500 mg/70 kg. person.

67. The use of:
(a) a non-steroidal anti-inflamatory agent, (b) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, and (c) optionally vitamin C
in the manufacture of a pharmaceutical composition to condition the human immune system to resist formation of one or more types of cancer tissues in a therapy wherein dosage amounts taken from the composition each comprise:
(1) a therapeutically effective amount of component (a); and (2) a therapeutically effective amount of the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, the pharmaceutical composition being characterized in that for each dosage amount taken from the pharmaceutical composition, the amount of components (a) and (b) condition the human immune system to resist formation of one or more types of cancer tissues.

68. The use of Claim 67 wherein component (b) is hyaluronic acid and/or salts thereof having a molecular weight less than about 750,000 daltons.

69. The use of Claim 67 or 68 wherein a dosage amount of the composition comprises component (b) in an amount greater than about 5 mg.

70. The use of Claim 67, 68 or 69 wherein the pharmaceutical composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg/cm2.

71. The use of Claim 67, 68 or 69 wherein the amount of component (b) is greater than 10 mg/70 kg person.

72. The use of Claim 69 wherein the pharmaceutical composition is for systemic administration and the amount of the form of hyaluronic acid exceeds about 200 mg/70 kg person.

73. The use of Claim 67, 68, 69, 70, 71 or 72 wherein component (a) the non-steroidal anti-inflamatory drug (NSAID), is selected from diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of ketorolac, IBUPROFEN, PIROXICAM, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin.

74. The use of:

(1) a non-steroidal anti-inflamatory agent (NSAID), (2) hyaluronic acid and/or salts thereof,and (3) optionally vitamin C
in the manufacture of a pharmaceutical composition for conditioning the immune system in humans to resist the formation of one or more cancerous tissue types is a therapy wherein a dosage amount comprises a therapeutically effective amount of said agent (1) and a therapeutically effective amount of the hyaluronic acid and/or salts thereof having a molecular weight less than about 750,000 daltons, the use being characterized in that the amount of components (1) and (2) is in a form in which it is immediately available upon administration to condition the immune system in humans to resist the formation of one or more cancerous tissue types.

75. The use of Claim 74 wherein the dosage amount of component (2) is present in a dosage amount greater than about 5 mg.

76. The use of Claim 74 wherein the dosage amount of component (2) is present in a dosage amount greater than about 10 mg/70 kg person.

77. The use of Claim 75 wherein the pharmaceutical composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid per dose exceeds about 5mg/cm2 of skin or exposed tissue.

78. The use of Claim 77 wherein the pharmaceutical composition is for systemic administration and the amount of the form of hyaluronic acid exceeds about 200 mg/70 kg person.

79. The use of:
(a) a non-steroidal anti-inflamatory agent, and (b) hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and subunits of hyaluronic acid, in the manufacture of a pharmaceutical composition for preventing the spread and/or metastasis of one or more cancer tissue types in humans in a therapy wherein dosage amounts taken from the composition each comprise:
(1) a therapeutically effective amount of component (a); and (2) a therapeutically effective amount of the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and sub-units of hyaluronic acid, the pharmaceutical composition being characterized in that for each dosage amount taken from the pharmaceutical composition, the amount of components (a) and (b) prevent the spread and/or metastasis of one or more cancer tissue types in humans.

80. The use of Claim 79 wherein component (b) is hyaluronic acid and/or salts thereof having a molecular weight less than about 750,000 daltons.

81. The use of Claim 79 or 80 wherein the dosage amount of component (b) in the amount of the composition taken from the composition (to be taken from the composition) and administered is present in a dose amount greater than about 5 mg.

82. The use of Claim 81 wherein the pharmaceutical composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg/cm2 of skin to which the composition is to be applied.

83. The use of Claim 81 wherein the amount of component (b) exceeds 10 mg/70 kg person.

84. The use of Claim 81 wherein the pharmaceutical composition is for systemic administration and the amount of the form of hyaluronic acid exceeds about 200 mg/70 kg person.

85. The use of Claim 79, 80, 81, 82, 83 or 84 wherein component (a) the non-steroidal anti-inflamatory drug (NSAID), is selected from diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of ketorolac, IBUPROFEN, PIROXICAM, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin.

86. The use of:
(1) a non-steroidal anti-inflamatory agent (NSAID), (2) hyaluronic acid and/or salts thereof,and (3) optionally vitamin C
in the manufacture of a pharmaceutical composition to prevent the spread and/or metastasis of one or more cancer tissue types in humans in a therapy wherein a dosage amount comprises a therapeutically effective amount of said agent (1) and a therapeutically effective amount of the hyaluronic acid and/or salts thereof having a molecular weight less than about 750,000 daltons, the use being characterized in that the amount of components (1) and (2) is in a form in which it is immediately available upon administration to prevent the spread and/or metastasis of one or more cancer tissue types in humans.

87. The use of Claim 86 wherein the dosage amount of component (2) is present in a dose greater than about 5 mg.

88. The use of Claim 87 wherein the pharmaceutical composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid per dose exceeds about 5mg/cm2 of skin or exposed tissue.

89. The use of Claim 87 wherein the dosage amount of component (2) is present in a dosage greater than about 10 mg/70 kg person.

90. The use of Claim 87 wherein the pharmaceutical composition is for systemic administration and the amount of the form of hyaluronic acid exceeds about 200 mg/70 kg person.

91. The pharmaceutical composition of Claim 86, 87, 88, 89 or 90 further comprising pharmaceutically compatible excipients to provide a form for ease of administration depending upon the route of administration.

92. The pharmaceutical composition of Claim 91 in a form for administering the composition systemically.

93. The pharmaceutical composition of Claim 91 administering the composition topically.

94. The pharmaceutical composition of Claim 91 in a form suitable for intravenous administration, the composition comprising vitamin C.

95. The use of an effective dosage amount of a composition comprising an effective dosage amount of an NSAID,optionally vitamin C and an effective non-toxic amount of hyaluronic acid and/or salts thereof sufficient upon administration to condition the immune system in humans to resist the formation of one or more cancerous tissue types.

96. The use of Claim 95 wherein the amount of hyaluronic acid and/or salts thereof exceeds at least about 5mg.

97. The use of Claim 96 wherein the pharmaceutical composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg/cm2 of skin and/or exposed tissue.

98. The use of Claim 96 wherein the pharmaceutical composition is for systemic administration and the amount of the forms of hyaluronic acid exceeds about 10 mg/70 kg person.

99. The use of Claim 96 wherein the pharmaceutical composition is for systemic administration and the amount of the form of hyaluronic acid exceeds about 200 mg/70 kg person.

100. The use of Claim 95, 96, 97 98 or 99 wherein the molecular weight of the hyaluronic acid and/or salts is less than about 750,000 daltons.

101. The use of Claim 95, 96, 97, 98 or 99 wherein the optional vitamin C is included in the use.

102. Use of a pharmaceutical composition to condition the immune system in humans to resist the formation of one or more cancerous tissue types by the administration of the composition to the patient, the amount of the composition, administered comprising together with pharmaceutical excipients suitable for the route of administration, a therapeutically effective non-toxic (to a human) amount of a non-steroidal anti-inflamatory and an effective non-toxic dosage amount of at least about 5 mg of hyaluronic acid and/or salts thereof having a molecular weight less than about 750,000 daltons effective to condition the immune system in humans to resist the formation of one or more cancerous tissue types.

103. The use of Claim 102 further comprising the use of an effective dosage amount of vitamin C.

104. The use of an effective dosage amount of a composition comprising an effective dosage amount of an NSAID,optionally vitamin C and an effective non-toxic amount of hyaluronic acid and/or salts thereof sufficient upon administration to prevent the spread and/or metastasis of one or more cancer tissue types in humans.

105. The use of Claim 104 further comprising an effective amount of vitamin C.

106. The use of Claim 104 or 105 wherein the amount of hyaluronic acid and/or salts thereof exceeds at least about 5mg.

107. The use of Claim 104 or 105 wherein the pharmaceutical composition is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg/cm2 of skin and/or exposed tissue.

108. The use of Claim 104 or 105 wherein the pharmaceutical composition is for systemic administration and the amount of the form of hyaluronic acid exceeds about 10 mg/70 kg person.

109. The use of Claim 108 wherein the amount of the form of hyaluronic acid exceeds about 200 mg/70 kg person.

110. The use of Claim 104, 105, 106, 107, 108 or 109 wherein the molecular weight of the hyaluronic acid and/or salts is less than about 750,000 daltons.

111. Use of a pharmaceutical composition to prevent the spread and/or metastasis of one or more cancer tissue types in humans by the administration of the composition to the patient, the amount of the composition, administered comprising together with pharmaceutical excipients suitable for the route of administration, a therapeutically effective non-toxic (to a human) amount of a non-steroidal anti-inflamatory and an effective non-toxic dosage amount of at least about 5 mg of hyaluronic acid and/or salts thereof having a molecular weight less than about 750,000 daltons effective to prevent the spread and/or metastasis of one or more cancer tissue types in humans.

112. The use of Claim 111 further comprising an effective amount of vitamin C.

113. A composition from which dosage amounts may be taken and administered to a human the composition comprising a plurality of dosage amounts which may be taken and administered, each dosage amount comprising an effective non-toxic dosage amount of an NSAID and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or subunits of hyaluronic acid exceeding 5 mg. to condition the human immune system to resist formation of one or more types of cancer tissues.

114. The composition of Claim 113 further comprising a effective amount of vitamin C.

115. The composition of Claim 113 or 114 wherein the form of hyaluronic acid is hyaluronic acid is hyaluronic acid and/or salts thereof.

116. The composition of Claim 113, 114 or 115 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

117. The composition of Claim 113, 114, 115 or 116 wherein the NSAID is Diclofenac and the effective dosage amount of Diclofenac in each of the plurality of dosage amounts of the composition comprises in excess of about 35 mg.

118. A sunscreen composition from which dosage amounts may be taken and administered to a human, the composition comprising a plurality of dosage amounts which may be taken and administered, each dosage amount comprising an effective non-toxic dosage amount of an NSAID and an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or subunits of hyaluronic acid exceeding 5 mg.
and a sunscreen agent containing an acceptable SPF number to preventing the spread and/or metastasis of one or more cancer tissue types in humans.

119. The composition of Claim 118 further comprising vitamin C.

120. The composition of Claim 118 or 119 wherein the form of hyaluronic acid is hyaluronic acid is hyaluronic acid and/or salts thereof.

121. The composition of Claim 118, 119 or 120 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

122. The composition of Claim 118, 119, 120 and 121 wherein the NSAID is Diclofenac and the effective dosage amount of Diclofenac in each of the plurality of dosage amounts of the composition comprises in excess of about 35 mg.

123. A method of preventing the spread and/or metastasis of one or more cancer tissue types in humans comprising administering a non-toxic dosage amount of a composition comprising sunscreen excipients suitable for administration to a human, a sunscreen agent having an acceptable SPF number (preferably greater than 15) and a therapeutically effective non-toxic dosage amount of at least two components selected from hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid, a NSAID ad vitamin C which is effective when the composition is administered to prevent the spread and/or metastasis of one or more cancer tissue types in humans.

124. The method of Claim 123 wherein at least two components comprises all three of the said components.

125. The method of Claim 123 or 124 wherein the form of hyaluronic acid is hyaluronic acid and salts thereof.

126. The method of Claim 123, 124 or 125 wherein the amount of the hyaluronic acid (where present) exceeds about 5mg.

127. The method of Claim 126 wherein the sunscreen composition comprising a sunscreen agent having an acceptable SPF number is for topical application to the skin and/or exposed tissue and the amount of the form of hyaluronic acid exceeds about 5mg/cm2 of skin and/or exposed tissue.

128. The method of Claim 123, 124, 125, 126, or 127, wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

129. The method of Claim 123, 124, 125, 126, 127 or 128 wherein the treatment is administered daily for a number of weeks.

130. The method of treatment of Claim 123, 124, 125, 126, 127, 128 or 129 wherein the treatment comprises administering effective dosage amounts of the composition, a number of times daily for a period of weeks to condition the human immune system to resist formation of one or more types of skin cancer tissues.

131. The method of Claim 123, 124, 125, 126, 127, 128, 129 or 130 in combination with any method of treating cancer.

132. The sunscreen composition of Claim 34, 35, 36, 37 or 38 wherein the non-steroidal anti-inflamatory drug (NSAID) is Diclofenac.

133. A sunscreen composition including a plurality of effective non-toxic dosage amounts of a composition for administration to humans to condition the human immune system to resist formation of one or more types of skin cancer tissues, each such dosage amount taken comprising ingredients, including sun-screening agents having an acceptable SPF number, constituting an effective sunscreen composition and a therapeutically effective non-toxic (to the patient) dosage amount of an non-steroidal anti-inflamatory drug to condition the human immune system to resist formation of one or more types of skin cancer tissues.

134. The sunscreen composition of Claim 133 further comprising vitamin C.

135. The sunscreen composition of Claim 133 or 134 further comprising an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid to cause an effective amount of the NSAID, sun-screening agent and vitamin C (if present) to be transported, immediately upon administration, to the site to be treated.

136. The sunscreen composition of Claim 135 wherein the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid is hyaluronic acid and/or a salt thereof.

137. The sunscreen composition of Claim 135 or 136 wherein each dosage amount of the sunscreen composition comprises at least about 5 mg/cm2 of the form of hyaluronic acid.

138. The sunscreen composition of Claim 133, 134, 135, 136 or 137 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

139. The sunscreen composition of Claim 133, 134, 135, 136, 137 or 138 wherein the non-steroidal anti-inflamatory drug (NSAID) is Diclofenac.

140. The sunscreen composition of Claim 133, 134, 135, 136, 137 or 138 wherein the NSAID is selected from diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of ketorolac, IBUPROFEN, PIROXICAM, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin.

141. A sunscreen composition including a plurality of effective non-toxic dosage amounts of a composition for preventing the spread and/or metastasis of one or more cancer tissue types in humans, each such dosage amount comprising ingredients including, sunscreen agents having an acceptable SPF
number, constituting an effective sunscreen composition, and a non-toxic (to the patient) dosage amount of an non-steroidal anti-inflamatory drug effective to condition the human immune system to prevent the spread and/or metastasis of one or more skin cancer tissue types in humans.

142. The sunscreen composition of Claim 141 further comprising vitamin C.

143. The sunscreen composition of Claim 141 or 142 further comprising an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid to cause an effective amount of the NSAID, sun-screening agent and vitamin C (if present) to be transported, immediately upon administration, to the site to be treated.

144. The sunscreen composition of Claim 143 wherein each dosage amount of the sunscreen composition comprises at least about 5 mg of the form of hyaluronic acid.

145. The sunscreen composition of Claim 143 wherein the amount of the form of hyaluronic acid exceeds about 5mg/cm2 of skin and/or exposed tissue.

146. The sunscreen composition of Claim 143, 144 or 145 wherein the hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid is hyaluronic acid and/or a salt thereof.

147. The sunscreen composition of Claim 141, 142, 143, 144, 145, or 146 wherein the molecular weight of the form of hyaluronic acid is less than about 750,000 daltons.

148. The sunscreen composition of Claim 141, 142, 143, 144, 145, 146 or 147 wherein the non-steroidal anti-inflamatory drug (NSAID) is Diclofenac.

149. The sunscreen composition of Claim 141, 142, 143, 144, 145, 146 or 147 wherein the NSAID is selected from diclofenac, indomethacin, naproxen, (+/-) tromethamine salt of ketorolac, IBUPROFEN, PIROXICAM, Propionic Acid derivatives, aceytylsalicylic acid and Flunixin.

150. A sunscreen composition including a plurality of effective non-toxic dosage amounts of a composition for administration to humans to condition the human immune system to resist formation of one or more types of skin cancer tissues, each such dosage amount taken comprising ingredients, including sun-screening agents having an acceptable SPF number, constituting an effective sunscreen composition and a therapeutically effective non-toxic (to the patient) dosage amount of vitamin C to condition the human immune system to resist formation of one or more types of skin cancer tissues.

151. The sunscreen composition of Claim 150 further comprising an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid to cause an effective amount of the sun-screening agent and vitamin C to be transported, immediately upon administration, to the site to be treated.

152. A sunscreen composition including a plurality of effective non-toxic dosage amounts of a composition for preventing the spread and/or metastasis of one or more cancer tissue types in humans, each such dosage amount comprising ingredients including, sunscreen agents having an acceptable SPF
number, constituting an effective sunscreen composition, and a non-toxic (to the patient) dosage amount of vitamin C effective to condition the human immune system to prevent the spread and/or metastasis of one or more skin cancer tissue types in humans.

153. The sunscreen composition of Claim 152 further comprising an effective non-toxic dosage amount of hyaluronic acid and/or salts thereof and/or homologues, analogues, derivatives, complexes, esters, fragments, and/or sub-units of hyaluronic acid to cause an effective amount the sun-screening agent and vitamin C to be transported, immediately upon administration, to the site to be treated.

154. The method, use or composition of any previous claim further comprising vitamin C.