CA2443461A1 - Pharmaceutical formulations containing anti-inflammatory active ingredients and the use of said formulations - Google Patents
Pharmaceutical formulations containing anti-inflammatory active ingredients and the use of said formulations Download PDFInfo
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- CA2443461A1 CA2443461A1 CA002443461A CA2443461A CA2443461A1 CA 2443461 A1 CA2443461 A1 CA 2443461A1 CA 002443461 A CA002443461 A CA 002443461A CA 2443461 A CA2443461 A CA 2443461A CA 2443461 A1 CA2443461 A1 CA 2443461A1
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- fatty acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
Abstract
The invention relates to compositions in the form of microemulsion preconcentrates containing: (a) a mixture consisting of a middle-chained triglyceride and an omega 9 fatty acid and/or an omega 6 fatty acid; (b) a surface-active component containing a polyoxyethylene-type surface-active agent; (c) a therapeutic active ingredient which is hardly soluble in water but soluble in component (a) and/or (b) from the category of non-steroidal anti-inflammatory drugs (NSAIDS). Microemulsions are formed when said microemulsions preconcentrates come into contact with water or an aqueous medium, wherein the oil-in-water type microemulsions have an average particle size of less than 150 nm, preferably less than 100 nm. The microemulsion preconcentrates and microemulsions according to the invention are suitable for oral and topical administration of non-steroidal anti-inflammatory drugs.
Description
pharmaceutical formulations containing antiinflammatory active ingredients and the use thereof The present invention relates to novel formulations in the form of microemulsion preconcentrates and micro-emulsions which contain an active ingredient which is slightly soluble in water from the NSAIDs (non-steroidal antiinflammatory drugs) class, and to the use thereof.
Inflammations occur inter alia due to mechanical, thermal and chemical injuries, exposure to radiation, and pathogens (bacteria and viruses), and allergic or autoimmune reactions. The progress and spread of the inflammation are associated with responses by the body's defenses such as antigen-antibody activation and the release of so-called mediators of inflammation, such as, for example, kinins, prostaglandins, leuko-trienes, histamine and lymphokines. This is where antiinflammatory drugs act, their activity deriving from intervention in the metabolism of the mediators.
The effect of antiinflammatory drugs, which are employed primarily as antiarthritics and antirheurna-' tics, is based for example on inhibition of prosta glandin biosynthesis. Non-steroidal antiinflammatory drugs (NSAIDs) which should be mentioned in particular are pyrazole derivatives, oxicams, and arylacetic and -propionic acids. The latter group includes inter alia indometacin, diclofenac, naproxen and ibuprofen.
Ibuprofen has been employed for more than 30 years in the therapy of rheumatism and pain. Besides the patent analgesic and antiinflammatory activity of ibuprofen, a positive emphasis should be placed in particular on the gastrointestinal tolerability - compared with other NSAIDs.
Ibuprofen is an active ingredient wi~~h a chirality center and exists both in a dextrorotatory R-(-) and a levorotatory S-(+) form. The R form is subject to intensive enantiomeric inversion in the human body to give the analgesically active S-(+)-ibuprofen or dexibuprofen.
The active ingredient ibuprofen, which, as remarked above, is one of the arylpropionic acids, is employed as free acid in conventional dosage forms as coated or uncoated tablet. The weakly acidic ibuprofen with a pKa of 4.4 is of low solubility in water and in the acidic medium of the gastric juice. Complete dissolution is achieved only in a slightly alkaline medium such as, for example, in the small intestine. The former is, however, the precondition for rapid absorption and thus also for a rapid onset of action. For this reason, conventional ibuprofen acid-containing coated and uncoated tablets shcw a relatively delayed onset of action. Maximum concentrations of active ingredient are not reached in the blood until ~-2 hours after oral intake.
Absorption can be speeded up by using buffered effer-vescent granules or tablets which are already dissolved for intake and thus ensure rapid transport from the stomach to the small intestine, which is the site of absorption. However, it is common to "effervescent"
pharmaceutical forms that preparation is somewhat troublesome, because the medicament must always be dissolved in water - which is not available in every situation - and/or the taste sensation is negative.
It is an obj ect of the present invention to develop a formulation with analgesic and antiinflammatory effect which combines the necessary rapid onset of action of the active ingredient formulation with a simple-, pleasant and neutral-taste intake. T_t has surprisingly been found that formulations based on a microemulsion preconcentrate or a microemulsion significantly increase the rate of absorption of ibuprofen after oral dosage compared with coated or uncoated tablets.
The microemulsion preconcentrate of the invention means a system which affords a microemulsion on contact with water or another aqueous medium such as gastrointestinal fluid, e.g. on addition to water. A
microemulsion of this type comprises in the conven-tionally acknowledged sense a non-opaque or virtually non-opaque colloidal dispersion which comprises water and organic components with inclusion of lipophilic (i.e. hydrophobic) components.
Microemulsions in the sense of the invention can be identified by the fact that they have one or more of the following properties:
- They are formed spontaneously when their com-ponents are brought into contact with one another;
thus, virtually no energy input is necessary for this, and the formation of such microemulsions therefore takes place without heating or use of a high shear force er another substantial mixing.
- They are virtually non-opaque, namely transparent or opalescent, when they are examined under an optical microscope. In their undisturbed state, they are optically isotropic, although an aniso-tropic structure can be detected on inspection for example using an X-ray technique.
- They contain a disperse or particulate (droplet) phase whose particles have a size of less than 200 nm, this being the origin of their optical transparency. The particles may be spherical or else have other structures; for example, they may be lia_uid crystals with larrellar, hexagonal or isotropic symmetries. In general, microemulsions comprise droplets or particles with a maximum dimension, for example a diameter, of less than 150 nm, usually about 10-100 nm.
Inflammations occur inter alia due to mechanical, thermal and chemical injuries, exposure to radiation, and pathogens (bacteria and viruses), and allergic or autoimmune reactions. The progress and spread of the inflammation are associated with responses by the body's defenses such as antigen-antibody activation and the release of so-called mediators of inflammation, such as, for example, kinins, prostaglandins, leuko-trienes, histamine and lymphokines. This is where antiinflammatory drugs act, their activity deriving from intervention in the metabolism of the mediators.
The effect of antiinflammatory drugs, which are employed primarily as antiarthritics and antirheurna-' tics, is based for example on inhibition of prosta glandin biosynthesis. Non-steroidal antiinflammatory drugs (NSAIDs) which should be mentioned in particular are pyrazole derivatives, oxicams, and arylacetic and -propionic acids. The latter group includes inter alia indometacin, diclofenac, naproxen and ibuprofen.
Ibuprofen has been employed for more than 30 years in the therapy of rheumatism and pain. Besides the patent analgesic and antiinflammatory activity of ibuprofen, a positive emphasis should be placed in particular on the gastrointestinal tolerability - compared with other NSAIDs.
Ibuprofen is an active ingredient wi~~h a chirality center and exists both in a dextrorotatory R-(-) and a levorotatory S-(+) form. The R form is subject to intensive enantiomeric inversion in the human body to give the analgesically active S-(+)-ibuprofen or dexibuprofen.
The active ingredient ibuprofen, which, as remarked above, is one of the arylpropionic acids, is employed as free acid in conventional dosage forms as coated or uncoated tablet. The weakly acidic ibuprofen with a pKa of 4.4 is of low solubility in water and in the acidic medium of the gastric juice. Complete dissolution is achieved only in a slightly alkaline medium such as, for example, in the small intestine. The former is, however, the precondition for rapid absorption and thus also for a rapid onset of action. For this reason, conventional ibuprofen acid-containing coated and uncoated tablets shcw a relatively delayed onset of action. Maximum concentrations of active ingredient are not reached in the blood until ~-2 hours after oral intake.
Absorption can be speeded up by using buffered effer-vescent granules or tablets which are already dissolved for intake and thus ensure rapid transport from the stomach to the small intestine, which is the site of absorption. However, it is common to "effervescent"
pharmaceutical forms that preparation is somewhat troublesome, because the medicament must always be dissolved in water - which is not available in every situation - and/or the taste sensation is negative.
It is an obj ect of the present invention to develop a formulation with analgesic and antiinflammatory effect which combines the necessary rapid onset of action of the active ingredient formulation with a simple-, pleasant and neutral-taste intake. T_t has surprisingly been found that formulations based on a microemulsion preconcentrate or a microemulsion significantly increase the rate of absorption of ibuprofen after oral dosage compared with coated or uncoated tablets.
The microemulsion preconcentrate of the invention means a system which affords a microemulsion on contact with water or another aqueous medium such as gastrointestinal fluid, e.g. on addition to water. A
microemulsion of this type comprises in the conven-tionally acknowledged sense a non-opaque or virtually non-opaque colloidal dispersion which comprises water and organic components with inclusion of lipophilic (i.e. hydrophobic) components.
Microemulsions in the sense of the invention can be identified by the fact that they have one or more of the following properties:
- They are formed spontaneously when their com-ponents are brought into contact with one another;
thus, virtually no energy input is necessary for this, and the formation of such microemulsions therefore takes place without heating or use of a high shear force er another substantial mixing.
- They are virtually non-opaque, namely transparent or opalescent, when they are examined under an optical microscope. In their undisturbed state, they are optically isotropic, although an aniso-tropic structure can be detected on inspection for example using an X-ray technique.
- They contain a disperse or particulate (droplet) phase whose particles have a size of less than 200 nm, this being the origin of their optical transparency. The particles may be spherical or else have other structures; for example, they may be lia_uid crystals with larrellar, hexagonal or isotropic symmetries. In general, microemulsions comprise droplets or particles with a maximum dimension, for example a diameter, of less than 150 nm, usually about 10-100 nm.
The microemulsion preconcentrates of the invention mentioned at the outset are pharmaceutical systems which comprise an active ingredient from the NSAIDs class which is slightly soluble in water, and are able to form a microemulsion spontaneously or virtually spontaneously, i.a. with a negligible energy input, on being brought into contact with water or gastric and intestinal fluid.
The microemulsion preconcentrates of the invention are characterized in particular in that they comprise (a) a mixture consisting of a medium chain tri-glyceride and of an omega-9 fatty acid and/or an 7.5 omega-6 fatty acid, and (b) a surface-active component comprising a surfactant of the polyoxyethylene type, and (c) a therapeutic active ingredient from the NSAIDs class which is slightly soluble in water but soluble in component (a) and/or (b).
The ratio of the ingredients (a) : (b) : (c) , (a) : (C) or (b):(c) of the microemulsion preconcentrates of the invention must, of course, be chosen so that the active ingredient (c) is stably solubilized, i.e. precipitates must not occur over several weeks.
In contrast to priox axt formulations, the micro-emulsion preconcentrates of the present invention are essentially free of water-miscible or water-soluble components despite high concentrations of active ingredient. T"nese are, in particular, the components C1-CS-alkyl or tetrahydrofurfuryl diethers or partial ethers of low molecular weight mono- or polyoxy-Cz-C,,2-alkanediols ;
- 1,2-propylene glycol;
- lower alkanols;
- products of the esterification of polycarboxylic acids with 2-10, in particular 3-5, carboxyl groups with C1-Cla alcohols; and - products of the esterification of polyols with 2-10, in particular 3-5, carboxyl groups with C~-C;1 carboxylic acids;
in particular essentially free of diethylene glycol monomethyl ether, glycofurol, 1,2-propylene glycol, triethyl citrate, tributy citrate, acetyl tributy citrate, acetyl triethyl citrate, triacetin, ethanol, polyethylene glycol, dimethyl isosorbitol and propylene carbonate.
The microemulsion preconcentrates of the invention can be produced by intimately mixing the individual ingredients with one another, where appropriate with heating. The microemulsion preconcentrates can also be produced by dissolving component (b) with stirring, where appropriate with heating, in component (a), and adding component (c) to the re9ulting solution with further stirring. It is particularly important in this connection that the component or the active ingredient (c) is soluble either in component (a) or component (b) or else in both components (a) and (b), and that the active ingredient always continues to be in dissolved form during production of the preconcentrate, i.e. the mixture of all three components (a), (b) and (c).
Suitable as component (a) are mixtures of a medium chain fatty acid triglyceride, expediently a fatty acid triglyceride in which the fatty acid residues have 4 to 18, preferably 6 to 18, C atoms, and of an omega-9 and/or an omega-6 fatty acid. These substances are immiscible with water or insoluble or practically insoluble in water and have no or virtually no surface-active function.
Preferred medium chain fatty acid triglycerides are caprylic/capric acid triglycerides as are known and available commercially for example under the trade name Miglyol (Fiedler, Lexikon der Hilfsstoffe, 3rd editzon, pages 808 to 809, 1989). These include, for example, the following products:
Miglyol 810, 812 and B18 This is a fractionated coconut oil which contains triglycerides of caprylic and capric acids and has a molecular weight of about 520 (Miglyol 810 and 812) or 510 (Miglyol 818). It has a fatty acid composition with a maximum of 2 percent (Miglyol 810) and 3 percent (Miglyol 812 and 618) C6, and with about 65 to 75 percent (Miglyol 810), 50 to 65 percent (Miglyol 812) and 45 to 60 percent (Miglyol 818) C8. clo represents 25 to 35 percent of Miglyol, about 30 to 45 percent of Miglyol 812 and about 25 to 40 percent of i~iiglyol 818 , and C12 a maximum of 2 percent (Miglyol 810), 5 percent (Miglyol 812) and 2 to 5 percent (Miglyol 818). Miglyol 818 additionally has a content of about 4 to 6 percent of Cle:z.
Also suitable are triglycerides of caprylic acid and capric acid which are known and obtainable under the trade name Myritol (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, page 834, 1989). These include, for example, the product Myritol 813.
Further suitable products of this class are Captex 355, Captex 300, Captex 800, Capmul MCT, Neobee M5 and Maaol 1400.
Suitable omega-9 fatty acids are mainly those having 12-24, in particular 16-24, preferably 18-22, C atom9, fo= example oleic acid and eicosatrienoic acid. oleic acid is particularly preferred.
Suitable omega-6 fatty acids are mainly those having 12-24, in particular 16-24, preferably 18-22, C atoms, for example linoleic acid, gamma-linolenic acid, dihommo-gamma-linolenic acid and arachidonic acid.
Linoleic acid is particularly preferred.
Tn a particularly preferred embodiment, a mixture consisting of a caprylic/capric acid triglyceride, oleic acid and/or linoleic acid is used as component ( a ) .
1o Component (b), the surface-active component comprising a surfactant of the polyoxyethylene type, may be a hydrophilic surface-active agent or a lipophilic surface-active agent, but mixtures of such agents are also suitable.
Examples of such surfactants are the following:
Products of the reaction of natural or hydro-genated vegetable oils and ethylene glycol, namely polyoxyethylene glycolated natural or hydrogenated vegetable oils such as polyoxyethylene glycolated natural or hydrogenated castor oils. The various surfactants known and obtainable under the name Cremophor (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, pages 326 to 327, 1989) are par ticularly suitable, especially the products with the names Cremophor RH 40, Cremophor RH 60 and Cremophor EL. Also suitable as such products are the various surfactants known and obtained under the name Nikkol, for example Nikkol HCO-60.
- Polyoxyethylene sorbitan fatty acid esters, for example the mono- and trilauryl esters, the mono-and tripalmityl esters, the mono- and tristearyl esters and the mono- arid trioleyl esters, as are known and obtainable under the name Tween (Fiedler, Lexikon der ~:ilfsstoffe, 3rd edition, paces 1300 to 7.304, 1989), for example the products Tween 20: polyoxyethylene 20 sorbitan rcr~nolaurate, Tween 40: polyoxyethylene 20 sorbitan r~onopalmitate, Tween 60: polyoxyethylene 20 sorbitan ~ronostearate, Tween 80: polyoxyethylere 20 sorbitan monooleate, Ttaeen 65: polya}.yethylene 20 sorbitan tristearate, Tween 85: polyoxyethylene 20 sorbitan trioleate, T~veen 21: polyoxyethylene 4 sorbita_n manolaurate, 'Keen 61: polyoxyethylene 4 sorbitan monostearate and Tween 81: polyoxyethylene 4 sorbitan rnonooleate.
Of this class of compounds, Tween 80 is particularly preferred.
Polyoxyethylene fatty acid esters, for example the polyoxyethylene stearic esters known and obtain-able commercially under the name Myrj (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, page 834, 1939), especially the product Myrj 52, and the polyoxyethylene fatty acid esters known and obtainable under the name Cetiol HE (Fiedler, Lexikon der Hilfsstof~e, 3rd edition, page 284, 1989).
- Copolymers of polyoxyethylene and polyox~-propylene like those known and obtainable for example under the names Pluronic and Emkalyx (Fiedler, Lexikon z5 der Hilfsstoffe, 3rd edition, pages 956 to 958, 1989), especially the product Pluron:.c F68.
- Block copolymers of polyoxyethylene and polyoxy-propylene like those known and obtainable for example under the name Poloxamer (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, page 959, 1989), especially the product Poloxamer 188.
- Polyethoxylated vitamin E derivatives, especially the product Vitamin ~ TPGS (d-alpha tocoperyl polyethylene glycol 1000 succinate, Eastman).
- Polyethoxylated hydroxy fatty acid esters, especially the product Solutol HS 15 (polyoxy-ethylene 660 hydroxystearate, BASF).
- Products of the transesterificatioa of natural g _ vegetable oil glycerides and polyethylene polyols.
These include products of the transesterification of various, fox example non-hydrogenated, vege-table oils such as corn oil, pumpkinseed oil, almond oil, peanut oil, olive oil and palm oil, and of mixtures thereof with polyethylene glycols, especially with those having an avexage molecular weight of 200-800. Various transesterification products of this type are known and obtainable under the name Labrafil (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, page 707, 1989); of these, the products Labrafil M 1944 CS and Labrafil M 2130 CS are particularly suitable.
- Ethylene oxide adducts of sterols and derivatives thereof, for example of cholesterol and deriva-tives thereof, such as products derived from sitosterol, campesterol, or stigmasterol, for example from soybean sterols and derivatives thereof (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, paces 554 and 555, 1989), as are known and obtainable under the names Generol, especially the products Generol 122 E5, 122 E10 and 122 E25.
The microemulsion pr~concentrates of the invention include both systems which comprise a single surface-active agent, and systems which comprise a mixture of two or more surface-active agents, e.g. Tween 80 +
Cremophor RH 40, Tween 80 + Cremophor RH 40 + Vitamin E
TPGS etc.
A surface-active component preferably used according to the invention comprises a polyoxyethyler~e sorbitan fatty acid ester, a polyoxyethylene glycolated natural or hydrogenated vegetable oil or mixtures thereof.
Component ~, the therapeutic active ingredient from the NSAIDs class which is slightly soluble in water but soluble in component (a) and/or (b), is preferably ibuprofen, dexibuprofen or naproxen; however, it is also possible to use another suitable NSAIDs, where appropriate in combination with antioxidants such as, S for example, vitamin E. Examples of other suitable NSAIDs are: anthranilic acid derivatives, acetic acid derivatives, oxicams, propionic acid derivatives, pyrazalone derivatives, salicylic acid derivatives and selective COX-2 inhibitors (cf. Arzneimittel Kompendium der Schweiz 2001, Documed AG, CH-4010 Basle, editors, Jurg Morant and Hans Rappaner).
The microemulsion preconcentrates of the invention may also comprise further substances such as, for example, antioxidants, thickeners, fragrances and/or flavorings, colors, etc.
The microemulsion preconcentrates of the invention are primarily intended for oral use. Preference is given in this connection to the so-called unit dose form, i.e.
the microemulsion preconceatrate is accommodated in a shaped article such as a soft or hard capsule, e.g.
made of gelatin or starch. When the active ingredient-containing premicroem~alsion is released there is spontaneous formation of a microemulsion in conjunction with gastrointestinal fluid. The compositions of the invention prove to be particularly suitable for oral administration in the for;a of unit dose forms also because addition o. volatile organic solvents, especially of the frequently used ethanol, is unneces-sary. when said solvents are employed, evaporation thereof through the ova er wall of the shaped article, especially of the soft or hard gelatin capsule, has an adverse effect on storability, and the active ingre-diem crystallizes out. The occurrence of these adverse effects must be prevented by elaborate measures during packaging and storage.
The novel compositions car. also be processed further to effervescent tablets or as granules.
The microemulsion preconcentrates of the invention expediently comprise from 5 to 45, preferably 20 to 40, percent by weight of a therapeutic active ingredient of the NSAIDs class (component (c)) which is slightly soluble in water but soluble in component (a) and/or (b), from 5 to 60, preferably 15 to 40 percent by weight, of a mixture consisting of a medium chain triglyceride and an omega-9 fatty acid and/or an omega-6 fatty acid (component (a)) and from 20 to 90, preferably fxom 25 to 65, percent by ureight of the surface-active component (b).
The present invention also rakes it possible to provide pharmaceutical compositions which comprise a thera-peutic active ingredient from the NSAIDs class which is slightly soluble in water but soluble in component (a) and/or (b), and which themselves represent microemulsions; the active ingredient is stably solubilized in these microemulsions, with no precipitates being observed over several weeks. For oral adr.~inistration it is Fossible for microemulsions, which are obtained for example by diluting the microemulsion preconcentrates of the invention with water or an aqueous mediurl, to be used directly as drinlcable formulations. If topical or paranteral use is intended, then compositions, in which further excipients may be present, likewise contain water, resulting in an aqueous microemulsion in the form of a spray, gel, lotion, cream, plaster, roll-on, solution for injection, solution for infusion or the like. Such pharmaceutical compositicns in the form of microemulsions are likewise novel, and the present invention relates thereto.
The microemulsions of the invention are characterized in particular in that they can be obtained by mixing a microemulsion preconcentrate of the compositions described above with water or an aqueous medium. When the preconcentrate is mixed with water or gastric and intestinal fluid there is spontaneous or virtually spontaneous, i.e. with negligible energy input, forma S tion of a microemulsion.
Depending on the amount of water present, the microemulsions are W/O microemulsions, bicontinuous microemulsions or 0/W microemulsions.
The O/w type (oil-in-water) microemulsions of the invention show stability properties like those des-cribed hereinbefore in connection with microemulsions, i.e. in particular that the active ingredient is stably solubilized in these microemulsions, and no precipitate is observable over several weeks. The particle size of these microemulsions is less than 150 nm, preferably less than 100 nm.
The compositions of the invention are explained further by the following examples. Examples 1.1 to 1.5 show the preparation of Compositions suitable, for example, for the therapy of pain and rheumatism. Examples 2.1 to 2.4 show the preparation of compositions suitable, for example, for the topical treatment of rheumatism.
Example 3.1 shows the preparation of a composition for parenteral use, which is suitable fox example for subcutaneous or intramuscular treatment of inflammatory pain. In example 4, the pharmacokinetic parameters (cm~, tm,~;, AUC) of a formulation of the invention which was administered orally in soft gelatin capsules are measured and compared with those of coated tablets.
The examples are described with particular reference to ibuprofen and dexibuprofen. However, comparable com-positions can be prepared through use of other suitable NSAIDs.
Example 1: Preparation of oral ibuprofen or dexibupro-fen dosage forms of the microemul9ion preconcentrate Example 1.1 Ibuprofen (c1) 20.00 Miglyol 812 (al) 20.00 Oleic acid (a2) 5.ooa Tween 80 (b1) 37.500 Cremophor RH 40 (b2) 12.50b Vitamin E acetate (c2) 5.00 The ibuprofen is dissolved by stirring at room tempera-ture, where appropriate with gentle heating, in components (a1), (a2), (b1), (b2) and (c2). The micro-emulsion preconcentrate which is formed is used to fill a soft or hard capsule made of gelatin or starch.
An alternative possibility is to use the microemulsion precor~centrate to fill a dispenser. In this case, the patient prepares an oral drinkable solution of the O/w microemulsion type from the microemulsion preconcentrate by appropriate dilution with water or another aqueous liquid.
The following compositions can also be prepared in an analogous manner and be used to fill capsules or dispensers.
Example 1.2 Ibuprofen (c) 20.00 Miglyol 812 (al) 25.oo°s Oleic acid (a2) 5.00%
c Tween 60 (b1) 37.50 Cremophor RH 40 (b2) 12.50a Examale 1.3 Ibuprofen (c1) 20.00a Miglyol 812 (al) 20, oohs Oleic acid (a2) 5.00 Tween 80 (b1) 37.50 Cremophor EL (b2) 12.50 Vitamin E acetate (c2) 5.00 _Example 1.4 Ibuprofen (c) 10.000 Miglyol 812 (al) 35.00a Oleic acid (a2) S.OOo Tween 80 (b1) 37.50ro Cremophor EL (b2) 12.50 Example 1.5 Dexibuprofen (c1) 30.00's Miglyol 812 (al) 17.50's Oleic acid (a2) 4.40%
Tween 80 (b1) 32.e0ro Cremophor RH 40 (b2) 10.90ro Vitam=n E acetate (c2) 4.40's Dilution, e.g. 1:100, of compositions of the above type with simulated gastric or intestinal fluid results in microemulsions having the following particle sizes in the case of representative examples (cf. table 1):
Table 1 Composition of microemulsion Particle diameterl~
preconcentrate of the O/W microemulsion Gastric Intestinal fluid [nm] fluid [nm]
Example 1.1 17.9 t 7.2 18.6 6.0 Example 1.2 25.6 10.1 18.8 6.5 Example 1.3 20.4 i 8.2 19.7 -~ 4.7 Example 1.4 25.0 6.72 Example 1.5 ~6.3 33.2 118.3 G.6 1) The particle diameters and particle size distribu-tions were determined by dynamic laser light scattering measurements (instrument: Nicomp 370 submicron particle sizer, evaluation: volume weighting).
2) These ibuprofen r:ticroemulsions were formed by a 1:10 dilution of the microemulsion preconcentrate with 10 mM phosphate buffer of pH 6 at room S temperature.
It is evident from the table below that the micro emulsion formation by the microemulsion preconcentrates remains unchanged after being used to fill and being l0 stored in soft gelatin capsules (SGC).
Table 2 Microemulsion preconcentrate Particle diameter of the of example 1.1 ibuprofen microemulsionl~
Hatch 201111 Gastric Intestinal fluid [nm] fluid [nmJ
Before SGC filling 17.9 7.2 18.6 6.0 After SGC filling 19.6 7.0 20.6 5.3 After storage in SGC at 25C 16.9 6.3 20.0 5.4 and 60% RH for 1 month After storage in SGC at 40C 17.7 6.8 19.8 5.5 and 75~ RH for 1 month After storage in SGC at 25C 13.6 -!- 6_9 18.4 5.9 and 60-s RH for 3 months 1) The ibuprofen microemulsions wexe, formed by 1:100 15 dilution of the microemulsion preconcentrates with simulated gastric and intestinal fluids at 37°C.
Microemulsion preconcentrates used to fill SGC
were removed from the SGC for the microemulsion formation. The particle diameters and particle 20 size distributions of the resulting ibuprofen microemulsions were determined by dynamic laser light scattering measurements (instrument:
Nicomp 370 submicron particle sizer, evaluation:
volume weighting).
Example 2: Preparation of ibuprofen forms of the microemulsion type which can be used topically The microemulsion preconcentrates described in example 1,1 to 1.5 are used hereinafter as basis for preparing sprays, gels, creams and other topical dosage forms by combining them with further additives such as water, thickeners and the like.
Example 2.1: Ibuprofen 1.0°s microemulsion pump spray Microemulsion preconcentrate of example 1.4 10.00 Naz EDTA 0 . 05 Benzalkonium chloride O.lOo 10 mM phosphate buffer pH 6 ad 100.000 The microemulsion preconcentrate is added to the phosphate buffer comprising Nay EDTA and benzalkonium chloride while stirring at room temperature. The resulting ibuprofen O/W microemulsion is used to fill a pump spray. Compressed gas or aerosol spray are also suitable in place of the pump spray.
Example 2.2: Ibuprofen 1.0a hydroqel Microemulsion preconcentrate of example 1.4 10.00 Nay EDTA 0.05 Henzalkonium chloride 0_10a Sodium carboxymethylcellulose 450 cP 3_50°
to mM phosphate buffer pH 6 ad 100.00a The microemulsion preconcentrate is added with stirring to the phosphate buffer containing Na2 EDTA and benzalkonium chloride. The resulting ibuprofen O/W
microemulsion is further processed with the sodium carboxymethylcellulose to give the hydrogel, and packaged, in a conventional way.
Example 2.3: Ibu rofen 1.0~ 0/W emulsion Microemulsion preconcentrate of example 1.4 10.000°s Isopropyl palmitate 8.OOOa Glyceryl stearate 7.0 Glycerol S.OOOa Steareth-2 + PEG-8 distearate 4.000a Liquid paraffin 4.000%
Microcrystalline wax 4.OOOE
Steareth-21 3.000 Dimethicone 1.OOOo 5uttocide A 0.2500 Lanolin alcohol 0.1003 Sodium hydroxide 0.005%
water ad 100.000 The microemulsion preconcentrate is added with stirring to the aqueous phase at room temperature. The resulting ibuprofen O/w microemulsion is further processed with the oil phase to give the O/w emulsion, and packaged, in a conventional way.
Example 2.4: Ibuprofen l.Oro microemulsion roll-on 2o Microemulsion preconcentrate of example 1.4 10.000 Na2 EDTA 0.05 Benzalkonium chloride 0.10 l0 mM phosphate buffer pH 6 ad 100.00 The microemulsion preconcentrate is added with stirring to the phosphate buffer, containing Na2 EDTA and benzalkonium chloride, at raom temperature. The result-ing ibuprofen 0/W microemulsion is used to fill a roll-on.
Example 3: Production of microemulsion-type ibuprofen forms which can be used parenterally The microemulsion preconcentrates described in example 1.1 to 1.5 can serve as basis for producing injection solutions by diluting them appropriately with further additives such as physiological saline or 5b strength glucose solution and the like.
Example 3_1: Ibuprofen 0.1~ injection solution Microemulsion preconcentrate of example 1.4 l.OOo 5's strength glucose solution ad 100.00%
The microemulsion preconcentrate is added with stirring to the glucose solution at room temperature. The resulting ibuprofen O/W microemulsion is sterilized by 0.2 ~m filtration and used to fill conventional sterile containers.
l0 Example 4: Pharmacokinetics of the ibuprofen micro-emulsion preconcentrate of example 1.1 after oral administration in soft capsules made of gelatin and starch The aim of this study was to establish the pharmaco kinetics of a single oral dose of 2 x 200 mg ibuprofen administered in the form of the microernulsion precon centrate of example 1.1 in soft capsules made of gelatin and starch.
Preparations A Soft gelatin capsules containing the ibuprofen microemulsion preconcentrate of example 1.1 Active ingredient content: 200 mg of ibuprofen per capsule B Starch capsules containing the ibuprofen micro-emulsion preconcentrate of example 1.1 Active ingredient content: 200 mg of ibuprofen per capsule Dosage: 2 x 200 mg of ibuprofen, orally in 2 capsules Intake In the morning, fasting Subjects: n = 4 Parameter measured: plasma level of ibuprofen [~m/ml plasma Results It is evident from the changes in the plasma levels of test products A and B of the invention that the maximum ibuprofen plasma levels of 45.3 and 49.0 E~m/ml are reached after 0.68 and 0. 63 hours (cf . figure 1) . Test products A and H thus show distinct differences in relation to the rate of rise in level and to the maximum reached in comparison with commercially available 200 mg ibuprofen coated tablets (cf.
table 3).
Table 3 Parameter Test Test 200 mg product A product B ibuprofen coated tabletsl~
Cma.c [~g/ml] 45.3 49.0 32.0 Tmax [h] 0.66 0.63 1.30 I AUC~"f [~g/ml/h] 123 121 108.0 1) Literature data from a study carried out analogously
The microemulsion preconcentrates of the invention are characterized in particular in that they comprise (a) a mixture consisting of a medium chain tri-glyceride and of an omega-9 fatty acid and/or an 7.5 omega-6 fatty acid, and (b) a surface-active component comprising a surfactant of the polyoxyethylene type, and (c) a therapeutic active ingredient from the NSAIDs class which is slightly soluble in water but soluble in component (a) and/or (b).
The ratio of the ingredients (a) : (b) : (c) , (a) : (C) or (b):(c) of the microemulsion preconcentrates of the invention must, of course, be chosen so that the active ingredient (c) is stably solubilized, i.e. precipitates must not occur over several weeks.
In contrast to priox axt formulations, the micro-emulsion preconcentrates of the present invention are essentially free of water-miscible or water-soluble components despite high concentrations of active ingredient. T"nese are, in particular, the components C1-CS-alkyl or tetrahydrofurfuryl diethers or partial ethers of low molecular weight mono- or polyoxy-Cz-C,,2-alkanediols ;
- 1,2-propylene glycol;
- lower alkanols;
- products of the esterification of polycarboxylic acids with 2-10, in particular 3-5, carboxyl groups with C1-Cla alcohols; and - products of the esterification of polyols with 2-10, in particular 3-5, carboxyl groups with C~-C;1 carboxylic acids;
in particular essentially free of diethylene glycol monomethyl ether, glycofurol, 1,2-propylene glycol, triethyl citrate, tributy citrate, acetyl tributy citrate, acetyl triethyl citrate, triacetin, ethanol, polyethylene glycol, dimethyl isosorbitol and propylene carbonate.
The microemulsion preconcentrates of the invention can be produced by intimately mixing the individual ingredients with one another, where appropriate with heating. The microemulsion preconcentrates can also be produced by dissolving component (b) with stirring, where appropriate with heating, in component (a), and adding component (c) to the re9ulting solution with further stirring. It is particularly important in this connection that the component or the active ingredient (c) is soluble either in component (a) or component (b) or else in both components (a) and (b), and that the active ingredient always continues to be in dissolved form during production of the preconcentrate, i.e. the mixture of all three components (a), (b) and (c).
Suitable as component (a) are mixtures of a medium chain fatty acid triglyceride, expediently a fatty acid triglyceride in which the fatty acid residues have 4 to 18, preferably 6 to 18, C atoms, and of an omega-9 and/or an omega-6 fatty acid. These substances are immiscible with water or insoluble or practically insoluble in water and have no or virtually no surface-active function.
Preferred medium chain fatty acid triglycerides are caprylic/capric acid triglycerides as are known and available commercially for example under the trade name Miglyol (Fiedler, Lexikon der Hilfsstoffe, 3rd editzon, pages 808 to 809, 1989). These include, for example, the following products:
Miglyol 810, 812 and B18 This is a fractionated coconut oil which contains triglycerides of caprylic and capric acids and has a molecular weight of about 520 (Miglyol 810 and 812) or 510 (Miglyol 818). It has a fatty acid composition with a maximum of 2 percent (Miglyol 810) and 3 percent (Miglyol 812 and 618) C6, and with about 65 to 75 percent (Miglyol 810), 50 to 65 percent (Miglyol 812) and 45 to 60 percent (Miglyol 818) C8. clo represents 25 to 35 percent of Miglyol, about 30 to 45 percent of Miglyol 812 and about 25 to 40 percent of i~iiglyol 818 , and C12 a maximum of 2 percent (Miglyol 810), 5 percent (Miglyol 812) and 2 to 5 percent (Miglyol 818). Miglyol 818 additionally has a content of about 4 to 6 percent of Cle:z.
Also suitable are triglycerides of caprylic acid and capric acid which are known and obtainable under the trade name Myritol (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, page 834, 1989). These include, for example, the product Myritol 813.
Further suitable products of this class are Captex 355, Captex 300, Captex 800, Capmul MCT, Neobee M5 and Maaol 1400.
Suitable omega-9 fatty acids are mainly those having 12-24, in particular 16-24, preferably 18-22, C atom9, fo= example oleic acid and eicosatrienoic acid. oleic acid is particularly preferred.
Suitable omega-6 fatty acids are mainly those having 12-24, in particular 16-24, preferably 18-22, C atoms, for example linoleic acid, gamma-linolenic acid, dihommo-gamma-linolenic acid and arachidonic acid.
Linoleic acid is particularly preferred.
Tn a particularly preferred embodiment, a mixture consisting of a caprylic/capric acid triglyceride, oleic acid and/or linoleic acid is used as component ( a ) .
1o Component (b), the surface-active component comprising a surfactant of the polyoxyethylene type, may be a hydrophilic surface-active agent or a lipophilic surface-active agent, but mixtures of such agents are also suitable.
Examples of such surfactants are the following:
Products of the reaction of natural or hydro-genated vegetable oils and ethylene glycol, namely polyoxyethylene glycolated natural or hydrogenated vegetable oils such as polyoxyethylene glycolated natural or hydrogenated castor oils. The various surfactants known and obtainable under the name Cremophor (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, pages 326 to 327, 1989) are par ticularly suitable, especially the products with the names Cremophor RH 40, Cremophor RH 60 and Cremophor EL. Also suitable as such products are the various surfactants known and obtained under the name Nikkol, for example Nikkol HCO-60.
- Polyoxyethylene sorbitan fatty acid esters, for example the mono- and trilauryl esters, the mono-and tripalmityl esters, the mono- and tristearyl esters and the mono- arid trioleyl esters, as are known and obtainable under the name Tween (Fiedler, Lexikon der ~:ilfsstoffe, 3rd edition, paces 1300 to 7.304, 1989), for example the products Tween 20: polyoxyethylene 20 sorbitan rcr~nolaurate, Tween 40: polyoxyethylene 20 sorbitan r~onopalmitate, Tween 60: polyoxyethylene 20 sorbitan ~ronostearate, Tween 80: polyoxyethylere 20 sorbitan monooleate, Ttaeen 65: polya}.yethylene 20 sorbitan tristearate, Tween 85: polyoxyethylene 20 sorbitan trioleate, T~veen 21: polyoxyethylene 4 sorbita_n manolaurate, 'Keen 61: polyoxyethylene 4 sorbitan monostearate and Tween 81: polyoxyethylene 4 sorbitan rnonooleate.
Of this class of compounds, Tween 80 is particularly preferred.
Polyoxyethylene fatty acid esters, for example the polyoxyethylene stearic esters known and obtain-able commercially under the name Myrj (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, page 834, 1939), especially the product Myrj 52, and the polyoxyethylene fatty acid esters known and obtainable under the name Cetiol HE (Fiedler, Lexikon der Hilfsstof~e, 3rd edition, page 284, 1989).
- Copolymers of polyoxyethylene and polyox~-propylene like those known and obtainable for example under the names Pluronic and Emkalyx (Fiedler, Lexikon z5 der Hilfsstoffe, 3rd edition, pages 956 to 958, 1989), especially the product Pluron:.c F68.
- Block copolymers of polyoxyethylene and polyoxy-propylene like those known and obtainable for example under the name Poloxamer (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, page 959, 1989), especially the product Poloxamer 188.
- Polyethoxylated vitamin E derivatives, especially the product Vitamin ~ TPGS (d-alpha tocoperyl polyethylene glycol 1000 succinate, Eastman).
- Polyethoxylated hydroxy fatty acid esters, especially the product Solutol HS 15 (polyoxy-ethylene 660 hydroxystearate, BASF).
- Products of the transesterificatioa of natural g _ vegetable oil glycerides and polyethylene polyols.
These include products of the transesterification of various, fox example non-hydrogenated, vege-table oils such as corn oil, pumpkinseed oil, almond oil, peanut oil, olive oil and palm oil, and of mixtures thereof with polyethylene glycols, especially with those having an avexage molecular weight of 200-800. Various transesterification products of this type are known and obtainable under the name Labrafil (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, page 707, 1989); of these, the products Labrafil M 1944 CS and Labrafil M 2130 CS are particularly suitable.
- Ethylene oxide adducts of sterols and derivatives thereof, for example of cholesterol and deriva-tives thereof, such as products derived from sitosterol, campesterol, or stigmasterol, for example from soybean sterols and derivatives thereof (Fiedler, Lexikon der Hilfsstoffe, 3rd edition, paces 554 and 555, 1989), as are known and obtainable under the names Generol, especially the products Generol 122 E5, 122 E10 and 122 E25.
The microemulsion pr~concentrates of the invention include both systems which comprise a single surface-active agent, and systems which comprise a mixture of two or more surface-active agents, e.g. Tween 80 +
Cremophor RH 40, Tween 80 + Cremophor RH 40 + Vitamin E
TPGS etc.
A surface-active component preferably used according to the invention comprises a polyoxyethyler~e sorbitan fatty acid ester, a polyoxyethylene glycolated natural or hydrogenated vegetable oil or mixtures thereof.
Component ~, the therapeutic active ingredient from the NSAIDs class which is slightly soluble in water but soluble in component (a) and/or (b), is preferably ibuprofen, dexibuprofen or naproxen; however, it is also possible to use another suitable NSAIDs, where appropriate in combination with antioxidants such as, S for example, vitamin E. Examples of other suitable NSAIDs are: anthranilic acid derivatives, acetic acid derivatives, oxicams, propionic acid derivatives, pyrazalone derivatives, salicylic acid derivatives and selective COX-2 inhibitors (cf. Arzneimittel Kompendium der Schweiz 2001, Documed AG, CH-4010 Basle, editors, Jurg Morant and Hans Rappaner).
The microemulsion preconcentrates of the invention may also comprise further substances such as, for example, antioxidants, thickeners, fragrances and/or flavorings, colors, etc.
The microemulsion preconcentrates of the invention are primarily intended for oral use. Preference is given in this connection to the so-called unit dose form, i.e.
the microemulsion preconceatrate is accommodated in a shaped article such as a soft or hard capsule, e.g.
made of gelatin or starch. When the active ingredient-containing premicroem~alsion is released there is spontaneous formation of a microemulsion in conjunction with gastrointestinal fluid. The compositions of the invention prove to be particularly suitable for oral administration in the for;a of unit dose forms also because addition o. volatile organic solvents, especially of the frequently used ethanol, is unneces-sary. when said solvents are employed, evaporation thereof through the ova er wall of the shaped article, especially of the soft or hard gelatin capsule, has an adverse effect on storability, and the active ingre-diem crystallizes out. The occurrence of these adverse effects must be prevented by elaborate measures during packaging and storage.
The novel compositions car. also be processed further to effervescent tablets or as granules.
The microemulsion preconcentrates of the invention expediently comprise from 5 to 45, preferably 20 to 40, percent by weight of a therapeutic active ingredient of the NSAIDs class (component (c)) which is slightly soluble in water but soluble in component (a) and/or (b), from 5 to 60, preferably 15 to 40 percent by weight, of a mixture consisting of a medium chain triglyceride and an omega-9 fatty acid and/or an omega-6 fatty acid (component (a)) and from 20 to 90, preferably fxom 25 to 65, percent by ureight of the surface-active component (b).
The present invention also rakes it possible to provide pharmaceutical compositions which comprise a thera-peutic active ingredient from the NSAIDs class which is slightly soluble in water but soluble in component (a) and/or (b), and which themselves represent microemulsions; the active ingredient is stably solubilized in these microemulsions, with no precipitates being observed over several weeks. For oral adr.~inistration it is Fossible for microemulsions, which are obtained for example by diluting the microemulsion preconcentrates of the invention with water or an aqueous mediurl, to be used directly as drinlcable formulations. If topical or paranteral use is intended, then compositions, in which further excipients may be present, likewise contain water, resulting in an aqueous microemulsion in the form of a spray, gel, lotion, cream, plaster, roll-on, solution for injection, solution for infusion or the like. Such pharmaceutical compositicns in the form of microemulsions are likewise novel, and the present invention relates thereto.
The microemulsions of the invention are characterized in particular in that they can be obtained by mixing a microemulsion preconcentrate of the compositions described above with water or an aqueous medium. When the preconcentrate is mixed with water or gastric and intestinal fluid there is spontaneous or virtually spontaneous, i.e. with negligible energy input, forma S tion of a microemulsion.
Depending on the amount of water present, the microemulsions are W/O microemulsions, bicontinuous microemulsions or 0/W microemulsions.
The O/w type (oil-in-water) microemulsions of the invention show stability properties like those des-cribed hereinbefore in connection with microemulsions, i.e. in particular that the active ingredient is stably solubilized in these microemulsions, and no precipitate is observable over several weeks. The particle size of these microemulsions is less than 150 nm, preferably less than 100 nm.
The compositions of the invention are explained further by the following examples. Examples 1.1 to 1.5 show the preparation of Compositions suitable, for example, for the therapy of pain and rheumatism. Examples 2.1 to 2.4 show the preparation of compositions suitable, for example, for the topical treatment of rheumatism.
Example 3.1 shows the preparation of a composition for parenteral use, which is suitable fox example for subcutaneous or intramuscular treatment of inflammatory pain. In example 4, the pharmacokinetic parameters (cm~, tm,~;, AUC) of a formulation of the invention which was administered orally in soft gelatin capsules are measured and compared with those of coated tablets.
The examples are described with particular reference to ibuprofen and dexibuprofen. However, comparable com-positions can be prepared through use of other suitable NSAIDs.
Example 1: Preparation of oral ibuprofen or dexibupro-fen dosage forms of the microemul9ion preconcentrate Example 1.1 Ibuprofen (c1) 20.00 Miglyol 812 (al) 20.00 Oleic acid (a2) 5.ooa Tween 80 (b1) 37.500 Cremophor RH 40 (b2) 12.50b Vitamin E acetate (c2) 5.00 The ibuprofen is dissolved by stirring at room tempera-ture, where appropriate with gentle heating, in components (a1), (a2), (b1), (b2) and (c2). The micro-emulsion preconcentrate which is formed is used to fill a soft or hard capsule made of gelatin or starch.
An alternative possibility is to use the microemulsion precor~centrate to fill a dispenser. In this case, the patient prepares an oral drinkable solution of the O/w microemulsion type from the microemulsion preconcentrate by appropriate dilution with water or another aqueous liquid.
The following compositions can also be prepared in an analogous manner and be used to fill capsules or dispensers.
Example 1.2 Ibuprofen (c) 20.00 Miglyol 812 (al) 25.oo°s Oleic acid (a2) 5.00%
c Tween 60 (b1) 37.50 Cremophor RH 40 (b2) 12.50a Examale 1.3 Ibuprofen (c1) 20.00a Miglyol 812 (al) 20, oohs Oleic acid (a2) 5.00 Tween 80 (b1) 37.50 Cremophor EL (b2) 12.50 Vitamin E acetate (c2) 5.00 _Example 1.4 Ibuprofen (c) 10.000 Miglyol 812 (al) 35.00a Oleic acid (a2) S.OOo Tween 80 (b1) 37.50ro Cremophor EL (b2) 12.50 Example 1.5 Dexibuprofen (c1) 30.00's Miglyol 812 (al) 17.50's Oleic acid (a2) 4.40%
Tween 80 (b1) 32.e0ro Cremophor RH 40 (b2) 10.90ro Vitam=n E acetate (c2) 4.40's Dilution, e.g. 1:100, of compositions of the above type with simulated gastric or intestinal fluid results in microemulsions having the following particle sizes in the case of representative examples (cf. table 1):
Table 1 Composition of microemulsion Particle diameterl~
preconcentrate of the O/W microemulsion Gastric Intestinal fluid [nm] fluid [nm]
Example 1.1 17.9 t 7.2 18.6 6.0 Example 1.2 25.6 10.1 18.8 6.5 Example 1.3 20.4 i 8.2 19.7 -~ 4.7 Example 1.4 25.0 6.72 Example 1.5 ~6.3 33.2 118.3 G.6 1) The particle diameters and particle size distribu-tions were determined by dynamic laser light scattering measurements (instrument: Nicomp 370 submicron particle sizer, evaluation: volume weighting).
2) These ibuprofen r:ticroemulsions were formed by a 1:10 dilution of the microemulsion preconcentrate with 10 mM phosphate buffer of pH 6 at room S temperature.
It is evident from the table below that the micro emulsion formation by the microemulsion preconcentrates remains unchanged after being used to fill and being l0 stored in soft gelatin capsules (SGC).
Table 2 Microemulsion preconcentrate Particle diameter of the of example 1.1 ibuprofen microemulsionl~
Hatch 201111 Gastric Intestinal fluid [nm] fluid [nmJ
Before SGC filling 17.9 7.2 18.6 6.0 After SGC filling 19.6 7.0 20.6 5.3 After storage in SGC at 25C 16.9 6.3 20.0 5.4 and 60% RH for 1 month After storage in SGC at 40C 17.7 6.8 19.8 5.5 and 75~ RH for 1 month After storage in SGC at 25C 13.6 -!- 6_9 18.4 5.9 and 60-s RH for 3 months 1) The ibuprofen microemulsions wexe, formed by 1:100 15 dilution of the microemulsion preconcentrates with simulated gastric and intestinal fluids at 37°C.
Microemulsion preconcentrates used to fill SGC
were removed from the SGC for the microemulsion formation. The particle diameters and particle 20 size distributions of the resulting ibuprofen microemulsions were determined by dynamic laser light scattering measurements (instrument:
Nicomp 370 submicron particle sizer, evaluation:
volume weighting).
Example 2: Preparation of ibuprofen forms of the microemulsion type which can be used topically The microemulsion preconcentrates described in example 1,1 to 1.5 are used hereinafter as basis for preparing sprays, gels, creams and other topical dosage forms by combining them with further additives such as water, thickeners and the like.
Example 2.1: Ibuprofen 1.0°s microemulsion pump spray Microemulsion preconcentrate of example 1.4 10.00 Naz EDTA 0 . 05 Benzalkonium chloride O.lOo 10 mM phosphate buffer pH 6 ad 100.000 The microemulsion preconcentrate is added to the phosphate buffer comprising Nay EDTA and benzalkonium chloride while stirring at room temperature. The resulting ibuprofen O/W microemulsion is used to fill a pump spray. Compressed gas or aerosol spray are also suitable in place of the pump spray.
Example 2.2: Ibuprofen 1.0a hydroqel Microemulsion preconcentrate of example 1.4 10.00 Nay EDTA 0.05 Henzalkonium chloride 0_10a Sodium carboxymethylcellulose 450 cP 3_50°
to mM phosphate buffer pH 6 ad 100.00a The microemulsion preconcentrate is added with stirring to the phosphate buffer containing Na2 EDTA and benzalkonium chloride. The resulting ibuprofen O/W
microemulsion is further processed with the sodium carboxymethylcellulose to give the hydrogel, and packaged, in a conventional way.
Example 2.3: Ibu rofen 1.0~ 0/W emulsion Microemulsion preconcentrate of example 1.4 10.000°s Isopropyl palmitate 8.OOOa Glyceryl stearate 7.0 Glycerol S.OOOa Steareth-2 + PEG-8 distearate 4.000a Liquid paraffin 4.000%
Microcrystalline wax 4.OOOE
Steareth-21 3.000 Dimethicone 1.OOOo 5uttocide A 0.2500 Lanolin alcohol 0.1003 Sodium hydroxide 0.005%
water ad 100.000 The microemulsion preconcentrate is added with stirring to the aqueous phase at room temperature. The resulting ibuprofen O/w microemulsion is further processed with the oil phase to give the O/w emulsion, and packaged, in a conventional way.
Example 2.4: Ibuprofen l.Oro microemulsion roll-on 2o Microemulsion preconcentrate of example 1.4 10.000 Na2 EDTA 0.05 Benzalkonium chloride 0.10 l0 mM phosphate buffer pH 6 ad 100.00 The microemulsion preconcentrate is added with stirring to the phosphate buffer, containing Na2 EDTA and benzalkonium chloride, at raom temperature. The result-ing ibuprofen 0/W microemulsion is used to fill a roll-on.
Example 3: Production of microemulsion-type ibuprofen forms which can be used parenterally The microemulsion preconcentrates described in example 1.1 to 1.5 can serve as basis for producing injection solutions by diluting them appropriately with further additives such as physiological saline or 5b strength glucose solution and the like.
Example 3_1: Ibuprofen 0.1~ injection solution Microemulsion preconcentrate of example 1.4 l.OOo 5's strength glucose solution ad 100.00%
The microemulsion preconcentrate is added with stirring to the glucose solution at room temperature. The resulting ibuprofen O/W microemulsion is sterilized by 0.2 ~m filtration and used to fill conventional sterile containers.
l0 Example 4: Pharmacokinetics of the ibuprofen micro-emulsion preconcentrate of example 1.1 after oral administration in soft capsules made of gelatin and starch The aim of this study was to establish the pharmaco kinetics of a single oral dose of 2 x 200 mg ibuprofen administered in the form of the microernulsion precon centrate of example 1.1 in soft capsules made of gelatin and starch.
Preparations A Soft gelatin capsules containing the ibuprofen microemulsion preconcentrate of example 1.1 Active ingredient content: 200 mg of ibuprofen per capsule B Starch capsules containing the ibuprofen micro-emulsion preconcentrate of example 1.1 Active ingredient content: 200 mg of ibuprofen per capsule Dosage: 2 x 200 mg of ibuprofen, orally in 2 capsules Intake In the morning, fasting Subjects: n = 4 Parameter measured: plasma level of ibuprofen [~m/ml plasma Results It is evident from the changes in the plasma levels of test products A and B of the invention that the maximum ibuprofen plasma levels of 45.3 and 49.0 E~m/ml are reached after 0.68 and 0. 63 hours (cf . figure 1) . Test products A and H thus show distinct differences in relation to the rate of rise in level and to the maximum reached in comparison with commercially available 200 mg ibuprofen coated tablets (cf.
table 3).
Table 3 Parameter Test Test 200 mg product A product B ibuprofen coated tabletsl~
Cma.c [~g/ml] 45.3 49.0 32.0 Tmax [h] 0.66 0.63 1.30 I AUC~"f [~g/ml/h] 123 121 108.0 1) Literature data from a study carried out analogously
Claims (21)
1. A composition in the form of a microemulsion preconcentrate comprising (a) a mixture consisting of a triglyceride, in particular a medium chain triglyceride, and of an omega-9 fatty acid and/or an omega-6 fatty acid; and (b) a surface-active component comprising a sur-factant, in particular of the polyoxyethylene type, (c) an active ingredient selected from the class of non-steroidal antiinflammatory drugs, where the active ingredient is soluble in (a) and/or (b).
2. A composition as claimed in claim 1, where the active ingredient is selected from the group consisting of heteroaryl- and arylacetic and -propionic acid and from the group of COX-2 inhibitors, in particular comprising indometacin, diclofenac, naproxen, ibuprofen, dexibuprofen, and celeoxib and rofaecoxib.
3. A composition as claimed in claim 1, characterized in that the active ingredient is ibuprofen.
4. A composition as claimed in claim 1, characterized in that the active ingredient is dexibuprofen.
5. A composition as claimed in claim 1, characterized in that the active ingredient is naproxen.
6. A composition in the form of a microemulsion obtainable by mixing a microemulsion preconcen-trate as claimed in any of claims 1 to 5 with water or an aqueous medium.
7. A composition as claimed in any of claims 1 to 6, comprising additional components which do not belong to the following groups of substances:
- C1-C5-alkyl or tetrahydrofurfuryl diethers or partial ethers of low molecular weight mono- or polyoxy-C2-C12-alkanediols;
- 1,2-propylene glycol;
- lower alkanols;
- products of the esterification of poly-carboxylic acids with 2-10, in particular 3-5, carboxyl groups with C1-C10 alcohols; and products of the esterification of polyols with 2-10, in particular 3-5, carboxyl groups with C2-C11 carboxylic acids.
- C1-C5-alkyl or tetrahydrofurfuryl diethers or partial ethers of low molecular weight mono- or polyoxy-C2-C12-alkanediols;
- 1,2-propylene glycol;
- lower alkanols;
- products of the esterification of poly-carboxylic acids with 2-10, in particular 3-5, carboxyl groups with C1-C10 alcohols; and products of the esterification of polyols with 2-10, in particular 3-5, carboxyl groups with C2-C11 carboxylic acids.
8. A composition as claimed in any of claims 1 to 7, characterized in that the fatty acid residues of the medium chain triglyceride have 4-18, preferably 6-18, C atoms.
9. A composition as claimed in claim 8, characterized in that the medium chain triglyceride is a caprylic/capric acid triglyceride.
10. A composition as claimed in any of claims 1 to 9, characterized in that the omega-9 fatty acid and/or the omega-6 fatty acid has 12-24, in particular 16-24, preferably 18-22, C atoms.
11. A composition as claimed in any of claims 1 to 10, characterized in that the omega-9 fatty acid is oleic acid.
12. A composition as claimed in either of claims 1 or 10, characterized in that the omega-6 fatty acid is linoleic acid.
13. A composition as claimed in any of claims 1 to 12, characterized in that it comprises as component (a) a mixture of a caprylic/capric acid tri-glyceride, oleic acid and/or linoleic acid.
14. A Composition as claimed in any of claims 1 to 13, characterized in that the ratio of the amounts of omega-9 tatty acid and/or omega-6 fatty acid to the medium chain triglyceride is from 1:1 to 1:200, preferably from 1:2 to 1:20.
15. A composition as claimed in any of claims 1 to 14, characterized in that the surface-active component (b) comprises a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene glycolated natural or hydrogenated vegetable oil or mixtures thereof.
16. A composition as claimed in any of claims 1 to 5 and 7 to 15, characterized in that component (a) is present in an amount of from 20 to 70 percent by weight based on the total weight of the composition.
17. A composition as claimed in any of claims 1 to 5 and 7 to 16, characterized in that the surface-active component (b) is present in an amount of from 20 to 80 percent by weight based on the total weight of the composition.
18. A composition as claimed in any of claims 6 to 17, characterized in that it is an O/W microemulsion with an average particle size below 150 nm, pre-ferably below 100 nm.
19. A shaped article for oral administration compris-ing an active ingredient from the class of non-steroidal antiinflammatory drugs in a com-position as claimed in any of claims 1 to 18 for administering the active ingredient.
20. A shaped article as claimed in claim 19, charac-terized in that it comprises a biopolymer, in particular gelatin.
21. A composition comprising an active ingredient from the class of non-steroidal antiinflammatory drugs as claimed in any of claims 1 to 18 for topical, in particular cutaneous, administration.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01109132 | 2001-04-12 | ||
| EP01109132.9 | 2001-04-12 | ||
| EP01110924.6 | 2001-05-05 | ||
| EP01110924A EP1249231B1 (en) | 2001-04-12 | 2001-05-05 | Pharmaceutical formulations comprising anti-inflammatory compounds and use thereof |
| PCT/EP2002/003922 WO2002083099A1 (en) | 2001-04-12 | 2002-04-09 | Pharmaceutical formulations containing anti-inflammatory active ingredients and the use of said formulations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2443461A1 true CA2443461A1 (en) | 2002-10-24 |
Family
ID=26076542
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002443461A Abandoned CA2443461A1 (en) | 2001-04-12 | 2002-04-09 | Pharmaceutical formulations containing anti-inflammatory active ingredients and the use of said formulations |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1249231B1 (en) |
| AT (1) | ATE258427T1 (en) |
| CA (1) | CA2443461A1 (en) |
| DE (1) | DE50101395D1 (en) |
| ES (1) | ES2215101T3 (en) |
| PT (1) | PT1249231E (en) |
| WO (1) | WO2002083099A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1728505A1 (en) * | 2004-03-24 | 2006-12-06 | Takeda Pharmaceutical Company Limited | Preparation with elevated content |
| CN105343002A (en) * | 2015-11-27 | 2016-02-24 | 济南康和医药科技有限公司 | Etoricoxib oral microemulsion preparation and preparation method thereof |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100507771B1 (en) * | 2002-11-08 | 2005-08-17 | 한미약품 주식회사 | A composition for oral administration of water-insoluble anti-cold drug and a preparation method thereof |
| DE50308456D1 (en) * | 2003-01-08 | 2007-12-06 | Swiss Caps Rechte & Lizenzen | Shaped body consisting of gelatin-free material and filled with a liquid filling material |
| DK2279729T3 (en) * | 2003-07-17 | 2016-11-28 | Banner Life Sciences Llc | Control release preparations |
| CA2683020A1 (en) * | 2007-05-24 | 2008-11-27 | Novartis Ag | Oral dosage form providing fast absorption of drug |
| PL214538B1 (en) | 2009-05-28 | 2013-08-30 | P P F Hasco Lek Spolka Akcyjna | Liposome composition containing naproxen and a method for production of liposome composition containing naproxen |
| KR102180667B1 (en) * | 2011-09-29 | 2020-11-20 | 피엘엑스 옵코 인코포레이티드 | Ph dependent carriers for targeted release of pharmaceuticals along the gastrointestinal tract, compositions therefrom, and making and using same |
| CN107115313A (en) * | 2017-07-03 | 2017-09-01 | 福建省福抗药业股份有限公司 | A kind of celecoxib composition and preparation method thereof |
| CN115666523A (en) | 2020-03-26 | 2023-01-31 | Plx 奥普科有限公司 | Drug carriers capable of pH dependent reconstitution and methods of making and using the same |
| WO2023118928A1 (en) * | 2021-12-21 | 2023-06-29 | Opella Healthcare Group Sas | Stable nanoformulation for lipophilic actives, oral dosage form and process for its preparation |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2326485C (en) * | 1998-04-01 | 2008-12-09 | Rtp Pharma Inc. | Anticancer compositions |
| WO1999056727A2 (en) * | 1998-05-07 | 1999-11-11 | Elan Corporation, Plc | Solvent/cosolvent free microemulsion and emulsion preconcentrate drug delivery systems |
| WO2001028519A1 (en) * | 1999-10-20 | 2001-04-26 | Vesifact Ag | Microemulsion preconcentrates and microemulsions |
-
2001
- 2001-05-05 EP EP01110924A patent/EP1249231B1/en not_active Expired - Lifetime
- 2001-05-05 DE DE50101395T patent/DE50101395D1/en not_active Expired - Lifetime
- 2001-05-05 PT PT01110924T patent/PT1249231E/en unknown
- 2001-05-05 ES ES01110924T patent/ES2215101T3/en not_active Expired - Lifetime
- 2001-05-05 AT AT01110924T patent/ATE258427T1/en active
-
2002
- 2002-04-09 WO PCT/EP2002/003922 patent/WO2002083099A1/en not_active Application Discontinuation
- 2002-04-09 CA CA002443461A patent/CA2443461A1/en not_active Abandoned
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1728505A1 (en) * | 2004-03-24 | 2006-12-06 | Takeda Pharmaceutical Company Limited | Preparation with elevated content |
| EP1728505B1 (en) * | 2004-03-24 | 2014-06-04 | Takeda Pharmaceutical Company Limited | Preparation with elevated content |
| CN105343002A (en) * | 2015-11-27 | 2016-02-24 | 济南康和医药科技有限公司 | Etoricoxib oral microemulsion preparation and preparation method thereof |
| CN105343002B (en) * | 2015-11-27 | 2019-07-26 | 济南康和医药科技有限公司 | A kind of Etoricoxib oral microemulsion preparation and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| DE50101395D1 (en) | 2004-03-04 |
| ATE258427T1 (en) | 2004-02-15 |
| WO2002083099A1 (en) | 2002-10-24 |
| EP1249231B1 (en) | 2004-01-28 |
| EP1249231A1 (en) | 2002-10-16 |
| PT1249231E (en) | 2004-06-30 |
| ES2215101T3 (en) | 2004-10-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 20050411 |