WO2001028555A1 - Emulsion compositions for polyfunctional active ingredients - Google Patents

Emulsion compositions for polyfunctional active ingredients Download PDF

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Publication number
WO2001028555A1
WO2001028555A1 PCT/US2000/028835 US0028835W WO0128555A1 WO 2001028555 A1 WO2001028555 A1 WO 2001028555A1 US 0028835 W US0028835 W US 0028835W WO 0128555 A1 WO0128555 A1 WO 0128555A1
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Prior art keywords
fatty acid
oil
acid esters
polyethoxylated
mixtures
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PCT/US2000/028835
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French (fr)
Inventor
Feng-Jing Chen
Mahesh V. Patel
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Lipocine, Inc.
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Priority to AU12139/01A priority Critical patent/AU1213901A/en
Publication of WO2001028555A1 publication Critical patent/WO2001028555A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/3533,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355Tocopherols, e.g. vitamin E
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/20Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/107Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to pharmaceutical delivery systems, and in particular to oil-in-water pharmaceutical emulsions for the improved delivery of polyfunctional active ingredients, such as pharmaceuticals, cosmeceuticals, nutritive agents, and diagnostic agents.
  • polyfunctional active ingredients such as pharmaceuticals, cosmeceuticals, nutritive agents, and diagnostic agents.
  • BACKGROUND Polyfunctional active ingredients i.e., active ingredients having at least some polar functionality, present difficult problems in formulating such compounds for effective administration to patients.
  • a well-designed formulation should, at a minimum, be capable of presenting a therapeutically effective amount of the polyfunctional compound to the desired site of action, in a bioavailable form. Particularly when the polyfunctional active ingredient is hydrophobic, this minimal functionality has proven difficult to achieve.
  • polyfunctional hydrophobic active ingredient requires interaction with aqueous physiological environments, such as blood, gastric fluids and intestinal fluids.
  • Pharmaceutical compositions for delivery of such polyfunctional hydrophobic active ingredients should preferably carry the active ingredient through the aqueous environment, while maintaining the active ingredient compound in a bioavailable form, and avoiding or substantially reducing the use of physiologically harmful solvents or excipients.
  • a number of approaches to formulating polyfunctional hydrophobic active ingredients for oral or parenteral delivery are known.
  • Several commercial formulations are available for parenteral dosage forms of polyfunctional active ingredients, based on organic cosolvent and/or synthetic surfactant solvent systems.
  • cyclosporin A SANDIMMUNE®
  • TAXOL® paclitaxel
  • VePesid® etoposide
  • Solvent/hydrophilic surfactant formulations suffer from a number of serious disadvantages.
  • Hydrophilic polyethoxylated surfactants commonly used in such formulations such as Cremophor® and Tween®, have a high toxicity potential. Pain at the injection site, thrombophlebitis, tissue necrosis and hypersensitivity reactions are commonly observed side effects of such formulations.
  • Cremophor EL for example, currently used in parenteral formulations of cyclosporin, paclitaxel and teniposide, has been found to be associated with severe anaphylactic/hypersensitive reactions. Cremophor EL has also been implicated at least partially responsible in the most significant side effect of cyclosporin concentrate for injection, acute nephrotoxicity.
  • hydrophilic polyethoxylated surfactants such as Cremophor EL, cause phthalate stripping and are incompatible with commonly used plasticized PVC infusion devices.
  • oil-in-water emulsion formulations have been used in polyfunctional hydrophobic active ingredient delivery. These formulations typically contain a long chain triglyceride oil phase dispersed in water and stabilized by an emulsifier layer of a phosphatide, such as soy or egg lecithin.
  • a phosphatide such as soy or egg lecithin.
  • Propofol for example, is available commercially as Diprivan®, an o/w emulsion formulation using long chain triglycerides contained in vegetable oils, and an emulsifying agent. While such formulations may overcome some of the safety liabilities of hydrophilic surfactant/solvent based systems, the oil component may not be appropriately polar to effectively incorporate polyfunctional active ingredients at desirable therapeutic levels, without compromising product safety.
  • MCT medium chain triglyceride
  • LCT long chain triglyceride
  • U.S. Patent No. 5,660,858 to Parikh et al. discloses cyclosporin oil-in-water emulsions with a synthetic MCT having predominantly C 8 -C 12 fatty acid chains.
  • U.S. Patent No. 5,364,632 to Benita et al. discloses an oil-in-water emulsion of a lipophilic drug having an MCT oil carrier and a combination of ionic and non-ionic surfactants.
  • caprylic acid the hydrolysis product of an MCT containing the caprylic acid ester moiety
  • Caprylic acid infusion simultaneously produced alterations in the sodium-potassium- adenosinetriphosphatase activity in brain tissue, and resulted in hyperventilation, coma, seizure, hypotonia and electroencaphalographic changes in rabbits. (Velazquez et al., Proceedings of the Nutrition Society, 55:49-78 (1996)).
  • the present invention provides pharmaceutical emulsions and methods utilizing the emulsions, to provide improved delivery of polyfunctional active ingredients.
  • the pharmaceutical emulsions of the present invention include an aqueous phase, an oil phase, and an emulsifier, wherein the oil phase includes components chosen to increase the polarity of the oil phase, without introducing into the emulsion excessive amounts of organic solvents, hydrophilic surfactants, or compounds which include or hydrolyze to form medium chain fatty acids.
  • the present invention provides a pharmaceutical emulsion for delivery of a polyfunctional active ingredient, the emulsion including an aqueous phase, an emulsifier, and a polar oil phase containing one or more structured triglycerides.
  • the structured triglyceride can include both medium and long chain fatty acids, and is preferably free of triglycerides having three medium chain fatty acid moieties.
  • the composition can include additional components, such as a polyfunctional active ingredient, a long chain triglyceride, a polarity modifier, ingredients to facilitate formulation stability and patient acceptability, and processing aids.
  • the present invention provides a pharmaceutical emulsion for delivery of a polyfunctional active ingredient, the emulsion including an aqueous phase, an emulsifier, and an oil phase containing a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides, acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated
  • the present invention provides a pharmaceutical emulsion for delivery of a polyfunctional active ingredient, the emulsion including an aqueous phase, an emulsifier, and an oil phase containing a long chain triglyceride and a monoglyceride, a diglyceride, a mixture of mono- and diglycerides, or a mixture of mono-, di- and triglycerides.
  • the composition can include additional components, such as a polyfunctional active ingredient, a structured triglyceride, a polarity modifier, ingredients to facilitate formulation stability and patient acceptability, and processing aids.
  • the present invention provides a pharmaceutical emulsion for delivery of a polyfunctional active ingredient, the emulsion including an aqueous phase, an emulsifier, and an oil phase containing a long chain triglyceride and an acetylated monoglyceride, an acetylated diglyceride, or a mixture thereof.
  • the composition can include additional components, such as a polyfunctional active ingredient, a structured triglyceride, a polarity modifier, ingredients to facilitate formulation stability and patient acceptability, and processing aids.
  • the present invention provides dosage forms of the pharmaceutical emulsions.
  • the present invention relates to methods of using the pharmaceutical emulsions to treat patients with a polyfunctional active ingredient.
  • the present invention relates to methods of treating a patient with a pharmaceutical composition, wherein the composition includes effective amounts of an oil phase and an emulsifier.
  • the amounts and components of the oil phase and emulsifier are effective to minimize drug precipitation upon administration, irritation and local toxicity at the site of administration; to alter drug biodistribution and clearance; and to minimize systemic drug toxicity, multi-drug resistance, intra-subject performance variability and/or inter-subject performance variability.
  • the present invention provides pharmaceutical emulsions and methods utilizing the emulsions, to provide improved delivery of polyfunctional active ingredients, particularly hydrophobic polyfunctional active ingredients.
  • the pharmaceutical emulsions of the present invention achieve effective and stable solubilization of the polyfunctional active ingredient without excessive amounts of organic solvents, hydrophilic synthetic surfactants, or medium chain fatty acid containing compounds, such as medium chain triglycerides.
  • the pharmaceutical emulsions of the present invention include an aqueous phase, an oil phase, and an emulsifier, wherein the oil phase includes safe and effective components chosen to increase the polarity of the oil phase, while maintaining formulation safety and stability.
  • the oil phase includes a structured triglyceride.
  • structured triglyceride means a triglyceride, or a mixture of triglycerides, of synthetic or natural origin, having a fatty acid chain composition including both medium chain fatty acids and long chain fatty acids.
  • Conventional oils such as vegetable oils, are primarily composed of triglycerides of long chain fatty acids.
  • MCT oils are synthetic oils primarily composed of triglycerides of Cs-Cio fatty acids.
  • long chain fatty acid means a saturated or unsaturated fatty acid having a carbon chain length of 6 to 12 carbon atoms
  • long chain fatty acid means a saturated or unsaturated fatty acid having a carbon chain length of greater than 12 carbon atoms
  • structured triglycerides include both medium chain and long chain fatty acid groups. Structured triglycerides are typically synthetically produced, and are typically a mixture of triglycerides having predominantly medium and long chain fatty acid groups.
  • An example of commercially available structured triglycerides is the Captex 810 series (Abitec), which is reported to have the following fatty acid distribution:
  • the structured triglyceride does not contain significant amounts of triglycerides having three medium chain fatty acid groups.
  • preferred structured triglycerides are those which are substantially free of MCTs, such as Captex 810D.
  • fractions of Captex 810A or similar compositions which are substantially free of triglycerides having three medium chain fatty acid groups, obtained by appropriate procedures, are also suitable for use in the emulsion compositions of the present invention.
  • Structured triglycerides can be produced by various methods known in the art, including hydrolysis and esterification; interesterification; traditional chemical reaction sequences; lipase interesterification; genetic manipulation; or other methods, as appropriate.
  • the oil phase can further include one or more oils having long chain triglycerides, such as vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, semi-synthetic triglycerides, synthetic triglycerides, or mixtures thereof. Fractionated, refined or purified oils of these types can also be used.
  • oils having long chain triglycerides such as vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, semi-synthetic triglycerides, synthetic triglycerides, or mixtures thereof. Fractionated, refined or purified oils of these types can also be used.
  • suitable long chain triglyceride-containing oils suitable for use in the compositions of the present invention include almond oil; babassu oil; borage oil; black currant seed oil; canola oil; castor oil; coconut oil; corn oil; cottonseed oil; emu oil; evening primrose oil; flax seed oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; a mixture of hydrogenated cottonseed oil and hydrogenated castor oil; partially hydrogenated soybean oil; a mixture of partially hydrogenated soybean oil and partially hydrogenated cottonseed oil; glyceryl
  • trioleate glyceryl trilinoleate
  • glyceryl trilinolenate glyceryl trilinolenate
  • Preferred long chain triglyceride containing oils include coconut oil; corn oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; hydrogenated coconut oil; partially hydrogenated soybean oil; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; a ⁇ 3 polyunsaturated fatty acid triglyceride containing
  • More preferred long chain triglyceride containing oils include corn oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; partially
  • the oil phase can further include one or more polarity modifiers.
  • these polarity modifiers can act as polarity enhancers, to assist in adjusting the polarity of the oil phase to maximize the beneficial properties of the present emulsions.
  • the polarity modifier is a compound or a mixture of compounds, capable of modifying the interaction between the polyfunctional active ingredient and the oil phase by serving as a bridge to reduce the effects of the gap in polarity between the active ingredient and the oil.
  • a polarity modifier in the oil phase creates a more favorable environment for a polyfunctional active ingredient through interaction with the polarity modifier.
  • These interactions may include hydrogen bonds, ion-dipole interactions, ion-induced dipole interactions, electrostatic interactions, and van der Waals forces, including dipole-dipole interactions (also known as Keesom forces), dipole-induced-dipole interactions (also known as Debye forces), and induced dipole-induced dipole interactions (also known as London dispersion forces).
  • Suitable polarity modifiers include acids; bases; monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
  • Suitable polarity modifiers include lipophilic reaction mixtures, or purified/fractionated lipophilic reaction mixtures, of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, or sterols.
  • the glyceride can be a monoglyceride, a diglyceride, a triglyceride, or a mixture thereof.
  • lipophilic means those members of the foregoing groups or classes of compounds which have significant solubility in oily solvents, and poor solubility in aqueous solvents.
  • HLB hydrophilic-lipophilic balance
  • lipophilic compounds are generally those having an HLB value of less than about 10.
  • a preferred lipophilic reaction mixture is the reaction mixture of a transesterification reaction of a polyol and a fatty acid, a glyceride, a vegetable oil, a hydrogenated vegetable oil, a sterol, or a mixture thereof.
  • Preferred lipophilic reaction mixtures are those in which the polyol reactant is a polyhydric aliphatic alcohol, such as pentaerythritol, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, sorbitol, glycerol, polyglycerol, a saccharide, a cyclodextrin, a synthetic polyhydric polymer, or a mixture thereof.
  • a polyhydric aliphatic alcohol such as pentaerythritol, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, sorbitol, glycerol, polyglycerol, a saccharide, a cyclodextrin, a synthetic polyhydric polymer, or a mixture thereof.
  • Preferred polarity modifiers include monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; acetylated monoglycerides; acetylated diglycerides; cholesterol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; lipophilic reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
  • Particularly preferred polarity modifiers are monoglycerides, diglycerides, mixtures of mono- and diglycerides.
  • the monoglycerides and diglycerides preferably have fatty acids with carbon chain lengths of greater than 10 carbon atoms.
  • Also particularly preferred are acetylated monoglycerides, acetylated diglycerides, and mixtures thereof.
  • polarity modifiers include sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
  • Still other preferred polarity modifiers include polyethoxylated esters, such as polyethoxylated monoglycerides, polyethoxylated diglycerides, polyethoxylated triglycerides, polyethoxylated bile acids, polyethoxylated cholesterol, polyethoxylated fatty acids, polyethoxylated propylene glycol esters, polyethoxylated vegetable oils, polyethoxylated hydrogenated vegetable oils, polyethoxylated sorbitan fatty acid esters, and mixtures thereof.
  • polyethoxylated esters such as polyethoxylated monoglycerides, polyethoxylated diglycerides, polyethoxylated triglycerides, polyethoxylated bile acids, polyethoxylated cholesterol, polyethoxylated fatty acids, polyethoxylated propylene glycol esters, polyethoxylated vegetable oils, polyethoxylated hydrogenated vegetable oils, polyeth
  • Suitable acids and bases are pharmaceutically acceptable acids and bases, preferably those which are oil-miscible, or which can interact with the polyfunctional active ingredient to bring the active and/or the acid or base into the oil phase.
  • the acid can be an inorganic acid, an aliphatic acid, an aromatic acid, an acidic salt, or a mixture thereof.
  • acids examples include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, carbonic acid, nitric acid, boric acid, phosphoric acid, acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, an amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, cinnamic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, hydroxybenzoic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulf
  • the base can be an inorganic base, an aliphatic base, an aromatic base, a basic salt, or a mixture thereof.
  • suitable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, glucamine and homologs thereof, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, trihydroxyethylamine, triisopropanolamine, basic salts of pharmaceutically acceptable cations and anions, and mixtures thereof.
  • the optional acids and bases can be included in amounts sufficient to adjust the pH and/or the osmolality of the emulsion, the solubility of the polyfunctional active ingredient, the kinetic release profile, or other properties of the emulsion, as desired.
  • the total amount of fatty acid groups of the oil phase including free fatty acids and the fatty acid moieties of fatty acid containing compounds, having a carbon chain length of from 6 to 12 carbon atoms, be less than about 50% by weight, preferably less than about 40% by weight, and more preferably less than about 30% by weight, based on the total weight of the fatty acid groups of the oil phase.
  • the total amount of fatty acid groups of the oil phase including free fatty acids and the fatty acid moieties of fatty acid containing compounds, having a carbon chain length of greater than 12 carbon atoms, be greater than about 10% by weight, preferably greater than about 30% by weight, and more preferably greater than about 50% by weight, based on the total weight of the fatty acid groups of the oil phase.
  • the oil phase itself can be up to about 30% of the total weight of the emulsion, more
  • the pharmaceutical emulsions of the present invention also include an emulsifier in
  • the emulsifier stabilizes the emulsion by increasing the
  • the emulsifier will be present in an amount of less than about 20%
  • a suitable emulsifier can be ceramide; a mixed chain phospholipid; a cationic
  • lipid 14 lipid; an oligolipid; a phospholipid; a carnitine; a sphingosine; a sphigomyelin; a glycolipid;
  • the glyceride of the reaction mixture can be a monoglyceride, a diglyceride, a 4 triglyceride, or a mixture thereof.
  • the polyol of the reaction mixture is preferably a polyhydric aliphatic alcohol, such as pentaerythritol, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, sorbitol, glycerol, polyglycerol, a saccharide, a cyclodextrin, a synthetic polyhydric polymer, or a mixture thereof.
  • the reaction mixture is preferably a reaction mixture of a transesterification reaction of a polyol and a fatty acid, a glycerides, a vegetable oil, a hydrogenated vegetable oil, a sterol, or a mixture thereof.
  • Preferred emulsifiers include phospholipids, such as egg phospholipids, soy phospholipids, phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phophatidylglycerols, phosphatidylinositols, phosphatidic acids, mixed chain phospholipids, lysophospholipids, hydrogenated phospholipids, partially hydrogenated phospholipids, and mixtures thereof.
  • phospholipids such as egg phospholipids, soy phospholipids, phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phophatidylglycerols, phosphatidylinositols, phosphatidic acids, mixed chain phospholipids, lysophospholipids, hydrogenated phospholipids, partially hydrogenated phospholipids, and mixtures thereof.
  • the emulsions of the present invention can also include other additives, such as glycerol, ethanol, propylene glycol, an antioxidant, an antiseptic, a buffering agent, a chelating agent, a colorant, a flavorant, an odorant, an osmotic modifier, a preservative, a solubilizer, a solvent, a tonicifier, a trace element, a viscomodulator, or a mixture thereof.
  • additives such as glycerol, ethanol, propylene glycol, an antioxidant, an antiseptic, a buffering agent, a chelating agent, a colorant, a flavorant, an odorant, an osmotic modifier, a preservative, a solubilizer, a solvent, a tonicifier, a trace element, a viscomodulator, or a mixture thereof.
  • additives such as glycerol, ethanol, propylene glycol, an antioxidant, an antiseptic,
  • the pharmaceutical emulsion includes a polyfunctional active ingredient; / e., an active ingredient having at least some polar functionality.
  • active ingredients can be drugs, cosmeceuticals, nutritional agents, diagnostic agents and the like.
  • the polyfunctional active ingredient is a hydrophilic active ingredient having an octanol/water partition coefficient (i.e., the ratio of its activity in octanol to its activity in water) of less than about 100, preferably less than about 10.
  • the polyfunctional active ingredient is a hydrophobic active ingredient having an intrinsic aqueous solubility of less than about 1 mg/mL, preferably less than about 0.1 mg/mL.
  • salts, isomers, derivatives, and mixtures of polyfunctional active ingredients can also be used.
  • Polyfunctional active ingredients can be, for example, analgesics and anti- inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-asthma agents, antibacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti- epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti- migraine agents, anti-muscarinic agents, anti-neoplastic agents and immunosuppressants, anti-protozoal agents, anti-thyroid agents, anti-tussives, anxiolytic, sedatives, hypnotics and
  • neuroleptics ⁇ -Blockers, cardiac inotropic agents, corticosteroids, diuretics, anti- parkinsonian agents, gastro-intestinal agents, histamine H,-receptor antagonists, keratolytics, lipid regulating agents, muscle relaxants, anti-anginal agents, sex hormones and stimulants,.
  • the polyfunctional active ingredient can also be a cytokine, a peptidomimetic, a protein, a peptide, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid, DNA, RNA, an oligodeoxynucleotide, or an oligonucleotide.
  • Suitable polyfunctional active ingredients include acarbose; acyclovir; acetyl cysteine; acetylcholine chloride; alatrofloxacin; alendronate; alglucerase; amantadine hydrochloride; ambenomium; amifostine; amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human); antihemophilic factor (porcine); antihemophilic factor (recombinant); aprotinin; asparaginase; atenolol; atracurium besylate; atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomycin sulfate; calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate; cefamandole na
  • Suitable polyfunctional active ingredients include tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, acetyl coenzyme Q10, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine, rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz, dicoumarol, tirof ⁇ bran, cilostazol, ticlidopine, clopid
  • Salts, derivatives, isomers and mixtures of polyfunctional active ingredients can also be used.
  • emulsions of the present invention can be produced by methods known in the art for forming emulsions, and examples of particular methods are shown in the Examples herein. It should be understood that formulation factors such as active characteristics, packaging, excipient purity and sourcing, and processing factors, such as sequence or method of excipient/drug addition, energy input, and sterilization cycle factors affect the commercial viability or therapeutic benefit of any given emulsion product.
  • An example of a typical process is as follows: An appropriate amount of the polyfunctional active is dissolved in the desired oil phase containing the appropriate polarity modifier(s) at the desired temperature. To further increase the load of the polyfuctional active or to facilitate the process, the active can be solubilized in an appropriate solvent or mixture of solvents prior to adding active to the oil phase. The solvents used in such processes can then be partially or completely removed, depending on the tolerance of the formulation to the residual solvents. Appropriate polarity modifier can also be added to the solvent along with the active. Alternatively, in the presence of the polarity modifier, the solvent can be removed prior to mixing with the other oil components.
  • the emulsifier such as a phospholipid
  • Chelators or bufferants can also be optionally included to improve stability of the final product.
  • the oil solution is then mixed with an aqueous solution at an appropriate temperature and for a sufficient amount of time to fully emulsify the oil.
  • the mean diameter of the resulting coarse emulsion is preferably less than 20 microns.
  • the resulting mixture is further homogenized at a desired pressure in batch-wise or continuous cycles until the desired particle size is obtained, typically a submicron particle size.
  • high pressure homogcnizers are available for this process, including EmulsiFlex (Avestin), microfluidizer (Microfluidics), and Rannie homogenizer (APV).
  • the resulting emulsion can be further pH adjusted and heat-, filter-, or radiation-sterilized.
  • Preferred emulsions can have a mean particle diameter of less than about 5 ⁇ m, preferably less than about 2 ⁇ m, more preferably less than about 1 ⁇ m, still more preferably less than about 0.5 ⁇ m, and most preferably less than about 0.3. ⁇ m.
  • Particle size can be determined by conventional methods, such as by measurement with a particle size analyzer.
  • the present invention is directed to a pharmaceutical emulsion for delivery of a polyfunctional active ingredient as described above, wherein the oil phase of the emulsion includes a long chain triglyceride, and at least one compound selected from the group consisting of acids, bases, monoglycerides, diglycerides, acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols: sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated al
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides; diglycerides; acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyoi fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; monoglycerides; diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides; diglycerides; acetylated monoglycerides; acetylated diglycerides; cholesterol fatty acid esters; fatty alcohols; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
  • a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides; diglycerides; acetylated monoglycerides; acetylated diglycerides; cholesterol
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; acetylated monoglycerides; acetylated diglycerides; cholesterol fatty acid esters; fatty alcohols; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; monoglycerides; diglycerides; cholesterol fatty acid esters; fatty alcohols; fusidic acids; derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
  • acetylated monoglycerides acetylated diglycerides
  • bile acids cholesterol
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides; diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
  • a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides; diglycerides; bile acids; cholesterol; cholesterol
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
  • bile acids cholesterol
  • cholesterol fatty acid esters fatty acids
  • fatty alcohols fusidic acids
  • lactic acid derivatives of mono/diglycerides lower alcohol fatty acid esters
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride, and at least one compound selected from the group consisting of monoglycerides, diglycerides, mixtures of mono- and diglycerides, and mixtures of mono-, di- and triglycerides.
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride, and at least one compound selected from the group consisting of acetylated monoglycerides, acetylated diglycerides, and mixtures thereof.
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride and a lipophilic reaction mixture, or a purified/fractionated lipophilic reaction mixture, of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of polyethoxylated esters, polyethoxylated alkyl ethers, polyethoxylated sterols, and mixtures thereof.
  • the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described.
  • the composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the present invention is directed to a pharmaceutical emulsion for delivery of a polyfunctional active ingredient as described above, wherein the oil phase of the emulsion includes a water-immiscible triglyceride, and at least one pharmaceutically acceptable acid or pharmaceutically acceptable base.
  • the water- immiscible triglyceride can be a long chain triglyceride or a structured triglyceride, and these and other components of the oil phase and the emulsifier can be any of those previously described.
  • the composition can further include a polarity modifier, a structured triglyceride, a long chain triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
  • the present invention is also directed to dosage forms of any of the pharmaceutical emulsions described herein.
  • the dosage form can be the pharmaceutical emulsion processed by lyophilization, encapsulation, extrusion, homogenization, sonication, melting, solubilizing, evaporation, mixing, coating, size reduction, spraying, sterilization, filtration, irradiation, or a combination thereof. It should be appreciated that the ability of the pharmaceutical composition to be processed by particular processing methods may depend upon the proper choice and sequence of processing steps, as is known to those skilled in the art.
  • the dosage form can be formulated as an injectable, a drink, an eye drop or spray, a nasal drop or spray, a buccal drop or spray, a cervical drop or spray, an inhalant, a lotion, a gel, a liniment, a cream, a paste, a solution, a suppository, an ovule, a wafer, a troche, a sachet, an elixir, a tincture, a douche, an aerosol, a patch, or a combination thereof, and can be adapted for parenteral, enteral, ocular, nasal, sublingual, buccal, topical, intra-cervical, rectal, intramuscular, intra-dermal, pulmonary, transmucosal, intra-thecal, intravenous, intra- arterial, epidural, intra-cavity, intra-organ transdermal, intra-lymphatic, intra-cranular, or intra-tumoral administration, or a combination thereof.
  • Preferred dosage forms
  • the dosage form also includes a polyfunctional active ingredient, although in some circumstances it may be desirable to formulate the polyfunctional active ingredient in a separate dosage form for administration to a patient prior to, concurrently with, or subsequently to, administration of the pharmaceutical emulsion.
  • the dosage form includes a polyfunctional active ingredient
  • the active ingredient can be present in a therapeutically effective amount, as determined by one skilled in the art according to the pharmacological effect of the active ingredient, the needs of the patient, and other considerations well known in the art.
  • part of the therapeutically effective amount of the polyfunctional active ingredient can also be formulated as a separate dosage form.
  • the present invention is directed to methods of treating an animal with a polyfunctional active ingredient.
  • the method includes the steps of administering to the animal a dosage form of a pharmaceutical emulsion, as described above, and a therapeutically effective amount of a polyfunctional active ingredient.
  • the active ingredient can be present in the dosage form of the pharmaceutical emulsion, in a separate dosage form, or both.
  • the polyfunctional active ingredient can be administered to the animal prior to, concurrently with, or subsequent to, administering the dosage form of the pharmaceutical emulsion.
  • the animal is preferably a mammal, and more preferably a human. Suitable emulsions include any of the emulsions described above.
  • the present invention is directed to methods of treating a patiem with a pharmaceutical composition, wherein the composition includes effective amounts of an oil phase and an emulsifier.
  • the amounts and components of the oil phase and emulsifier are effective to minimize drug precipitation upon administration, irritation and local toxicity at the site of administration; to alter drug biodistribution and clearance; and to minimize systemic drug toxicity, multi-drug resistance, intra-subject performance variability and/or inter-subject performance variability.
  • compositions and methods of the present invention provide significant advantages over conventional formulations of polyfunctional active ingredients. These advantages include:
  • compositions are free of toxic hydrophilic polyethoxylated surfactants, such as Cremophors® and Tweens®, that are traditionally used in parenteral formulations of polyfunctional hydrophobic active ingredients.
  • toxic hydrophilic polyethoxylated surfactants such as Cremophors® and Tweens®
  • Cremophors® and Tweens® are traditionally used in parenteral formulations of polyfunctional hydrophobic active ingredients.
  • the present emulsion formulations can alleviate irritation, thrombophlebitis, and necrosis of local tissue at the injection site.
  • these emulsion formulations are believed to reduce the irritation and necrosis of local tissue at the injection site caused by the direct contact with the irritating/cytotoxic actives by encapsulating the actives inside the oil phase.
  • encapsulation in emulsion droplets enables the active to overcome this limitation.
  • Polarity modifiers such as mono- and diglycerides, especially of longer chain fatty acids, are expected to be less "leaky” from the oil particles upon injection, or less prone to rapid debinding/desorption from the lipoprotein blood fraction, due to the high hydrophobicity. Thus, these additives have lower free monomer activity in the blood, leading to superior bioacceptability of additives relative to high HLB surfactants.
  • MCT-based emulsions must be stored in glass containers and administered through specialized infusion equipment and devices. MCT-free or reduced chain emulsions have the benefits of lowering the manufacturing cost and reducing the potential hazards to patients and to the environment.
  • bile salts such as cholate and deoxycholate
  • surface active bile salts can orient themselves at the oil-water interface in such a way as to fix the structural defects on the interfacial membrane primarily composed of phospholipids, or can interact with the phospholipids, thus preventing the dissociation of phospholipids from the interface.
  • the stability of the emulsion also can be improved by charge repulsion imparted by the incorporation of appropriate charged or charge-inducing emulsifiers or polarity modifiers to the emulsion formulation.
  • a negatively charged phospholipid such as DMPG
  • DMPG can decrease the zeta potential of the emulsion particles (or increase the surface charge) to about -30 to -60 mV, which would provide significant repulsion forces to prevent the emulsion particles from agglomeration, fusion, etc.
  • polyethoxylated surfactants, amphiphilic synthetic polymers and certain amphiphilic proteins/peptides can form shields surrounding emulsion particles to prevent the close contact of two or more particles through steric hindrance. The enormous van der Waals forces will repel particles when the shields of different particles are approaching to a close distance.
  • the stability of the active can potentially be improved.
  • the oil droplets would shield the actives from the outside aqueous environment.
  • the polyfunctional active formulated in the present emulsions should enjoy better stability upon storage compared to those in a cosolvent system, for example.
  • the emulsion oil droplets can potentially protect the active from enzymatic attack by making the active less accessible to enzymes such as esterase, peptidase, nuclease, etc.
  • the emulsions composition of the present invention through the unique combination of the polarity modifiers as well as the emulsifiers, possess unique size, surface, and polarity characteristics to alter the biodistribution and clearance of the emulsion particles as well as the pharmacokinetic and pharmacological profile of the polyfunctional actives either incorporated in the emulsion formulation or co-administered with the emulsion.
  • These altered characteristics of the actives and the emulsion oil droplets are potentially useful in targeting the actives to a variety of cells, tissue, and organs.
  • Such compositions can be injected directly to a target organ or a tumor to improve the therapeutic performance of the active.
  • hydrophobic polyfunctional actives to blood components such as erythrocytes, lymphocytes, platelet, and plasma proteins
  • blood components such as erythrocytes, lymphocytes, platelet, and plasma proteins
  • albumin, ⁇ -acid glycoprotein, lipoproteins, etc. can be modulated by the interaction of the polarity modifiers as well as the emulsifiers with the blood components or the drugs themselves. Targeted, more favorable binding to the lipoprotein fraction results in an altered biodistribution and clearance. More selective binding to specific fractions, such as high density lipoprotein, can potentially reduce toxicity and reduce variability in patients with varying cholesterol levels.
  • hydrophilic polyfunctional actives including conventional anti- infectives, peptides, and oligonucleotides
  • the emulsion formulations of the present invention can further include a ligand or receptor on the surface of the emulsion particles to promote more specific recognition between the emulsion particles and the intended sites for targeted delivery.
  • a ligand or receptor on the surface of the emulsion particles to promote more specific recognition between the emulsion particles and the intended sites for targeted delivery.
  • an antibody can be grafted to the surface of the emulsion particles to specifically l target cancerous cells expressing particular antigens recognized by the antibody. Through such antibody-antigen interaction, a given anticancer drug can be more effectively delivered to the site of action by the emulsion formulation to alleviate potential dose-limiting systemic toxicity.
  • the present compositions provide another needed administration option, the parenteral route, to the current therapeutic choices.
  • azole antifungal agents with systemic efficacy currently do not have a parenteral product available.
  • Such polyfunctional actives can be effectively formulated in parenteral dosage forms of the pharmaceutical emulsions of the present invention for therapeutic benefit or bioavailability assessment in product development.
  • 1 Better calorie control, such as in applications when faster energy production is needed in critically ill patients.
  • the present compositions offer faster energy production than plain long chain triglycerides, but slower than medium chain triglycerides, which could be unsafe in some situations.
  • emulsions provide benefits by incorporating the active ingredient into the oil phase, thus lowering its activity in the aqueous phase coming into contact with the palate.
  • Example 1 Cyclosporin Emulsion I An emulsion according to the present invention was prepared, with cyclosporin A as the polyfunctional active ingredient dissolved in an oil phase including a structured triglyceride (Captex 810D) and a long chain triglyceride (safflower oil).
  • the emulsion had the following components:
  • the emulsion was prepared as follows. Captex 810D and safflower oil were mixed to form a homogeneous oil. Cyclosporin A and BHT were added to the oil and dissolved at room temperature. Egg phospholipid and DMPG were added to the oil mixture and dispersed in the oil phase. The oil phase was heated to 60°-70°C, then added to an aqueous phase of water, glycerol and EDTA. The mixture was then mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession.
  • IKA UltraTurrax homogenizer
  • Example 2 Cyclosporin Emulsion II An emulsion according to the present invention was prepared, with cyclosporin A as the polyfunctional active ingredient dissolved in an oil phase including a structured triglyceride (Captex 810D) and polarity modifiers (monoglycerides and acetylated monoglycerides).
  • the emulsion had the following components:
  • the emulsion was prepared as follows. Captex 810D, Eastman 9-45 and Peceol were mixed to form a homogeneous oil. Cyclosporin A was added to the oil and dissolved at room temperature. Egg phospholipid was added to the oil mixture and dispersed in the oil phase. The oil phase was heated to 60°-70°C, then added to an aqueous phase of water, glycerol and EDTA. The mixture was then mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession.
  • IKA UltraTurrax homogenizer
  • Example 3 Cyclosporin Emulsion III An emulsion according to the present invention was prepared, with cyclosporin A as the polyfunctional active ingredient dissolved in an oil phase including a long chain triglyceride (safflower oil) and a polarity modifier (acetylated monoglycerides).
  • the emulsion had the following components:
  • the emulsion was prepared as follows. Safflower oil and Eastman 9-45 were mixed to form a homogeneous oil. Cyclosporin A and BHT were added to the oil and dissolved at room temperature. Egg phospholipid was dispersed in an aqueous phase containing water, glycerol ⁇ and EDTA. Both the oil phase and the aqueous phase were heate ⁇ 0t ⁇ -60°-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession.
  • a microfluidizer Microfluidics
  • Example 4 Progesterone Emulsion I An emulsion according to the present invention was prepared, with progesterone as the polyfunctional active ingredient dissolved in an oil phase including a long chain triglyceride (soybean oil) and polarity modifiers (monoglycerides and acetylated monoglycerides).
  • the emulsion had the following components:
  • the emulsion was prepared as follows. Soybean oil, Eastman 9-45 and Peceol were mixed to form a homogeneous oil. Progesterone and BHT were added to the oil and dissolved at room temperature. Egg phospholipid was added to the oil mixture ana dispersed in the oil phase. The oil mixture was heated to 60°C-70°C, then added to an aqueous phase containing water, glycerol and EDTA. The mixture was mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 200 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.).
  • Example 5 Progesterone Emulsion II An emulsion according to the present invention was prepared, with progesterone as the polyfunctional active ingredient dissolved in an oil phase including a structured triglyceride (Captex 810D), a long chain triglyceride (glycerol trioleate), and a polarity modifier (mono-,diglyceride mixture).
  • the emulsion had the following components:
  • the emulsion was prepared as follows. Captex 810D, Captex GTO and Capmul MCM were mixed to form a homogeneous oil. Progesterone and BHT were added to the oil and dissolved at room temperature. Egg phospholipid and DMPG were dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 150 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.).
  • Example 6 Tretinoin Emulsion I An emulsion according to the present invention was prepared, with tretinoin as the polyfunctional active ingredient dissolved in an oil phase including a long chain triglyceride (safflower oil), an oil-miscible base (triethylamine) and polarity modifiers (acetylated monoglycerides and a mono-,diglyceride mixture).
  • tretinoin as the polyfunctional active ingredient dissolved in an oil phase including a long chain triglyceride (safflower oil), an oil-miscible base (triethylamine) and polarity modifiers (acetylated monoglycerides and a mono-,diglyceride mixture).
  • the emulsion had the following components:
  • the emulsion was prepared as follows. Safflower oil, triethylamine, Eastman 9-45 and Imwitor 988 were mixed to form a homogeneous oil. Tretinoin and BHT were added to the oil and dissolved at room temperature. Egg phospholipid was dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer
  • the resulting emulsion had a mean particle diameter of less than 100 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.).
  • Example 2 was repeated, but after combining the oil and aqueous phases, the mixture was sonicated at room temperature using a Branson sonifier. The pooled sonified material was then high pressure homogenized as previously described. The resulting emulsion had mean particle diameter of less than 80 nm.
  • Example 7 Tretinoin Emulsion II An emulsion according to the present invention was prepared, with tretinoin as the polyfunctional active ingredient dissolved in an oil phase including a structured triglyceride (Captex 810D), an oil-miscible base (triethylamine) and polarity modifiers (monoglycerides and a mono-,diglyceride mixture).
  • the emulsion had the following components: Component % (w/w)
  • the emulsion was prepared as follows. Captex 810D, triethylamine, Peceol and Capmul MCM were mixed to form a homogeneous oil. Tretinoin and BHT were added to the oil and dissolved at room temperature. Egg phospholipid was dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer
  • Example 8 Ketoconazole Emulsion An emulsion according to the present invention can be prepared, with ketoconazole as the polyfunctional active ingredient dissolved in an oil phase including a long chain triglyceride (soybean oil), an oil-miscible acid (oleic acid) and a polarity modifier (acetylated monoglycerides).
  • a suitable emulsion can have the following components:
  • the emulsion can be prepared as follows. Soybean oil, oleic acid and Eastman 9-45 are mixed to form a homogeneous oil. Ketoconazole and BHT are added to the oil and dissolved at room temperature. Egg phospholipid is dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase are heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture is further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. Examples 9-14 illustrate pharmaceutical emulsions according to the present invention which do not contain an active ingredient. These emulsions are suitable for delivery of a wide variety of polyfunctional active ingredients, as described herein.
  • Example 9 Drug-Free Emulsion I
  • An emulsion according to the present invention was prepared with an oil phase including a structured triglyceride (Captex 810D), a long chain triglyceride (soybean oil), and a polarity modifier (low HLB polyethoxylated vegetable oil).
  • the emulsion had the following components:
  • the emulsion was prepared as follows. Captex 810D, soybean oil and Labrafil M2125 CS were mixed to form a homogeneous oil. Egg phospholipid was dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were healed to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 150 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.).
  • Example 10 Drug-Free Emulsion II An emulsion according to the present invention was prepared with an oil phase including a structured triglyceride (Captex 810D), a long chain triglyceride (safflower oil), and a polarity modifier (propylene glycol fatty acid esters).
  • the emulsion had the following components:
  • the emulsion was prepared as follows. Captex 810D, safflower oil and Lauroglycol FCC were mixed to form a homogeneous oil. Egg phospholipid was dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated IO 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession.
  • a microfluidizer Microfluidics
  • Example 11 Drug-Free Emulsion III An emulsion according to the present invention was prepared with an oil phase including a long chain triglyceride (safflower oil), and a polarity modifier (polyglycerized fatty acid esters). The emulsion had the following components:
  • the emulsion was prepared as follows. Safflower oil and Plurol Oleique CC497 were mixed to form a homogeneous oil. Egg phospholipid and DMPG were dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession.
  • a microfluidizer Microfluidics
  • Example 12 Drug-Free Emulsion IV An emulsion according to the present invention was prepared with an oil phase including a long chain triglyceride (soybean oil) and a polarity modifier (low HLB polyethoxylated fatty acid esters). The emulsion had the following components:
  • the emulsion was prepared as follows. Soybean oil and Kessco PEG 400 DO were mixed to form a homogeneous oil. Egg phospholipid was dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer
  • the resulting emulsion had a mean particle diameter of less than 100 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.).
  • Example 13 Drug-Free Emulsion V An emulsion according to the present invention was prepared with an oil phase including a structured triglyceride (Captex 810D) and a polarity modifier (mixture of mono- ,di- and triglycerides).
  • the emulsion had the following components: Component % (w/w)
  • the emulsion was be prepared as follows. Captex 810D and Maisine 35-1 were mixed to form a homogeneous oil. Egg phospholipid and DMPG were dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession.
  • IKA UltraTurrax homogenizer
  • Example 14 Drug-Free Emulsion VI
  • An emulsion according to the present invention can be prepared with an oil phase including a structured triglyceride (Captex 810D), a long chain triglyceride (safflower oil) and an oil-dispersible acid (deoxycholic acid).
  • the emulsion can have the following components: Component % (w/w)
  • the emulsion can be prepared as follows. Captex .810D, safflower oil and deoxycholic acid are mixed to form a homogeneous oil. Egg phospholipid is dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase are heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture is further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession.
  • a microfluidizer Microfluidics

Abstract

The present invention provides pharmaceutical oil-in-water emulsions for delivery of polyfunctional active ingredients. The emulsions include an aqueous phase, an emulsifier, and an oil phase, wherein the oil phase includes a structured triglyceride that is substantially free of triglycerides having three C6-C12 fatty acid moieties, or a combination of a long chain triglyceride and a polarity-enhancing polarity modifier. The present invention also provides methods of treating an animal with a polyfunctional active ingredient, using dosage forms of the pharmaceutical emulsions.

Description

EMULSION COMPOSITIONS FOR POLYFUNCTIONAL ACTIVE INGREDIENTS
FIELD OF THE INVENTION The present invention relates to pharmaceutical delivery systems, and in particular to oil-in-water pharmaceutical emulsions for the improved delivery of polyfunctional active ingredients, such as pharmaceuticals, cosmeceuticals, nutritive agents, and diagnostic agents. BACKGROUND Polyfunctional active ingredients, i.e., active ingredients having at least some polar functionality, present difficult problems in formulating such compounds for effective administration to patients. A well-designed formulation should, at a minimum, be capable of presenting a therapeutically effective amount of the polyfunctional compound to the desired site of action, in a bioavailable form. Particularly when the polyfunctional active ingredient is hydrophobic, this minimal functionality has proven difficult to achieve. Delivery of a polyfunctional hydrophobic active ingredient requires interaction with aqueous physiological environments, such as blood, gastric fluids and intestinal fluids. Pharmaceutical compositions for delivery of such polyfunctional hydrophobic active ingredients should preferably carry the active ingredient through the aqueous environment, while maintaining the active ingredient compound in a bioavailable form, and avoiding or substantially reducing the use of physiologically harmful solvents or excipients. A number of approaches to formulating polyfunctional hydrophobic active ingredients for oral or parenteral delivery are known. Several commercial formulations are available for parenteral dosage forms of polyfunctional active ingredients, based on organic cosolvent and/or synthetic surfactant solvent systems. For example, cyclosporin A (SANDIMMUNE®), paclitaxel (TAXOL®) and etoposide (VePesid®) are all commercially available in injectable dosage forms containing organic solvents and/or synthetic hydrophilic surfactants. See, Physician 's Desk Reference, Medical Economics Co. (1999).
Solvent/hydrophilic surfactant formulations, however, suffer from a number of serious disadvantages. Hydrophilic polyethoxylated surfactants commonly used in such formulations, such as Cremophor® and Tween®, have a high toxicity potential. Pain at the injection site, thrombophlebitis, tissue necrosis and hypersensitivity reactions are commonly observed side effects of such formulations. Cremophor EL, for example, currently used in parenteral formulations of cyclosporin, paclitaxel and teniposide, has been found to be associated with severe anaphylactic/hypersensitive reactions. Cremophor EL has also been implicated at least partially responsible in the most significant side effect of cyclosporin concentrate for injection, acute nephrotoxicity. Besides being irritating and hemolytic, such formulations are potentially subject to active precipitation during storage, upon admixing prior to administration, or upon parenteral administration, leading to further safety challenges. In addition, some hydrophilic polyethoxylated surfactants, such as Cremophor EL, cause phthalate stripping and are incompatible with commonly used plasticized PVC infusion devices.
As an alternative to hydrophilic surfactant/cosolvent systems, oil-in-water ("o/w") emulsion formulations have been used in polyfunctional hydrophobic active ingredient delivery. These formulations typically contain a long chain triglyceride oil phase dispersed in water and stabilized by an emulsifier layer of a phosphatide, such as soy or egg lecithin. Propofol, for example, is available commercially as Diprivan®, an o/w emulsion formulation using long chain triglycerides contained in vegetable oils, and an emulsifying agent. While such formulations may overcome some of the safety liabilities of hydrophilic surfactant/solvent based systems, the oil component may not be appropriately polar to effectively incorporate polyfunctional active ingredients at desirable therapeutic levels, without compromising product safety.
In an attempt to improve drug loading capacity in emulsions, some approaches incorporate additional stabilizers, or include undesirably high levels of compounds which hydrolyze to form medium chain fatty acids. Such approaches, however, present problems in processing, stability, and safety.
Several formulations have been developed based on medium chain triglyceride ("MCT") oil phases, rather than (or in addition to) the more traditional long chain triglyceride ("LCT") oil phases. U.S. Patent No. 5,660,858 to Parikh et al. discloses cyclosporin oil-in-water emulsions with a synthetic MCT having predominantly C8-C12 fatty acid chains. U.S. Patent No. 5,364,632 to Benita et al. discloses an oil-in-water emulsion of a lipophilic drug having an MCT oil carrier and a combination of ionic and non-ionic surfactants.
Reportedly, such formulations enable better solubilization of polyfunctional active ingredients, compared to the less polar long chain triglycerides. See, e.g., Velazquez et al., "The scientific rationale and clinical application of short-chain fatty acids and medium-chain triglycerides," Proceedings of the Nutrition Society, 55:49-78 (1996). However, the presence of predominantly medium chain (i.e., having fatty acids with carbon chain lengths of six to ten carbon atoms) triglycerides of higher polarity in the oil phase presents significant safety and stability issues that could limit the shelf live of MCT-based formulations, or place safety limits on the infusion rate. See, Velazquez et al., ibid, and Van de Velde et al., "Comparative hemodynamic effects of three different parenterally administered lipid emulsions in conscious dogs," Crit. Care Med., 26:132-137 (1998). The adverse effects of parenteral MCT-based emulsions reported in animals include poor growth and nitrogen balance, and increased energy expenditure. Some reports have indicated that medium chain triglycerides may not spare protein catabolism as well as do long chain triglycerides. More importantly, MCT-based emulsions do not seem to be well- tolerated by patients. Moderate to severe side effects have been reported, such as neurotoxicity, emesis, somnolence, coma, narcosis, essential fatty acid deficiency, and ketosis in susceptible patients. Since physical mixing of MCTs and LCTs does not alter the subsequent clearance kinetics, the corresponding triacyl glycerols are cleared from the blood and oxidized unaffected in the mixture. As a result, very rapid hydrolysis of MCTs and rapid uptake of the medium chain fatty acid hydrolysis products have been observed even in a one-to-one mixture of MCTs and LCTs administered parenterally. Some of the reported side effects have been attributed to uncoupling of oxidative phosphorylation resulting from the uncontrolled entry of medium chain fatty acids into the mitochondria, due to the rapid hydrolysis of MCTs.
As a specific example, caprylic acid, the hydrolysis product of an MCT containing the caprylic acid ester moiety, has been demonstrated to have neurological side effects. Caprylic acid infusion simultaneously produced alterations in the sodium-potassium- adenosinetriphosphatase activity in brain tissue, and resulted in hyperventilation, coma, seizure, hypotonia and electroencaphalographic changes in rabbits. (Velazquez et al., Proceedings of the Nutrition Society, 55:49-78 (1996)). These events coincide with hemodynamic events, such as a decrease in cardiac output, stroke volume, and myocardial wall-thickening fraction, and an increase in aortic blood pressure and systemic vascular resistance when an MCT/LCT mixture is infused parentally in dogs. (Van de Velde et al., Crit. Care Med., 26:132-137 (1998)). Thus, medium chain triglycerides and medium-chain- containing additives, such as medium chain mono- or diglycerides, which hydrolyze to medium chain fatty acids, present potentially severe safety problems in pharmaceutical emulsions.
Thus, there is a need for safe and effective pharmaceutical formulations of polyfunctional active ingredients that do not suffer from the foregoing disadvantages.
SUMMARY OF THE INVENTION
It is an object of the invention to provide pharmaceutical delivery systems capable of delivering polyfunctional active ingredients.
It is another object of the invention to provide pharmaceutical emulsions for delivery of polyfunctional active ingredients with improved loading capacity.
It is another. objecLof the invention to provide pharmaceutical emulsions for delivery of polyfunctional active ingredients that are substantially free of toxic hydrophilic surfactants.
It is another object of the invention to provide pharmaceutical emulsions for delivery of polyfunctional active ingredients which reduce irritation and local toxicity at the site of administration.
It is another object of the invention to provide pharmaceutical emulsions for delivery of polyfunctional active ingredients which overcome drug precipitation upon administration.
It is another object of the invention to provide pharmaceutical emulsions for delivery of polyfunctional active ingredients with fewer side effects associated with medium chain triglycerides or their hydrolysis products.
It is another object of the invention to provide pharmaceutical emulsions for delivery of polyfunctional active ingredients with enhanced stability. It is another object of the invention to provide safer and more effective methods of treatment with polyfunctional active ingredients.
In accordance with these and other objects, the present invention provides pharmaceutical emulsions and methods utilizing the emulsions, to provide improved delivery of polyfunctional active ingredients. The pharmaceutical emulsions of the present invention include an aqueous phase, an oil phase, and an emulsifier, wherein the oil phase includes components chosen to increase the polarity of the oil phase, without introducing into the emulsion excessive amounts of organic solvents, hydrophilic surfactants, or compounds which include or hydrolyze to form medium chain fatty acids.
In one embodiment, the present invention provides a pharmaceutical emulsion for delivery of a polyfunctional active ingredient, the emulsion including an aqueous phase, an emulsifier, and a polar oil phase containing one or more structured triglycerides. The structured triglyceride can include both medium and long chain fatty acids, and is preferably free of triglycerides having three medium chain fatty acid moieties. Optionally, the composition can include additional components, such as a polyfunctional active ingredient, a long chain triglyceride, a polarity modifier, ingredients to facilitate formulation stability and patient acceptability, and processing aids.
In another embodiment, the present invention provides a pharmaceutical emulsion for delivery of a polyfunctional active ingredient, the emulsion including an aqueous phase, an emulsifier, and an oil phase containing a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides, acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; and polyethoxylated sterols. Optionally, the composition can include additional components, such as a polyfunctional active ingredient, a structured triglyceride, a mono- or diglyceride, an acid or base, ingredients to facilitate formulation stability and patient acceptability, and processing aids.
In another embodiment, the present invention provides a pharmaceutical emulsion for delivery of a polyfunctional active ingredient, the emulsion including an aqueous phase, an emulsifier, and an oil phase containing a long chain triglyceride and a monoglyceride, a diglyceride, a mixture of mono- and diglycerides, or a mixture of mono-, di- and triglycerides. Optionally, the composition can include additional components, such as a polyfunctional active ingredient, a structured triglyceride, a polarity modifier, ingredients to facilitate formulation stability and patient acceptability, and processing aids.
In another embodiment, the present invention provides a pharmaceutical emulsion for delivery of a polyfunctional active ingredient, the emulsion including an aqueous phase, an emulsifier, and an oil phase containing a long chain triglyceride and an acetylated monoglyceride, an acetylated diglyceride, or a mixture thereof. Optionally, the composition can include additional components, such as a polyfunctional active ingredient, a structured triglyceride, a polarity modifier, ingredients to facilitate formulation stability and patient acceptability, and processing aids.
In another embodiment, the present invention provides dosage forms of the pharmaceutical emulsions. In another aspect, the present invention relates to methods of using the pharmaceutical emulsions to treat patients with a polyfunctional active ingredient.
In another aspect, the present invention relates to methods of treating a patient with a pharmaceutical composition, wherein the composition includes effective amounts of an oil phase and an emulsifier. The amounts and components of the oil phase and emulsifier are effective to minimize drug precipitation upon administration, irritation and local toxicity at the site of administration; to alter drug biodistribution and clearance; and to minimize systemic drug toxicity, multi-drug resistance, intra-subject performance variability and/or inter-subject performance variability.
These and other objects and features of the present invention will become more fully apparent from the following description and appended claims, or may be learned by the practice of the invention as set forth hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides pharmaceutical emulsions and methods utilizing the emulsions, to provide improved delivery of polyfunctional active ingredients, particularly hydrophobic polyfunctional active ingredients. Unlike conventional formulations, the pharmaceutical emulsions of the present invention achieve effective and stable solubilization of the polyfunctional active ingredient without excessive amounts of organic solvents, hydrophilic synthetic surfactants, or medium chain fatty acid containing compounds, such as medium chain triglycerides. The pharmaceutical emulsions of the present invention include an aqueous phase, an oil phase, and an emulsifier, wherein the oil phase includes safe and effective components chosen to increase the polarity of the oil phase, while maintaining formulation safety and stability. In one embodiment, the oil phase includes a structured triglyceride. The term "structured triglyceride" as used herein means a triglyceride, or a mixture of triglycerides, of synthetic or natural origin, having a fatty acid chain composition including both medium chain fatty acids and long chain fatty acids. Conventional oils, such as vegetable oils, are primarily composed of triglycerides of long chain fatty acids. In contrast, MCT oils are synthetic oils primarily composed of triglycerides of Cs-Cio fatty acids. As used herein, the term "medium chain fatty acid" means a saturated or unsarurated fatty acid having a carbon chain length of 6 to 12 carbon atoms, whereas the term "long chain fatty acid" means a saturated or unsaturated fatty acid having a carbon chain length of greater than 12 carbon atoms. Typical long chain and medium chain triglycerides can be characterized by their fatty acid content, reported in one literature source as follows:
Fatty Acid Soybean Oil Safflower Oil MCT Oil
C6 < 2%
C8 70%
CIO 30%
C12 < 2%
C14 0.1 % 0.1%
C16 10.5% 6.7%
C18 88.5% 93.1%
C20 1.1% 1.0%
(Babayan, Lipids, 22(6):417-420 (1987); different degrees of saturation combined).
In contrast to both medium chain and long chain triglycerides, structured triglycerides include both medium chain and long chain fatty acid groups. Structured triglycerides are typically synthetically produced, and are typically a mixture of triglycerides having predominantly medium and long chain fatty acid groups. An example of commercially available structured triglycerides is the Captex 810 series (Abitec), which is reported to have the following fatty acid distribution:
Fatty Acid Chain 810A 810B 810C 810D Distribution
3 medium 62 39 15 3
2 medium 32 43 40 20 1 long
1 medium 6 16 27 44
2 long
3 long < 1 2 3 34
(Babayan, ibid.) In order to avoid the adverse effects of MCT oils and their hydrolysis products, preferably the structured triglyceride does not contain significant amounts of triglycerides having three medium chain fatty acid groups. Thus, preferred structured triglycerides are those which are substantially free of MCTs, such as Captex 810D. Alternatively, fractions of Captex 810A or similar compositions which are substantially free of triglycerides having three medium chain fatty acid groups, obtained by appropriate procedures, are also suitable for use in the emulsion compositions of the present invention.
Structured triglycerides can be produced by various methods known in the art, including hydrolysis and esterification; interesterification; traditional chemical reaction sequences; lipase interesterification; genetic manipulation; or other methods, as appropriate.
Mixtures of long chain triglycerides and structured triglycerides are also within the scope of the present invention. In this embodiment, the oil phase can further include one or more oils having long chain triglycerides, such as vegetable oils, fish oils, animal fats, hydrogenated vegetable oils, partially hydrogenated vegetable oils, semi-synthetic triglycerides, synthetic triglycerides, or mixtures thereof. Fractionated, refined or purified oils of these types can also be used. Specific examples of suitable long chain triglyceride-containing oils suitable for use in the compositions of the present invention include almond oil; babassu oil; borage oil; black currant seed oil; canola oil; castor oil; coconut oil; corn oil; cottonseed oil; emu oil; evening primrose oil; flax seed oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; a mixture of hydrogenated cottonseed oil and hydrogenated castor oil; partially hydrogenated soybean oil; a mixture of partially hydrogenated soybean oil and partially hydrogenated cottonseed oil; glyceryl
trioleate; glyceryl trilinoleate; glyceryl trilinolenate; a Ω3 polyunsaturated fatty acid
triglyceride containing oil; and mixtures thereof.
Preferred long chain triglyceride containing oils include coconut oil; corn oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; hydrogenated coconut oil; partially hydrogenated soybean oil; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; a Ω3 polyunsaturated fatty acid triglyceride containing
oil; and mixtures thereof.
More preferred long chain triglyceride containing oils include corn oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; partially
hydrogenated soybean oil; glyceryl trioleate; glyceryl trilinoleate; a Ω3 polyunsaturated fatty acid triglyceride containing oil; and mixtures thereof.
The oil phase can further include one or more polarity modifiers. Without wishing to be bound by theory, it is believed that these polarity modifiers can act as polarity enhancers, to assist in adjusting the polarity of the oil phase to maximize the beneficial properties of the present emulsions. The polarity modifier is a compound or a mixture of compounds, capable of modifying the interaction between the polyfunctional active ingredient and the oil phase by serving as a bridge to reduce the effects of the gap in polarity between the active ingredient and the oil.
Without wishing to be bound by theory, it is believed that the presence of a polarity modifier in the oil phase creates a more favorable environment for a polyfunctional active ingredient through interaction with the polarity modifier. These interactions may include hydrogen bonds, ion-dipole interactions, ion-induced dipole interactions, electrostatic interactions, and van der Waals forces, including dipole-dipole interactions (also known as Keesom forces), dipole-induced-dipole interactions (also known as Debye forces), and induced dipole-induced dipole interactions (also known as London dispersion forces).
These interactions can be in such a way that the incorporation of the polyfunctional active into the emulsion formulation is facilitated, or the behavior of the active upon administration is augmented in the presence of the emulsion formulation.
Suitable polarity modifiers include acids; bases; monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
Other suitable polarity modifiers include lipophilic reaction mixtures, or purified/fractionated lipophilic reaction mixtures, of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, or sterols. The glyceride can be a monoglyceride, a diglyceride, a triglyceride, or a mixture thereof. It will be apparent to those skilled in the art that the term "lipophilic" means those members of the foregoing groups or classes of compounds which have significant solubility in oily solvents, and poor solubility in aqueous solvents. For compounds that can be characterized by a hydrophilic-lipophilic balance ("HLB") number, such as non-ionic compounds, lipophilic compounds are generally those having an HLB value of less than about 10.
A preferred lipophilic reaction mixture is the reaction mixture of a transesterification reaction of a polyol and a fatty acid, a glyceride, a vegetable oil, a hydrogenated vegetable oil, a sterol, or a mixture thereof.
Preferred lipophilic reaction mixtures are those in which the polyol reactant is a polyhydric aliphatic alcohol, such as pentaerythritol, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, sorbitol, glycerol, polyglycerol, a saccharide, a cyclodextrin, a synthetic polyhydric polymer, or a mixture thereof.
Preferred polarity modifiers include monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; acetylated monoglycerides; acetylated diglycerides; cholesterol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; lipophilic reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
Particularly preferred polarity modifiers are monoglycerides, diglycerides, mixtures of mono- and diglycerides. The monoglycerides and diglycerides preferably have fatty acids with carbon chain lengths of greater than 10 carbon atoms. Also particularly preferred are acetylated monoglycerides, acetylated diglycerides, and mixtures thereof.
Other particularly preferred polarity modifiers include sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
Still other preferred polarity modifiers include polyethoxylated esters, such as polyethoxylated monoglycerides, polyethoxylated diglycerides, polyethoxylated triglycerides, polyethoxylated bile acids, polyethoxylated cholesterol, polyethoxylated fatty acids, polyethoxylated propylene glycol esters, polyethoxylated vegetable oils, polyethoxylated hydrogenated vegetable oils, polyethoxylated sorbitan fatty acid esters, and mixtures thereof.
Suitable acids and bases are pharmaceutically acceptable acids and bases, preferably those which are oil-miscible, or which can interact with the polyfunctional active ingredient to bring the active and/or the acid or base into the oil phase. The acid can be an inorganic acid, an aliphatic acid, an aromatic acid, an acidic salt, or a mixture thereof. Examples of suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, carbonic acid, nitric acid, boric acid, phosphoric acid, acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, an amino acid, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, cinnamic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, hydroxybenzoic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, acidic salts of pharmaceutically acceptable cations and anions, and mixtures thereof.
The base can be an inorganic base, an aliphatic base, an aromatic base, a basic salt, or a mixture thereof. Examples of suitable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide, glucamine and homologs thereof, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, trihydroxyethylamine, triisopropanolamine, basic salts of pharmaceutically acceptable cations and anions, and mixtures thereof.
The optional acids and bases can be included in amounts sufficient to adjust the pH and/or the osmolality of the emulsion, the solubility of the polyfunctional active ingredient, the kinetic release profile, or other properties of the emulsion, as desired.
In order to fully realize the important safety, stability, and other advantages of the compositions of the present invention, it is preferred that the total amount of fatty acid groups of the oil phase, including free fatty acids and the fatty acid moieties of fatty acid containing compounds, having a carbon chain length of from 6 to 12 carbon atoms, be less than about 50% by weight, preferably less than about 40% by weight, and more preferably less than about 30% by weight, based on the total weight of the fatty acid groups of the oil phase. Similarly, it is preferred that the total amount of fatty acid groups of the oil phase, including free fatty acids and the fatty acid moieties of fatty acid containing compounds, having a carbon chain length of greater than 12 carbon atoms, be greater than about 10% by weight, preferably greater than about 30% by weight, and more preferably greater than about 50% by weight, based on the total weight of the fatty acid groups of the oil phase. 1 The oil phase itself can be up to about 30% of the total weight of the emulsion, more
2 typically up to about 20% of the total weight of the emulsion, and most typically up to about
3 10%) of the total weight of the emulsion.
4 The pharmaceutical emulsions of the present invention also include an emulsifier in
5 an amount sufficient to form an oil in water emulsion. It should be appreciated that the
6 appropriate amount of emulsifier may be different, depending upon whether or not a
7 polyfunctional active ingredient is present in the emulsion, since some active ingredients
8 may have self-emulsifying properties, or may become self-emulsifying after interacting with
9 certain polarity modifiers. The emulsifier stabilizes the emulsion by increasing the
10 mechanical bilayer strength, and/or by charge repulsion and/or steric hindrance
I I modifications. Typically, the emulsifier will be present in an amount of less than about 20%
12 by weight, more typically less than about 10% by weight, based on the total weight of the
13 composition. A suitable emulsifier can be ceramide; a mixed chain phospholipid; a cationic
14 lipid; an oligolipid; a phospholipid; a carnitine; a sphingosine; a sphigomyelin; a glycolipid;
15 a lipoprotein; an apoprotein; an amphiphilic protein/peptide; an amphiphilic synthetic
16 polymer; a bile salt; a fatty acid; a fatty alcohol; a fatty amine; a fatty quaternary ammonium
17 salt; a polyethoxylated fatty acid; a polyethoxylated glyceride; a polyethoxylated
18 phospholipid; a polyethoxylated sorbitan fatty acid ester; a polyethoxylated sterol; a
19 polyethoxylated vegetable oil; a polyethoxylated hydrogenated vegetable oil; a reaction 0 mixture of a polyol and at least one member of the group consisting of fatty acidi,. 1 glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; a sorbitan fatty acid 2 ester; or a mixture thereof. 3 The glyceride of the reaction mixture can be a monoglyceride, a diglyceride, a 4 triglyceride, or a mixture thereof. The polyol of the reaction mixture is preferably a polyhydric aliphatic alcohol, such as pentaerythritol, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, sorbitol, glycerol, polyglycerol, a saccharide, a cyclodextrin, a synthetic polyhydric polymer, or a mixture thereof. The reaction mixture is preferably a reaction mixture of a transesterification reaction of a polyol and a fatty acid, a glycerides, a vegetable oil, a hydrogenated vegetable oil, a sterol, or a mixture thereof.
Preferred emulsifiers include phospholipids, such as egg phospholipids, soy phospholipids, phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phophatidylglycerols, phosphatidylinositols, phosphatidic acids, mixed chain phospholipids, lysophospholipids, hydrogenated phospholipids, partially hydrogenated phospholipids, and mixtures thereof.
The emulsions of the present invention can also include other additives, such as glycerol, ethanol, propylene glycol, an antioxidant, an antiseptic, a buffering agent, a chelating agent, a colorant, a flavorant, an odorant, an osmotic modifier, a preservative, a solubilizer, a solvent, a tonicifier, a trace element, a viscomodulator, or a mixture thereof. Such additional additives can be present in the oil phase, the aqueous phase, or both.
Preferably, the pharmaceutical emulsion includes a polyfunctional active ingredient; / e., an active ingredient having at least some polar functionality. Such active ingredients can be drugs, cosmeceuticals, nutritional agents, diagnostic agents and the like. In one embodiment, the polyfunctional active ingredient is a hydrophilic active ingredient having an octanol/water partition coefficient (i.e., the ratio of its activity in octanol to its activity in water) of less than about 100, preferably less than about 10. In another embodiment, the polyfunctional active ingredient is a hydrophobic active ingredient having an intrinsic aqueous solubility of less than about 1 mg/mL, preferably less than about 0.1 mg/mL. Of course, salts, isomers, derivatives, and mixtures of polyfunctional active ingredients can also be used.
Polyfunctional active ingredients can be, for example, analgesics and anti- inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-asthma agents, antibacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti- epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti- migraine agents, anti-muscarinic agents, anti-neoplastic agents and immunosuppressants, anti-protozoal agents, anti-thyroid agents, anti-tussives, anxiolytic, sedatives, hypnotics and
neuroleptics, β -Blockers, cardiac inotropic agents, corticosteroids, diuretics, anti- parkinsonian agents, gastro-intestinal agents, histamine H,-receptor antagonists, keratolytics, lipid regulating agents, muscle relaxants, anti-anginal agents, sex hormones and stimulants,. The polyfunctional active ingredient can also be a cytokine, a peptidomimetic, a protein, a peptide, a toxoid, a serum, an antibody, a vaccine, a nucleoside, a nucleotide, a portion of genetic material, a nucleic acid, DNA, RNA, an oligodeoxynucleotide, or an oligonucleotide.
Examples of suitable polyfunctional active ingredients include acarbose; acyclovir; acetyl cysteine; acetylcholine chloride; alatrofloxacin; alendronate; alglucerase; amantadine hydrochloride; ambenomium; amifostine; amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human); antihemophilic factor (porcine); antihemophilic factor (recombinant); aprotinin; asparaginase; atenolol; atracurium besylate; atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomycin sulfate; calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate; cefamandole nafate; cefazolin sodium; cefepime hydrochloride; cefixime; cefonicid sodium; cefoperazone; cefotetan disodium; cefotoxime; cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; cephapirin sodium; cholera vaccine; chrionic gonadotropin; cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin and clindamycin derivatives; ciprofloxacin; clondronate; colistimethate sodium; colistin sulfate; cortocotropin; cosyntropin; cromalyn sodium; cytarabine; daltaperin sodium; danaproid; deforoxamine; denileukin diftitox; desmopressin; diatrizoate megluamine and diatrizoate sodium; dicyclomine; didanosine; dirithromycin; dopamine hydrochloride; dornase alpha; doxacurium chloride; doxorubicin; editronate disodium; elanaprilat; enkephalin; enoxacin; enoxaprin sodium; ephedrine; epinephrine; epoetin alpha; erythromycin; esmol hydrochloride; factor IX; famiciclovir; fludarabine; fluoxetine; foscarnet sodium; ganciclovir; granulocyte colony stimulating factor; granulocyte-macrophage stimulating factor; growth hormones- recombinant human; growth hormone- bovine; gentamycin; glucagon; glycopyrolate; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; grepafloxacin; hemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated; Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine; interleukin-2; interleukin-3; insulin- human; insulin lispro; insulin procine; insulin NPH; insulin aspart; insulin glargine; insulin detemir; interferon alpha; interferon beta; ipratropium bromide; isofosfamide; Japanese encephalitis virus vaccine; lamivudine; leucovorin calcium; leuprolide acetate; levofloxacin; lincomycin and lincomycin derivatives; lobucavir; lomefloxacin; loracarbef; mannitol; measles virus vaccine; meningococcal vaccine; menotropins; mephenzolate bromide; mesalmine; methanamine; methotrexate; methscopolamine; metformin hydrochloride; metroprolol; mezocillin sodium; mivacurium chloride; mumps viral vaccine; nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate; neutontin; norfloxacin; octreotide acetate; ofloxacin; olpadronate; oxytocin; pamidronate disodium; pancuronium bromide; paroxetine; pefloxacin; pentamindine isethionate; pentostatin; pentoxifylline; periciclovir; pentagastrin; phentolamine mesylate; phenylalanine; physostigmine salicylate; plague vaccine; piperacillin sodium; platelet derived growth factor-human; pneumococcal vaccine polyvalent; poliovirus vaccine inactivated; poliovirus vaccine live (OPV); polymixin B sulfate; pralidoxine chloride; pramlintide; pregabalin; propofenone; propenthaline bromide; pyridostigmine bromide; rabies vaccine; residronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine; salmetrol xinafoate; sincalide; small pox vaccine; solatol; somatostatin; sparfloxacin; spectinomycin; stavudine; streptokinase; streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate; thiopeta; ticarcillin; tiludronate; timolol; tissue type plasminogen activator; TNFR.Fc; TNK-tPA; trandolapril; trimetrexate gluconate; trospectinomyein; trovafloxacin; tubocurarine chloride; tumor necrosis factor; typhoid vaccine live; urea; urokinase; vancomycin; valaciclovir; valsartan; varicella virus vaccine live; vasopressin and vasopressin derivatives; vecoronium bromide; vinblastin; vincristine; vinorelbine; vitamin B12 ; warfarin sodium; yellow fever vaccine; zalcitabine; zanamavir; zolandronate; and zidovudine.
Additional examples of suitable polyfunctional active ingredients include tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, acetyl coenzyme Q10, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine, rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz, dicoumarol, tirofϊbran, cilostazol, ticlidopine, clopidrogel, oprevelkin, paroxetine, sertraline, venlafaxine, bupropion, clomipramine, miglitol, repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine, vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole, flucanazole, miconazole, lycopene, ketoconazole, metronidazole, griseofulvin, nitrofurantoin, spironolactone, lisinopril, benezepril, nifedipine, nilsolidipine, telmisartan, irbesartan, eposartan, valsartan, candesartan, minoxidil, terzosin, halofantrine, mefloquine, dihydroergotamine, ergotamine, frovatriptan, pizofetin, sumatriptan, zolmitriptan, naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide, ephedrine, toremifene, atovaquone, metronidazole, furazolidone, paricalcitol, benzonatate, midazolam, zolpidem, gabapentin, zopiclone, digoxin, beclomethsone, budesonide, betamethasone, prednisolone, cisapride, cimetidine, loperamide, famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine, chlo heniramine, acutretin, tazarotene, calciprotiene, calcitriol, targretin, ergocalciferol, cholecalciferol, isotreinoin, tretinoin, calcifεdiol, fenofibrate, probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin, tizanidine, dantrolene, isosorbide dinatrate, a carotene, dihydrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, an essential fatty acid source, codeine, fentanyl, methadone, nalbuphine, pentazocine, clomiphene, danazol, dihydro epiandrosterone, medroxyprogesterone, progesterone, rimexolone, megesterol acetate, osteradiol, finasteride, mefepristone, amphetamine, L-thryroxine, tamsulosin, methoxsalen, tacrine, donepezil, raloxifene, vertoporfϊn, sibutramine and pyridostigmine.
Salts, derivatives, isomers and mixtures of polyfunctional active ingredients can also be used.
The emulsions of the present invention can be produced by methods known in the art for forming emulsions, and examples of particular methods are shown in the Examples herein. It should be understood that formulation factors such as active characteristics, packaging, excipient purity and sourcing, and processing factors, such as sequence or method of excipient/drug addition, energy input, and sterilization cycle factors affect the commercial viability or therapeutic benefit of any given emulsion product.
An example of a typical process is as follows: An appropriate amount of the polyfunctional active is dissolved in the desired oil phase containing the appropriate polarity modifier(s) at the desired temperature. To further increase the load of the polyfuctional active or to facilitate the process, the active can be solubilized in an appropriate solvent or mixture of solvents prior to adding active to the oil phase. The solvents used in such processes can then be partially or completely removed, depending on the tolerance of the formulation to the residual solvents. Appropriate polarity modifier can also be added to the solvent along with the active. Alternatively, in the presence of the polarity modifier, the solvent can be removed prior to mixing with the other oil components. The emulsifier, such as a phospholipid, can be dispersed in the oil phase directly, or it can be dispersed in an aqueous solution of glycerol or other tonicfier, with or without an antioxidant and with or without a preservative at the desired temperature. Chelators or bufferants can also be optionally included to improve stability of the final product.
The oil solution is then mixed with an aqueous solution at an appropriate temperature and for a sufficient amount of time to fully emulsify the oil. The mean diameter of the resulting coarse emulsion is preferably less than 20 microns. The resulting mixture is further homogenized at a desired pressure in batch-wise or continuous cycles until the desired particle size is obtained, typically a submicron particle size. Several high pressure homogcnizers are available for this process, including EmulsiFlex (Avestin), microfluidizer (Microfluidics), and Rannie homogenizer (APV). The resulting emulsion can be further pH adjusted and heat-, filter-, or radiation-sterilized.
Of course, in embodiments which do not include a polyfunctional active ingredient, the same general procedure can be followed, omitting the active.
Preferred emulsions can have a mean particle diameter of less than about 5 μm, preferably less than about 2 μm, more preferably less than about 1 μm, still more preferably less than about 0.5 μm, and most preferably less than about 0.3.μm. Particle size can be determined by conventional methods, such as by measurement with a particle size analyzer.
In another embodiment, the present invention is directed to a pharmaceutical emulsion for delivery of a polyfunctional active ingredient as described above, wherein the oil phase of the emulsion includes a long chain triglyceride, and at least one compound selected from the group consisting of acids, bases, monoglycerides, diglycerides, acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols: sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; and polyethoxylated sterols. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides; diglycerides; acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyoi fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; monoglycerides; diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides; diglycerides; acetylated monoglycerides; acetylated diglycerides; cholesterol fatty acid esters; fatty alcohols; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; acetylated monoglycerides; acetylated diglycerides; cholesterol fatty acid esters; fatty alcohols; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; monoglycerides; diglycerides; cholesterol fatty acid esters; fatty alcohols; fusidic acids; derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides; diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride, and at least one compound selected from the group consisting of monoglycerides, diglycerides, mixtures of mono- and diglycerides, and mixtures of mono-, di- and triglycerides. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride, and at least one compound selected from the group consisting of acetylated monoglycerides, acetylated diglycerides, and mixtures thereof. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride and a lipophilic reaction mixture, or a purified/fractionated lipophilic reaction mixture, of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the oil phase includes a long chain triglyceride and at least one compound selected from the group consisting of polyethoxylated esters, polyethoxylated alkyl ethers, polyethoxylated sterols, and mixtures thereof. In this embodiment, the long chain triglyceride, the other components of the oil phase, and the emulsifier can be any of those previously described. The composition can further include a structured triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
In another embodiment, the present invention is directed to a pharmaceutical emulsion for delivery of a polyfunctional active ingredient as described above, wherein the oil phase of the emulsion includes a water-immiscible triglyceride, and at least one pharmaceutically acceptable acid or pharmaceutically acceptable base. The water- immiscible triglyceride can be a long chain triglyceride or a structured triglyceride, and these and other components of the oil phase and the emulsifier can be any of those previously described. The composition can further include a polarity modifier, a structured triglyceride, a long chain triglyceride, a polyfunctional active ingredient, or any of the other additives described above.
The present invention is also directed to dosage forms of any of the pharmaceutical emulsions described herein. The dosage form can be the pharmaceutical emulsion processed by lyophilization, encapsulation, extrusion, homogenization, sonication, melting, solubilizing, evaporation, mixing, coating, size reduction, spraying, sterilization, filtration, irradiation, or a combination thereof. It should be appreciated that the ability of the pharmaceutical composition to be processed by particular processing methods may depend upon the proper choice and sequence of processing steps, as is known to those skilled in the art.
The dosage form can be formulated as an injectable, a drink, an eye drop or spray, a nasal drop or spray, a buccal drop or spray, a cervical drop or spray, an inhalant, a lotion, a gel, a liniment, a cream, a paste, a solution, a suppository, an ovule, a wafer, a troche, a sachet, an elixir, a tincture, a douche, an aerosol, a patch, or a combination thereof, and can be adapted for parenteral, enteral, ocular, nasal, sublingual, buccal, topical, intra-cervical, rectal, intramuscular, intra-dermal, pulmonary, transmucosal, intra-thecal, intravenous, intra- arterial, epidural, intra-cavity, intra-organ transdermal, intra-lymphatic, intra-cranular, or intra-tumoral administration, or a combination thereof. Preferred dosage forms are those adapted for parenteral and pulmonary administration.
Preferably, the dosage form also includes a polyfunctional active ingredient, although in some circumstances it may be desirable to formulate the polyfunctional active ingredient in a separate dosage form for administration to a patient prior to, concurrently with, or subsequently to, administration of the pharmaceutical emulsion. When the dosage form includes a polyfunctional active ingredient, the active ingredient can be present in a therapeutically effective amount, as determined by one skilled in the art according to the pharmacological effect of the active ingredient, the needs of the patient, and other considerations well known in the art. In addition, part of the therapeutically effective amount of the polyfunctional active ingredient can also be formulated as a separate dosage form.
In another aspect, the present invention is directed to methods of treating an animal with a polyfunctional active ingredient. The method includes the steps of administering to the animal a dosage form of a pharmaceutical emulsion, as described above, and a therapeutically effective amount of a polyfunctional active ingredient. The active ingredient can be present in the dosage form of the pharmaceutical emulsion, in a separate dosage form, or both. The polyfunctional active ingredient can be administered to the animal prior to, concurrently with, or subsequent to, administering the dosage form of the pharmaceutical emulsion. The animal is preferably a mammal, and more preferably a human. Suitable emulsions include any of the emulsions described above.
In another aspect, the present invention is directed to methods of treating a patiem with a pharmaceutical composition, wherein the composition includes effective amounts of an oil phase and an emulsifier. The amounts and components of the oil phase and emulsifier are effective to minimize drug precipitation upon administration, irritation and local toxicity at the site of administration; to alter drug biodistribution and clearance; and to minimize systemic drug toxicity, multi-drug resistance, intra-subject performance variability and/or inter-subject performance variability.
In use, the compositions and methods of the present invention provide significant advantages over conventional formulations of polyfunctional active ingredients. These advantages include:
1. The present compositions are free of toxic hydrophilic polyethoxylated surfactants, such as Cremophors® and Tweens®, that are traditionally used in parenteral formulations of polyfunctional hydrophobic active ingredients. By substantially reducing the need for these toxic surfactants, the present compositions eliminate potentially serious side effects associated with polyethoxylated surfactants, including potential hemolytic activity. In addition, compositions free of Cremophor EL also have the advantage of being compatible with plasticized PVC infusion devices.
2. Potential reduction in irritation, thrombophlebitis, and necrosis of local tissue at the injection site. Without wishing to be bound by theory, it is believed that being void of the large amount of surfactants present in the currently commercially available formulations of polyfunctional active ingredients, the present emulsion formulations can alleviate irritation, thrombophlebitis, and necrosis of local tissue at the injection site. In addition, these emulsion formulations are believed to reduce the irritation and necrosis of local tissue at the injection site caused by the direct contact with the irritating/cytotoxic actives by encapsulating the actives inside the oil phase. For hydrophobic or hydrophilic actives that are intrinsically irritating, encapsulation in emulsion droplets enables the active to overcome this limitation.
3. Ease of administration. Current polyethoxylated surfactant-containing formulations require dilution in 0.9% sodium chloride injection or 5% dextrose injection to different extents immediately before intravenous infusion, depending on the concentration of the surfactant present in the formulations. However, for a hydrophilic surfactant-free emulsion formulation, no extra step is expected to dilute the formulation prior to administration, thus potentially reducing costs and eliminating the chance of mistakes inherent in the extra step of dilution.
4. Higher loading capacity for polyfunctional hydrophobic actives than long chain triglyceride-based emulsion formulations, and more stable than medium chain-based emulsions. Structured triglycerides are believed to have a higher solubilizing potential for polyfunctional hydrophobic actives than do long chain triglycerides alone. The presence of shorter chain fatty acid groups makes the structured triglyceride more polar than long chain triglycerides, but not so polar as to negatively affect drug solubility and product stability, as is believed to be the case with medium chain triglycerides. These stable, higher drug loading formulations offer more practical dosing and rates of infusions without undesirable excessive lipid and volume doping in patients. Moreover, higher drug loading present sufficient production, storage, and shipping opportunities.
5. Fewer side effects than MCT-based emulsion formulations. By avoiding the use of medium chain triglycerides, and minimizing the amounts of compounds which can hydrolyze to medium chain fatty acids, the adverse effects observed with parenteral MCT emulsion formulations reported in animal studies can be minimized. In addition, structured triglycerides are known to offer improved protein sparing, weight gain, N balance and hepatic and muscle protein synthesis. Structured triglycerides do not increase energy expenditure as do MCTs, nor do structured triglycerides adversely affect the RES. Presumably, these effects are due to the structured triglycerides having intermediate clearance and oxidation rates, relative to LCTs and MCTS. Since the hydrolysis of structured triglycerides is slower than that of MCTs, it is believed that the adverse hemodynamic effects associated with uncontrolled excess build up of medium chain fatty acid concentrations are eliminated.
6. Safer additives. Polarity modifiers, such as mono- and diglycerides, especially of longer chain fatty acids, are expected to be less "leaky" from the oil particles upon injection, or less prone to rapid debinding/desorption from the lipoprotein blood fraction, due to the high hydrophobicity. Thus, these additives have lower free monomer activity in the blood, leading to superior bioacceptability of additives relative to high HLB surfactants.
7. Compatibility with plasticized PVC-containing packaging material, infusion equipment and devices. Since medium chain triglycerides are stronger solvents for some plasticizers, such as phthalates, MCT-based emulsions must be stored in glass containers and administered through specialized infusion equipment and devices. MCT-free or reduced chain emulsions have the benefits of lowering the manufacturing cost and reducing the potential hazards to patients and to the environment.
8. Greater stability over current emulsion formulations. It has been demonstrated that bile salts, such as cholate and deoxycholate, can improve the stability of oil-in-water emulsions. Presumably, surface active bile salts can orient themselves at the oil-water interface in such a way as to fix the structural defects on the interfacial membrane primarily composed of phospholipids, or can interact with the phospholipids, thus preventing the dissociation of phospholipids from the interface.
The stability of the emulsion also can be improved by charge repulsion imparted by the incorporation of appropriate charged or charge-inducing emulsifiers or polarity modifiers to the emulsion formulation. Typically, a negatively charged phospholipid, such as DMPG, can decrease the zeta potential of the emulsion particles (or increase the surface charge) to about -30 to -60 mV, which would provide significant repulsion forces to prevent the emulsion particles from agglomeration, fusion, etc. Similarly, polyethoxylated surfactants, amphiphilic synthetic polymers and certain amphiphilic proteins/peptides, can form shields surrounding emulsion particles to prevent the close contact of two or more particles through steric hindrance. The enormous van der Waals forces will repel particles when the shields of different particles are approaching to a close distance.
In the case of emulsions which contain a polyfunctional active ingredient, the stability of the active can potentially be improved. For actives are prone to hydrolysis, the oil droplets would shield the actives from the outside aqueous environment. As a result, the polyfunctional active formulated in the present emulsions should enjoy better stability upon storage compared to those in a cosolvent system, for example. For those actives that are prone to enzymatic degradation in a biological milieu upon administration, the emulsion oil droplets can potentially protect the active from enzymatic attack by making the active less accessible to enzymes such as esterase, peptidase, nuclease, etc.
9. More favorable binding. The emulsions composition of the present invention, through the unique combination of the polarity modifiers as well as the emulsifiers, possess unique size, surface, and polarity characteristics to alter the biodistribution and clearance of the emulsion particles as well as the pharmacokinetic and pharmacological profile of the polyfunctional actives either incorporated in the emulsion formulation or co-administered with the emulsion. These altered characteristics of the actives and the emulsion oil droplets are potentially useful in targeting the actives to a variety of cells, tissue, and organs. Such compositions can be injected directly to a target organ or a tumor to improve the therapeutic performance of the active. This can potentially lead to the improvement of efficacies of current indications as well as to the discovery of new indications with existing actives. Since the polyfunctional active can be delivered more effectively to the site of action, the undesirable exposure of the active to other local tissues or systemic circulation could be reduced. This will lead to the reduction of systemic or local toxicity.
For example, the binding profile of hydrophobic polyfunctional actives to blood components such as erythrocytes, lymphocytes, platelet, and plasma proteins including
albumin, α-acid glycoprotein, lipoproteins, etc., can be modulated by the interaction of the polarity modifiers as well as the emulsifiers with the blood components or the drugs themselves. Targeted, more favorable binding to the lipoprotein fraction results in an altered biodistribution and clearance. More selective binding to specific fractions, such as high density lipoprotein, can potentially reduce toxicity and reduce variability in patients with varying cholesterol levels.
Relatively more hydrophilic polyfunctional actives, including conventional anti- infectives, peptides, and oligonucleotides, can be sequestered into the emulsion oil phase a°. a result of the interactions with the polarity modifiers. Consequently, the circulating half- time of typical low-molecular weight water-soluble compounds can frequently be prolonged significantly. This will enable these actives to circulate and accumulate to an effective level at the site of action, such as brain, liver, and sites of inflammation or solid tumors. It is also possible that this will alleviate the toxicity of the active toward organs, such as the kidney and liver, involved in the clearance of the active.
In addition, the emulsion formulations of the present invention can further include a ligand or receptor on the surface of the emulsion particles to promote more specific recognition between the emulsion particles and the intended sites for targeted delivery. For example, an antibody can be grafted to the surface of the emulsion particles to specifically l target cancerous cells expressing particular antigens recognized by the antibody. Through such antibody-antigen interaction, a given anticancer drug can be more effectively delivered to the site of action by the emulsion formulation to alleviate potential dose-limiting systemic toxicity.
5 10. Parenteral formulations. The present compositions provide another needed administration option, the parenteral route, to the current therapeutic choices. For example, azole antifungal agents with systemic efficacy currently do not have a parenteral product available. Such polyfunctional actives can be effectively formulated in parenteral dosage forms of the pharmaceutical emulsions of the present invention for therapeutic benefit or bioavailability assessment in product development. 1 11. Better calorie control, such as in applications when faster energy production is needed in critically ill patients. The present compositions offer faster energy production than plain long chain triglycerides, but slower than medium chain triglycerides, which could be unsafe in some situations.
12. Taste masking. For delivery of unpalatable active ingredients, emulsions provide benefits by incorporating the active ingredient into the oil phase, thus lowering its activity in the aqueous phase coming into contact with the palate.
13. Benefits in delivery, storage and dosing. Unlike solid particulate delivery for pulmonary, nasal or buccal delivery, the present compositions offer more reproducible, bioacceptable emulsion particles of size more amenable to better absorption from the absorption site, consistent dosing, and better storage properties. EXAMPLES
Example 1 : Cyclosporin Emulsion I An emulsion according to the present invention was prepared, with cyclosporin A as the polyfunctional active ingredient dissolved in an oil phase including a structured triglyceride (Captex 810D) and a long chain triglyceride (safflower oil). The emulsion had the following components:
Component
Figure imgf000039_0001
* dimyristoyl phosphatidyl glycerol The emulsion was prepared as follows. Captex 810D and safflower oil were mixed to form a homogeneous oil. Cyclosporin A and BHT were added to the oil and dissolved at room temperature. Egg phospholipid and DMPG were added to the oil mixture and dispersed in the oil phase. The oil phase was heated to 60°-70°C, then added to an aqueous phase of water, glycerol and EDTA. The mixture was then mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 300 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.). Example 2: Cyclosporin Emulsion II An emulsion according to the present invention was prepared, with cyclosporin A as the polyfunctional active ingredient dissolved in an oil phase including a structured triglyceride (Captex 810D) and polarity modifiers (monoglycerides and acetylated monoglycerides). The emulsion had the following components:
Component % (w/w)
Cyclosporin A 1.0
Captex 810D 7.0
Eastman 9-45* 2.0
Peceol** 1.0
Egg Phospholipid 3.6
Glycerol 2.25
EDTA 0.01
Water q.s.
* acetylated monoglycerides ** monoglycerides
The emulsion was prepared as follows. Captex 810D, Eastman 9-45 and Peceol were mixed to form a homogeneous oil. Cyclosporin A was added to the oil and dissolved at room temperature. Egg phospholipid was added to the oil mixture and dispersed in the oil phase. The oil phase was heated to 60°-70°C, then added to an aqueous phase of water, glycerol and EDTA. The mixture was then mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 200 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.). Example 3: Cyclosporin Emulsion III An emulsion according to the present invention was prepared, with cyclosporin A as the polyfunctional active ingredient dissolved in an oil phase including a long chain triglyceride (safflower oil) and a polarity modifier (acetylated monoglycerides). The emulsion had the following components:
Component % (w/w)
Cyclosporin A 1.0
Safflower Oil USP 8.0
Eastman 9-45* 2.0
BHT 0.02
Egg Phospholipid 2.4
Glycerol 2.25
EDTA 0.01
Water q.s. * acetylated monoglycerides
The emulsion was prepared as follows. Safflower oil and Eastman 9-45 were mixed to form a homogeneous oil. Cyclosporin A and BHT were added to the oil and dissolved at room temperature. Egg phospholipid was dispersed in an aqueous phase containing water, glycerol ^and EDTA. Both the oil phase and the aqueous phase were heateα0tθ-60°-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 300 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.). Example 4: Progesterone Emulsion I An emulsion according to the present invention was prepared, with progesterone as the polyfunctional active ingredient dissolved in an oil phase including a long chain triglyceride (soybean oil) and polarity modifiers (monoglycerides and acetylated monoglycerides). The emulsion had the following components:
Component % (w/w)
Progesterone 0.3
Soybean Oil USP 6.0
Eastman 9-45* 3.0
Peceol** 1.0
BHT 0.02
Egg Phospholipid 2.4
Glycerol 2.25
EDTA 0.01
Water q.s.
* acetylated monoglycerides ** monoglycerides
The emulsion was prepared as follows. Soybean oil, Eastman 9-45 and Peceol were mixed to form a homogeneous oil. Progesterone and BHT were added to the oil and dissolved at room temperature. Egg phospholipid was added to the oil mixture ana dispersed in the oil phase. The oil mixture was heated to 60°C-70°C, then added to an aqueous phase containing water, glycerol and EDTA. The mixture was mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 200 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.).
Example 5: Progesterone Emulsion II An emulsion according to the present invention was prepared, with progesterone as the polyfunctional active ingredient dissolved in an oil phase including a structured triglyceride (Captex 810D), a long chain triglyceride (glycerol trioleate), and a polarity modifier (mono-,diglyceride mixture). The emulsion had the following components:
Component % (w/w)
Progesterone 0.3
Captex 810D 4.0
Captex GTO* 4.0
Capmul MCM** 2.0
BHT 0.02
Egg Phospholipid 2.4
DMPG*** 0.4
Glycerol 2.25
EDTA 0.01
Water q.s.
* glycerol trioleate
** mixture of monoglycerides and diglycerides
*** dimyristoyl phosphatidyl glycerol
The emulsion was prepared as follows. Captex 810D, Captex GTO and Capmul MCM were mixed to form a homogeneous oil. Progesterone and BHT were added to the oil and dissolved at room temperature. Egg phospholipid and DMPG were dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 150 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.).
Example 6: Tretinoin Emulsion I An emulsion according to the present invention was prepared, with tretinoin as the polyfunctional active ingredient dissolved in an oil phase including a long chain triglyceride (safflower oil), an oil-miscible base (triethylamine) and polarity modifiers (acetylated monoglycerides and a mono-,diglyceride mixture). The emulsion had the following components:
Component % (w/w)
Tretinoin 0.2
Triethylamine 0.1
Safflower Oil USP 6.0
Eastman 9-45* 2.0
Imwitor 988** 2.0
BHT 0.02
Egg Phospholipid 1.2
Glycerol 2.25
EDTA 0.01
Water q.s.
* acetylated monoglycerides
** mixture of monoglycerides and diglycerides The emulsion was prepared as follows. Safflower oil, triethylamine, Eastman 9-45 and Imwitor 988 were mixed to form a homogeneous oil. Tretinoin and BHT were added to the oil and dissolved at room temperature. Egg phospholipid was dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer
(Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 100 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.).
The Example was repeated, but after combining the oil and aqueous phases, the mixture was sonicated at room temperature using a Branson sonifier. The pooled sonified material was then high pressure homogenized as previously described. The resulting emulsion had mean particle diameter of less than 80 nm.
Example 7: Tretinoin Emulsion II An emulsion according to the present invention was prepared, with tretinoin as the polyfunctional active ingredient dissolved in an oil phase including a structured triglyceride (Captex 810D), an oil-miscible base (triethylamine) and polarity modifiers (monoglycerides and a mono-,diglyceride mixture). The emulsion had the following components: Component % (w/w)
Tretinoin 0.2
Triethylamine 0.1
Captex 810D 6.0
Peceol* 3.0
Capmul MCM** 1.0
BHT 0.02
Egg Phospholipid 1.2
Glycerol 2.25
EDTA 0.01
Water q.s.
* monoglycerides
** mixture of monoglycerides and diglycerides
The emulsion was prepared as follows. Captex 810D, triethylamine, Peceol and Capmul MCM were mixed to form a homogeneous oil. Tretinoin and BHT were added to the oil and dissolved at room temperature. Egg phospholipid was dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer
(Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 100 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.). Example 8: Ketoconazole Emulsion An emulsion according to the present invention can be prepared, with ketoconazole as the polyfunctional active ingredient dissolved in an oil phase including a long chain triglyceride (soybean oil), an oil-miscible acid (oleic acid) and a polarity modifier (acetylated monoglycerides). A suitable emulsion can have the following components:
Component % (w/w)
Ketoconazole 1.0
Oleic Acid 2.0
Soybean Oil USP 6.0
Eastman 9-45* 4.0
BHT 0.02
Egg Phospholipid 2.4
Glycerol 2.25
EDTA 0.01
Water q.s. * acetylated monoglycerides
The emulsion can be prepared as follows. Soybean oil, oleic acid and Eastman 9-45 are mixed to form a homogeneous oil. Ketoconazole and BHT are added to the oil and dissolved at room temperature. Egg phospholipid is dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase are heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture is further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. Examples 9-14 illustrate pharmaceutical emulsions according to the present invention which do not contain an active ingredient. These emulsions are suitable for delivery of a wide variety of polyfunctional active ingredients, as described herein.
Example 9: Drug-Free Emulsion I An emulsion according to the present invention was prepared with an oil phase including a structured triglyceride (Captex 810D), a long chain triglyceride (soybean oil), and a polarity modifier (low HLB polyethoxylated vegetable oil). The emulsion had the following components:
Component % (w/w)
Captex 810D 6.0
Soybean Oil USP 4.0
Labrafil M2125 CS* 1.0
Egg Phospholipid 1.8
Glycerol 2.25
EDTA 0.01
Water q.s.
* low HLB polyethoxylated vegetable oil
The emulsion was prepared as follows. Captex 810D, soybean oil and Labrafil M2125 CS were mixed to form a homogeneous oil. Egg phospholipid was dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were healed to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 150 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.). Example 10: Drug-Free Emulsion II An emulsion according to the present invention was prepared with an oil phase including a structured triglyceride (Captex 810D), a long chain triglyceride (safflower oil), and a polarity modifier (propylene glycol fatty acid esters). The emulsion had the following components:
Component % (w/w)
Captex 810D 6.0
Safflower Oil USP 4.0
Lauroglycol FCC* 1.0
Egg Phospholipid 1.8
Glycerol 2.25
EDTA 0.01
Water q.s. * propylene glycol fatty acid esters
The emulsion was prepared as follows. Captex 810D, safflower oil and Lauroglycol FCC were mixed to form a homogeneous oil. Egg phospholipid was dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated IO 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 100 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.). Example 11 : Drug-Free Emulsion III An emulsion according to the present invention was prepared with an oil phase including a long chain triglyceride (safflower oil), and a polarity modifier (polyglycerized fatty acid esters). The emulsion had the following components:
Component % (w/w)
Safflower Oil USP 8.0
Plurol Oleique CC497* 2.0
Egg Phospholipid 1.2
DPMG** 0.2
Glycerol 2.25
EDTA 0.01
Water q.s.
* polyglycerized fatty acid esters
* * dimyristoyl phosphatidyl glycerol
The emulsion was prepared as follows. Safflower oil and Plurol Oleique CC497 were mixed to form a homogeneous oil. Egg phospholipid and DMPG were dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 100 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.). Example 12: Drug-Free Emulsion IV An emulsion according to the present invention was prepared with an oil phase including a long chain triglyceride (soybean oil) and a polarity modifier (low HLB polyethoxylated fatty acid esters). The emulsion had the following components:
Component % (w/w)
Soybean Oil USP 9.0
Kessco PEG 400 DO* 1.0
Egg Phospholipid 1.8
Glycerol 2.25
EDTA 0.01
Water q.s. low HLB. polyethoxylated. fatty acid- esters
The emulsion was prepared as follows. Soybean oil and Kessco PEG 400 DO were mixed to form a homogeneous oil. Egg phospholipid was dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer
(Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession. The resulting emulsion had a mean particle diameter of less than 100 nm, as measured by a Nicomp particle size analyzer (Particle Size Systems, Inc.).
Example 13: Drug-Free Emulsion V An emulsion according to the present invention was prepared with an oil phase including a structured triglyceride (Captex 810D) and a polarity modifier (mixture of mono- ,di- and triglycerides). The emulsion had the following components: Component % (w/w)
Captex 810D 8.0
Maisine 35-1 * 2.0
Egg Phospholipid 1.2
DMPG** 0.2
Glycerol 2.25
EDTA 0.01
Water q.s.
* mixture of mono-, di- and triglycerides ** dimethyl propylene glycol
The emulsion was be prepared as follows. Captex 810D and Maisine 35-1 were mixed to form a homogeneous oil. Egg phospholipid and DMPG were dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase were heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture was further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession.
Example 14: Drug-Free Emulsion VI An emulsion according to the present invention can be prepared with an oil phase including a structured triglyceride (Captex 810D), a long chain triglyceride (safflower oil) and an oil-dispersible acid (deoxycholic acid). The emulsion can have the following components: Component % (w/w)
Captex 810D 5.0
Safflower Oil USP 4.5
Deoxycholic Acid 0.5
Egg Phospholipid 2.4
Glycerol 2.25
EDTA ' 0.01
Water q.s.
The emulsion can be prepared as follows. Captex .810D, safflower oil and deoxycholic acid are mixed to form a homogeneous oil. Egg phospholipid is dispersed in an aqueous phase containing water, glycerol and EDTA. Both the oil phase and the aqueous phase are heated to 60°C-70°C, then combined and mixed well using an UltraTurrax homogenizer (IKA). The mixture is further high pressure homogenized by a microfluidizer (Microfluidics) at a pressure of 16,000 psi for 10 cycles in succession.
The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. Ali changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

Claims

1. A pharmaceutical oil-in-water emulsion for delivery of a polyfunctional active ingredient, the emulsion comprising:
(a) an aqueous phase;
(b) an oil phase comprising a structured triglyceride; and
(c) an emulsifier.
2. The pharmaceutical emulsion of claim 1, which further comprises a polyfunctional active ingredient.
3. The pharmaceutical emulsion of claim 2, wherein the polyfunctional active ingredient is hydrophobic and has an intrinsic aqueous solubility of less than about 1 mg/mL.
4. The pharmaceutical emulsion of claim 2, wherein the polyfunctional active ingredient is hydrophobic and has an intrinsic aqueous solubility of less than about 0.1 mg/mL.
5. The pharmaceutical emulsion of claim 2, wherein the polyfunctional active ingredient is hydrophilic and has an octanol/water partition coefficient of less than about 100.
6. The pharmaceutical emulsion of claim 2, wherein the polyfunctional active ingredient is hydrophilic and has an octanol/water partition coefficient of less than about 10.
7. The pharmaceutical emulsion of claim 1 , wherein the structured triglyceride comprises triglycerides or mixtures of triglycerides having at least one fatty acid group with a carbon chain length of from 6 to 12 carbon atoms and at least one fatty acid group with a carbon chain length of more than 12 carbon atoms.
8. The pharmaceutical emulsion of claim 7, wherein the structured triglyceride is substantially free of triglycerides having three fatty acid groups with a carbon chain length of from 6 to 12 carbon atoms.
9. The pharmaceutical emulsion of claim 1, wherein the oil phase further comprises a long chain triglyceride.
10. The pharmaceutical emulsion of claim 1, wherein the oil phase further comprises a vegetable oil, a fish oil, an animal fat, a hydrogenated vegetable oil, a partially hydrogenated vegetable oil, a semi-synthetic triglyceride, a synthetic triglyceride, or a mixture thereof.
1 1. The pharmaceutical emulsion of claim 1 , wherein the oil phase further comprises almond oil; babassu oil; borage oil; black currant seed oil; canola oil; castor oil; coconut oil; corn oil; cottonseed oil; emu oil; evening primrose oil; flax seed oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; rapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; a mixture of hydrogenated cottonseed oil and hydrogenated castor oil; partially hydrogenated soybean oil; a mixture of partially hydrogenated soybean oil and partially hydrogenated cottonseed oil; glyceryl trioleate; glyceryl trilinoleate;
glyceryl trilinolenate; a Ω3 polyunsaturated fatty acid triglyceride containing oil; or a mixture thereof.
12. The pharmaceutical composition of claim 1, wherein the oil phase further comprises coconut oil; corn oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; hydrogenated coconut oil; partially hydrogenated
soybean oil; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; a Ω3 polyunsaturated fatty acid triglyceride containing oil; or a mixture thereof.
13. The pharmaceutical composition of claim 1, wherein the oil phase further comprises corn oil; olive oil; palm oil; peanut oil; safflower oil; sesame oil; soybean oil; hydrogenated castor oil; partially hydrogenated soybean oil; glyceryl trioleate; glyceryl
trilinoleate; a Ω3 polyunsaturated fatty acid triglyceride containing oil; or a mixture thereof.
14. The pharmaceutical emulsion of claim 1, wherein the oil phase further comprises a polarity modifier or a mixture of polarity modifiers.
15. The pharmaceutical emulsion of claim 14, wherein the polarity modifier is selected from the group consisting of acids; bases; monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
16. The pharmaceutical emulsion of claim 14, wherein the polarity modifier is selected from the group consisting of monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatt> alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
17. The pharmaceutical emulsion of claim 15, wherein the polyol of the lipophilic reaction mixture is a polyhydric aliphatic alcohol.
18. The pharmaceutical emulsion of claim 15, wherein the polyol of the lipophilic reaction mixture is pentaerythritol, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, sorbitol, glycerol, polyglycerol, a saccharide, a cyclodextrin, a synthetic polyhydric polymer, or a mixture thereof.
19. The pharmaceutical emulsion of claim 15, wherein the glyceride of the lipophilic reaction mixture is a monoglyceride, a diglyceride, a triglyceride or a mixture thereof.
20. The pharmaceutical emulsion of claim 14, wherein the polarity modifier is selected from the group consisting of monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; acetylated monoglycerides; acetylated diglycerides; cholesterol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; and mixtures thereof.
21. The pharmaceutical emulsion of claim 14, wherein the polarity modifier is selected from the group consisting of monoglycerides, diglycerides, mixtures of mono- and di-glycerides, mixtures of mono-, di- and triglycerides, and mixtures thereof.
22. The pharmaceutical emulsion of claim 14, wherein the polarity modifier is an acid or a base.
23. The pharmaceutical emulsion of claim 20, wherein the monoglycerides comprise monoglycerides having fatty acid groups with a carbon chain length of greater than 10 carbon atoms.
24. The pharmaceutical emulsion of claim 20, wherein the diglycerides comprise diglycerides having at least one fatty acid group with a carbon chain length of greater than 10 carbon atoms.
25. The pharmaceutical emulsion of claim 14, wherein the polarity modifier is selected from the group consisting of sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; and mixtures thereof.
26. The pharmaceutical emulsion of claim 25, wherein the lipophilic reaction mixture comprises a transesterification product of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
27. The pharmaceutical emulsion of claim 14, wherein the polarity modifier is a polyethoxylated ester selected from the group consisting of polyethoxylated monoglycerides, polyethoxylated diglycerides, polyethoxylated triglycerides, polyethoxylated bile acids, polyethoxylated cholesterol, polyethoxylated fatty acids, polyethoxylated propylene glycol esters, polyethoxylated vegetable oils, polyethoxylated hydrogenated vegetable oils, polyethoxylated sorbitan fatty acid esters, and mixtures thereof.
28. The pharmaceutical emulsion of claim 14, wherein the total amount of fatty acid groups of the oil phase having a carbon chain length of from 6 to 12 carbon atoms is less than about 50% by weight, based on the total weight of the fatty acid groups of the oil phase.
29. The pharmaceutical emulsion of claim 14, wherein the total amount of fatty acid groups of the oil phase having a carbon chain length of from 6 to 12 carbon atoms is less than about 40% by weight, based on the total weight of the fatty acid groups of the oil phase.
30. The pharmaceutical emulsion of claim 14, wherein the total amount of fatty acid groups of the oil phase having a carbon chain length of from 6 to 12 carbon atoms is less than about 30% by weight, based on the total weight of the fatty acid groups of the oil phase.
31. The pharmaceutical emulsion of claim 14, wherein the total amount of fatty acid groups of the oil phase having a carbon chain length of greater than 12 carbon atoms is greater than about 10% by weight, based on the total weight of the fatty acid groups of the oil phase.
32. The pharmaceutical emulsion of claim 14, wherein the total amount of fatty acid groups of the oil phase having a carbon chain length of greater than 12 carbon atoms is greater than about 30% by weight, based on the total weight of the fatty acid groups of the oil phase.
33. The pharmaceutical emulsion of claim 14, wherein the total amount of fatty acid groups of the oil phase having a carbon chain length of greater than 12 carbon atoms is greater than about 50% by weight, based on the total weight of the fatty acid groups of the oil phase.
34. The pharmaceutical emulsion of claim 1 , wherein the emulsifier comprises ceramide; a mixed chain phospholipid; a cationic lipid; an oligolipid; a phospholipid; a carnitine; a sphingosine; a sphigomyelin; a glycolipid; a lipoprotein; an apoprotein; an amphiphilic protein/peptide; an amphiphilic synthetic polymer; a bile salt; a fatty acid; a fatty alcohol; a fatty amine; a fatty quaternary ammonium salt; a polyethoxylated fatty acid; a polyethoxylated glyceride; a polyethoxylated phospholipid; a polyethoxylated sorbitan fatty acid ester; a polyethoxylated sterol; a polyethoxylated vegetable oil; a polyethoxylated hydrogenated vegetable oil; a reaction mixture of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; a sorbitan fatty acid ester; or a mixture thereof.
35. The pharmaceutical emulsion of claim 34, wherein the glyceride is a monoglyceride, a diglyceride, a triglyceride or a mixture thereof.
36. The pharmaceutical emulsion of claim 34, wherein the polyol is a polyhydric aliphatic alcohol.
37. The pharmaceutical emulsion of claim 34, wherein the polyol is pentaerythritol, ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, sorbitol, glycerol, polyglycerol, a saccharide, a cyclodextrin, a synthetic polyhydric polymer, or a mixture thereof.
38. The pharmaceutical emulsion of claim 34, wherein the reaction mixture comprises a transesterification product of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
39. The pharmaceutical emulsion of claim 1, wherein the emulsifier comprises a phospholipid selected from the group consisting of egg phospholipids, soy phospholipids, phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phophatidylglycerols, phosphatidylinositols, phosphatidic acids, mixed chain phospholipids, lysophospholipids, hydrogenated phospholipids, partially hydrogenated phospholipids, and mixtures thereof.
40. The pharmaceutical emulsion of claim 1, which further comprises glycerol, ethanol, propylene glycol, an antioxidant, an antiseptic, a buffering agent, a chelating agent, a colorant, a flavorant, an odorant, an osmotic modifier, a preservative, a solubilizer, solvent, a tonicifier, a trace element, a viscomodulator, or a mixture thereof.
41. The pharmaceutical emulsion of claim 2, wherein the polyfunctional active ingredient is selected from the group consisting of acarbose; acyclovir; acetyl cysteine; acetylcholine chloride; alatrofloxacin; alendronate; alglucerase; amantadine hydrochloride; ambenomium; amifostine; amiloride hydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor (human); antihemophilic factor (porcine); antihemophilic factor (recombinant); aprotinin; asparaginase; atenolol; atracurium besylate; atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin; belladona; bepridil hydrochloride; bleomycin sulfate; calcitonin human; calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate; cefamandole nafate; cefazolin sodium; cefepime hydrochloride; cefixime; cefonicid sodium; cefoperazone; cefotetan disodium; cefotoxime; cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil; cephalexin; cephapirin sodium; cholera vaccine; chrionic gonadotropin; cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin and clindamycin derivatives; ciprofloxacin; clondronate; colistimethate sodium; colistin sulfate; cortocotropin; cosyntropin; cromalyn sodium; cytarabine; daltaperin sodium; danaproid; deforoxamine; denileukin diftitox; desmopressin; diatrizoate megluamine and diatrizoate sodium; dicyclomine; didanosine; dirithromycin; dopamine hydrochloride; dornase alpha; doxacurium chloride; doxorubicin; editronate disodium; elanaprilat; enkephalin; enoxacin; enoxaprin sodium; ephedrine; epinephrine; epoetin alpha; erythromycin; esmol hydrochloride; factor IX; famiciclovir; fludarabine; fluoxetine; foscarnet sodium; ganciclovir; granulocyte colony stimulating factor; granulocyte-macrophage stimulating factor; growth hormones- recombinant human; growth hormone- bovine; gentamycin; glucagon; glycopyrolate; gonadotropin releasing hormone and synthetic analogs thereof; GnRH; gonadorelin; grepafloxacin; hemophilus B conjugate vaccine; Hepatitis A virus vaccine inactivated; Hepatitis B virus vaccine inactivated; heparin sodium; indinavir sulfate; influenza virus vaccine; interleukin-2; interleukin-3; insulin- human; insulin lispro; insulin procine; insulin NPH; insulin aspart; insulin glargine; insulin detemir; interferon alpha; interferon beta; ipratropium bromide; isofosfamide; Japanese encephalitis virus vaccine; lamivudine; leucovorin calcium; leuprolide acetate; levofloxacin; lincomycin and lincomycin derivatives; lobucavir; lomefloxacin; loracarbef; mannitol; 1 measles virus vaccine; meningococcal vaccine; menotropins; mephenzolate bromide;
2 mesalmine; methanamine; methotrexate; methscopolamine; metformin hydrochloride;
3 metroprolol; mezocillin sodium; mivacurium chloride; mumps viral vaccine; nedocromil
4 sodium; neostigmine bromide; neostigmine methyl sulfate; neutontin; norfloxacin;
5 octreotide acetate; ofloxacin; olpadronate; oxytocin; pamidronate disodium; pancuronium
6 bromide; paroxetine; pefloxacin; pentamindine isethionate; pentostatin; pentoxifylline;
7 periciclovir; pentagastrin; phentolamine mesylate; phenylalanine; physostigmine salicylate;
8 plague vaccine; piperacillin sodium; platelet derived growth factor-human; pneumococcal
9 vaccine polyvalent; poliovirus vaccine inactivated; poliovirus vaccine live (OPV);
10 polymixin B sulfate; pralidoxine chloride; pramlintide; pregabalin; propofenone;
I I propenthaline bromide; pyridostigmine bromide; rabies vaccine; residronate; ribavarin;
12 rimantadine hydrochloride; rotavirus vaccine; salmetrol xinafoate; sincalide; small pox
13 vaccine; solatol; somatostatin; sparfloxacin; spectinomycin; stavudine; streptokinase;
14 streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutaline sulfate; thiopeta;
15 ticarcillin; tiludronate; timolol; tissue type plasminogen activator; TNFR:Fc; TNK-tPA;
16 trandolapril; trimetrexate gluconate; trospectinomycin; trovafloxacin; tubocurarine chloride;
17 tumor necrosis factor; typhoid vaccine live; urea; urokinase; vancomycin; valaciclovir;
18 valsartan; varicella virus vaccine live; vasopressin and vasopressin derivatives; vecoronium
19 bromide; vinblastin; vincristine; vinorelbine; vitamin B12 ; warfarin sodium; yellow fever 0 vaccine; zalcitabine; zanamavir; zolandronate; zidovudine; a pharmaceutically acceptable 1 salt, isomer or derivative thereof; and mixtures thereof. 2
3 42. The pharmaceutical emulsion of claim 2, wherein the polyfunctional active 4 ingredient is selected from the group consisting of tramadol, celecoxib, etodolac, refocoxib, oxaprozin, leflunomide, diclofenac, nabumetone, acetyl coenzyme Q10, ibuprofen, flurbiprofen, tetrahydrocannabinol, capsaicin, ketorolac, albendazole, ivermectin, amiodarone, zileuton, zafirlukast, albuterol, montelukast, azithromycin, ciprofloxacin, clarithromycin, dirithromycin, rifabutine, rifapentine, trovafloxacin, baclofen, ritanovir, saquinavir, nelfinavir, efavirenz, dicoumarol, tirofibran, cilostazol, ticlidopine, clopidrogel, oprevelkin, paroxetine, sertraline, venlafaxine, bupropion, clomipramine, miglitol, repaglinide, glymepride, pioglitazone, rosigiltazone, troglitazone, glyburide, glipizide, glibenclamide, carbamezepine, fosphenytion, tiagabine, topiramate, lamotrigine, vigabatrin, amphotericin B, butenafine, terbinafine, itraconazole, flucanazole, miconazole, lycopene, ketoconazole, metronidazole, griseofulvin, nitrofurantoin, spironolactone, lisinopril, benezepril, nifedipine, nilsolidipine, telmisartan, irbesartan, eposartan, valsartan, candesartan, minoxidil, terzosin, halofantrine, mefloquine, dihydroergotamine, ergotamine, frovatriptan, pizofetin, sumatriptan, zolmitriptan, naratiptan, rizatriptan, aminogluthemide, busulphan, cyclosporine, mitoxantrone, irinotecan, etoposide, teniposide, paclitaxel, tacrolimus, sirolimus, tamoxifen, camptothecan, topotecan, nilutanide, bicalutanide, ephedrine, toremifene, atovaquone, metronidazole, furazolidone, paricalcitol, benzonatate, midazolam, zolpidem, gabapentin, zopiclone, digoxin, beclomethsone, budesonide, betamethasone, prednisolone, cisapride, cimetidine, loperamide, famotidine, lanosprazole, rabeprazole, nizatidine, omeprazole, citrizine, cinnarizine, dexchlopheniramine, loratadine, clemastine, fexofenadine, chloφheniramine, acutretin, tazarotene, calciprotiene, calcitriol, targretin, ergocalciferol, cholecalciferol, isotreinoin, tretinoin, calcifediol, fenofibrate, probucol, gemfibrozil, cerivistatin, pravastatin, simvastatin, fluvastatin, atorvastatin, tizanidine, dantrolene, isosorbide dinatrate, a carotene, dihydrotachysterol, vitamin A, vitamin D, vitamin E, vitamin K, an essential fatty acid source, codeine, fentanyl, methadone, nalbuphine, pentazocine, clomiphene, danazol, dihydro epiandrosterone, medroxyprogesterone, progesterone, rimexolone, megesterol acetate, osteradiol, finasteride, mefepristone, amphetamine, L-thryroxine, tamsulosin, methoxsalen, tacrine, donepezil, raloxifene, vertoporfin, sibutramine, pyridostigmine, pharmaceutically acceptable salts, isomers and derivatives thereof, and mixtures thereof.
43. A dosage form of the pharmaceutical emulsion of claim 1.
44. The dosage form of claim 43, wherein the dosage form comprises the pharmaceutical emulsion processed by lyophilization, encapsulation, extrusion, homogenization, sonication, melting, solubilizing, evaporation, sterilization, filtration, irradiation, mixing, coating, size reduction, spraying, or a combination thereof.
45. The dosage form of claim 43, which comprises the pharmaceutical emulsion formulated as an injectable, a drink, an eye drop or spray, a nasal drop or spray, a buccal drop or spray, a cervical drop or spray, an inhalant, a lotion, a gel, a liniment, a cream, a paste, a solution, a suppository, an ovule, a wafer, a troche, a sachet, an elixir, a tincture, a douche, an aerosol, a patch, or a combination thereof.
46. The dosage form of claim 43, wherein the dosage form is adapted for parenteral, enteral, ocular, nasal, sublingual, buccal, topical, intra-cervical, rectal, intramuscular, intra-dermal, pulmonary, transmucosal, intra-thecal, intravenous, intra- arterial, epidural, intra-cavity, intra-organ transdermal, intra-lymphatic, intra-cranular, or intra-tumoral administration, or a combination thereof.
47. The dosage form of claim 43, which further comprises a polyfunctional active ingredient.
48. A method of treating an animal with a polyfunctional active ingredient, the method comprising administering to the animal the dosage form of clam 43 and a polyfunctional active ingredient.
49. The method of claim 48, wherein the animal is a mammal.
50. The method of claim 49, wherein the mammal is a human.
51. The method of claim 48, wherein the polyfunctional active ingredient is administered to the animal prior to, concurrently with, or subsequent to the administration of the dosage form of the pharmaceutical emulsion.
52. A method of treating an animal with a polyfunctional active ingredient, the method comprising administering to the animal the dosage form of claim 47.
53. The method of claim 52, wherein the animal is a mammal.
54. The method of claim 53, wherein the mammal is a human.
55. A pharmaceutical oil-in-water emulsion for delivery of a polyfunctional active ingredient, the emulsion comprising:
(a) an aqueous phase;
(b) an oil phase comprising a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and
(c) an emulsifier.
56. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
57. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; acetylated monoglycerides; acetylated diglycerides; cholesterol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; and mixtures thereof.
58. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
59. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; acetylated monoglycerides; acetylated diglycerides; cholesterol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; and mixtures thereof.
60. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
61. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; cholesterol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; and mixtures thereof.
62. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of acetylated monoglycerides; acetylated diglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
63. The pharmaceutical emulsion of claim 55, wherein he oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of acetylated monoglycerides; acetylated diglycerides; cholesterol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; and mixtures thereof.
64. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
65. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides; diglycerides; mixtures of mono- and diglycerides; mixtures of mono-, di- and triglycerides; cholesterol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; and mixtures thereof.
66. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids; lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
67. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of acids; bases; cholesterol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; and mixtures thereof.
68. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of bile acids; cholesterol; cholesterol fatty acid esters; fatty acids; fatty alcohols; fusidic acids: lactic acid derivatives of mono/diglycerides; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; polyol alkyl ethers; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated alkyl ethers; polyethoxylated sterols; and mixtures thereof.
69. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of cholesterol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; polyol fatty acid esters; lipophilic reaction mixtures of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sorbitan fatty acid esters; polyethoxylated esters; polyethoxylated sterols; and mixtures thereof.
70. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and a lipophilic reaction mixture or a purified or fractionated lipophilic reaction mixture, of a polyol and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols, or a mixture thereof.
71. The pharmaceutical emulsion of claim 55, wherein the oil phase comprises a long chain triglyceride and at least one compound selected from the group consisting of polyethoxylated esters, polyethoxylated alkyl ethers, polyethoxylated sterols, and mixtures thereof.
72. The pharmaceutical emulsion of claim 55, which further comprises a polyfunctional active ingredient.
1 73. The pharmaceutical emulsion of claim 72, wherein the polyfunctional active
2 ingredient is hydrophobic and has an intrinsic aqueous solubility of less than about
3 1 mg/mL.
4
5 74. The pharmaceutical emulsion of claim 72, wherein the polyfunctional active
6 ingredient is hydrophobic and has an intrinsic aqueous solubility of less than about
7 0.1 mg/mL.
8
9 75. The pharmaceutical emulsion of claim 72, wherein the polyfunctional active
10 ingredient is hydrophilic and has an octanol/water partition coefficient of less than about
1 1 100.
12
13 76. The pharmaceutical emulsion of claim 72, wherein the polyfunctional active
14 ingredient is hydrophilic and has an octanol/water partition coefficient of less than about 10.
15
16 77. The pharmaceutical emulsion of claim 55, wherein the oil phase further
17 comprises a structured triglyceride.
18
19 78. The pharmaceutical emulsion of claim 77, wherein the total amount of fatty 0 acid groups of the oil phase having a carbon chain length of from 6 to 12 carbon atoms is 1 less than about 50% by weight, based on the total weight of the fatty acid groups of the oil 2 phase. 3
4 79. The pharmaceutical emulsion of claim 77, wherein the total amount of fatty acid groups of the oil phase having a carbon chain length of from 6 to 12 carbon atoms is less than about 40% by weight, based on the total weight of the fatty acid groups of the oil phase.
80. The pharmaceutical emulsion of claim 77, wherein the total amount of fatty acid groups of the oil phase having a carbon chain length of from 6 to 12 carbon atoms is less than about 30% by weight, based on the total weight of the fatty acid groups of the oil phase.
81. The pharmaceutical emulsion of claim 77, wherein the total amount of fatty acid groups of the oil phase having a carbon chain length of greater than 12 carbon atoms is greater than about 10% by weight, based on the total weight of the fatty acid groups of the oil phase.
82. The pharmaceutical emulsion of claim 77, wherein the total amount of fatty acid groups of the oil phase having a carbon chain length of greater than 12 carbon atoms is greater than about 30% by weight, based on the total weight of the fatty acid groups of the oil phase.
83. The pharmaceutical emulsion of claim 77, wherein the total amount of fatty acid groups of the oil phase having a carbon chain length of greater than 12 carbon atoms is greater than about 50% by weight, based on the total weight of the fatty acid groups of the oil phase.
84. The pharmaceutical emulsion of claim 55, which further comprises glycerol, ethanol, propylene glycol, an antioxidant, an antiseptic, a buffering agent, a chelating agent, a colorant, a flavorant, an odorant, an osmotic modifier, a preservative, a solubilizer, a solvent, a tonicifier, a trace element, a viscomodulator, or a mixture thereof
85. A dosage form of the pharmaceutical emulsion of claim 55.
86. The dosage form of claim 85, which further comprises a polyfunctional active ingredient.
87. A method of treating an animal with a polyfunctional active ingredient, the method comprising administering to the animal the dosage form of claim 85 and a polyfunctional active ingredient.
88. A method of treating an animal with a polyfunctional active ingredient, the method comprising administering to the animal the dosage form of claim 86.
89. A pharmaceutical oil-in-water emulsion for delivery of a polyfunctional active ingredient, the emulsion comprising:
(a) an aqueous phase;
(b) an oil phase comprising a long chain triglyceride and at least one compound selected from the group consisting of monoglycerides, diglycerides, mixtures of mono- and diglycerides, and mixtures of mono-, di- and triglycerides; and
(c) an emulsifier.
90. The pharmaceutical emulsion of claim 89, which further comprises a polyfunctional active ingredient.
91. A dosage form of the pharmaceutical emulsion of claim 89.
92. The dosage form of claim 91, which further comprises a polyfunctional active ingredient.
93. A method of treating an animal with a polyfunctional active ingredient, the method comprising administering to the animal the dosage form of claim 91 and a polyfunctional active ingredient.
94. A method of treating an animal with a polyfunctional active ingredient, the method comprising administering to the animal the dosage form of claim 90.
95. A pharmaceutical oil-in-water emulsion for delivery of a polyfunctional active ingredient, the emulsion comprising:
(a) an aqueous phase;
(b) an oil phase comprising a long chain triglyceride and at least one compound selected from the group consisting of acetylated monoglycerides, acetylated diglycerides, and mixtures thereof; and
(c) an emulsifier.
96. The pharmaceutical emulsion of claim 95, which further comprises a polyfunctional active ingredient.
97. A dosage form of the pharmaceutical emulsion of claim 95.
98. The dosage form of claim 97, which further comprises a polyfunctional active ingredient.
99. A method of treating an animal with a polyfunctional active ingredient, the method comprising administering to the animal the dosage form of claim 97 and a polyfunctional active ingredient.
100. A method of treating an animal with a polyfunctional active ingredient, the method comprising administering to the animal the dosage form of claim 96.
PCT/US2000/028835 1999-10-18 2000-10-18 Emulsion compositions for polyfunctional active ingredients WO2001028555A1 (en)

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Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001052859A1 (en) * 2000-01-20 2001-07-26 F. Hoffmann-La Roche Ag Pharmaceutical parenteral composition containing a biphosphonate
WO2002005848A2 (en) * 2000-07-13 2002-01-24 Pharmacia Corporation Use of cox-2 inhibitors in the treatment and prevention of ocular cox-2 mediated disorders
WO2002034267A1 (en) * 2000-10-20 2002-05-02 Neurobiotec Gmbh Combination of a transdermal therapeutic system and an oral and/or parenteral preparation containing dopamine agonists for the treatment of dopaminergic disease states
WO2003099337A2 (en) * 2002-05-23 2003-12-04 Glaxo Group Limited Inclusion complexes of rosiglitazone
DE10248412A1 (en) * 2002-08-01 2004-02-19 Bernd Rauscher Rapidly acting, easily administered suppositories for treatment and/or prophylaxis of hypoglycemia, preferably comprising monosaccharide (source) as active agent
EP1411951A2 (en) 2001-07-27 2004-04-28 N.V. Nutricia Enteral compositions for the prevention and/or treatment of sepsis
WO2004041259A1 (en) * 2002-11-06 2004-05-21 Pfizer Limited Treatment of female sexual dysfunction
EP1455730A1 (en) * 2001-12-06 2004-09-15 Ranbaxy Laboratories, Ltd. Isotretinoin nanoparticulate compositions
WO2004093886A1 (en) * 2003-04-24 2004-11-04 Galderma S.A. Topical formulation of ivermectin for the treatment of dermatological conditions
WO2005067914A1 (en) * 2004-01-20 2005-07-28 Suntory Limited Preventive or ameliorating agent for liver disease involving hepatopathy
US6964979B2 (en) 2002-05-21 2005-11-15 Wyeth R-enantiomers of pyranoindole derivatives and the use thereof for the treatment of hepatitis C virus infection or disease
US7217730B2 (en) 2002-05-21 2007-05-15 Wyeth Method for the use of pyranoindole derivatives to treat infection with Hepatitis C virus
US7306819B2 (en) 2002-06-12 2007-12-11 The Coca-Cola Company Beverages containing plant sterols
US7335389B2 (en) 2002-06-12 2008-02-26 The Coca-Cola Company Beverages containing plant sterols
WO2008039864A1 (en) * 2006-09-26 2008-04-03 Novavax, Inc. Emulsion formulations for transdermal delivery of poorly water soluble active agents
WO2008062413A2 (en) * 2006-11-21 2008-05-29 Mitam Ltd. Formulations of entomopathogenic fungi for insect control
WO2008154705A1 (en) * 2007-06-20 2008-12-24 Apollo Life Sciences Limited Transdermal delivery of active agents
WO2009068458A3 (en) * 2007-11-27 2009-08-20 Univ Friedrich Alexander Er Encapsulated microparticles with virus-containing core and production method for microparticles
CN101627996A (en) * 2009-08-20 2010-01-20 山东罗欣药业股份有限公司 Rabeprazole sodium composition and preparation method thereof
WO2009120885A3 (en) * 2008-03-26 2010-01-21 Taro Pharmaceuticals U.S.A., Inc. Stabilizing lipid compositions for oral pharmaceutical agents
US7696162B2 (en) 2001-03-23 2010-04-13 Sanofi-Aventis Deutschland Gmbh Zinc-free and low-zinc insulin preparations having improved stability
WO2010141586A3 (en) * 2009-06-02 2011-03-10 Abbott Medical Optics Inc. Therapeutic ophthalmic emulsions
US7932263B2 (en) 2003-09-26 2011-04-26 Astrazeneca Ab Therapeutic treatment
WO2011134937A2 (en) 2010-04-26 2011-11-03 Besins Healthcare Luxembourg Sarl Pharmaceutical emulsion compositions comprising progestogen
US8106040B2 (en) 2006-09-26 2012-01-31 Taro Pharmaceuticals North America, Inc. Stabilizing compositions for antibiotics and methods of use
US8263581B2 (en) 2009-07-03 2012-09-11 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
GB2497728A (en) * 2011-12-14 2013-06-26 Londonpharma Ltd Statin formulations for transmucosal delivery
US8513259B2 (en) 2009-07-03 2013-08-20 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US8580954B2 (en) 2006-03-28 2013-11-12 Hospira, Inc. Formulations of low dose diclofenac and beta-cyclodextrin
CN103800353A (en) * 2003-04-24 2014-05-21 盖尔德玛公司 Topical application of ivermectin for the treatment of dermatological conditions/afflictions
US8754126B2 (en) 2010-12-29 2014-06-17 Abbott Laboratories Methods for improving tolerance, digestion, and lipid soluble nutrient absorption in an infant, toddler, or child
US8828412B2 (en) 2009-06-02 2014-09-09 Abbott Medical Optics Inc. Stable polyphenol containing ophthalmic emulsion for treating dry eyes
US8865695B2 (en) 2009-01-08 2014-10-21 Lipocine Inc. Steroidal compositions
US9034858B2 (en) 2010-11-30 2015-05-19 Lipocine Inc. High-strength testosterone undecanoate compositions
US9089587B2 (en) 2013-07-08 2015-07-28 Galderma S.A. Treatment of papulopustular rosacea with ivermectin
WO2015158823A1 (en) * 2014-04-16 2015-10-22 Veyx-Pharma Gmbh Veterinary pharmaceutical composition and use thereof
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9364519B2 (en) 2011-09-01 2016-06-14 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition for use in the treatment of a neurodegenerative disease
US9408893B2 (en) 2011-08-29 2016-08-09 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
US9480645B2 (en) 2009-06-02 2016-11-01 Abbott Medical Optics Inc. Omega-3 oil containing ophthalmic emulsions
US9498485B2 (en) 2014-08-28 2016-11-22 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US9526764B2 (en) 2008-10-17 2016-12-27 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1-agonist
US9630949B2 (en) 2008-11-04 2017-04-25 Galderma Research & Development Oxoazetidine derivatives, process for the preparation thereof and use thereof in human medicine and in cosmetics
EP1952700B1 (en) 2002-04-05 2017-05-17 Nestec S.A. Method of improving absorption of vitamin E by a pet animal
US9707176B2 (en) 2009-11-13 2017-07-18 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist and methionine
EP3104841A4 (en) * 2014-02-14 2017-09-06 Jingjun Huang Compositions of nanoemulsion delivery systems
US9782425B2 (en) 2013-07-08 2017-10-10 Galderma S.A. Treatment of papulopustular rosacea with ivermectin
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
US9950039B2 (en) 2014-12-12 2018-04-24 Sanofi-Aventis Deutschland Gmbh Insulin glargine/lixisenatide fixed ratio formulation
US9981013B2 (en) 2010-08-30 2018-05-29 Sanofi-Aventis Deutschland Gmbh Use of AVE0010 for the treatment of diabetes mellitus type 2
US10029011B2 (en) 2009-11-13 2018-07-24 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist, an insulin and methionine
US10159713B2 (en) 2015-03-18 2018-12-25 Sanofi-Aventis Deutschland Gmbh Treatment of type 2 diabetes mellitus patients
CN109432003A (en) * 2018-12-26 2019-03-08 江苏盈科生物制药有限公司 A kind of high oxidation resistance long chain fat emulsion injection
US10434147B2 (en) 2015-03-13 2019-10-08 Sanofi-Aventis Deutschland Gmbh Treatment type 2 diabetes mellitus patients
US10561615B2 (en) 2010-12-10 2020-02-18 Lipocine Inc. Testosterone undecanoate compositions
US20220339153A1 (en) * 2012-02-02 2022-10-27 Kenneth Gek-Jin Ooi Tear film stability
US11559530B2 (en) 2016-11-28 2023-01-24 Lipocine Inc. Oral testosterone undecanoate therapy
US11707467B2 (en) 2014-08-28 2023-07-25 Lipocine Inc. (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use

Families Citing this family (263)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030100532A1 (en) * 1997-02-14 2003-05-29 Gary S. Jacob Use of n-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds in combination therapy for treating hepatitis virus infections
DE69941212D1 (en) * 1998-03-23 2009-09-17 Gen Mills Inc PLASTERING COMPONENTS IN EDIBLE PRODUCTS
EP1165080A2 (en) * 1999-02-12 2002-01-02 G.D. SEARLE &amp; CO. Use of substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds for treating hepatitis virus infections
US6248363B1 (en) * 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
IL144828A0 (en) * 1999-03-11 2002-06-30 Fujisawa Pharmaceutical Co A pipecolic acid derivative containing liposome composition
US7655252B2 (en) 1999-04-28 2010-02-02 The Regents Of The University Of Michigan Antimicrobial nanoemulsion compositions and methods
US7767216B2 (en) * 1999-04-28 2010-08-03 The Regents Of The University Of Michigan Antimicrobial compositions and methods of use
US20030236236A1 (en) * 1999-06-30 2003-12-25 Feng-Jing Chen Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
FR2803206A1 (en) * 1999-12-30 2001-07-06 Aventis Pharma Sa New composition, used in in vitro or ex vivo cellular transfection, comprises a nucleic acid and a mineral particle with an exchangeable layer structure
GB0001928D0 (en) * 2000-01-27 2000-03-22 Novartis Ag Organic compounds
US20030147017A1 (en) * 2000-02-15 2003-08-07 Jean-Daniel Bonny Display device with multiple row addressing
MXPA02009587A (en) * 2000-03-28 2003-05-14 Biochemie Gmbh Granulated particles with masked taste.
US20030162733A1 (en) * 2000-11-27 2003-08-28 Haynes Joel R. Nucleic acid adjuvants
DE10141650C1 (en) 2001-08-24 2002-11-28 Lohmann Therapie Syst Lts Safe transdermal therapeutic system for administration of fentanyl or analogous analgesics, having matrix layer of carboxy group-free polyacrylate adhesive providing high permeation rate
AU2002357012A1 (en) * 2001-11-27 2003-06-10 Transform Pharmaceuticals, Inc. Oral pharmaceutical formulations comprising paclitaxel, derivatives and methods of administration thereof
US7763663B2 (en) * 2001-12-19 2010-07-27 University Of Massachusetts Polysaccharide-containing block copolymer particles and uses thereof
US7914801B1 (en) 2002-03-21 2011-03-29 The United States Of America As Represented By The Secretary Of Agriculture Metabolizable oil emulsion adjuvants and vaccines for enhancing immuno-properties of antibodies and their subpopulations
GB0210397D0 (en) 2002-05-07 2002-06-12 Ferring Bv Pharmaceutical formulations
DE10227232A1 (en) * 2002-06-18 2004-01-15 Aventis Pharma Deutschland Gmbh Sour insulin preparations with improved stability
US6764999B2 (en) * 2002-07-11 2004-07-20 Stephen E. Bachman Nasal delivery of parasiticides
US7431986B2 (en) * 2002-07-24 2008-10-07 General Mills, Inc. Encapsulation of sensitive components using pre-emulsification
UY27412A1 (en) * 2002-08-12 2003-06-30 Carlson Internat Inc A NEW PRODUCT FOR TICKET FIGHTING AND THE PREPAACINN PROCESS.
ES2594758T3 (en) * 2002-10-23 2016-12-22 Glaxosmithkline Biologicals S.A. Vaccination procedures against malaria
US20050026877A1 (en) * 2002-12-03 2005-02-03 Novacea, Inc. Pharmaceutical compositions comprising active vitamin D compounds
US6635654B1 (en) * 2003-01-09 2003-10-21 Allergan, Inc. Ophthalmic compositions containing loratadine
US7476692B2 (en) * 2003-02-21 2009-01-13 Childrens Hospital Los Angeles Pharmaceutical compositions of safingol and methods of using the same
DE10307728B4 (en) * 2003-02-24 2005-09-22 Clariant Gmbh Corrosion and gas hydrate inhibitors with improved water solubility and increased biodegradability and such compounds
US20040185119A1 (en) * 2003-02-26 2004-09-23 Theuer Richard C. Method and compositions for treating gastric hyperacidity while diminishing the likelihood of producing vitamin deficiency
US7323206B1 (en) 2003-03-04 2008-01-29 B. Braun Medical Inc. Reagents and methods for all-in-one total parenteral nutrition for neonates and infants
WO2004084859A2 (en) 2003-03-21 2004-10-07 Nastech Pharmaceutical Company Inc. Nasal calcitonin formulations containing chlorobutanol
JP2006522815A (en) * 2003-04-08 2006-10-05 アルゴルクス ファーマスーティカルズ,インク Production and purification of synthetic capsaicin
US7033998B2 (en) * 2003-04-11 2006-04-25 All Natural Fmg, Inc. Alcohol-free transdermal insulin composition and processes for manufacture and use thereof
ATE425760T1 (en) * 2003-05-22 2009-04-15 Bioniche Life Sciences Inc INSECT REPELLENT
US20050208083A1 (en) 2003-06-04 2005-09-22 Nanobio Corporation Compositions for inactivating pathogenic microorganisms, methods of making the compositons, and methods of use thereof
US20050020546A1 (en) * 2003-06-11 2005-01-27 Novacea, Inc. Pharmaceutical compositions comprising active vitamin D compounds
US20050004221A1 (en) * 2003-07-01 2005-01-06 Medtronic, Inc. Intrathecal gabapentin compositions
US20050049209A1 (en) * 2003-08-06 2005-03-03 Chen Andrew Xian Pharmaceutical compositions for delivering macrolides
US20050187278A1 (en) * 2003-08-28 2005-08-25 Pharmacia Corporation Treatment or prevention of vascular disorders with Cox-2 inhibitors in combination with cyclic AMP-specific phosphodiesterase inhibitors
US20050090549A1 (en) * 2003-10-23 2005-04-28 Medtronic, Inc. Intrathecal gabapentin for treatment of pain
US20050090548A1 (en) * 2003-10-23 2005-04-28 Medtronic, Inc. Intrathecal gabapentin for treatment of epilepsy
US20050096365A1 (en) * 2003-11-03 2005-05-05 David Fikstad Pharmaceutical compositions with synchronized solubilizer release
US20060003002A1 (en) * 2003-11-03 2006-01-05 Lipocine, Inc. Pharmaceutical compositions with synchronized solubilizer release
PT1530965E (en) 2003-11-11 2006-05-31 Udo Mattern ADMINISTRATION SYSTEM FOR CONTROLLED LIBERATION OF SEXUAL HORMONES FOR NASAL APPLICATION
US8784869B2 (en) 2003-11-11 2014-07-22 Mattern Pharma Ag Controlled release delivery system for nasal applications and methods of treatment
US20050118194A1 (en) * 2003-12-01 2005-06-02 Sin Yoke M. Oral vaccine, method for its preparation and use thereof
GB0400804D0 (en) 2004-01-14 2004-02-18 Innoscience Technology Bv Pharmaceutical compositions
KR20140104986A (en) * 2004-02-17 2014-08-29 트랜스셉트 파마슈티칼스, 인코포레이티드 Compositions for delivering hypnotic agents across the oral mucosa and methods of use thereof
CA2559208A1 (en) 2004-03-17 2005-09-29 Mpex Pharmaceuticals, Inc. Use and administration of bacterial efflux pump inhibitors
US20060116336A1 (en) * 2004-03-17 2006-06-01 American Pharmaceutical Partners, Inc. Lyophilized azithromycin formulation
US7468428B2 (en) * 2004-03-17 2008-12-23 App Pharmaceuticals, Llc Lyophilized azithromycin formulation
UA88464C2 (en) * 2004-04-29 2009-10-26 Колдуэлл Гейлер, Инк. Method of topical methadone administration providing systemic effect
US8147867B2 (en) 2004-05-03 2012-04-03 Hermes Biosciences, Inc. Liposomes useful for drug delivery
WO2005117911A2 (en) * 2004-05-06 2005-12-15 Cydex, Inc. Taste-masked formulations containing sertraline and sulfoalkyl ether cyclodextrin
WO2005118166A2 (en) 2004-06-04 2005-12-15 Teva Pharmaceutical Industries, Ltd. Pharmaceutical composition containing irbesartan
US7871632B2 (en) * 2004-07-12 2011-01-18 Adventrx Pharmaceuticals, Inc. Compositions for delivering highly water soluble drugs
US20090149533A1 (en) * 2004-08-06 2009-06-11 Transform Pharmaceuticals, Inc. Novel fenofibrate formulations and related methods of treatment
US7740875B2 (en) * 2004-10-08 2010-06-22 Mediquest Therapeutics, Inc. Organo-gel formulations for therapeutic applications
US20060078580A1 (en) * 2004-10-08 2006-04-13 Mediquest Therapeutics, Inc. Organo-gel formulations for therapeutic applications
US8026281B2 (en) * 2004-10-14 2011-09-27 Lupin Atlantis Holdings, S.A. Treating metabolic syndrome with fenofibrate
NZ582975A (en) 2004-10-21 2011-07-29 Durect Corp Transdermal delivery systems delivering sufentanil
US8252320B2 (en) 2004-10-21 2012-08-28 Durect Corporation Transdermal delivery system for sufentanil
US20080096979A1 (en) * 2004-11-08 2008-04-24 Rubicon Research Pvt. Ltd. Aqueous Pharmaceutical Coating
JP2008521815A (en) * 2004-11-24 2008-06-26 アルゴルクス ファーマスーティカルズ,インク Capsinoid gel preparation and use thereof
WO2006060723A2 (en) * 2004-12-03 2006-06-08 Vical Incorporated Methods for producing block copolymer/amphiphilic particles
WO2006062933A2 (en) * 2004-12-06 2006-06-15 Reliant Pharmaceuticals, Inc. Stable compositions of fenofibrate with fatty acid esters
KR101356335B1 (en) * 2004-12-06 2014-02-06 릴라이언트 파마슈티컬스 인코퍼레이티드 Omega-3 fatty acids and dyslipidemic agent for lipid therapy
KR20070118069A (en) * 2004-12-09 2007-12-13 인시스 테라퓨틱스, 인코포레이티드 Room-temperature stable dronabinol formulations
MX2007011031A (en) * 2005-03-08 2008-04-21 Reliant Pharmaceuticals Inc Treatment with statin and omega-3 fatty acids and a combination product thereof.
AR054336A1 (en) * 2005-03-30 2007-06-20 Astion Dev As TREATMENT OF DERMATOLOGICAL AND PRURITE DISEASES
EP1871349A1 (en) * 2005-04-11 2008-01-02 Nanobio Corporation Quaternary ammonium halides for treatment of infectious conditions
KR20130042041A (en) * 2005-05-25 2013-04-25 트랜스셉트 파마슈티칼스, 인코포레이티드 Solid compositions and methods for treating middle-of-the night insomnia
US20070287740A1 (en) * 2005-05-25 2007-12-13 Transcept Pharmaceuticals, Inc. Compositions and methods of treating middle-of-the night insomnia
US20070225322A1 (en) * 2005-05-25 2007-09-27 Transoral Pharmaceuticals, Inc. Compositions and methods for treating middle-of-the night insomnia
US8252326B2 (en) * 2005-06-01 2012-08-28 Catalent Australia Pty Ltd. Self-microemulsifying dosage forms of low solubility active ingredients such as co-enzyme Q10
BRPI0612596A2 (en) * 2005-07-01 2010-11-23 Sigma Tau Ind Farmaceuti use of l-carnitine or alkanoyl-l-carnitines for the preparation of a physiological supplement or medicament for ophthalmic use in the form of eye drops
US20070015691A1 (en) * 2005-07-13 2007-01-18 Allergan, Inc. Cyclosporin compositions
US7202209B2 (en) * 2005-07-13 2007-04-10 Allergan, Inc. Cyclosporin compositions
CN101384247B (en) * 2005-07-18 2013-05-22 麻萨诸塞州洛厄尔大学 Compositions and methods for making and using nanoemulsions
US7605122B2 (en) * 2005-07-29 2009-10-20 Millennium Medical Spa Human chorionic gonadotropin (hCG) formulations for facilitating weight loss and body contouring
CA2618974C (en) * 2005-08-09 2014-01-28 Nanobio Corporation Nanoemulsion compositions having anti-inflammatory activity
US7797337B2 (en) * 2005-09-29 2010-09-14 Scenera Technologies, Llc Methods, systems, and computer program products for automatically associating data with a resource as metadata based on a characteristic of the resource
US9839667B2 (en) 2005-10-14 2017-12-12 Allergan, Inc. Prevention and treatment of ocular side effects with a cyclosporin
US7745400B2 (en) * 2005-10-14 2010-06-29 Gregg Feinerman Prevention and treatment of ocular side effects with a cyclosporin
US7803413B2 (en) * 2005-10-31 2010-09-28 General Mills Ip Holdings Ii, Llc. Encapsulation of readily oxidizable components
US20070148194A1 (en) * 2005-11-29 2007-06-28 Amiji Mansoor M Novel nanoemulsion formulations
HUE054852T2 (en) 2005-12-01 2021-10-28 Univ Massachusetts Lowell Botulinum nanoemulsions
US9486408B2 (en) 2005-12-01 2016-11-08 University Of Massachusetts Lowell Botulinum nanoemulsions
NZ596494A (en) 2006-01-13 2013-07-26 Us Gov Nat Inst Health Codon optimized il-15 and il-15r-alpha genes for expression in mammalian cells
US20070190141A1 (en) * 2006-02-16 2007-08-16 Aaron Dely Extended release opiate composition
US8784886B2 (en) * 2006-03-09 2014-07-22 GlaxoSmithKline, LLC Coating capsules with active pharmaceutical ingredients
US20070218183A1 (en) * 2006-03-14 2007-09-20 Bunge Oils, Inc. Oil composition of conjugated linoleic acid
ES2397659T3 (en) * 2006-03-15 2013-03-08 Novo Nordisk A/S Mixtures of amylin and insulin
EP2003970A4 (en) * 2006-03-28 2012-07-11 Javelin Pharmaceuticals Inc Formulations of low dose non-steroidal anti-inflammatory drugs and beta-cyclodextrin
BRPI0715328A2 (en) * 2006-08-04 2013-07-09 Insys Therapeutics Inc formulation and unit dose or multiple dose device for sublingual administration of a drug
US20110165236A1 (en) * 2006-09-22 2011-07-07 Biokey, Inc. Controlled release hydrogel formulation
US20080075785A1 (en) * 2006-09-22 2008-03-27 San-Laung Chow Controlled release hydrogel formulation
US20080081067A1 (en) * 2006-10-03 2008-04-03 Gupta Manishkumar Sustained release pharmaceutical compositions of venlafaxine and process for preparation thereof
ATE496617T1 (en) 2006-10-04 2011-02-15 M & P Patent Ag CONTROLLED RELEASE DELIVERY SYSTEM FOR NASAL USE OF NEUROTRANSMITTERS
US20080098900A1 (en) * 2006-11-01 2008-05-01 Babatunde Aremu Beverage manufacture using a static mixer
WO2008060934A2 (en) * 2006-11-14 2008-05-22 Acusphere, Inc. Formulations of tetrahydropyridine antiplatelet agents for parenteral or oral administration
KR20090106493A (en) 2006-12-01 2009-10-09 안테리오스, 인코퍼레이티드 Micellar nanoparticles comprising botulinum toxin
KR101518077B1 (en) 2006-12-01 2015-05-28 안테리오스, 인코퍼레이티드 Peptide nanoparticles and uses therefor
US8530436B2 (en) * 2007-01-29 2013-09-10 Transderm, Inc. Methods and compositions for transdermal delivery of nucleotides
ES2401914T3 (en) 2007-04-25 2013-04-25 Concert Pharmaceuticals Inc. Cilostazol analogues
US8343995B2 (en) 2007-04-27 2013-01-01 Cydex Pharmaceuticals, Inc. Formulations containing clopidogrel and sulfoalkyl ether cyclodextrin and methods of use
US8747872B2 (en) 2007-05-02 2014-06-10 The Regents Of The University Of Michigan Nanoemulsion therapeutic compositions and methods of using the same
WO2008151022A2 (en) 2007-05-31 2008-12-11 Anterios, Inc. Nucleic acid nanoparticles and uses therefor
US8217083B2 (en) * 2007-06-08 2012-07-10 Aptalis Pharma Canada Inc. Mesalamine suppository
US7541384B2 (en) 2007-06-08 2009-06-02 Axcan Pharma Inc. Mesalamine suppository
US8436051B2 (en) 2007-06-08 2013-05-07 Aptalis Pharma Canada Inc. Mesalamine suppository
US20090004284A1 (en) * 2007-06-26 2009-01-01 Watson Pharmaceuticals, Inc. Controlled release tamsulosin hydrochloride formulation
US20090036414A1 (en) * 2007-08-02 2009-02-05 Mutual Pharmaceutical Company, Inc. Mesalamine Formulations
CA2698752A1 (en) * 2007-08-06 2009-02-12 Insys Therapeutics Inc. Oral cannabinoid liquid formulations and methods of treatment
EP2197532A1 (en) 2007-08-06 2010-06-23 Serenity Pharmaceuticals Corporation Methods and devices for desmopressin drug delivery
CN101152186B (en) * 2007-09-05 2011-07-06 杭州平和安康医药科技有限公司 Progesterone injection and method for preparing the same
EP2036539A1 (en) * 2007-09-11 2009-03-18 Novo Nordisk A/S Stable formulations of amylin and its analogues
WO2009066299A2 (en) * 2007-11-23 2009-05-28 Rappaport Family Institute For Research Use of haptoglobin genotyping in diagnosis and treatment of cardiovascular disease
CA2718416C (en) * 2008-03-13 2018-01-02 Mallinckrodt Inc. Multi-function, foot-activated controller for imaging system
SG157299A1 (en) 2008-05-09 2009-12-29 Agency Science Tech & Res Diagnosis and treatment of kawasaki disease
HUE046050T2 (en) * 2008-05-21 2020-01-28 Ferring Bv Orodispersible desmopressin for increasing initial period of sleep undisturbed by nocturia
US20100286045A1 (en) 2008-05-21 2010-11-11 Bjarke Mirner Klein Methods comprising desmopressin
US20110223204A1 (en) * 2008-06-04 2011-09-15 Bradford J Duft Treatment of pain with gap junction modulation compounds
CN105147608B (en) * 2008-06-26 2019-12-10 安特里奥公司 Dermal delivery
EP2317873A4 (en) * 2008-07-22 2015-04-22 Gen Mills Inc Fruit products containing omega-3 fatty acids
US9034389B2 (en) 2009-03-11 2015-05-19 Stable Solutions Llc Omega-3 enriched fish oil-in-water parenteral nutrition emulsions
US8993625B2 (en) * 2009-03-11 2015-03-31 Stable Solutions Llc Method of mitigating adverse drug events using omega-3 fatty acids as a parenteral therapeutic drug vehicle
US20110071090A1 (en) * 2009-03-11 2011-03-24 Stable Solutions Llc Method of mitigating adverse drug events using omega-3-fatty acids as a parenteral therapeutic drug vehicle
CN102458382B (en) * 2009-05-12 2015-03-18 咖勒尼卡公司 Oil-in-water emulsion of mometasone and propylene glycol
SG176000A1 (en) * 2009-05-13 2011-12-29 Protein Delivery Solutions Llc Pharmaceutical system for trans-membrane delivery
US8236782B2 (en) 2009-05-13 2012-08-07 Cydex Pharmaceuticals, Inc. Pharmaceutical compositions comprising prasugrel and cyclodextrin derivatives and methods of making and using the same
US20100310728A1 (en) * 2009-06-05 2010-12-09 General Mills, Inc. Encapsulated omega-3 fatty acids for baked goods production
EP3053583B1 (en) 2009-07-10 2020-10-14 Scott III, Linzy O. Compositions comprising reduced folates for use in treating thyroid-related medical conditions
US8470304B2 (en) * 2009-08-04 2013-06-25 Avidas Pharmaceuticals Llc Therapeutic vitamin D sun-protecting formulations and methods for their use
LT2501234T (en) * 2009-11-20 2017-12-11 Tonix Pharma Holdings Limited Methods and compositions for treating symptoms associated with post-traumatic stress disorder using cyclobenzaprine
CA2822435C (en) 2009-12-31 2018-09-11 Differential Drug Development Associates, Llc Modulation of solubility, stability, absorption, metabolism, and pharmacokinetic profile of lipophilic drugs by sterols
US8603568B2 (en) 2010-01-15 2013-12-10 Kemin Industries, Inc. Hydrolyzed lecithin product to improve digestibility
TWI438009B (en) * 2010-02-19 2014-05-21 Teikoku Pharma Usa Inc Taxane pro-emulsion formulations and methods making and using the same
US20130052221A1 (en) 2010-02-26 2013-02-28 The Govt. of the U.S, as represented by The Sec. of The Dept. of Health and Human Services Dna-protein vaccination protocols
TWI540319B (en) 2010-03-29 2016-07-01 中央研究院 Quantitative measurement of nano/micro particle endocytosis with cell mass spectrometry
SG185389A1 (en) 2010-05-03 2012-12-28 Teikoku Pharma Usa Inc Non-aqueous taxane pro-emulsion formulations and methods of making and using the same
ES2510416T3 (en) * 2010-05-13 2014-10-21 Astrazeneca Ab Injectable injection of a sedative hypnotic agent
WO2011153513A2 (en) * 2010-06-03 2011-12-08 Latitude Pharma Nanoemulsion composition containing vitamin k
US20110319389A1 (en) 2010-06-24 2011-12-29 Tonix Pharmaceuticals, Inc. Methods and compositions for treating fatigue associated with disordered sleep using very low dose cyclobenzaprine
BR112013003934A2 (en) * 2010-08-20 2016-06-07 Reddys Lab Ltd Dr phospholipid depot
US20180153904A1 (en) 2010-11-30 2018-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US20120178813A1 (en) 2011-01-12 2012-07-12 Thetis Pharmaceuticals Llc Lipid-lowering antidiabetic agent
US20120232159A1 (en) 2011-03-07 2012-09-13 Tonix Pharmaceuticals, Inc. Methods and Compositions for Treating Depression using Cyclobenzaprine
EP2696964A2 (en) * 2011-04-13 2014-02-19 MAN OIL Group AG Liquid products and method for emulsifying oil, and use thereof in the treatment of oil contaminations
US9364433B2 (en) * 2011-04-28 2016-06-14 Borje S. Andersson Parenteral formulations of lipophilic pharmaceutical agents and methods for preparing and using the same
US20130045958A1 (en) 2011-05-13 2013-02-21 Trimel Pharmaceuticals Corporation Intranasal 0.15% and 0.24% testosterone gel formulations and use thereof for treating anorgasmia or hypoactive sexual desire disorder
AR086400A1 (en) 2011-05-13 2013-12-11 Trimel Pharmaceuticals Corp FORMULATIONS IN INTRANASAL GEL OF TESTOSTERONE IN DOSE OF LOWER POWER AND USE OF THE SAME FOR THE TREATMENT OF ANORGASMIA OR THE DISORDER OF HYPOACTIVE SEXUAL DESIRE
US9757388B2 (en) 2011-05-13 2017-09-12 Acerus Pharmaceuticals Srl Intranasal methods of treating women for anorgasmia with 0.6% and 0.72% testosterone gels
WO2013049621A1 (en) * 2011-09-29 2013-04-04 The Board Of Regents Of The University Of Oklahoma Ophthalmic compositions comprising ppar-alpha agonists and methods of production and use thereof
US9301920B2 (en) 2012-06-18 2016-04-05 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
ES2885523T3 (en) 2011-11-23 2021-12-14 Therapeuticsmd Inc Natural combination hormone replacement formulations and therapies
EP2797585A4 (en) * 2011-12-29 2015-10-07 Latitude Pharmaceuticals Inc Stabilized glucagon nanoemulsions
WO2013110077A1 (en) 2012-01-19 2013-07-25 Hybrid Medical, Llc Topical therapeutic formulations
CN104736709A (en) 2012-03-27 2015-06-24 科达治疗公司 Compositions and treatments based on cadherin modulation
US11224619B2 (en) 2012-04-16 2022-01-18 Zemtsov Enterprises, Llc Formulations and methods for treatment of inflammatory skin diseases
EP2849774A4 (en) 2012-05-18 2015-11-25 Otago Innovation Ltd Combination treatments and compositions for wound healing
US9717724B2 (en) 2012-06-13 2017-08-01 Ipsen Biopharm Ltd. Methods for treating pancreatic cancer using combination therapies
AU2013202947B2 (en) 2012-06-13 2016-06-02 Ipsen Biopharm Ltd. Methods for treating pancreatic cancer using combination therapies comprising liposomal irinotecan
US20150196640A1 (en) 2012-06-18 2015-07-16 Therapeuticsmd, Inc. Progesterone formulations having a desirable pk profile
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US20130338122A1 (en) 2012-06-18 2013-12-19 Therapeuticsmd, Inc. Transdermal hormone replacement therapies
US10806697B2 (en) 2012-12-21 2020-10-20 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US8765811B2 (en) 2012-07-10 2014-07-01 Thetis Pharmaceuticals Llc Tri-salt form of metformin
US9382187B2 (en) 2012-07-10 2016-07-05 Thetis Pharmaceuticals Llc Tri-salt form of metformin
US9713616B2 (en) 2012-08-06 2017-07-25 Spectrum Pharmaceuticals, Inc. Pharmaceutical compositions comprising L-leucovorin
JO3685B1 (en) 2012-10-01 2020-08-27 Teikoku Pharma Usa Inc Non-aqueous taxane nanodispersion formulations and methods of using the same
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10568891B2 (en) 2012-12-21 2020-02-25 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
EP2953613B1 (en) 2013-02-06 2020-01-08 Jingjun Huang Stable pharmaceutical composition of clopidogrel free base for oral and parenteral delivery
US9314417B2 (en) 2013-03-13 2016-04-19 Transdermal Biotechnology, Inc. Treatment of skin, including aging skin, to improve appearance
US20140271731A1 (en) 2013-03-13 2014-09-18 Transdermal Biotechnology, Inc. Cardiovascular disease treatment and prevention
US9314433B2 (en) 2013-03-13 2016-04-19 Transdermal Biotechnology, Inc. Methods and systems for treating or preventing cancer
US9393265B2 (en) 2013-03-13 2016-07-19 Transdermal Biotechnology, Inc. Wound healing using topical systems and methods
US9387159B2 (en) 2013-03-13 2016-07-12 Transdermal Biotechnology, Inc. Treatment of skin, including aging skin, to improve appearance
US9849160B2 (en) 2013-03-13 2017-12-26 Transdermal Biotechnology, Inc. Methods and systems for treating or preventing cancer
US20140271938A1 (en) 2013-03-13 2014-09-18 Transdermal Biotechnology, Inc. Systems and methods for delivery of peptides
US20140271937A1 (en) 2013-03-13 2014-09-18 Transdermal Biotechnology, Inc. Brain and neural treatments comprising peptides and other compositions
US9295637B2 (en) 2013-03-13 2016-03-29 Transdermal Biotechnology, Inc. Compositions and methods for affecting mood states
US9320758B2 (en) 2013-03-13 2016-04-26 Transdermal Biotechnology, Inc. Brain and neural treatments comprising peptides and other compositions
US9314422B2 (en) 2013-03-13 2016-04-19 Transdermal Biotechnology, Inc. Peptide systems and methods for metabolic conditions
US9750787B2 (en) 2013-03-13 2017-09-05 Transdermal Biotechnology, Inc. Memory or learning improvement using peptide and other compositions
US9687520B2 (en) 2013-03-13 2017-06-27 Transdermal Biotechnology, Inc. Memory or learning improvement using peptide and other compositions
US9724419B2 (en) 2013-03-13 2017-08-08 Transdermal Biotechnology, Inc. Peptide systems and methods for metabolic conditions
US9295636B2 (en) 2013-03-13 2016-03-29 Transdermal Biotechnology, Inc. Wound healing using topical systems and methods
US9339457B2 (en) 2013-03-13 2016-05-17 Transdermal Biotechnology, Inc. Cardiovascular disease treatment and prevention
US9314423B2 (en) 2013-03-13 2016-04-19 Transdermal Biotechnology, Inc. Hair treatment systems and methods using peptides and other compositions
US9320706B2 (en) 2013-03-13 2016-04-26 Transdermal Biotechnology, Inc. Immune modulation using peptides and other compositions
US9295647B2 (en) 2013-03-13 2016-03-29 Transdermal Biotechnology, Inc. Systems and methods for delivery of peptides
US9241899B2 (en) 2013-03-13 2016-01-26 Transdermal Biotechnology, Inc. Topical systems and methods for treating sexual dysfunction
US20140275261A1 (en) * 2013-03-15 2014-09-18 Dr. Reddy's Laboratories, Inc. Diclofenac parenteral compositions
TWI740136B (en) 2013-03-15 2021-09-21 愛爾蘭商托尼克製藥控股有限公司 Eutectic formulations of cyclobenzaprine hydrochloride and amitriptyline hydrochloride
CN105188670B (en) 2013-03-15 2018-11-02 马留斯医药有限责任公司 Emulsion formulations
US11744838B2 (en) 2013-03-15 2023-09-05 Acerus Biopharma Inc. Methods of treating hypogonadism with transnasal testosterone bio-adhesive gel formulations in male with allergic rhinitis, and methods for preventing an allergic rhinitis event
WO2014176501A1 (en) * 2013-04-25 2014-10-30 Seachaid Pharmaceuticals, Inc. Oral cefepime compositions and uses thereof
RU2016136430A (en) * 2014-02-11 2018-03-15 Др. Редди'С Лабораторис Лтд. Parenteral compositions of celecoxib
SI3388064T1 (en) 2014-04-02 2021-08-31 Minoryx Therapeutics S.L. 2,4-thiazolidinedione derivatives in the treatment of central nervous system disorders
EP3140316A1 (en) 2014-05-05 2017-03-15 Thetis Pharmaceuticals LLC Compositions and methods relating to ionic salts of peptides
MX2016014281A (en) 2014-05-22 2017-02-22 Therapeuticsmd Inc Natural combination hormone replacement formulations and therapies.
ES2706493T3 (en) 2014-06-18 2019-03-29 Thetis Pharmaceuticals Llc Mineral amino acid complexes of active agents
US9242008B2 (en) 2014-06-18 2016-01-26 Thetis Pharmaceuticals Llc Mineral amino-acid complexes of fatty acids
WO2016172712A2 (en) 2015-04-23 2016-10-27 Sydnexis, Inc. Ophthalmic composition
US9421199B2 (en) 2014-06-24 2016-08-23 Sydnexis, Inc. Ophthalmic composition
US9855234B2 (en) 2014-07-08 2018-01-02 Insys Development Company, Inc. Diclofenac sublingual spray
EP3174542A4 (en) 2014-07-29 2018-01-03 TherapeuticsMD, Inc. Transdermal cream
US20180094205A1 (en) * 2014-08-22 2018-04-05 FAIN-Biomedical Inc. Lubricant regulating agent
US11382909B2 (en) 2014-09-05 2022-07-12 Sydnexis, Inc. Ophthalmic composition
EP3193854A4 (en) 2014-09-18 2018-05-02 Tonix Pharma Holdings Limited Eutectic formulations of cyclobenzaprine hydrochloride
CN107106659B (en) 2014-10-27 2022-07-08 莱迪杜德制药公司 Parenteral glucagon formulations
US9815886B2 (en) 2014-10-28 2017-11-14 Adma Biologics, Inc. Compositions and methods for the treatment of immunodeficiency
US9925233B2 (en) 2015-01-30 2018-03-27 Par Pharmaceutical, Inc. Vasopressin formulations for use in treatment of hypotension
US9750785B2 (en) 2015-01-30 2017-09-05 Par Pharmaceutical, Inc. Vasopressin formulations for use in treatment of hypotension
US9744209B2 (en) 2015-01-30 2017-08-29 Par Pharmaceutical, Inc. Vasopressin formulations for use in treatment of hypotension
US9937223B2 (en) 2015-01-30 2018-04-10 Par Pharmaceutical, Inc. Vasopressin formulations for use in treatment of hypotension
US9687526B2 (en) 2015-01-30 2017-06-27 Par Pharmaceutical, Inc. Vasopressin formulations for use in treatment of hypotension
US9375478B1 (en) 2015-01-30 2016-06-28 Par Pharmaceutical, Inc. Vasopressin formulations for use in treatment of hypotension
WO2016127022A1 (en) * 2015-02-06 2016-08-11 Foreman James Michael Preparation of an oil-in-water emulsion for polymer stabilized pharmaceutical formulations
US20170042806A1 (en) 2015-04-29 2017-02-16 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
US11318131B2 (en) 2015-05-18 2022-05-03 Ipsen Biopharm Ltd. Nanoliposomal irinotecan for use in treating small cell lung cancer
CN117547528A (en) 2015-05-28 2024-02-13 瑞迪博士实验室有限公司 Celecoxib oral composition for treating pain
WO2016196367A1 (en) 2015-05-29 2016-12-08 Sydnexis, Inc. D2o stabilized pharmaceutical formulations
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
WO2017022793A1 (en) * 2015-08-06 2017-02-09 日東電工株式会社 Immunity induction promoting composition, and vaccine pharmaceutical composition
US9585867B2 (en) 2015-08-06 2017-03-07 Charles Everett Ankner Cannabinod formulation for the sedation of a human or animal
MX2018001659A (en) 2015-08-20 2018-05-28 Ipsen Biopharm Ltd Combination therapy using liposomal irinotecan and a parp inhibitor for cancer treatment.
EP3337478B1 (en) 2015-08-21 2020-08-12 Ipsen Biopharm Ltd. Drug combination comprising liposomal irinotecan, oxaliplatin, 5-fluorouracil and leucovorin for treating metastatic pancreatic cancer
BR122021024957B1 (en) 2015-10-16 2023-12-12 Ipsen Biopharm Ltd Processes for producing a storage-stabilized liposomal irinotecan composition
US10857085B2 (en) * 2015-12-15 2020-12-08 Symrise Ag Preparations comprising carnosines
WO2017173044A1 (en) 2016-04-01 2017-10-05 Therapeuticsmd Inc. Steroid hormone compositions in medium chain oils
AU2017239645A1 (en) 2016-04-01 2018-10-18 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US10130719B2 (en) 2016-06-03 2018-11-20 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
WO2018002673A1 (en) 2016-07-01 2018-01-04 N4 Pharma Uk Limited Novel formulations of angiotensin ii receptor antagonists
BR112019007844A2 (en) 2016-11-02 2019-07-16 Ipsen Biopharm Ltd treatment of gastric cancer using combination therapies comprising liposomal irinotecan, oxaliplatin, 5-fluoroacyl (and leucovorin)
MX2019005833A (en) 2016-11-21 2019-10-30 Eirion Therapeutics Inc Transdermal delivery of large agents.
US10259865B2 (en) 2017-03-15 2019-04-16 Adma Biologics, Inc. Anti-pneumococcal hyperimmune globulin for the treatment and prevention of pneumococcal infection
WO2019014651A1 (en) 2017-07-13 2019-01-17 Tonix Pharmaceuticals Holding Corp. Analogs of cyclobenzaprine and amitryptilene
WO2019116091A1 (en) 2017-12-11 2019-06-20 Tonix Pharma Holdings Limited Cyclobenzaprine treatment for agitation, psychosis and cognitive decline in dementia and neurodegenerative conditions
KR102011714B1 (en) * 2018-01-16 2019-08-19 동국제약 주식회사 Oral emulsion formulation comprising Risedronic acid or its salts and vitamin D and the method for preparation thereof
KR102556874B1 (en) * 2018-02-14 2023-07-18 동국제약 주식회사 A pharmaceutical composition comprising bisphosphonate and cholecalciferol, and its manufacturing method
US10799138B2 (en) 2018-04-05 2020-10-13 University Of Maryland, Baltimore Method of administering sotalol IV/switch
CA3079509C (en) 2018-07-04 2020-11-03 AMEZCUA AMEZCUA, Federico Synergic drug combination of the active enantiomer (s)-ketorolac and gabapentin for the treatment of neuropathic pain
US11696902B2 (en) 2018-08-14 2023-07-11 AltaThera Pharmaceuticals, LLC Method of initiating and escalating sotalol hydrochloride dosing
US10512620B1 (en) 2018-08-14 2019-12-24 AltaThera Pharmaceuticals, LLC Method of initiating and escalating sotalol hydrochloride dosing
US11344518B2 (en) 2018-08-14 2022-05-31 AltaThera Pharmaceuticals LLC Method of converting atrial fibrillation to normal sinus rhythm and loading oral sotalol in a shortened time frame
US11610660B1 (en) 2021-08-20 2023-03-21 AltaThera Pharmaceuticals LLC Antiarrhythmic drug dosing methods, medical devices, and systems
AU2019334202A1 (en) 2018-09-06 2021-03-25 Innopharmascreen, Inc. Methods and compositions for treatment of asthma or parkinson's disease
CN109315783A (en) * 2018-09-29 2019-02-12 南京财经大学 A kind of preparation method for the structured lipid base nanoemulsions loading curcumin
US11504326B2 (en) * 2019-02-19 2022-11-22 Jack Donaldson, IV Lipid emulsion therapy for treating acute cannabinoid intoxication
MX2019008467A (en) 2019-07-16 2019-11-07 Federico Amezcua Amezcua A synergistic combination of s-ketorolaco and pregabalin in a pharmaceutical composition for the treatment of neuropathic pain.
US11633405B2 (en) 2020-02-07 2023-04-25 Therapeuticsmd, Inc. Steroid hormone pharmaceutical formulations
US11638722B2 (en) 2020-03-25 2023-05-02 Therapeutica Borealis Oy C/O Avance Attorneys Ltd. Medicine for Covid-19 and treatment
US11278602B2 (en) 2020-03-25 2022-03-22 Therapeutica Borealis Oy Medicine for Covid-19 and treatment
US11007187B1 (en) * 2020-03-25 2021-05-18 Therapeutica Borealis Oy Medicine for Covid-19 and treatment
CN115702880B (en) * 2021-08-12 2023-11-03 山东新时代药业有限公司 Recombinant insulin glargine injection and preparation process thereof
CN115721607B (en) * 2022-11-19 2023-07-21 华夏生生药业(北京)有限公司 Levofloxacin lactate injection and preparation method thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4753963A (en) * 1985-09-26 1988-06-28 The Procter & Gamble Company Nutritional fat suitable for enteral and parenteral products
US4871768A (en) * 1984-07-12 1989-10-03 New England Deaconess Hospital Corporation Dietary supplement utilizing ω-3/medium chain trigylceride mixtures
US5661180A (en) * 1993-01-15 1997-08-26 Abbott Laboratories Structured lipid containing gama-linolenic or dihogamma-linolenic fatty acid residue, a medium chain (C6 -C12) fatty acid residue, and a n-3 fatty acid residue
US6013665A (en) * 1997-12-16 2000-01-11 Abbott Laboratories Method for enhancing the absorption and transport of lipid soluble compounds using structured glycerides
US6130244A (en) * 1998-02-25 2000-10-10 Abbott Laboratories Product and method to reduce stress induced immune suppression

Family Cites Families (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3339236A1 (en) 1983-10-28 1985-05-09 Bayer Ag PREPARATION OF MEDICINAL PRODUCTS
DE3406497A1 (en) 1984-02-23 1985-09-05 Mueller Bernhard Willi Werner HIGHLY DISPERSAL PHARMACEUTICAL MULTI-COMPONENT SYSTEMS AND METHOD FOR THEIR PRODUCTION
US4816247A (en) 1985-09-11 1989-03-28 American Cyanamid Company Emulsion compositions for administration of sparingly water soluble ionizable hydrophobic drugs
CA1326995C (en) 1988-01-29 1994-02-15 Kozo Kurihara Cyclosporin compositions
IL90069A (en) * 1988-04-26 1994-04-12 Us Health 13-cis- retinoic acid for use in the preparation of a medicament for treating conglobate and nodulocystic acne
US5342625A (en) * 1988-09-16 1994-08-30 Sandoz Ltd. Pharmaceutical compositions comprising cyclosporins
US5364632A (en) 1989-04-05 1994-11-15 Yissum Research Development Company Of The Hebrew University Of Jerusalem Medicinal emulsions
JP2785981B2 (en) 1989-11-20 1998-08-13 株式会社資生堂 Emulsion composition
US5407683A (en) 1990-06-01 1995-04-18 Research Corporation Technologies, Inc. Pharmaceutical solutions and emulsions containing taxol
US5601860A (en) * 1990-11-30 1997-02-11 American Home Products Corporation Corandomized fat compositions for infant formulas
US5780676A (en) * 1992-04-22 1998-07-14 Ligand Pharmaceuticals Incorporated Compounds having selective activity for Retinoid X Receptors, and means for modulation of processes mediated by Retinoid X Receptors
US6320074B1 (en) * 1992-04-22 2001-11-20 Ligand Pharmaceuticals Incorporated Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors
DE59310166D1 (en) 1992-05-18 2001-05-31 Ciclomulsion Ag Pharmaceutical preparation containing cyclosporin (s) for intravenous administration and process for its preparation
WO1994008603A1 (en) * 1992-10-16 1994-04-28 Smithkline Beecham Corporation Compositions
DE4309579C3 (en) 1993-03-24 2000-01-27 Sanol Arznei Schwarz Gmbh Pharmaceutical composition in the form of a pack
US5622714A (en) 1993-05-12 1997-04-22 Dietl; Hans Pharmaceutical preparation containing cyclosporine(s) for intravenous administration and process for its production
WO1995003028A1 (en) * 1993-07-23 1995-02-02 Morris Herstein Cosmetic, skin-renewal stimulating composition with long-term irritation control
US5731355A (en) 1994-03-22 1998-03-24 Zeneca Limited Pharmaceutical compositions of propofol and edetate
CA2153553A1 (en) 1994-07-13 1996-01-14 Hidekazu Suzuki Stable lipid emulsion
US5616330A (en) 1994-07-19 1997-04-01 Hemagen/Pfc Stable oil-in-water emulsions incorporating a taxine (taxol) and method of making same
US5534261A (en) * 1995-01-17 1996-07-09 University Of Southern California Retinoid-based compositions and method for preventing adhesion formation using the same
US5616342A (en) 1995-04-11 1997-04-01 Pdt, Inc. Emulsioin suitable for administering a poorly water-soluble photosensitizing compound and use thereof
GB9601120D0 (en) * 1996-01-19 1996-03-20 Sandoz Ltd Organic compounds
US5660858A (en) 1996-04-03 1997-08-26 Research Triangle Pharmaceuticals Cyclosporin emulsions
US20030133974A1 (en) * 1997-07-01 2003-07-17 Curatolo William John Encapsulated solution dosage forms of sertraline
US6030374A (en) * 1998-05-29 2000-02-29 Mcdaniel; David H. Ultrasound enhancement of percutaneous drug absorption
US20010025046A1 (en) * 1999-06-24 2001-09-27 Rong(Ron) Liu Self-emulsifying systems containing anticancer medicament
US6333999B1 (en) * 1998-11-06 2001-12-25 International Business Machines Corporation Systematic enumerating of strings using patterns and rules
US6267985B1 (en) * 1999-06-30 2001-07-31 Lipocine Inc. Clear oil-containing pharmaceutical compositions
US6294192B1 (en) * 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
US6309663B1 (en) * 1999-08-17 2001-10-30 Lipocine Inc. Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents
US6339107B1 (en) * 2000-08-02 2002-01-15 Syntex (U.S.A.) Llc Methods for treatment of Emphysema using 13-cis retinoic acid

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4871768A (en) * 1984-07-12 1989-10-03 New England Deaconess Hospital Corporation Dietary supplement utilizing ω-3/medium chain trigylceride mixtures
US4753963A (en) * 1985-09-26 1988-06-28 The Procter & Gamble Company Nutritional fat suitable for enteral and parenteral products
US5661180A (en) * 1993-01-15 1997-08-26 Abbott Laboratories Structured lipid containing gama-linolenic or dihogamma-linolenic fatty acid residue, a medium chain (C6 -C12) fatty acid residue, and a n-3 fatty acid residue
US6013665A (en) * 1997-12-16 2000-01-11 Abbott Laboratories Method for enhancing the absorption and transport of lipid soluble compounds using structured glycerides
US6160007A (en) * 1997-12-16 2000-12-12 Abbott Laboratories Method for enhancing the absorption and transport of lipid soluble compounds using structured glycerides
US6130244A (en) * 1998-02-25 2000-10-10 Abbott Laboratories Product and method to reduce stress induced immune suppression

Cited By (129)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HRP20020594B1 (en) * 2000-01-20 2011-03-31 F. Hoffmann - La Roche Ag Pharmaceutical parenteral composition containing a biphosphonate
WO2001052859A1 (en) * 2000-01-20 2001-07-26 F. Hoffmann-La Roche Ag Pharmaceutical parenteral composition containing a biphosphonate
US6677320B2 (en) 2000-01-20 2004-01-13 Hoffmann-La Roches Inc. Parenteral bisphosphonate composition with improved local tolerance
WO2002005848A2 (en) * 2000-07-13 2002-01-24 Pharmacia Corporation Use of cox-2 inhibitors in the treatment and prevention of ocular cox-2 mediated disorders
WO2002005848A3 (en) * 2000-07-13 2002-07-04 Pharmacia Corp Use of cox-2 inhibitors in the treatment and prevention of ocular cox-2 mediated disorders
WO2002034267A1 (en) * 2000-10-20 2002-05-02 Neurobiotec Gmbh Combination of a transdermal therapeutic system and an oral and/or parenteral preparation containing dopamine agonists for the treatment of dopaminergic disease states
US7696162B2 (en) 2001-03-23 2010-04-13 Sanofi-Aventis Deutschland Gmbh Zinc-free and low-zinc insulin preparations having improved stability
EP1411951B2 (en) 2001-07-27 2010-11-10 N.V. Nutricia Enteral compositions for the prevention and/or treatment of sepsis
EP1411951A2 (en) 2001-07-27 2004-04-28 N.V. Nutricia Enteral compositions for the prevention and/or treatment of sepsis
US7758893B2 (en) 2001-07-27 2010-07-20 N.V. Nutricia Enteral compositions for the prevention and/or treatment of sepsis
EP1455730A4 (en) * 2001-12-06 2006-01-18 Ranbaxy Lab Ltd Isotretinoin nanoparticulate compositions
EP1455730A1 (en) * 2001-12-06 2004-09-15 Ranbaxy Laboratories, Ltd. Isotretinoin nanoparticulate compositions
EP1952700B1 (en) 2002-04-05 2017-05-17 Nestec S.A. Method of improving absorption of vitamin E by a pet animal
US7217730B2 (en) 2002-05-21 2007-05-15 Wyeth Method for the use of pyranoindole derivatives to treat infection with Hepatitis C virus
US6964979B2 (en) 2002-05-21 2005-11-15 Wyeth R-enantiomers of pyranoindole derivatives and the use thereof for the treatment of hepatitis C virus infection or disease
EP1867343A2 (en) * 2002-05-23 2007-12-19 Glaxo Group Limited Novel compounds
WO2003099337A2 (en) * 2002-05-23 2003-12-04 Glaxo Group Limited Inclusion complexes of rosiglitazone
WO2003099337A3 (en) * 2002-05-23 2004-02-26 Glaxo Group Ltd Inclusion complexes of rosiglitazone
EP1867343A3 (en) * 2002-05-23 2008-04-16 Glaxo Group Limited Inclusion complexes of a cyclodextrin with a thiazolidine-2,4-dione
US7306819B2 (en) 2002-06-12 2007-12-11 The Coca-Cola Company Beverages containing plant sterols
US7335389B2 (en) 2002-06-12 2008-02-26 The Coca-Cola Company Beverages containing plant sterols
DE10248412B4 (en) * 2002-08-01 2009-05-20 Bernd Rauscher Suppository for the treatment or prevention of hypoglycemia
DE10248412A1 (en) * 2002-08-01 2004-02-19 Bernd Rauscher Rapidly acting, easily administered suppositories for treatment and/or prophylaxis of hypoglycemia, preferably comprising monosaccharide (source) as active agent
WO2004041259A1 (en) * 2002-11-06 2004-05-21 Pfizer Limited Treatment of female sexual dysfunction
US7550440B2 (en) 2003-04-24 2009-06-23 Galderma S.A. Topical application of ivermectin for the treatment of dermatological conditions/afflictions
US8415311B2 (en) 2003-04-24 2013-04-09 Galderma S.A. Topical application of ivermectin for the treatment of dermatological conditions/afflictions
US8080530B2 (en) 2003-04-24 2011-12-20 Galderma S.A. Topical application of ivermectin for the treatment of dermatological conditions/afflictions
US8093219B2 (en) 2003-04-24 2012-01-10 Galderma S.A. Topical application of ivermectin for the treatment of dermatological conditions/afflictions
US8470788B2 (en) 2003-04-24 2013-06-25 Galderma S.A. Topical application of ivermectin for the treatment of dermatological conditions/afflictions
US8815816B2 (en) 2003-04-24 2014-08-26 Galderma S.A. Topical application of ivermectin for the treatment of dermatological conditions/afflictions
US11033565B2 (en) 2003-04-24 2021-06-15 Galderma Holding SA Topical application of ivermectin for the treatment of dermatological conditions/afflictions
US8598129B2 (en) 2003-04-24 2013-12-03 Galderma S.A. Topical application of ivermectin for the treatment of dermatological conditions/afflictions
WO2004093886A1 (en) * 2003-04-24 2004-11-04 Galderma S.A. Topical formulation of ivermectin for the treatment of dermatological conditions
CN103800353A (en) * 2003-04-24 2014-05-21 盖尔德玛公司 Topical application of ivermectin for the treatment of dermatological conditions/afflictions
US7932263B2 (en) 2003-09-26 2011-04-26 Astrazeneca Ab Therapeutic treatment
WO2005067914A1 (en) * 2004-01-20 2005-07-28 Suntory Limited Preventive or ameliorating agent for liver disease involving hepatopathy
US8436047B2 (en) 2004-01-20 2013-05-07 Suntory Holdings Limited Preventive or ameliorating agent for liver disease involving hepatopathy
JP4721642B2 (en) * 2004-01-20 2011-07-13 サントリーホールディングス株式会社 Preventive or ameliorating agent for liver diseases associated with liver damage
JP2005206476A (en) * 2004-01-20 2005-08-04 Suntory Ltd Prophylactic or ameliorating agent for liver disease accompanied with hepatopathy
US8580954B2 (en) 2006-03-28 2013-11-12 Hospira, Inc. Formulations of low dose diclofenac and beta-cyclodextrin
US8946292B2 (en) 2006-03-28 2015-02-03 Javelin Pharmaceuticals, Inc. Formulations of low dose diclofenac and beta-cyclodextrin
WO2008039864A1 (en) * 2006-09-26 2008-04-03 Novavax, Inc. Emulsion formulations for transdermal delivery of poorly water soluble active agents
US8106040B2 (en) 2006-09-26 2012-01-31 Taro Pharmaceuticals North America, Inc. Stabilizing compositions for antibiotics and methods of use
US8461143B2 (en) 2006-09-26 2013-06-11 Taro Pharmaceuticals North America, Inc. Stabilizing compositions for antibiotics and methods of use
US20100112060A1 (en) * 2006-11-21 2010-05-06 Pesah Maor Formulations of entomopathogenic fungi for insect control
WO2008062413A2 (en) * 2006-11-21 2008-05-29 Mitam Ltd. Formulations of entomopathogenic fungi for insect control
WO2008062413A3 (en) * 2006-11-21 2009-03-12 Mitam Ltd Formulations of entomopathogenic fungi for insect control
WO2008154705A1 (en) * 2007-06-20 2008-12-24 Apollo Life Sciences Limited Transdermal delivery of active agents
WO2009068458A3 (en) * 2007-11-27 2009-08-20 Univ Friedrich Alexander Er Encapsulated microparticles with virus-containing core and production method for microparticles
WO2009120885A3 (en) * 2008-03-26 2010-01-21 Taro Pharmaceuticals U.S.A., Inc. Stabilizing lipid compositions for oral pharmaceutical agents
US9526764B2 (en) 2008-10-17 2016-12-27 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1-agonist
US10117909B2 (en) 2008-10-17 2018-11-06 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1 agonist
US9630949B2 (en) 2008-11-04 2017-04-25 Galderma Research & Development Oxoazetidine derivatives, process for the preparation thereof and use thereof in human medicine and in cosmetics
US8865695B2 (en) 2009-01-08 2014-10-21 Lipocine Inc. Steroidal compositions
US11052096B2 (en) 2009-01-08 2021-07-06 Lipocine Inc. Steroidal compositions
US11304960B2 (en) 2009-01-08 2022-04-19 Chandrashekar Giliyar Steroidal compositions
US9480645B2 (en) 2009-06-02 2016-11-01 Abbott Medical Optics Inc. Omega-3 oil containing ophthalmic emulsions
US8828412B2 (en) 2009-06-02 2014-09-09 Abbott Medical Optics Inc. Stable polyphenol containing ophthalmic emulsion for treating dry eyes
AU2010256679B2 (en) * 2009-06-02 2015-04-16 Johnson & Johnson Surgical Vision, Inc. Therapeutic ophthalmic emulsions
WO2010141586A3 (en) * 2009-06-02 2011-03-10 Abbott Medical Optics Inc. Therapeutic ophthalmic emulsions
US8513259B2 (en) 2009-07-03 2013-08-20 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US9119771B2 (en) 2009-07-03 2015-09-01 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US8314083B2 (en) 2009-07-03 2012-11-20 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US8263581B2 (en) 2009-07-03 2012-09-11 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US9180090B2 (en) 2009-07-03 2015-11-10 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US9161902B2 (en) 2009-07-03 2015-10-20 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
CN101627996A (en) * 2009-08-20 2010-01-20 山东罗欣药业股份有限公司 Rabeprazole sodium composition and preparation method thereof
US9707176B2 (en) 2009-11-13 2017-07-18 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist and methionine
US10029011B2 (en) 2009-11-13 2018-07-24 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist, an insulin and methionine
US10028910B2 (en) 2009-11-13 2018-07-24 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1-agonist and methionine
EP2801353A1 (en) 2010-04-26 2014-11-12 Besins Healthcare Luxembourg Pharmaceutical Emulsion Compositions Comprising Progestogen
WO2011134944A3 (en) * 2010-04-26 2012-02-09 Besins Healthcare Luxembourg Sarl Low-oil pharmaceutical emulsion compositions comprising progestogen
KR101822680B1 (en) * 2010-04-26 2018-01-26 베생 헬스케어 룩셈부르크 에스에이알엘 Low-oil pharmaceutical emulsion compositions comprising progestogen
JP2013525402A (en) * 2010-04-26 2013-06-20 ブザン・ヘルスケア・ルクセンブルク・エスエーアールエル Low oil content pharmaceutical emulsion composition containing progestogen
WO2011134937A2 (en) 2010-04-26 2011-11-03 Besins Healthcare Luxembourg Sarl Pharmaceutical emulsion compositions comprising progestogen
CN102946865A (en) * 2010-04-26 2013-02-27 博赏医药卢森堡责任有限公司 Low-oil pharmaceutical emulsion compositions comprising progestogen
US9572818B2 (en) 2010-04-26 2017-02-21 Besins Healthcare Luxembourg Sarl Pharmaceutical emulsion compositions comprising progestogen
WO2011134944A2 (en) 2010-04-26 2011-11-03 Besins Healthcare Luxembourg Sarl Low-oil pharmaceutical emulsion compositions comprising progestogen
WO2011134937A3 (en) * 2010-04-26 2012-02-02 Besins Healthcare Luxembourg Sarl Pharmaceutical emulsion compositions comprising progestogen
EA022460B1 (en) * 2010-04-26 2016-01-29 Безен Хелткэа Люксембург Сарл Low-oil pharmaceutical emulsion compositions comprising progestogen
US20140335133A1 (en) * 2010-04-26 2014-11-13 Besins Healthcare Luxembourg Sarl Low-oil pharmaceutical emulsion compositions comprising progestogen
EP2857042A1 (en) 2010-04-26 2015-04-08 Besins Healthcare Luxembourg Low-oil pharmaceutical emulsion compositions comprising progestogen
AU2011246527B2 (en) * 2010-04-26 2016-09-15 Besins Healthcare Luxembourg Sarl Low-oil pharmaceutical emulsion compositions comprising progestogen
US9981013B2 (en) 2010-08-30 2018-05-29 Sanofi-Aventis Deutschland Gmbh Use of AVE0010 for the treatment of diabetes mellitus type 2
US9943527B2 (en) 2010-11-30 2018-04-17 Lipocine Inc. High-strength testosterone undecanoate compositions
US10799513B2 (en) 2010-11-30 2020-10-13 Lipocine Inc. High-strength testosterone undecanoate compositions
US9949985B2 (en) 2010-11-30 2018-04-24 Lipocine Inc. High-strength testosterone undecanoate compositions
US10973833B2 (en) 2010-11-30 2021-04-13 Lipocine Inc. High-strength testosterone undecanoate compositions
US9480690B2 (en) 2010-11-30 2016-11-01 Lipocine Inc. High-strength testosterone undecanoate compositions
US10716794B2 (en) 2010-11-30 2020-07-21 Lipocine Inc. High-strength testosterone undecanoate compositions
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9205057B2 (en) 2010-11-30 2015-12-08 Lipocine Inc. High-strength testosterone undecanoate compositions
US9034858B2 (en) 2010-11-30 2015-05-19 Lipocine Inc. High-strength testosterone undecanoate compositions
US9757390B2 (en) 2010-11-30 2017-09-12 Lipocine Inc. High-strength testosterone undecanoate compositions
US10226473B2 (en) 2010-11-30 2019-03-12 Lipocine Inc. High-strength testosterone undecanoate compositions
US10561615B2 (en) 2010-12-10 2020-02-18 Lipocine Inc. Testosterone undecanoate compositions
US9433586B2 (en) 2010-12-29 2016-09-06 Abbott Laboratories Methods of improving tolerance related to feeding in an infant, toddler, or child
US8754126B2 (en) 2010-12-29 2014-06-17 Abbott Laboratories Methods for improving tolerance, digestion, and lipid soluble nutrient absorption in an infant, toddler, or child
US9078847B2 (en) 2010-12-29 2015-07-14 Abbott Laboratories Nutritional products including a novel fat system including monoglycerides
US8877812B2 (en) 2010-12-29 2014-11-04 Abbott Laboratories Methods for decreasing the incidence of necrotizing enterocolitis, colic, and short bowel syndrome in an infant, toddler, or child
US9844517B2 (en) 2010-12-29 2017-12-19 Abbott Laboratories Nutritional products including a novel fat system including fatty acids
US9446005B2 (en) 2010-12-29 2016-09-20 Abbott Laboratories Methods for improving tolerance, digestion, and lipid soluble nutrient absorption in an infant, toddler, or child
US9078846B2 (en) 2010-12-29 2015-07-14 Abbott Laboratories Nutritional products including monoglycerides and fatty acids
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
US9408893B2 (en) 2011-08-29 2016-08-09 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
US9364519B2 (en) 2011-09-01 2016-06-14 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition for use in the treatment of a neurodegenerative disease
US9987332B2 (en) 2011-09-01 2018-06-05 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition for use in the treatment of a neurodegenerative disease
US9849083B2 (en) 2011-12-14 2017-12-26 Londonpharma Ltd. Sublingual administration of statins
GB2497728A (en) * 2011-12-14 2013-06-26 Londonpharma Ltd Statin formulations for transmucosal delivery
US20220339153A1 (en) * 2012-02-02 2022-10-27 Kenneth Gek-Jin Ooi Tear film stability
US9089587B2 (en) 2013-07-08 2015-07-28 Galderma S.A. Treatment of papulopustular rosacea with ivermectin
US10206939B2 (en) 2013-07-08 2019-02-19 Galderma S.A. Treatment of papulopustular rosacea with ivermectin
US9233117B2 (en) 2013-07-08 2016-01-12 Galderma S. A. Treatment of inflammatory lesions of rosacea with ivermectin
US9782425B2 (en) 2013-07-08 2017-10-10 Galderma S.A. Treatment of papulopustular rosacea with ivermectin
US9233118B2 (en) 2013-07-08 2016-01-12 Galderma S.A. Treatment of papulopustular rosacea with ivermectin
EP3104841A4 (en) * 2014-02-14 2017-09-06 Jingjun Huang Compositions of nanoemulsion delivery systems
WO2015158823A1 (en) * 2014-04-16 2015-10-22 Veyx-Pharma Gmbh Veterinary pharmaceutical composition and use thereof
US20170189328A1 (en) * 2014-04-16 2017-07-06 Veyx-Pharma Gmbh Veterinary Pharmaceutical Composition and Use Thereof
US9956164B2 (en) 2014-04-16 2018-05-01 Veyx-Pharma Gmbh Veterinary pharmaceutical composition and use thereof
US9757389B2 (en) 2014-08-28 2017-09-12 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US9498485B2 (en) 2014-08-28 2016-11-22 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US11298365B2 (en) 2014-08-28 2022-04-12 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US11707467B2 (en) 2014-08-28 2023-07-25 Lipocine Inc. (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use
US11872235B1 (en) 2014-08-28 2024-01-16 Lipocine Inc. Bioavailable solid state (17-β)-Hydroxy-4-Androsten-3-one esters
US9950039B2 (en) 2014-12-12 2018-04-24 Sanofi-Aventis Deutschland Gmbh Insulin glargine/lixisenatide fixed ratio formulation
US10434147B2 (en) 2015-03-13 2019-10-08 Sanofi-Aventis Deutschland Gmbh Treatment type 2 diabetes mellitus patients
US10159713B2 (en) 2015-03-18 2018-12-25 Sanofi-Aventis Deutschland Gmbh Treatment of type 2 diabetes mellitus patients
US11559530B2 (en) 2016-11-28 2023-01-24 Lipocine Inc. Oral testosterone undecanoate therapy
CN109432003A (en) * 2018-12-26 2019-03-08 江苏盈科生物制药有限公司 A kind of high oxidation resistance long chain fat emulsion injection

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