Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents
First Claim
1. A pharmaceutical system for enhanced absorption of a hydrophilic therapeutic agent, the system consisting essentially of:
- (a) a dosage form of an absorption enhancing composition, the composition comprising;
(i) at least one hydrophilic surfactant selected from the group consisting of ionized ionizable surfactants, non-ionic hydrophilic surfactants having an HLB value greater than or equal to about 10, and combinations thereof, and (ii) at least one hydrophobic surfactant selected from the group consisting of hydrophobic (a) alcohols, polyoxyethylene alkylethers, bile acids, glycerol fatty acid monoesters, glycerol fatty acid diesters, acetylated glycerol fatty acid monoesters, acetylated glycerol fatty acid diesters, lower alcohol fatty acid monoesters, lower alcohol fatty acid diesters, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polypropylene glycol fatty acid esters, polyoxyethylene glycerides, lactic acid derivatives of mono- and diglycerides, propylene glycol diglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, transesterified vegetable oils, sugar esters, sugar ethers, sucroglycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, and hydrogenated vegetable oils, and hydrophobic, un-ionized (b) fatty acids, carnitine fatty acid esters, alkylsulfates, acyl lactylates, mono-acetylated tartaric acid esters of mono- and diglycerides, diacetylated tartaric acid esters of mono- and diglycerides, succinylated monoglycerides, citric acid esters of mono- and diglycerides, and mixtures thereof, wherein the hydrophilic and hydrophobic surfactants are present in amounts such that upon mixing with an aqueous diluent at 100×
dilution, the composition forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm; and
(b) a therapeutically effective amount of a hydrophilic therapeutic agent, wherein the pharmaceutical system is free of triglycerides.
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Abstract
The present invention relates to pharmaceutical compositions, pharmaceutical systems, and methods for enhanced absorption of hydrophilic therapeutic agents. Compositions and systems of the present invention include an absorption enhancing carrier, where the carrier is formed from a combination of at least two surfactants, at least one of which is hydrophilic. A hydrophilic therapeutic agent can be incorporated into the composition, or can be co-administered with the composition as part of a pharmaceutical system. The invention also provides methods of treatment with hydrophilic therapeutic agents using these compositions and systems.
496 Citations
170 Claims
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1. A pharmaceutical system for enhanced absorption of a hydrophilic therapeutic agent, the system consisting essentially of:
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(a) a dosage form of an absorption enhancing composition, the composition comprising;
(i) at least one hydrophilic surfactant selected from the group consisting of ionized ionizable surfactants, non-ionic hydrophilic surfactants having an HLB value greater than or equal to about 10, and combinations thereof, and (ii) at least one hydrophobic surfactant selected from the group consisting of hydrophobic (a) alcohols, polyoxyethylene alkylethers, bile acids, glycerol fatty acid monoesters, glycerol fatty acid diesters, acetylated glycerol fatty acid monoesters, acetylated glycerol fatty acid diesters, lower alcohol fatty acid monoesters, lower alcohol fatty acid diesters, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polypropylene glycol fatty acid esters, polyoxyethylene glycerides, lactic acid derivatives of mono- and diglycerides, propylene glycol diglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, transesterified vegetable oils, sugar esters, sugar ethers, sucroglycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, and hydrogenated vegetable oils, and hydrophobic, un-ionized (b) fatty acids, carnitine fatty acid esters, alkylsulfates, acyl lactylates, mono-acetylated tartaric acid esters of mono- and diglycerides, diacetylated tartaric acid esters of mono- and diglycerides, succinylated monoglycerides, citric acid esters of mono- and diglycerides, and mixtures thereof, wherein the hydrophilic and hydrophobic surfactants are present in amounts such that upon mixing with an aqueous diluent at 100×
dilution, the composition forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm; and
(b) a therapeutically effective amount of a hydrophilic therapeutic agent, wherein the pharmaceutical system is free of triglycerides. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75)
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76. A pharmaceutical system for enhanced absorption of a hydrophilic therapeutic agent, the system consisting essentially of:
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(a) a dosage form of an absorption enhancing composition, the composition comprising;
(i) at least one hydrophilic surfactant selected from the group consisting of ionized surfactants, non-ionic hydrophilic surfactants having an HLB value greater than or equal to about 10, and combinations thereof, (ii) at least one hydrophobic surfactant selected from the group consisting of hydrophobic (a) alcohols, polyoxyethylene alkylethers, bile acids, glycerol fatty acid monoesters, glycerol fatty acid diesters, acetylated glycerol fatty acid monoesters, acetylated glycerol fatty acid diesters, lower alcohol fatty acid monoesters, lower alcohol fatty acid diesters, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polypropylene glycol fatty acid esters, polyoxyethylene glycerides, lactic acid derivatives of mono- and diglycerides, propylene glycol diglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, transesterified vegetable oils, sugar esters, sugar ethers, sucroglycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, and hydrogenated vegetable oils, and hydrophobic, un-ionized (b) fatty acids, carnitine fatty acid esters, alkylsulfates, acyl lactylates, mono-acetylated tartaric acid esters of mono- and diglycerides, diacetylated tartaric acid esters of mono- and diglycerides, succinylated monoglycerides, citric acid esters of mono- and diglycerides, and mixtures thereof, wherein the hydrophilic and hydrophobic surfactants are present in amounts such that upon mixing with an aqueous diluent at 100×
dilution, the composition forms an aqueous dispersion having an average particle size of less than about 200 nm, and(iii) at least one solubilizer; and
(b) a therapeutically effective amount of a hydrophilic therapeutic agent, wherein the pharmaceutical system is free of triglycerides. - View Dependent Claims (77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152)
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- 153. An absorption enhancing composition for co-administration to a patient with a hydrophilic therapeutic agent, the composition consisting essentially of an effective amount of am absorption enhancer comprising at least one hydrophilic surfactant selected from the group consisting of ionized surfactants, non-ionic hydrophilic surfactants having an HLB value greater than or equal to 10, mid combinations thereof, and at least cast one hydrophobic surfactant selected from the group consisting of hydrophobic (a) alcohols, polyoxyethylene alkylethers, bile acids, glycerol fatty acid monoesters, glycerol fatty acid diesters, acetylated glycerol fatty acid monoesters, acetylated glycerol fatty acid diesters, lower alcohol fatty acid monoesters, lower alcohol fatty acid diesters, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polypropylene glycol fatty acid esters, polyoxyethylene glycerides, lactic acid derivatives of mono- and diglycerides, propylene glycol diglycerides, soibitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, transesterified vegetable oils, sugar esters, sugar ethers, sucroglycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, reaction prodeucts of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, and hydrogenated vegetable oils, and hydrophobic, un-ionized (b) fatty acids, carmitine fatty acid esters, alkylsulfates, acyl lactylates, mono-acetylated tartaric acid esters of mono- and diglycerides, diacetylated tartaric acid esters of mono- and diglycerides, succinylated monoglycerides, citric acid esters of mono- and diglycerides, and mixtures thereof, wherein the hydrophilic and hydrophobic surfactants are present in amounts such that upon mixing with an aqueous diluent the composition forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm, the absorption enhancing composition being free of triglycerides.
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156. A method of controlling the rate, the extent, or both the rate ant extent of bioabsorption of a hydrophilic therapeutic agent administered to a patient, the method comprising:
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(a) providing a dosage form of an absorption enhancing composition, the composition consisting essentially of at least one hydrophilic surfactant selected from the group consisting of ionized surfactants, non-ionic hydrophilic surfactants having an HLB value greater than or equal to 10, and combinations thereof, and at least one hydrophobic surfactant selected from the group consisting of hydrophobic (a) alcohols, polyoxyethylene alkylethers, bile acids, glycerol fatty acid monoesters, glycerol fatty acid diesters, acctylated glycerol fatty acid monoesters, glycerol fatty acid diesters, lower alcohol fatty acid monoesters, lower alcohol fatty acid diesters, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polypropylene glycol fatty acid esters, polyoxyethylene glycerides, lactic acid derivatives of mono- and diglycerides, propylene glycol diglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, transesterified vegetable oils, sugar esters, sugar ethers, sucroglycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, and hydrogenated vegetable oils, and hydrophobic, un-ionized (b) fatty acids, carnitine fatty acid esters, alkylsulfates, acyl lactylates, mono-acetylated tartaric acid esters of mono- and diglycerides, diacetylated tartaric acid esters of mono- and diglycerdied, succinylated monoglycerides, citric acid esters of mono- and diglycerides, and mixtures thereof, wherein the hydrophilic and hydrophobic surfactants are present in amounts such that upon mixing with an aqueous diluent the composition forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm, and wherein the composition is free of triglycerides;
(b) providing a hydrophilic therapeutic agent; and
(c) administering the dosage form of the absorption enhancing composition and the hydrophilic therapeutic agent to the patient. - View Dependent Claims (157, 158, 159, 160, 161, 162, 163, 164)
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165. A pharmaceutical system for enhanced absorption of a hydrophilic therapeutic agent in the form of a diluted preconcentrate, the system consisting essentially of:
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(a) a dosage form of an absorption enhancing composition, the composition comprising;
(i) at least one hydrophilic surfactant selected from the group consisting of ionized ionizable surfactants, non-ionic hydrophilic surfactants having an HLB value greater than or equal to 10, and combinations thereof, (ii) at least one hydrophobic surfactant selected from the group consisting of hydrophobic (a) alcohols, polyoxyethylene alkylethers, bile acids, glycerol fatty acid monoesters, glycerol fatty acid diesters, acetylated glycerol fatty acid monoesters, acctylated glycerol fatty acid diesters, lower alcohol fatty acid monoesters, lower alcohol fatty acid diestes, polyethylene glycol fatty acid esters, polyethylene glycol glycerol fatty acid esters, polypropylene glycol fatty acid esters, polyoxyethylene glycerides, lactic acid derivatives of mono- and diglycerides, propylene glycol diglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, transesterified vegetable oils, sugar esters, sugar ethers, sucroglycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, and hydrogenated vegetable oils, and hydrophobic, un-ionized (b) fatty acids, carmitine fatty acid esters, alkylsulfates, acyl lactylates, mono-acetylated tartaric acid esters of mono- and diglycerides, diacetylated tartaric acid esters of mono- and diglycerides, succinylated monoglycerides, citric acid esters of mono- and diglycerides, and mixtures thereof, wherein the hydrophilic aid hydrophobic surfactants are present in amounts such that upon mixing with an aqueous diluent at 100×
dilution, the composition forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm,(iii) a liquid diluent; and
(b) a therapeutically effective amount of a hydrophilic therapeutic agent;
wherein the pharmaceutical system is free of triglycerides. - View Dependent Claims (167, 168)
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166. A pharmaceutical system for enhancing absorption, or a hydrophilic therapeutic agent in the form of a diluted preconcentrate, the system consisting essentially of:
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(a) a dosage form of an absorption enhancing composition, the composition comprising;
(i) at least one hydrophilic surfactant selected from the group consisting of ionized ionizable surfactants, non-ionic hydrophilic surfactants having an HLB value greater than or equal to 10, and combinations thereof, (ii) at least one hydrophobic surfactant selected from the group consisting of hydrophobic (a) alcohols, polyoxyethylene alkylethers, bile acids, glycerol fatty acid monoesters, glycerol fatty acid diesters, acetylated glycerol fatty acid monoesters, acetylated glycerol fatty acid diesters, lower alcohol fatty acid monoesters, lower alcohol fatty acid diesters, polyethylene glycol fatty acid monoesters, polyethylene glycol glycerol fatty acid esters, polypropylene glycol fatty acid esters, polyoxyethylene glycerides, lactic acid derivatives of mono- and diglycerides, propylene glycol diglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, transesterified vegetable oils, sugar esters, sugar ethers, sucroglycerides, polyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils, reaction products of polyols and at least one member of the group consisting of fatty acids, glycerides, vegetable oils, and hydrogenated vegetable oils, and hydrophobic, un-ionized (b) fatty acids, carnitine fatty acid esters, alkylsulfates, acyl lactylates, mono-acetylated tartarie acid esters of mono- and diglycerides, diacetylated tartaric acid esters of mono- and diglycerides, succinylated monoglycerides, citric acid esters of mono- and diglycerides, and mixtures thereof, wherein the hydrophilic and hydrophobic surfactants are present in amounts such that upon mixing with an aqueous diluent at 100×
dilution, the composition forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm, wherein the hydrophilic and hydrophobic surfactants are present in amounts such that upon mixing with an aqueous diluent at 100×
dilution, The composition forms a clear aqueous dispersion having an absorbance of less than about 0.3 at 400 nm,(iii) at least one solubilizer, and (iv) a liquid diluent; and
(b) a therapeutically effective amount of a hydrophilic therapeutic agent;
wherein the pharmaceutical system is free of triglycerides. - View Dependent Claims (169, 170)
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Specification