Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents

A capsule containing a pharmaceutical composition comprising:

• (a) a hydrophobic therapeutic agent having an intrinsic water solubility of less than about 1 percent by weight and present in a therapeutically effective dosage for oral administration, and
• (b) a carrier comprised of
• a hydrophilic surfactant selected from the group consisting of hydropllilic non-ioliic suifactants, hydrophilic ionic surfactants, and combinations thereof,
• a hydrophobic surfactant selected from the group consisting of monoglycerides, diglycerides, acetylated monoglycerides, acetylated diglyceridcs, propylene glycol mono fatty acid esters, propylene glycol di fatty acid esters, and mixtures thereof, and
• a solubilizer selected from the group consisting of alcohols, polyols, amides, esters, propylene glycol ethers and mixtures thereof and present in an amount of about 1% to about 100% by weight relative to the combined weight of the hydroplhilic and hydrophobic surfactants,
• wherein the hydrophobic surfactant is present in an amount of about 5% to about 100% by weight relative to the hydrophilic surfactant, and the hydrophilic and hydrophobic surfactants are each present in amounts such that upon dilution with an aqueous solution at an aqueous solution to carrier ratio of 100:1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.1 at a wavelength of about 400 nm, and further wherein the composition is substantially free of water and glycerol triesters of C6 to about C25 fatty acids.

A nultiparticulate dosage form for oral administration of a therapeutic agent, comprised of a plurality of beads each coated with a composition comprising

• (a) a hydrophobic therapeutic agent having an intrinsic water solubility of less than about 1 wt. % at 25° C., and present in a therapeutically effective amount for oral administration, and
• (b) a carrier comprised of
• (i) at least one hydrophilic surfactant selected from the group consisting of hydrophilic non-ionic surfactants, hydrophilic ionic surfactants, and combinations thereof, and
• (ii) at least one hydrophobic surfactant having an HLB value less than about 10 and selected from the group consisting of alcohols;
• polyoxyethylene alkylethers;
• fatty acids;
• glycerol fatty acid monoesters;
• glycerol fatty acid dicstets;
• acetylated glycerol fatty acid monoestors;
• acetylated glycerol fatty acid diesters, lower alcohol fatty acid esters;
• polyethylene glycol fatty acid esters;
• polyethylene glycol glycerol fatty acid esters;
• polypropylene glycol fatty acid esters;
• polyoxyethylene glycerides;
• lactic acid derivatives of monoglycerides;
• lactic acid derivatives of diglycerides;
• propylene glycol diglycorides;
• sorbitan fatty acid esters;
• polyoxyethylene sorbitan fatty acid esters;
• polyoxyethylene-polyoxypropylene block copolymers;
• transesterilied vegetable oils;
• sterols;
• sterol derivatives;
• sugar esters;
• sugar ethers;
• sucroglycerides;
• polyoxyethylene vegetable oils;
• polyoxyctlhylene hydrogenated vegetable oils;
• reaction products 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,
• said hydrophilic and hydrophobic surfactants being present in amounts such that upon dilution with an aqueous solution at an aqueous solution to carrier ratio of 100:1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.1 at a wavelength of about 400 nm, and wherein the composition is substantially free of water and glycerol triesters of C6 to about C25 fatty acids.

A multiparticulate dosage form for oral administration of a therapeutic agent, comprised of a plurality of particles each comprising a composition of

• (a) a hydrophobic therapeutic agent having and intrinsic water solubility of less than about 1 wt. % at 25° C. and present in a therapeutically effective amount for oral administration, and
• (b) a carrier comprised of
• (i) at least one hydrophilic surfactant selected from the group consisting of hydrophilic non-ionic surfactants, hydrophilic ionic surfactants, and combinations thereof, and
• (ii) at least one hydrophobic surfactant having an HLB value less than about 10 and selected from the group consisting of alcohols;
• polyoxyethylene alkylethers;
• fatty acids;
• glycerol fatty acid monoesters;
• glycerol fatty acid diesters;
• acetylated glycerol fatty acid monoesters;
• acetylated glycerol fatty acid diesters, lower alcohol fatty acid esters;
• polyethylene glycol fatty acid esters;
• polyethylene glycol glycerol fatty acid esters;
• polypropylene glycol fatty acid esters;
• polyoxyethylene glycerides;
• lactic acid derivatives of monoglycorides;
• lactic acid derivatives of diglycerides;
• propylene glycol diglycerides;
• sorbitan fatty acid esters;
• polyoxyetliylene sorbitan fatty acid esters;
• polyoxyethylene-polyoxypropylene block copolymers;
• transesterilied vegetable oils;
• sterols;
• sterol derivatives;
• 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, hydrogenated vegetable oils, and sterols;
• and mixtures thereof,
• said hydrophilic and hydrophobic surfactants being present in amounts such that upon dilution with an aqueous solution at an aqueous solution to carrier ratio of 100:1 by weight, the carrier forms a clear aqueous dispersion having an absorbance of less than about 0.1 at a wavelength of about 400 nm, and wherein the composition is substantially free of water and glycerol triesters of C6 to about C25 fatty acids.