Self-emulsifying formulations of CETP inhibitors
View Patent ↗A liquid formulation for oral administration of the CETP inhibitor of formula (I) has improved bioavailability compared with conventional solid formulations. The formulation comprises the CETP inhibitor, or a pharmaceutically acceptable salt thereof; an oil; and one or more nonionic surfactants having a hydrophilic lipophilic balance (HLB)>10.
1. An orally bioavailable self-emulsifying or self-microemulsifying pharmaceutical formulation comprising:
(1) 1-30% by weight of a compound which is a CETP inhibitor, or a pharmaceutically acceptable salt thereof;
(2) a fatty acid ester oil phase, wherein said fatty acid ester oil phase comprises one or more compounds selected from the group consisting of fatty acid monoglycerides, fatty acid diglycerides, fatty acid monoesters of propylene glycol, fatty acid diesters of propylene glycol, fatty acid monoesters of sorbitan, fatty acid diesters of sorbitan, fatty acid triesters of sorbitan, and mixtures thereof, wherein said fatty acids are selected from medium chain C 6 -C 12 fatty acids and long chain C 14 -C 20 fatty acids, and mixtures thereof, wherein said fatty acid ester oil phase optionally also comprises one or more triglycerides of medium chain C 6 -C 12 fatty acids, long chain C 14 -C 20 fatty acids, and mixtures thereof; and
(3) one or more nonionic surfactants having a hydrophilic lipophilic balance (HLB) in the range of 10-20;
wherein the ratio of the fatty acid ester oil phase and the one or more nonionic surfactants is 1:4 to 4:1 by weight; wherein the formulation does not include a cosolvent selected from the group consisting of triacetin, propylene carbonate, transcutol, ethyl lactate, triethyl citrate, N-methyl-2-pyrrolidinone, dimethylisosorbide, glycofurol, ethanol, and ethoxyethylene glycol;
wherein the CETP inhibitor has formula II:
2. The formulation of claim 1 , comprising 5% to 25% by weight of the compound of formula II.
3. The formulation of claim 1 , comprising
(1) 10% to 20% by weight of the compound of formula II, or a pharmaceutically acceptable salt thereof;
(2) a fatty acid ester oil phase; and
(3) one or more nonionic surfactants, having an HLB in the range of 10-20; wherein the ratio of the fatty acid oil ester phase, and the one or more nonionic surfactants is 3:1 to 1:3 by weight.
4. The formulation of claim 2 , wherein the nonionic surfactant is selected from PEG-40 hydrogenated castor oil (Cremophor RH40); PEG-35 castor oil (Cremophor EL); polysorbate 80 (Tween-80); Vitamin E TPGS; and mixtures thereof.
5. The formulation of claim 4 , wherein the fatty acid ester oil phase comprises one or more medium chain monoglycerides, medium chain diglycerides, medium chain monoesters of propylene glycol, medium chain diesters of propylene glycol, or long chain sorbitan monoesters; and optionally one or more medium chain triglycerides or long chain triglycerides.
6. The formulation of claim 4 , wherein the fatty acid ester oil phase comprises one or more caprylate and caprate mono- and diglycerides, or a mixture thereof; and one or more caprylate and caprate triglycerides, or a mixture thereof; and the nonionic surfactant is a mixture of polysorbate 80 and PEG-35 castor oil.
7. The formulation of claim 2 , wherein the fatty acid ester oil phase comprises one or more caprylate and caprate mono- and diglycerides, or a mixture thereof; the non-ionic surfactant is polysorbate 80; and the formulation does not include a triglyceride.