17-hydroxyprogesterone ester-containing oral compositions and related methods

Abstract

The present invention provides for bioavailable oral dosage forms containing esters of 17-hydroxyprogesterone as well as related methods. The oral dosage forms can be formulated for pregnancy support and can include a therapeutically effective amount of an ester of 17-hydroxyprogesterone and a pharmaceutically acceptable carrier. In another embodiment, a pharmaceutically acceptable oral dosage form for pregnancy support is provided. The pharmaceutically acceptable oral dosage can include a therapeutically effective amount of an ester of 17-hydroxyprogesterone and a pharmaceutically acceptable carrier. The oral dosage form can, when measured using a USP Type-II dissolution apparatus in 900 mL of deionized water with 0.5 (w/v) of sodium lauryl sulfate at 50 RPM at 37° C., release at least 20 wt % of the dose of the ester of 17-hydroxyprogesterone after 60 minutes, or in the alternative release at least 20 wt % more after 60 minutes than an equivalently dosed oral dosage form without the carrier.

What is claimed is: 
     
         1 . A oral pharmaceutical composition comprising: a therapeutically effective amount of 17-hydroxyprogesterone caproate, and a pharmaceutically acceptable carrier. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the composition is formulated for pregnancy support. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the 17-hydroxyprogesterone caproate is present in the composition in particulate form having a mean particulate diameter of about 50.mu.m or less. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the carrier includes benzyl benzoate, benzyl alcohol, or mixtures thereof. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the amount of the 17-hydroxyprogesterone caproate to the sum of the amounts of benzyl benzoate and benzyl alcohol, in the oral dosage form is about 1:0.01 (W/W) to about 1:5 (W/W). 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the amount of the 17-hydroxyprogesterone caproate is from about 5% to about 80% w/w of the total composition. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is in the form of a capsule or a tablet. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the composition is in the form of a capsule and the capsule includes from about 30 mg to about 300 mg of 17-hydroxyprogesterone caproate. 
     
     
         9 . The pharmaceutical composition of  claim 7 , wherein the composition is in the form of a tablet and the tablet includes from about 20 mg to about 800 mg of 17-hydroxyprogesterone caproate. 
     
     
         10 . The pharmaceutical composition of  claim 7 , wherein the capsule or tablet is a controlled release oral dosage form. 
     
     
         11 . The pharmaceutical composition of  claim 7 , wherein the ratio of the amount of 17-hydroxyprogesterone caproate in the composition to the fill volume of the capsule is from about 0.02 g/mL to about 0.8 g/mL. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the carrier includes a hydrophilic additive. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the carrier includes a lipophilic additive. 
     
     
         14 . The pharmaceutical composition of  claim 12 , wherein the carrier includes a compound selected from the group consisting of salts of citric acid, maleic acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid and lactic acid, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, magnesium aluminum silicate, hydroxypropyl cyclodextrin, fatty acid glycerides, salts of bile acids, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, carbomer, chitosan, methacrylates, polyvinyl alcohol, gelatin, PEG-8 caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium oleate, sodium lauryl sulfate, sodium lauryl sarcosinate, sodium dioctyl sulfosuccinate, PEG-10 laurate, PEG-20 oleate, PEG-30 stearate, PEG-40 laurate, PEG-20 glyceryl laurate, PEG-20 glyceryl tearate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, PEG-10 sorbitan laurate, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monooleate, polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, poloxamer 188, poloxamer 108, maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof. 
     
     
         15 . The pharmaceutical composition of  claim 12 , wherein the carrier includes a compound selected from the group consisting of salts of citric acid, maleic acid, tartaric acid, acetic acid, ascorbic acid, benzoic acid and lactic acid, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, calcium carbonate, silicon dioxide, magnesium aluminum silicate, hydroxypropyl cyclodextrin, pyrrolidone, polyvinylpyrrolidone, ethyl alcohol, benzyl alcohol, glycerol, propylene glycol, polyethylene glycol, methyl cellulose, hydroxypropyl methyl cellulose, cellulose esters, carbomer, chitosan, methacrylates, polyvinyl alcohol, gelatin, maltose, sucrose, fructose, mannitol, xylitol, and combinations thereof. 
     
     
         16 . The pharmaceutical composition of  claim 13 , wherein the carrier includes a compound selected from the group consisting of tributylcitrate, triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetates butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, benzyl benzoate, corn oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, hydrogenated castor oil, glyceryl tricaprate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate, saturated polyglycolized glycerides linoleic glycerides, caprylic/capric glycerides capric acid, caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glycerol monostearate, glyceryl distearate, glyceryl palmitostearate, glyceryl laurate, glyceryl caprylate, distearin, monopalmitolein, monolaurin, ethyl oleate, PEG-6 corn oil, PEG-6 apricot kernel oil, PEG-4 caprylic/capric triglyceride, PEG-20 sorbitan monostearate, PEG-4 laurate, PEG-6 dilaurate, polyglyceryl-3 oleate, polyglyceryl-6 dioleate, poloxamer 182, propylene glycol monocaprylate, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, propylene glycol caprylate/caprate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan sesquioleate, sorbitan sesquistearate, and combinations thereof. 
     
     
         17 . The pharmaceutical composition of  claim 13 , wherein the carrier includes a compound selected from the group consisting of tributylcitrate, triethylcitrate, triacetin, ethyl cellulose, cellulose esters, cellulose acetate, cellulose acetates butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, tocopherol, tocopherol acetate, tocopherol succinate, corn oil, olive oil, peanut oil, safflower oil, sesame oil, soybean oil, hydrogenated castor oil, glyceryl tricaprate, glyceryl trilaurate, glyceryl trioleate, glyceryl trilinoleate, glyceryl tricaprylate/caprate, glyceryl tricaprylate/caprate/laurate, glyceryl tricaprylate/caprate/linoleate, glyceryl tricaprylate/caprate/stearate, capric acid, caprylic acid, palmitic acid, lauric acid, stearic acid, linoleic acid, oleic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, ethyl oleate, and combinations thereof. 
     
     
         18 . The pharmaceutical composition of  claim 13 , wherein the carrier includes at least 50 wt % of a lipophilic additive. 
     
     
         19 . The pharmaceutical composition of  claim 1 , wherein the carrier includes at least one hydrophilic additive and at least one lipophilic additive at a lipophilic additive to hydrophilic additive ratio of about 90:10 to about 1:99. 
     
     
         20 . A method of treating a pregnant female subject at risk of preterm birth, comprising, administering to the female subject the pharmaceutical composition of  claim 1 .