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 . An oral pharmaceutical composition comprising:
 a therapeutically effective amount of 17-hydroxyprogesterone caproate, and a pharmaceutically acceptable carrier said therapeutically effective amount ranging from 150 mg to 750 mg 17-hydroxyprogesterone caproate.   
     
     
         2 . The oral pharmaceutical pharmaceutical composition of  claim 1 , wherein the composition releases greater than 10% after 1 hour when tested using a USP Type II apparatus at 50 rpm in an aqueous media having 1.5× or greater sink condition at 37.0° C. (±0.5). 
     
     
         3 . The oral pharmaceutical pharmaceutical composition of  claim 1 , wherein the composition releases greater than 10% after 1 hour when tested using a USP Type II apparatus at 50 rpm in an aqueous media having 3× or greater sink condition at 37.0° C. (±0.5). 
     
     
         4 . The oral pharmaceutical composition of  claim 1 , wherein the composition has from about 225 mg to 800 mg of 17-hydroxyprogesterone caproate. 
     
     
         5 . The oral pharmaceutical composition of  claim 1 , said pharmaceutically acceptable carrier having one or more of a diluent, binder, disintegrant, lubricant or surfactant. 
     
     
         6 . The oral pharmaceutical composition of  claim 1 , said pharmaceutically acceptable carrier having a lipophilic or hydrophilic additive. 
     
     
         7 . The oral pharmaceutical composition of  claim 1 , said pharmaceutically acceptable carrier having a lipophilic or hydrophilic surfactant. 
     
     
         8 . The oral pharmaceutical composition of  claim 1 , said pharmaceutically acceptable carrier having a lipophilic or hydrophilic surfactant. 
     
     
         9 . The oral pharmaceutical composition of  claim 1 , said pharmaceutically acceptable carrier having a non-ionic or ionic surfactant. 
     
     
         10 . The oral pharmaceutical composition of  claim 1 , said 17 HPC being fully solubilized, partially solubilized, crystalline particulate, amorphous particulate, or a combination thereof. 
     
     
         11 . The oral pharmaceutical composition of  claim 1 , said 17 HPC being particulate and having a mean particle diameter of less than 200 nm, from 200 to 500 nm, from 500 to 1000 nm, from 1 to 50 μm, from 50 to 250 μm, from 250 to 500 μm, from 500 to 1000 μm, or greater than 1000 μm. 
     
     
         12 . The oral pharmaceutical composition of  claim 1 , said 17 HPC being particulate and having a mean particle diameter of from 50-40 μm, 40-30 μm, 30-20 μm, 20-10 μm, or 10-1 μm. 
     
     
         13 . The oral pharmaceutical composition of  claim 1 , wherein the composition has a crystallization inhibitor or a particle agglomeration inhibitor. 
     
     
         14 . The oral pharmaceutical composition of  claim 1 , wherein the composition is a powder, granulate, particulate, bead, pellet, sprinkle, suspension, solution, tablet, caplet, capsule, or a combination thereof. 
     
     
         15 . The oral pharmaceutical composition of  claim 1 , wherein the composition is controlled release or immediate release. 
     
     
         16 . The oral pharmaceutical composition of  claim 1 , wherein the compmosition is a coated or uncoated tablet or caplet. 
     
     
         17 . The oral pharmaceutical composition of  claim 1 , wherein the composition is a monolithic or multilayered tablet. 
     
     
         18 . The oral pharmaceutical composition of  claim 1 , which when administered once, twice or three times a day as one to twelve unit dosage forms total per day to human subject, provides a 17-hydroxyprogesterone caproate C avg-24h  of greater than about 0.1, 0.5 or 1.0 ng/mL. 
     
     
         19 . A method of treatment said method comprising administering to a subject an oral pharmaceutical composition comprising:
 a therapeutically effective amount of 17-hydroxyprogesterone caproate, and a pharmaceutically acceptable carrier and one or more additional agents chosen from pharmaceutical agents, vitamins, minerals, supplements.   
     
     
         20 . The method of  claim 19 , wherein said method comprises administering said pharmaceutical composition once, twice or three times a day as one to twelve unit dosage forms total per day to human subject, to provide a 17-hydroxyprogesterone caproate C avg-24h  of greater than about 0.1, 0.5 or 1.0 ng/mL. 
     
     
         21 . The method of  claim 19 , wherein said administering is for 7 days or more. 
     
     
         22 . The method of  claim 19 , wherein said administering is for 14 days or more. 
     
     
         23 . The method of  claim 19 , wherein said administering is for 28 days or more. 
     
     
         24 . The method of  claim 19 , wherein said administering is for 2 months or more. 
     
     
         25 . The method of  claim 19 , wherein said administering is to a pregnant female for 7 days or more. 
     
     
         26 . The method of  claim 19 , wherein said administering is to a pregnant female from at least 1 day after conception through birth of an infant. 
     
     
         27 . The method of  claim 19 , wherein said administering is to a pregnant that has had preterm labor arrested. 
     
     
         28 . The method of  claim 19 , wherein said administering is to a pregnant that has had preterm labor arrested with a tocolytic. 
     
     
         29 . The method of  claim 19 , wherein said administering is twice a day. 
     
     
         30 . The method of  claim 19 , wherein said pharmaceutical composition has from 200 mg to 900 mg of 17-hydroxyprogesterone caproate. 
     
     
         31 . The method of  claim 19 , wherein said pharmaceutical composition is a tablet, capsule or caplet. 
     
     
         32 . The method of  claim 19 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier having one or more of a diluent, binder, disintegrant, lubricant or surfactant. 
     
     
         33 . The method of  claim 19 , wherein the pharmaceutical composition comprises a lipohilic, hydrophilic additive or both. 
     
     
         34 . The method of  claim 19 , wherein the one or more additional agents are chosen from a progestogen, a corticosteroid, a tocolytic, an antibiotic, a vitamin D compound or a combination thereof. 
     
     
         35 . The method of  claim 19 , wherein the one or more additional agents are chosen from vitamin A, B3, B6, C, D, folic acid, calcium, iron, magnesium, manganese, phosphorus, potassium, sodium, zinc, omega-3, eicosapentaenoic acid (EPA), docosahexaenoic (DHA) or a combination thereof. 
     
     
         36 . The method of  claim 19 , said pharmaceutical composition releasing greater than 10% after 1 hour when tested using a USP Type II apparatus at 50 rpm in an aqueous media having 3x or greater sink condition at 37.0° C. (±0.5). 
     
     
         37 . A method of treatment said method comprising administering to a subject an oral pharmaceutical composition comprising:
 a therapeutically effective amount of 17-hydroxyprogesterone caproate, and a pharmaceutically acceptable carrier said method further comprising a dose evaluation, change or titration based on a target biomarker, gestational age or a combination thereof.   
     
     
         38 . The method of  claim 37 , wherein said method comprises administering said pharmaceutical composition once, twice or three times a day as one to twelve unit dosage forms total per day to human subject, to provide a 17-hydroxyprogesterone caproate C avg-24h  of greater than about 0.1, 0.5 or 1.0 ng/mL. 
     
     
         39 . The method of  claim 37 , wherein said administering is for 7 days or more. 
     
     
         40 . The method of  claim 37 , wherein said administering is for 14 days or more. 
     
     
         41 . The method of  claim 37 , wherein said administering is for 28 days or more. 
     
     
         42 . The method of  claim 37 , wherein said administering is for 2 months or more. 
     
     
         43 . The method of  claim 37 , wherein said administering is to a pregnant female for 7 days or more. 
     
     
         44 . The method of  claim 37 , wherein said administering is to a pregnant female from at least 1 day after conception through birth of an infant. 
     
     
         45 . The method of  claim 37 , wherein said administering is to a pregnant that has had preterm labor arrested. 
     
     
         46 . The method of  claim 37 , wherein said administering is to a pregnant that has had preterm labor arrested with a tocolytic. 
     
     
         47 . The method of  claim 37 , wherein said administering is twice a day. 
     
     
         48 . The method of  claim 37 , wherein said pharmaceutical composition has from 200 mg to 900 mg of 17-hydroxyprogesterone caproate. 
     
     
         49 . The method of  claim 37 , wherein said pharmaceutical composition is a tablet, capsule or caplet. 
     
     
         50 . The method of  claim 37 , wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier having one or more of a diluent, binder, disintegrant, lubricant or surfactant. 
     
     
         51 . The method of  claim 37 , wherein the pharmaceutical composition comprises a lipophilic or hydrophilic additive. 
     
     
         52 . The method of  claim 37 , wherein the pharmaceutical composition comprises a lipophilic or hydrophilic surfactant. 
     
     
         53 . The method of  claim 37 , wherein the pharmaceutical composition releases greater than 10% after 1 hour when tested using a USP Type II apparatus at 50 rpm in an aqueous media having 1.5× or greater sink condition at 37.0° C. (±0.5). 
     
     
         54 . The method of  claim 37 , wherein the pharmaceutical composition releases greater than 10% after 1 hour when tested using a USP Type II apparatus at 50 rpm in an aqueous media having 3× or greater sink condition at 37.0° C. (±0.5). 
     
     
         55 . The method of  claim 37 , wherein the target biomarker is a serum 17-hydroxyprogesterone caproate level with a C avg-24h  greater than about 0.05, 0.1, 0.5, 0.7, 1.0, 1.5, 2.0, 3.0, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 35.0, 40.0, 45.0, 50.0 60.0, 75.0 or 100 ng/mL; less than any of these values; or within a range defined by any two of these values. 
     
     
         56 . The method of  claim 37 , wherein the dose evaluation or titration comprises determining serum or plasma 17 HPC levels after single dose administration at steady state. 
     
     
         57 . The method of  claim 37 , wherein the dose evaluation or titration comprises determining serum or plasma 17 HPC levels after single dose administration at steady state at a single time point within 12 hours of administering the single dose. 
     
     
         58 . The method of  claim 37 , wherein the dose evaluation or titration comprises determining serum or plasma 17 HPC levels after single dose administration at steady state at a single time point at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after administering the single dose. 
     
     
         59 . The method of  claim 37 , wherein the dose evaluation or titration comprises determining serum or plasma 17 HPC levels after single dose administration at steady state at a single time point at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after administering the single dose or between any two consecutive values. 
     
     
         60 . The method of  claim 37 , wherein when the serum or plasma 17 HPC levels of the dose evaluation or titration after single dose administration at steady state at a single time point at about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after administering the single dose are too low, the daily dose of 17 HPC is increased or too high the daily dose of 17 HPC is decreased. 
     
     
         61 . The pharmaceutical composition of  claim 1 , having a pharmaceutically acceptable carrier including at least a hydrophilic surfactant chosen from a poloxamer, a polyethylene glycol sorbitan fatty acid ester, a sorbitan fatty acid ester, a polyethylene glycol glycerol fatty acid ester, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, a lecithin, a bile salt or a combination thereof and said pharmaceutically acceptable carrier further comprising polyvinylpyrrolidone, croscarmellose, microcrystalline cellulose, magnesium stearate, silicon dioxide, stearic acid, mannitol, a polyvinyl alcohol copolymer, a polyvinylpyrrolidone copolymer, a polyethylene glycol copolymer, a methacrylic acid copolymer or a combination thereof.