High penetration prodrug compositions of prostaglandins and related compounds

Abstract

The invention provides compositions of novel high penetration compositions (HPC) or high penetration prodrugs (HPP) of prostaglandins which are capable of crossing biological barriers with high penetration efficiency. The HPPs are capable of being converted to parent active drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, the HPPs are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPPs can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.

What is claimed is: 
     
         1 . A method for treating a disease or condition in a biological subject in need thereof, comprising administering to the biological subject a therapeutically effective amount of a compound selected from:
 N,N-diethylaminoethyl 11,15-dihydroxy-9-oxoprost-13-en-I-oate·HA;   N,N-diethylaminoethyl 9,11,15-trihydroxyprost-13-en-1-oate·HA;   N,N-diethylaminoethyl 9,11,15-trihydroxy-15-methylprosta-5,13-dien-1-oate·HA;   N,N-diethylaminoethyl 9,11,15-trihydroxy-15-methylprosta-4,5,13-trien-1-oate·HA;   N,N-diethylaminoethyl 9,11-dihydroxy-15-keto-20-ethylprosta-5,13-dien-1-oate·HA; and   N,N-diethylaminoethyl 11,16-dihydroxy-9-oxo-16-methylprost-13-en-1-oate·HA,   
       wherein HA is nothing or a pharmaceutically acceptable acid. 
     
     
         2 . The method of  claim 1 , wherein the pharmaceutically acceptable acid is selected from hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfuric acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid, and pamoic acid. 
     
     
         3 . The method of  claim 1 , wherein the compound is selected from:
 N,N-diethylaminoethyl 11,15-dihydroxy-9-oxoprost-13-en-1-oate·AcOH; and   N,N-diethylaminoethyl 11,16-dihydroxy-9-oxo-16-methylprost-13-en-I-oate·AcOH.   
     
     
         4 . The method of  claim 1 , wherein the disease or condition is selected from reproduction disease or abnormal birth of a human or animal, peptic ulcers, severe Raynaud's phenomenon or ischemia of a limb, abnormal blood pressure, cardiovascular diseases or dysfunction, eye disease, sexual dysfunctions, bone diseases, pulmonary diseases, gastrointestinal disease, inflammation, shock and fertility. 
     
     
         5 . The method of  claim 4 , wherein the abnormal birth of a human or animal is inducing childbirth (parturition) or abortion. 
     
     
         6 . The method of  claim 4 , wherein the eye disease is glaucoma or conjunctival hyperemia ocular hypertension, loss of vision after ophthalmic surgery, vision of a warm-blooded animal impaired by cystoid macular edema or cataract. 
     
     
         7 . The method of  claim 4 , wherein the abnormal blood pressure is hypertension, hypotension or pulmonary hypertension. 
     
     
         8 . The method of  claim 4 , wherein the sexual dysfunctions is male erectile or female sexual arousal dysfunction. 
     
     
         9 . The method of  claim 1 , wherein the compound is administered to the biological subject through a route selected from oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and parenteral administration. 
     
     
         10 . A method for treating a disease or condition in a biological subject, comprising administering to the biological subject a pharmaceutical composition comprising a compound selected from:
 N,N-diethylaminoethyl 11,15-dihydroxy-9-oxoprost-13-en-I-oate·HA;   N,N-diethylaminoethyl 9,11,15-trihydroxyprost-13-en-1-oate·HA;   N,N-diethylaminoethyl 9,11,15-trihydroxy-15-methylprosta-5,13-dien-1-oate·HA;   N,N-diethylaminoethyl 9,11,15-trihydroxy-15-methylprosta-4,5,13-trien-1-oate·HA;   N,N-diethylaminoethyl 9,11-dihydroxy-15-keto-20-ethylprosta-5,13-dien-1-oate·HA; and   N,N-diethylaminoethyl 11,16-dihydroxy-9-oxo-16-methylprost-13-en-I-oate·HA,   
       wherein HA is nothing or a pharmaceutically acceptable acid, and a pharmaceutically acceptable carrier. 
     
     
         11 . The method of  claim 10 , wherein the pharmaceutically acceptable acid is selected from hydrochloride, hydrobromide, hydroiodide, nitric acid, sulfuric acid, phosphoric acid, phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid, and pamoic acid. 
     
     
         12 . The method of  claim 10 , wherein the compound is selected from:
 N,N-diethylaminoethyl 11,15-dihydroxy-9-oxoprost-13-en-I-oate·AcOH; and   N,N-diethylaminoethyl 11,16-dihydroxy-9-oxo-16-methylprost-13-en-I-oate·AcOH.   
     
     
         13 . The method of  claim 10 , wherein the pharmaceutically acceptable carrier is selected from sugars, starches, cellulose, cellulose derivatives, tragacanth, malt, gelatin, talc, cocoa butter, suppository waxes, oils, glycols, polyols, esters, agar, buffering agents, alginic acid, water, aqueous solutions, buffered saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, acetone, sodium citrate, and dicalcium phosphate. 
     
     
         14 . The method of  claim 10 , wherein the pharmaceutically acceptable carrier is selected from ethyl alcohol, acetone, esters, water, and aqueous solutions. 
     
     
         15 . The method of  claim 10 , wherein the disease or condition is selected from reproduction disease or abnormal birth of a human or animal, peptic ulcers, severe Raynaud's phenomenon or ischemia of a limb, abnormal blood pressure, cardiovascular diseases or dysfunction, eye disease, sexual dysfunctions, bone diseases, pulmonary diseases, gastrointestinal disease, inflammation, shock and fertility. 
     
     
         16 . The method of  claim 15 , wherein the abnormal birth of a human or animal is inducing childbirth (parturition) or abortion. 
     
     
         17 . The method of  claim 15 , wherein the eye disease is glaucoma or conjunctival hyperemia ocular hypertension, loss of vision after ophthalmic surgery, vision of a warm-blooded animal impaired by cystoid macular edema or cataract. 
     
     
         18 . The method of  claim 15 , wherein the abnormal blood pressure is hypertension, hypotension or pulmonary hypertension. 
     
     
         19 . The method of  claim 15 , wherein the sexual dysfunctions is male erectile or female sexual arousal dysfunction. 
     
     
         20 . The method of  claim 15 , wherein the pharmaceutical composition is administered to the biological subject through a route selected from oral, enteral, buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, and parenteral administration.