Compositions comprising bioreversible derivatives of hydroxy n-substituted-2-aminotetralins, and related dosage forms

Abstract

Described are compositions that may be orally administered that comprise a bioreversible derivative of hydroxy N-substituted-2-aminotetralin or an enantiomer or salt or prodrug thereof, and a pharmaceutically acceptable carrier suitable for oral administration in the amount present, wherein the composition is orally bioavailable when administered to a subject. The bioreversible derivative has an intrinsic lipophilicity C log P value of about 7 to about 11.5. A method comprises oral administering such composition to a human subject in need of hydroxy N-substituted-2-aminotetralin therapy.

What is claimed is: 
     
         1 . A composition comprising:
 a bioreversible ester derivative of hydroxy N-substituted-2-aminotetralin or an enantiomer or salt of the bioreversible derivative; and   a pharmaceutically acceptable carrier,   wherein the hydroxy N-substituted-2-aminotetralin has formula (I), where R a  is selected from the group consisting of H, 2-thiophen-2-ylethyl, and n-propyl,   
       
         
           
           
               
               
           
         
         wherein the hydroxyl group of (I) is substituted with an ester, and 
         wherein the bioreversible ester derivative comprises from 27 to 35 carbon atoms and from 37 to 51 hydrogen atoms when R a  is 2-thiophen-2-ylethyl. 
       
     
     
         2 . The composition of  claim 1 , wherein the bioreversible ester derivative has an intrinsic lipophilicity C log P value of about 7 to about 11.5. 
     
     
         3 . The composition of  claim 1 , wherein the hydroxy N-substituted-2-aminotetralin is selected from the group consisting of (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol compound of formula (IA), (6S)-(−)-5-hydroxy-N-propyl-2-aminotetralin compound of formula (IB), 8-hydroxy-N,N-dipropyl-2-aminotetralin compound of formula (IC), 5-hydroxy-N,N-dipropyl-2-aminotetralin compound of formula (ID), and 7-hydroxy-N,N-dipropyl-2-aminotetralin compound of formula (1E). 
       
         
           
           
               
               
           
         
       
     
     
         4 . A composition comprising:
 a bioreversible derivative of hydroxy N-substituted-2-aminotetralin or an enantiomer or salt thereof, wherein the bioreversible derivative has the following structure:   
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aralkyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acetal, ketal, —C(O)NR 2 R 3 , —C(O)NHR 2 , —S(O) 2 R 2 , —S(O) 2 OR 2 , —P(O 2 H)OR 2 ; and 
         R 2  and R 3  are independently selected from the group consisting of H, C 1-16  alkyl or alkenyl or alkynyl, C 3-16  cycloalkyl or cycloalkenyl or cycloalkynl, benzyl, and phenyl. 
       
     
     
         5 . The composition of  claim 4 , wherein the bioreversible derivative of the hydroxy N-substituted-2-aminotetralin has the following structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group of C 3-14  cycloalkylcarbonyl, —C(O)NR 2 R 3 , and —C(O)NHR 2 , and 
         R 2  and R 3  are independently selected from the group consisting of C 1-12  alkylcarbonyl, and C 3-12  cycloalkylcarbonyl. 
       
     
     
         6 . The composition of  claim 1 , wherein the bioreversible ester derivative, when administered to a human body, is cleaved, processed or metabolized to (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol, or a metabolite thereof. 
     
     
         7 . The composition of  claim 1 , wherein the bioreversible ester derivative comprises a carbonyl, carbamate, carbonate, ketal, acetate, phosphate, phosphonate, sulfate, or sulfonate. 
     
     
         8 . The composition of  claim 1 , wherein the pharmaceutically acceptable carrier comprises at least one of a lipophilic additive and a hydrophilic additive. 
     
     
         9 . The composition of  claim 8 , wherein solubility of the bioreversible derivative in a lipophilic additive under ambient conditions is from about 5 mg/g to about 300 mg/g. 
     
     
         10 . The composition of  claim 8 , wherein solubility of the bioreversible derivative in a lipophilic additive is from about 20 mg/g to about 200 mg/g. 
     
     
         11 . The composition of  claim 8 , wherein the lipophilic additive includes a constituent selected from the group consisting of lipophilic surfactant(s), triglyceride(s), oil(s), fatty acid(s), fatty acid glyceride(s), tocopherol(s), tocopherol derivative(s), and a mixture of any thereof. 
     
     
         12 . The composition of  claim 1 , wherein the pharmaceutically acceptable carrier comprises at least one constituent selected from the group consisting of hydrophilic triglyceride, hydrophilic surfactant(s), cellulose(s), polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, polyethylene glycol, and a mixture of any thereof. 
     
     
         13 . The composition of  claim 1 , further comprising at least one other active agent selected from the group consisting of an anticonvulsant, an opioid, a CGRP antagonist, a NMDA receptor blocker, a cannabinoid, a bradykinin antagonist, acetaminophen, dextromethorphan, a NTHE, a COX-2 selective inhibitor, a sedative, an antidepressant, a tranquilizer, a neuroprotective agent, an antipsychotic, an anxiolytic, an anti-migraine agent, and a mixture of any thereof. 
     
     
         14 . A method of treating a human subject for at least one syndrome selected from the group consisting of Parkinson's disease and restless leg syndrome, wherein the method comprises:
 orally administering to the human subject the composition of  claim 1 .   
     
     
         15 . An oral unit dosage form for a human subject, wherein the oral unit dosage form comprises:
 the composition of  claim 1 ,   which oral dosage form provides a daily dose of the (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol, or the salt or enantiomer thereof, of about 0.5 mg to about 400 mg of the (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol equivalent to the human subject, based on single unit or multiple unit oral dosing.   
     
     
         16 . The oral unit dosage form of  claim 15 , wherein the oral unit dosage form provides a mean serum rotigotine or its metabolite Cmax value in a subject orally administered such oral dosage form of at least about 0.04 ng/ml after single dose. 
     
     
         17 . The oral unit dosage form of  claim 15 , wherein the oral unit dosage form provides a mean serum rotigotine or its metabolite Cmax/mg value in a subject orally administered such oral dosage form of at least about 1.0×10 −10  ml −1 . 
     
     
         18 . The oral unit dosage form of  claim 15 , wherein the oral unit dosage form provides a mean Css-max/mg value in a subject orally administered such oral dosage form of at least about 2.5×10 −10  ml −1 . 
     
     
         19 . The oral unit dosage form of  claim 15 , wherein the oral unit dosage form provides a serum rotigotine or its metabolite Cavg value in a subject orally administered such oral dosage form of at least about 0.04 ng/ml. 
     
     
         20 . A dosage form for oral administration to a mammalian subject, the dosage form comprising:
 a 5-hydroxy bioreversible derivative of (S)-6-[propyl(2-thiophen-2-ylethyl) amino]-5,6,7,8-tetrahydronaphthalen-1-ol, or an enantiomer or salt thereof; and   a pharmaceutically acceptable carrier,   wherein the 5-hydroxy bioreversible derivative has an intrinsic lipophilicity C log P value of from 9 to 12.65, and   wherein the dosage form provides a mean serum AUC 0-24  of (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol of at least about 0.5 ng·hr·ml −1  after a single dose oral administration of a therapeutically effective amount to the mammalian subject when administered with a meal to the subject.   
     
     
         21 . The dosage form of  claim 20 , wherein the dosage form provides a mean serum (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol AUC 0-24  per mg of the 5-hydroxy bioreversible derivative equivalent administered of at least about 1.25×10 −9  hr·ml −1 . 
     
     
         22 . The dosage form of  claim 20 , wherein the dosage form provides a mean serum AUC 0-24  of (S)-6-[propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8-tetrahydronaphthalen-1-ol of no greater than about 94 ng·hr·ml −1 , upon single dose oral administration to the mammalian subject. 
     
     
         23 . The dosage form of  claim 20 , wherein the dosage form is orally administered to the mammalian subject with a meal that comprises at least about 15 g of fat. 
     
     
         24 . A composition comprising:
 a bioreversible ester derivative of hydroxy N-substituted-2-aminotetralin, or an enantiomer or salt of the bioreversible ester derivative; and   a pharmaceutically acceptable carrier,   wherein the bioreversible ester derivative has an intrinsic lipophilicity C log P value of from 9 to 12.65, and   wherein upon oral administration of the bioreversible derivative to a human subject, at least about 1% of the hydroxy N-substituted-2-aminotetralin equivalent dose is bioavailable as hydroxy N-substituted-2-aminotetralin to the human subject.   
     
     
         25 . The composition of  claim 24 , wherein the hydroxy N-substituted-2-aminotetralin is selected from the group consisting of (S)-6-[propyl(2-thiophen-2-ylethyl) amino]-5,6,7,8-tetrahydronaphthalen-1-ol, (6S)-(−)-5-hydroxy-N-propyl-2aminotetralin, 5-hydroxy-N,N-dipropyl-2-aminotetralin (5-OH-DPAT), 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT), and 7-hydroxy-N,N-dipropyl-2-aminotetralin (7-OH-DPAT). 
     
     
         26 . The composition of  claim 24 , wherein upon mixing the composition with an aqueous phosphate buffer at pH 7.4, at least about 0.1% of the bioreversible derivative exists in un-ionized form. 
     
     
         27 . A method of treating a human subject in need thereof, the method comprising:
 orally administering to the human subject the composition of  claim 24 ,   wherein the composition is administered with a meal.   
     
     
         28 . The method according to  claim 27 , wherein the meal comprises at least about 15 g of fat.