US2017326159A1PendingUtilityA1

Methods of use to orally and topically treat acne and other skin conditions by administering a 19-nor containing vitamin d analog with or without a retinoid

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Assignee: WISCONSIN ALUMNI RES FOUNDPriority: Dec 29, 2006Filed: Aug 3, 2017Published: Nov 16, 2017
Est. expiryDec 29, 2026(~0.4 yrs left)· nominal 20-yr term from priority
Inventors:Margaret Clagett-DameHector F. DelucaNirca J. NievesLori A. PlumMary E. Kaiser
A61P 35/00A61P 43/00A61P 17/10A61K 2800/92A61K 9/0053A61K 47/10A61K 31/203A61P 17/06A61P 17/00A61K 9/0014A61K 9/0095A61K 8/67A61Q 19/00A61Q 19/08A61Q 19/004A61K 47/44A61K 31/59A61P 17/02
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Claims

Abstract

Oral and topical pharmaceutical compositions, kits and methods of treatment thereof for treating various skin disorder including acne, psoriasis, ichthyosis, photoaging, photodamaged skin, and, skin cancer. Exemplary vitamin D analogs as active pharmaceutical ingredients include 2-methylene-19-nor-20(S)-1α-hydroxy-bishomopregnacalciferol, 19-nor-26,27-dimethylene-20(S)-2-methylene-1α,25-dihydroxyvitamin D 3 , 2-methylene-1α,25-dihydroxy-(17E)-17(20)-dehydro-19-nor-vitamin D 3 , 2-methylene-19-nor-(24R)-1α,25-dihydroxyvitamin D 2 , 2-methylene-(20R,25S)-19,26-dinor-1α,25-dihydroxyvitamin D 3 , 2-methylene-19-nor-1α-hydroxy-pregnacalciferol, 1α-hydroxy-2-methylene-19-nor-homopregnacalciferol, (20R)-1α-hydroxy-2-methylene-19-nor-bishomopregnacalciferol, 2-methylene-19-nor-(20S)-1α-hydroxy-trishomopregnacalciferol, 2-methylene-23,23-difluoro-1α-hydroxy-19-nor-bishomopregnacalciferol, 2-methylene-(20S)-23,23-difluoro-1α-hydroxy-19-nor-bishomopregnancalciferol, (2-(3′hydroxypropyl-1′,2′-idene)-19,23,24-trinor-(20S)-1α-hydroxyvitamin D 3 , 2-methylene-18,19-dinor-(20S)-1α,25-dihydroxyvitamin D 3 , a stereoisomer thereof, a prodrug thereof in oral compositions, a salt thereof, and/or a solute thereof. Compounds that activate retinoic acid receptors, such as retinoyls and retinoyl esters, include 13-cis-retinoic acid, all-trans-retinoic acid, (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexeneyl)nona-2,4,6,8-tetraenoic acid, 9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraenoic acid, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-napthoic acid, 4-[1-(3,5,5,8,8-pentamethyl-tetralin-2-yl)ethenyl]benzoic acid, retinobenzoic acid, ethyl 6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]pyridine-3-carboxylate, retinoyl t-butyrate, retinoyl pinacol, retinoyl cholesterol, an isomer thereof, a prodrug thereof for oral compositions, an ester thereof, a salt thereof, and/or, a solute thereof. Combinations of such active ingredients demonstrate synergistic efficacy.

Claims

exact text as granted — not AI-modified
We claim: 
     
         1 . A composition for use in treating acne, the composition comprising a therapeutically effective dose of a 19-nor-containing vitamin D compound, a stereoisomer thereof, a salt thereof or a solute thereof, wherein the 19-nor-containing vitamin D compound has the structure: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein R 2  is selected from the group consisting of ═CH 2  and 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The composition of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (2MbisP), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         3 . The composition of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (2MPregna), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         4 . The composition of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (2MP), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         5 . The composition of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (20R-2MbisP), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         6 . The composition of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (2MTrisP), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         7 . The composition of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (FF-44), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         8 . The composition of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (FF-55), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         9 . The composition of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       (HPBS), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         10 . The composition of  claim 1  further comprising a therapeutically effective dose of a retinoid compound. 
     
     
         11 . The composition of  claim 10 , wherein the retinoid compound is selected from the group consisting of 13-cis-retinoic acid, all-trans-retinoic, 9-cis-retinoic acid, acitretin, adapalene, bexarotene, tamibarotene, tazarotene, retinoyl t-butyrate, retinoyl pinacol and retinoyl cholesterol, an isomer thereof, an ester thereof, a salt thereof, and a solute thereof. 
     
     
         12 . The composition of  claim 11 , wherein the retinoid compound is 13-cis-retinoic acid. 
     
     
         13 . The composition of  claim 10 , wherein the composition comprises
 (1) a therapeutically effective dose of 2MbisP, a stereoisomer thereof, a salt thereof, and a solute thereof, and   (2) a therapeutically effective dose of 13-cis-retinoic acid, an isomer thereof, an ester thereof, a salt thereof, and a solute thereof.   
     
     
         14 . The composition of  claim 13 , wherein the 2MbisP, the stereoisomer thereof, the salt thereof, and the solute thereof is administered topically, and the 13-cis-retinoic acid, the isomer thereof, the ester thereof, the salt thereof, and the solute thereof is administered orally. 
     
     
         15 . The composition of  claim 1 , wherein the compound is administered topically. 
     
     
         16 . The composition of  claim 1 , wherein the compound is administered orally. 
     
     
         17 . The composition of  claim 1 , wherein the compound further comprises a pharmaceutically acceptable carrier system, the carrier system comprising 30% to 70% ethanol and 70% to 30% propylene glycol. 
     
     
         18 . A method of treating a skin disorder, comprising administering an effective amount of a composition comprising a therapeutically effective dose of a 19-nor-containing vitamin D compound, a stereoisomer thereof, a salt thereof or a solute thereof, wherein the 19-nor-containing vitamin D compound has the structure: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of 
       
       
         
           
           
               
               
           
         
         wherein R 2  is selected from the group consisting of ═CH 2  and 
       
       
         
           
           
               
               
           
         
       
       and wherein the composition is administrable daily or intermittently and wherein the symptoms of the skin disorder are treated. 
     
     
         19 . The method of  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (2MbisP), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         20 . The method of  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (2MPregna), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         21 . The method of  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (2MP), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         22 . The method of  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (20R-2MbisP), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         23 . The method of  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (2MTrisP), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         24 . The method of  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (FF-44), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         25 . The method of  claim 18 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       (FF-55), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         26 . The method of  claim 18 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       (HPBS), a stereoisomer thereof, a salt thereof, and a solute thereof. 
     
     
         27 . The method of  claim 18  further comprising administering a therapeutically effective dose of a retinoid compound. 
     
     
         28 . The method of  claim 27 , wherein the retinoid compound is selected from the group consisting of 13-cis-retinoic acid, all-trans-retinoic, 9-cis-retinoic acid, acitretin, adapalene, bexarotene, tamibarotene, tazarotene, retinoyl t-butyrate, retinoyl pinacol and retinoyl cholesterol, an isomer thereof, an ester thereof, a salt thereof, and a solute thereof. 
     
     
         29 . The method of  claim 28 , wherein the retinoid compound is 13-cis-retinoic acid. 
     
     
         30 . The method of  claim 27 , wherein the composition comprises
 (1) a therapeutically effective dose of 2MbisP, a stereoisomer thereof, a salt thereof, and a solute thereof, and   (2) a therapeutically effective dose of 13-cis-retinoic acid, an isomer thereof, an ester thereof, a salt thereof, and a solute thereof.   
     
     
         31 . The method of  claim 30 , wherein the 2MbisP, the stereoisomer thereof, the salt thereof, and the solute thereof is administered topically, and the 13-cis-retinoic acid, the isomer thereof, the ester thereof, the salt thereof, and the solute thereof is administered orally. 
     
     
         32 . The method of  claim 14 , wherein the compound is administered topically or orally.

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