Foamable Vehicles and Pharmaceutical Compositions Comprising Aprotic Polar Solvents and Uses Thereof

Abstract

The present invention teaches a foamable pharmaceutical and cosmetic compositions comprising an aprotic polar solvent; foam compositions and uses thereof.

1 - 45 . (canceled) 
     
     
         46 . A foamable composition comprising:
 a. about 15% to about 97% by weight of at least one aprotic polar solvent comprising DMSO;   b. at least one foaming or stabilizing member selected from the group consisting of:
 i. a surface-active agent; 
 ii. a foam adjuvant; and 
 iii. a polymeric agent; 
   c. optionally at least one solvent selected from the group consisting of:
 i. water; 
 ii. a protic polar solvent; and 
 iii. a hydrophobic carrier; 
   and   d. a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition.   
       wherein the resultant foam formed from the composition is thermally stable and breaks easily upon application of shear force. 
     
     
         47 . The foamable composition of  claim 46 , wherein the DMSO concentration is in the range between about 30% and about 60% by weight. 
     
     
         48 . The foamable composition of  claim 47 , wherein the DMSO concentration is about 45% by weight. 
     
     
         49 . The foamable composition of  claim 46 , wherein the composition comprises two or more of the foaming or stabilizing members. 
     
     
         50 . The foamable composition of  claim 49 , further comprising one of a protic polar solvent or a hydrophobic carrier or mixtures thereof. 
     
     
         51 . The foamable composition of  claim 46 , wherein the composition is waterless and further comprises a protic polar solvent. 
     
     
         52 . The foamable composition of  claim 46 , further comprising a therapeutically effective concentration of at least one active agent. 
     
     
         53 . The foamable composition of  claim 52 , wherein the active agent is selected from the group consisting of:
 a. a non-steroidal anti-inflammatory agent;   b. a non-steroidal anti-inflammatory agent selected from the group consisting of:
 i. a pharmaceutically active compound, other than a corticosteroid, which affects the immune system in a fashion that results in a reduction, inhibition, prevention, amelioration or prevention of an inflammatory process and/or the symptoms of inflammation and or the production pro-inflammatory cytokines and other pro-inflammatory mediators, thereby treating or preventing a disease that involves inflammation; 
 ii. an inhibitor of the cyclooxygenase (COX) enzyme; 
 iii. a COX-1 inhibitor; 
 iv. a COX-2 inhibitor; 
 v. a non-selective NSAID, which simultaneously inhibits both COX-1 and COX-2; 
 vi. an agent selected from the group consisting of salicylic acid, aspirin, sodium salicylate, choline magnesium trislicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, olsalazine, an ester of salicylic acid with a carboxylic acid, an ester of salicylic acid with a dicarboxylic acid, an ester of salicylic acid with a fatty acid, an ester of salicylic acid with a hydroxyl fatty acid, an ester of salicylic acid with an essential fatty acid, an ester of salicylic acid with a polycarboxylic acid, and any compound wherein salicylic acid is linked to an organic moiety through a covalent bond; 
 vii. an agent selected from the group consisting of para-aminophenol an indole-acetic acid derivative, indomethacin, sulindac, etodolac an aryl acetic acids, tolmetin, diclofenac, ketorolac, an arylpropionic acid, ibuprofen, naproxen, flubiprofen, ketoprofen, fenoprofen, oxaprozin, anthranilic acids, an anthranilic acid derivative, mefenamic acid, meclofenamic acid, an enolic acid, an oxicam, piroxicam, tenoxicam, a pyrazolidinedione, phenylbutazone and oxyphenthratrazone, an alkanone, nabumetone, a diaryl-substituted furanone, a diaryl-substituted pyrazoles, an indole acetic acid and a sulfonanilide; 
 and analogs, derivatives, salts, ions and complexes thereof. 
   c. a local anesthetic agent;   d. a local anesthetic agent selected from the group consisting of benzocaine, lidocaine, bupivacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine and phenol;   e. a steroid;   f. a steroid selected from the group consisting of:
 i. a corticosteroid, selected from the group consisting of hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethsone dipropionate, clobetasol valemate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortmate, mepreddisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, and triamcinolone; 
 ii. a hormone or a vitamin, selected from the group consisting of pregnane, cholestane, ergostane, aldosterone, androsterone, calcidiol, calciol, calcitriol, calcipotriol, clomegestone, cholesterol, corticosterone, cortisol, cortisone, dihydrotestosterone, ergosterol, estradiol, estriol, estrone, ethinylestradiol, fusidic acid, lanosterol, prednisolone, prednisone, progesterone, spironolactone, timobesone and testosterone; 
 and analogs, derivatives, salts, ions and complexes thereof; 
   g. a keratolytically active agent;   h. a keratolytically active agent selected from the group consisting of:
 i. an agent selected from the group consisting of a phenol or a substituted phenolic compound, resorcinol, hydroquinone and a cresol; 
 ii. a vitamin A or vitamin A derivative or analog selected from the group consisting of retinoic acid, isoretinoic acid, retinol, retinal, adapalene and tazarotene; 
 iii. a hydroxy acid selected from the group consisting of an alpha-hydroxy acid and a beta-hydroxy acid; 
 iv. urea and urea derivatives; 
   i. an immunomodulator;   j. an immunomodulator selected from the group consisting of a cyclic peptide, cyclosporine, tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus, laflunimus, laquinimod and imiquimod;   k. a retinoid;   l. a retinoid selected from the group consisting of retinol, retinal, retinoic acid, isotretinoin, tazarotene, adapalene, 13-cis-retinoic acid, acitretin, all-trans beta carotene, alpha carotene, lycopene, 9-cis-beta-carotene, lutein and zeaxanthin;   m. an anti-acne or an anti-rosacea active agent;   n. an anti-acne or an anti-rosacea active agent selected from the group consisting of resorcinol, sulfur, salicylic acid, a salicylate, an alpha-hydroxy acid, a nonsteroidal anti-inflammatory agent, an oxidating agent, benzoyl peroxide, retinoic acid, isoretinoic acid, adapalene, tazarotene, azelaic acid, an azelaic acid derivative, an antibiotic agent, erythromycin and clyndamycin, coal tar and a zinc salt;   o. an antipsoriasis agent;   p. an antipsoriasis agent selected from the group consisting of a keratolytically-active agents, salicylic acid, coal tar, anthralin, a corticosteroid, a vitamin D, a vitamin D derivative, a vitamin D analog, a vitamin D3 analog, calcitriol, calcipotriol, a retinoid, tazarotene and a photodymamic therapy agent;   q. an antiinfective agent;   r. an anti-infective agent selected from the group consisting of a beta-lactam antibiotic, an aminoglycoside, an ansa-type antibiotic, an anthraquinone, an azole, metronidazole, an antibiotic glycopeptide, a macrolide, erythromycin, clindamycin, an antibiotic nucleoside, an antibiotic peptide, polymyxin B, an antibiotic polyene, an antibiotic polyether, an antibiotic quinolone, an antibiotic steroid, fucidic acid, mupirocin, chloramphenicol, a sulfonamide, tetracycline, minocycline, docycycline, an antibiotic metal, silver, copper, zinc, mercury, tin, lead, bismuth, cadmium, chromium, an oxidizing agent, iodine, iodate, a periodate, a hypochlorite, a permanganate, a substance that release free radicals and/or active oxygen, a cationic antimicrobial agent, a quaternary ammonium compound, a biguanide, chlorohexidine, a triguanide, a bisbiguanide, a polymeric biguanide and a naturally occurring antibiotic compound;   s. an agent selected from the group consisting of: an active herbal extract, an acaricides, an age spot and keratose removing agent, an allergen, an analgesic agent, an antiallergic agent, an antiaging agent, an antibacterial agent, an antiburn agent, an anticancer agent, an antidandruff agent, an antidepressant, an antidermatitis agent, an antiedemic anent, an antifungal agent, an antihistamine, an antiirritant, an antilipemic agent, an antimycotic agent, an antioxidant, an antiparasitic agent, an antiproliferative agent, an antipruritic agent, an antiseborrheic agent, an antiseptic agent, an antiswelling agent, an antiviral agent, an anti-wart agent, an anti-wrinkle agent, an astringent, a beta-hydroxy acid, a topical cardiovascular agent, a chemotherapeutic agent, an immunogenic substance, a dicarboxylic acid, a disinfectant, a fungicide, a hair growth regulator, a haptene, a hormone, an immunosuppressant, an immunoregulating agent, an insecticide, an insect repellent, a lactam, a lubricating agent, a masking agent, a metal, a metal oxide, a mitocide, a neuropeptide, an oxidizing agent, a pediculicide, a peptide, a protein, a photodynamic therapy agent, a radical scavenger, a refatting agent, a sanative, a scabicide, a self tanning agent, a skin protective agent, a skin whitening agent, a vasoconstrictor, a vasodilator, a vitamin, a vitamin B, a vitamin B derivative, a vitamin C, a vitamin C derivative, a vitamin F, a vitamin F derivative, a vitamin K, a vitamin K derivative, a wound healing agent and a wart remover.   
     
     
         54 . The foamable composition of  claim 52 , wherein the active agent is insoluble in water and wherein the active agent is solubilized the in the composition. 
     
     
         55 . The foamable composition of  claim 52 , wherein the aprotic polar solvent is present in the composition in an amount sufficient to solubilize the active agent in the composition. 
     
     
         56 . The foamable composition of  claim 52 , wherein the active agent is intended for transdermal delivery; and wherein the aprotic polar solvent in included in the composition in a concentration which is sufficient to increase the rate of absorption of such active agent through organic tissues including skin and nails. 
     
     
         57 . The foamable composition of  claim 46 , wherein the aprotic polar solvent possesses inherent therapeutic properties; and wherein the aprotic polar solvent is included in the composition in a therapeutically effective concentration. 
     
     
         58 . The foamable composition of  claim 46 , wherein the foaming or stabilizing member comprises a polymeric agent that is a gelling agent. 
     
     
         59 . The foamable composition of  claim 58 , wherein the gelling agent is selected from the group consisting of cellulose ethers, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose, carboxymethyl cellulose, carboxymethylcellulose carboxymethylhydroxyethylcellulose, cationic celluloses, carbomer (homopolymer of acrylic acid is crosslinked with an allyl ether pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene), poloxamer and polyethylene glycol, having molecular weight of 1000 or more. 
     
     
         60 . The foamable composition of  claim 47 , comprising water, a hydrophobic carrier and a surface-active agent; wherein the composition is an emulsion between the aprotic polar solvent/water mixture and the hydrophobic carrier. 
     
     
         61 . The foamable composition of  claim 60 , wherein the amount of water is about 5% to about 85% by weight of the composition. 
     
     
         62 . A method of treating a dermatological or mucosal disorder of a mammalian subject, the method comprising:
 1) releasing from a container a foamable composition comprising:
 a. about 15% to about 97% by weight of at least one aprotic polar solvent comprising DMSO; 
 b. at least one foaming or stabilizing member selected from the group consisting of:
 i. a surface-active agent; 
 ii. a foam adjuvant; and 
 iii. a polymeric agent; 
 
 c. optionally at least one solvent, selected from the group, consisting of:
 i. water; 
 ii. a protic polar solvent; and 
 iii. a hydrophobic carrier; 
 
 d. a therapeutically effective concentration of an active agent; and 
 e. a liquefied or compressed gas propellant at a concentration of about 3% to about 25% by weight of the total composition; 
   
       wherein upon release from the container, the foamable composition forms a breakable foam that does not readily collapse upon exposure to body temperature;
 2) applying the breakable foam to a body surface of the subject; and 
 3) collapsing the breakable foam by applying shear force; 
 wherein the breakable foam readily spreads and is absorbed on the body surface. 
 
     
     
         63 . The method of  claim 62 , wherein the composition is waterless and comprises a protic polar solvent. 
     
     
         64 . The method of  claim 46 , wherein the foaming or stabilizing member comprises a polymeric agent that is a gelling agent. 
     
     
         65 . The method of  claim 62 , comprising water, a hydrophobic carrier and a surface-active agent; wherein the composition is an emulsion between the aprotic polar solvent/water mixture and the hydrophobic carrier. 
     
     
         66 . The method of  claim 62 , wherein the active agent is selected from the group consisting of
 a) a non-steroidal anti-inflammatory agent;   b) a non-steroidal anti-inflammatory agent selected from the group consisting of:
 i. a pharmaceutically active compound, other than a corticosteroid, which affects the immune system in a fashion that results in a reduction, inhibition, prevention, amelioration or prevention of an inflammatory process and/or the symptoms of inflammation and or the production pro-inflammatory cytokines and other pro-inflammatory mediators, thereby treating or preventing a disease that involves inflammation; 
 ii. an inhibitor of the cyclooxygenase (COX) enzyme; 
 iii. a COX-1 inhibitor; 
 iv. a COX-2 inhibitor; 
 v. a non-selective NSAID which simultaneously inhibits both COX-1 and COX-2; 
 vi. an agent selected from the group consisting of salicylic acid, aspirin, sodium salicylate, choline magnesium trislicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, olsalazine, an ester of salicylic acid with a carboxylic acid, an ester of salicylic acid with a dicarboxylic acid, an ester of salicylic acid with a fatty acid, an ester of salicylic acid with a hydroxyl fatty acid, an ester of salicylic acid with an essential fatty acid, an ester of salicylic acid with a polycarboxylic acid, and any compound wherein salicylic acid is linked to an organic moiety through a covalent bond; 
 vii. an agent selected from the group consisting of para-aminophenol an indole-acetic acid derivative, indomethacin, sulindac, etodolac an aryl acetic acids, tolmetin, diclofenac, ketorolac, an arylpropionic acid, ibuprofen, naproxen, flubiprofen, ketoprofen, fenoprofen, oxaprozin, anthranilic acids, an anthranilic acid derivative, mefenamic acid, meclofenamic acid, an enolic acid, an oxicam, piroxicam, tenoxicam, a pyrazolidinedione, phenylbutazone and oxyphenthratrazone, an alkanone, nabumetone, a diaryl-substituted furanone, a diaryl-substituted pyrazoles, an indole acetic acid and a sulfonanilide; 
 and analogs, derivatives, salts, ions and complexes thereof. 
   c) a local anesthetic agent;   d) a local anesthetic agent selected from the group consisting of benzocaine, lidocaine, bupivacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine and phenol;   e) a steroid;   f) a steroid selected from the group consisting of:
 i. a corticosteroid selected from the group consisting of hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethsone dipropionate, clobetasol valemate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortmate, mepreddisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, and triamcinolone; 
 ii. a hormone or a vitamin selected from the group consisting of pregnane, cholestane, ergostane, aldosterone, androsterone, calcidiol, calciol, calcitriol, calcipotriol, clomegestone, cholesterol, corticosterone, cortisol, cortisone, dihydrotestosterone, ergosterol, estradiol, estriol, estrone, ethinylestradiol, fusidic acid, lanosterol, prednisolone, prednisone, progesterone, spironolactone, timobesone and testosterone; 
 and analogs, derivatives, salts, ions and complexes thereof. 
   g) a keratolytically active agent;   h) a keratolytically active agent selected from the group consisting of:
 i. an agent selected from the group consisting of a phenol or a substituted phenolic compound, resorcinol, hydroquinone and a cresol; 
 ii. a vitamin A or vitamin A derivative or analog selected from the group consisting of retinoic acid, isoretinoic acid, retinol, retinal, adapalene and tazarotene; 
 iii. a hydroxy acid selected from the group consisting of an alpha-hydroxy acid and a beta-hydroxy acid; 
 iv. urea and urea derivatives; 
   i) an immunomodulator;   j) an immunomodulator selected from the group consisting of a cyclic peptide, cyclosporine, tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus, laflunimus, laquinimod and imiquimod;   k) a retinoid;   l) a retinoid selected from the group consisting of retinol, retinal, retinoic acid, isotretinoin, tazarotene, adapalene, 13-cis-retinoic acid, acitretin, all-trans beta carotene, alpha carotene, lycopene, 9-cis-beta-carotene, lutein and zeaxanthin;   m) an anti-acne or an anti-rosacea active agent;   n) an anti-acne or an anti-rosacea active agent selected from the group consisting of resorcinol, sulfur, salicylic acid, a salicylate, an alpha-hydroxy acid, a nonsteroidal anti-inflammatory agent, an oxidating agent, benzoyl peroxide, retinoic acid, isoretinoic acid, adapalene, tazarotene, azelaic acid, an azelaic acid derivative, an antibiotic agent, erythromycin and clyndamycin, coal tar and a zinc salt;   o) an antipsoriasis agent;   p) an antipsoriasis agent selected from the group consisting of a keratolytically-active agents, salicylic acid, coal tar, anthralin, a corticosteroid, a vitamin D, a vitamin D derivative, a vitamin D analog, a vitamin D3 analog, calcitriol, calcipotriol, a retinoid, tazarotene and a photodymamic therapy agent;   q) an antiinfective agent;   r) an anti-infective agent selected from the group consisting of a beta-lactam antibiotic, an aminoglycoside, an ansa-type antibiotic, an anthraquinone, an azole, metronidazole, an antibiotic glycopeptide, a macrolide, erythromycin, clindamycin, an antibiotic nucleoside, an antibiotic peptide, polymyxin B, an antibiotic polyene, an antibiotic polyether, an antibiotic quinolone, an antibiotic steroid, fucidic acid, mupirocin, chloramphenicol, a sulfonamide, tetracycline, minocycline, docycycline, an antibiotic metal, silver, copper, zinc, mercury, tin, lead, bismuth, cadmium, chromium, an oxidizing agent, iodine, iodate, a periodate, a hypochlorite, a permanganate, a substance that release free radicals and/or active oxygen, a cationic antimicrobial agent, a quaternary ammonium compound, a biguanide, chlorohexidine, a triguanide, a bisbiguanide, a polymeric biguanide and a naturally occurring antibiotic compound;   s) an agent selected from the group consisting of: an active herbal extract, an acaricides, an age spot and keratose removing agent, an allergen, an analgesic agent, an antiallergic agent, an antiaging agent, an antibacterial agent, an antiburn agent, an anticancer agent, an antidandruff agent, an antidepressant, an antidermatitis agent, an antiedemic anent, an antifungal agent, an antihistamine, an antiirritant, an antilipemic agent, an antimycotic agent, an antioxidant, an antiparasitic agent, an antiproliferative agent, an antipruritic agent, an antiseborrheic agent, an antiseptic agent, an antiswelling agent, an antiviral agent, an anti-wart agent, an anti-wrinkle agent, an astringent, a beta-hydroxy acid, a topical cardiovascular agent, a chemotherapeutic agent, an immunogenic substance, a dicarboxylic acid, a disinfectant, a fungicide, a hair growth regulator, a haptene, a hormone, an immunosuppressant, an immunoregulating agent, an insecticide, an insect repellent, a lactam, a lubricating agent, a masking agent, a metal, a metal oxide, a mitocide, a neuropeptide, an oxidizing agent, a pediculicide, a peptide, a protein, a photodynamic therapy agent, a radical scavenger, a refatting agent, a sanative, a scabicide, a self tanning agent, a skin protective agent, a skin whitening agent, a vasoconstrictor, a vasodilator, a vitamin, a vitamin B, a vitamin B derivative, a vitamin C, a vitamin C derivative, a vitamin F, a vitamin F derivative, a vitamin K, a vitamin K derivative, a wound healing agent and a wart remover.   
     
     
         67 . The method of  claim 62 , wherein the composition further comprises one or more additional agents selected from the group consisting of anti oxidants, anti-static agents, buffering agents, bulking agents, chelating agents, cleansers, colorants, diluents, dyes, emollients, fragrances, herbal extracts, humectants, keratolytic agents, pearlescent aids, perfuming agents, permeation enhancers, pH-adjusting agents, preservatives, skin penetration enhancers, softeners, solubilizers, sunscreens, sun blocking agents, viscosity modifiers, flavonoids and vitamins. 
     
     
         68 . The foamable carrier composition of  claim 51 , wherein the at least one foaming or stabilizing member selected from the group consisting of:
 i. a solid surface-active agent at room temperature having a HLB of less than about 5;   ii. a foam adjuvant;   iii. hydroxypropyl methylcellulose;   iv. a surface active agent and a foam adjuvant and or hydroxypropyl methylcellulose;   v. a surface active agent and a foam adjuvant and a polymeric agent; and   vi. a foam adjuvant and a polymeric agent.   
     
     
         69 . The composition of  claim 68 , further comprising urea. 
     
     
         70 . The composition of  claim 61  comprising at least two foaming or stabilizing members selected from the group consisting of:
 i. a surface-active agent; 
 ii. a foam adjuvant; 
 iii. a polymeric agent; and 
 iv. a foam adjuvant and a polymeric agent; 
 
       wherein the hydrophobic solvent comprises a petrolatum and wherein the protic polar solvent comprises ethanol. 
     
     
         71 . The composition of  claim 70 , further comprising urea. 
     
     
         72 . The composition of  claim 49 , comprising water, wherein the water is less than about 5%.