Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses

Abstract

The present invention relates to stable substantially non-aqueous, non-alcoholic, non-silicone, foamable carrier compositions comprising petrolatum or mixtures thereof, at least one foam agent, at least one propellant, and with and without the addition of an active agent. The formulations may contain a solvent substantially miscible therein. The present invention further provides a method of treating, alleviating or preventing a disorder of mammalian subject in need thereof, comprising administering the above-mentioned compositions to an afflicted target site of said mammalian subject.

1 . A non-aqueous, non-alcoholic foamable composition comprising:
 a foamable carrier and at least one liquefied or compressed gas propellant, wherein the foamable carrier comprises:   (1) a petrolatum or mixtures thereof at a concentration of about 25% to about 95% by weight;   (2) a solvent substantially miscible in the petrolatum at a concentration of about 0% to about 70% by weight;   (3) at least one foam agent selected from the group consisting of a surfactant, a surfactant system, a foam adjuvant and combinations thereof; at a concentration of about 0.1% to about 20% by weight;   wherein, in the absence of the solvent, the petrolatum is present in the foamable carrier at a concentration of at least about 50% by weight;   wherein, in the presence of the solvent:
 (i) the petrolatum is present in the foamable carrier at a concentration of at least about 25% by weight and the solvent and petrolatum are together present in the foamable carrier at a concentration of least about 55% by weight; or 
 (ii) the amount of petrolatum is about the same as or in excess of the solvent and, together, the solvent and petrolatum are present in the foamable carrier at a concentration of at least about 80%; 
   wherein the ratio of the foamable carrier to the propellant is 100:10 to 100:35;   wherein the composition is substantially free of silicone; and   wherein the composition is stored in an aerosol container and upon release expands to form a breakable foam.   
     
     
         2 . The composition of  claim 1  wherein the carrier further comprises at least one active pharmaceutical agent. 
     
     
         3 . The composition of  claim 2 , wherein the composition is flowable or flowable to a degree and or is shakable or substantially so when stored in an aerosol container and upon release expands to form a breakable foam having no substantial or sustained cooling affect and having a foam hardness in the range of about 5 g to about 100 g. 
     
     
         4 . The composition of  claim 3 , wherein the solvent is hydrophobic and is selected from the group consisting of an unctuous additive, an oil, a therapeutic oil, a PPG alkyl ether, or a combination thereof. 
     
     
         5 . The composition of  claim 4  wherein the solvent is PPG15 stearyl ether. 
     
     
         6 . The composition of  claim 4  wherein the solvent is a light mineral oil. 
     
     
         7 . The composition of  claim 4  wherein the solvent is a combination of an oil or therapeutic oil and a PPG alkyl ether. 
     
     
         8 . The composition of  claim 4  wherein the carrier further comprises at least one additional solvent selected from the group consisting of a hydrophobic solvent, a polar solvent, a penetrating agent, polyethylene glycol (PEG), isosorbide derivatives, dimethyl isosorbide, propylene gycol (PG), hexylene glycol and glycerin, diethylene glycol monoethyl ether, a liquid polyethylene glycol, glycofurol, tetrahydrofurfuryl alcohol, polyethyleneglycol, ether, DMSO, a pyrrolidone, N-methylpyrrolidones, N-Methyl-2-pyrrolidone, 1-Methyl-2-pyrrolidinone, ethyl proxitol, dimethylacetamide, a PEG-type surfactant, an alpha hydroxy acid, lactic acid and glycolic acid, hexylene glycol, benzyl alcohol, DMSO, glycofurol and ethoxydiglycol (transcutol), butylene glycols, glycerol, pentaerythritol, sorbitol, mannitol, oligosaccharides, monooleate of ethoxylated glycerides having about 8 to 10 ethylene oxide units, and cyclodextrins, esters, ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl butyrate, propylene glycol monoacetate, propylene glycol diacetate, epsilon-caprolactone and isomers thereof, delta-valerolactone and isomers thereof, beta-butyrolactone and isomers thereof dimethyl acetamide, and monooctanoin. 
     
     
         9 . The composition of  claim 1  wherein the carrier can hold one or more active agents at a concentration of up to about 33% by weight and still produce a good quality stable breakable foam. 
     
     
         10 . The composition of  claim 1  wherein the carrier has a relatively high viscosity from about 12,000 CP to about 500,000 CP. 
     
     
         11 . The composition of  claim 4  wherein the propellant dissolves in the composition. 
     
     
         12 . The composition of  claim 11  wherein the propellant is selected from the group consisting of a propellant comprising n-butane; a propellant comprising a mixture of n-butane, isobutene and propane and a propellant comprising a hydrofluorocarbon. 
     
     
         13 . The composition of  claim 1  wherein the surfactant or surfactant system is selected from the group consisting of: a polysorbate; polyoxyethylene (20) sorbitan monostearate; sorbitan monooleate; polyoxyethylene (20) sorbitan monooleate; sorbitan laurate; a polyoxyethylene fatty acid ester; Myrj 45, Myrj 49, Myrj 52 and Myrj 59; a polyoxyethylene alkylyl ether; polyoxyethylene cetyl ether;
 polyoxyethylene palmityl ether; polyethylene oxide hexadecyl ether; polyethylene glycol cetyl ether; brij 38, brij 52, brij 56 and brij W1; behenyl alcohol; a sucrose ester; a partial ester of sorbitol; sorbitan monolaurate; sorbitan monolaurate a monoglyceride; a diglyceride; isoceteth-20; ceteth 20 steareth 2; steareth 20; steareth 21; glyceryl monostearate; glucose methyl stearate; methyl glucose sesquistearate; Span 20; Span 80; Tween 20; Tween 80. a mono, di or tri fatty acid sucrose ester; laureth-4; glyceryl stearate and PEG-100 stearate; ceteareth-6 and stearyl alcohol; myrj 52; poyglyceryl 10 laurate; POE (2) cetyl ether; cetearyl glucoside and cetyryl alcohol; methyl glucose sesquistearate; span 60; sucrose stearic acid esters; sorbitan stearate and sucrose cocoate; Peg 40 stearate; isosteareth 20; a polymeric emulsifier, particularly Permulen (TRI or TR2); liquid crystal systems, particularly Arlatone (2121), Stepan (Mild RM1), Nikomulese (41) and Montanov (68) or   
       wherein the surfactant or surfactant system is a combination of at least two surfactants selected from the group consisting of combinations of: polyoxyethylene alkyl ethers, particularly Brij 59/Brij 10; Brij 52/Brij 10; Steareth 2/Steareth 20; Steareth 2/Steareth 21 (Brij 72/BRIJ 721); Myrj 52/Myrj 59; combinations of sucrose esters, particularly Surphope 1816/Surphope 1807; combinations of sorbitan esters, particularly Span 20/Span 80; Span 20/Span 60; combinations of sucrose esters and sorbitan esters, particularly Surphope 1811 and Span 60; combinations of liquid polysorbate detergents and PEG compounds, particularly Twin 80/PEG-40 stearate/methyl glucaso sequistearate. glyceryl stearate and PEG-100 stearate; ceteareth-6 and stearyl alcohol; cetearyl glucoside and cetyryl alcohol; sorbitan stearate and sucrose cocoate; and polysorbate 80 and PEG-40 stearate. 
     
     
         14 . The composition of  claim 1  wherein the foam adjuvant is selected from one or more of the group consisting of cetyl alcohol, stearyl alcohol, myristyl alcohol, oleyl alcohol, behenyl alcohol, and cetostearyl alcohol. 
     
     
         15 . The composition of  claim 1  wherein the petrolatum is substantially free of wax crystals. 
     
     
         16 . The composition of  claim 1  wherein the petrolatum is a mixture of a low melting point petrolatum and a higher melting point petrolatum. 
     
     
         17 . The composition of  claim 2  wherein the carrier further comprises at least one modulating agent selected from the group consisting of a pH adjuster, a buffering agent, a chelator, an antioxidant and an antionisation agent. 
     
     
         18 . The composition of  claim 2  wherein the carrier further comprises a stabilizing agent or preservative. 
     
     
         19 . The composition of  claim 1  wherein the carrier further comprises a polymeric agent
 wherein the polymeric agent is 0.01% to 5% by weight and is selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent.   
     
     
         20 . The composition of  claim 2  wherein the carrier further comprises a polymeric agent
 wherein the polymeric agent is 0.01% to 5% by weight and is selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent.   
     
     
         21 . The composition of  claim 2 , wherein the foam resulting from the foamable composition demonstrates at least eighteen of the following properties:
 x) a foam quality of 5-6;   y) a color of white to off-white; or a yellowish color:   z) no odor or faint odor; or substantially masked odor;   aa) a foam quality of 5-6 after one freeze-thaw cycle;   bb) a foam quality of 5-6 after two freeze-thaw cycles;   cc) a foam quality of 5-6 after three freeze-thaw cycles;   dd) a foam quality of 5-6 after four freeze-thaw cycles;   ee) a foam quality of 5-6 after about 3 weeks' storage at 30° C.;   ff) a foam quality of 5-6 after about 3 weeks' storage at 40° C.;   gg) a foam quality of 5-6 after about 3 months' storage at 30° C.;   hh) a foam quality of 5-6 after about 3 months' storage at 40° C.;   ii) a collapse time of more than 50 seconds;   jj) a collapse time of more than 120 seconds;   kk) a collapse time of more than 180 seconds;   ll) a collapse time of more than 300 seconds;   mm) a foam hardness in the range of about 5 g to about 100 g;   nn) a foam hardness in the range of about 15 g to about 55 g;   oo) a foam hardness in the range of about 30 g to about 85 g;   pp) a density of less than 0.5 g;   qq) a density of less than 0.3 g;   rr) a density of less than 0.2 g;   ss) a foam corneometer value of at least 50 after washing a formulation applied to the skin; and   tt) an average focus group score of 60 or more   
     
     
         22 . The composition of  claim 21 , wherein the foam demonstrates all of said properties. 
     
     
         23 . A non-aqueous, non-alcoholic foamable carrier composition comprising:
 a foamable carrier and at least one liquefied or compressed gas propellant, wherein the foamable carrier comprises:   (1) a petrolatum or mixtures thereof at a concentration of about 50% to about 95% by weight;   (2) a solvent substantially miscible in the petrolatum at a concentration of about 0% to about 45% by weight;   (3) at least one foam agent selected from the group consisting of a surfactant, a surfactant system; a foam adjuvant and combinations thereof at a concentration of about 0.1% to about 20% by weight; and   (4) an effective amount of an active pharmaceutical agent;   wherein the ratio of the foamable carrier to the propellant ranges from about 100:10 to about 100:35;   wherein the composition is substantially free of silicone; and   wherein the composition is resistant to centrifugation at 1000 rpm for about 10 minutes; wherein the composition is flowable or flowable to a degree and or is shakable or substantially so when stored in an aerosol container and upon release expands to form a breakable foam having no substantial or sustained cooling affect and having a foam hardness in the range of about 5 g to about 100 g.   
     
     
         24 . The composition of  claim 23  wherein the carrier further comprises at least one solvent selected from the group consisting of a hydrophilic solvent, a hydrophobic solvent, a polar solvent, and a penetrating agent. 
     
     
         25 . A kit comprising a dual chamber device or dual dispenser head, a first canister comprising a first foamable composition according to  claim 3  comprising a first active pharmaceutical ingredient and a second canister comprising a second foamable composition according to  claim 3  comprising a second active pharmaceutical ingredient, wherein each canister is connectable to the said device or head. 
     
     
         26 . The kit of  claim 25 , wherein the first active pharmaceutical ingredient is a steroid and the second active pharmaceutical ingredient is a vitamin D derivative. 
     
     
         27 . A method of treating, alleviating or preventing a disorder of a mammalian subject in need thereof, comprising administering a therapeutically effective amount of a foam produced from the composition of  claim 3  to an afflicted target site of said mammalian subject. 
     
     
         28 . A method of treating, alleviating or preventing nappy rash of a mammalian subject in need thereof, comprising administering a therapeutically effective amount of a foam produced from the compositions of  claim 23  to an afflicted target site of said mammalian subject. 
     
     
         29 . The composition of  claim 4  wherein the hydrophobic solvent is selected from the group consisting of:
 1 a high-melting point hydrocarbon;   2 a liquid oil originating from vegetable, marine or animal sources;   3 an oil selected from the group consisting of (1) a saturated oil; (2) an unsaturated oil; and (3) a polyunsaturated oil;   4 an oil selected from the group consisting of olive oil, corn oil, soybean oil, canola oil, cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seed oil, syzigium aromaticum oil, hempseed oil, herring oil, cod-liver oil, salmon oil, flaxseed oil, wheat germ oil and evening primrose oil;   5 an poly-unsaturated fatty acid selected from the group consisting of (1) an omega-3 fatty acid and (2) an omega-6 fatty acid;   6 an poly-unsaturated fatty acid selected from the group consisting of linoleic acid, linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA);   7 a therapeutically active oil;   8 an essential oil;   9 an oil derived from a plant selected from the group consisting of anise, basil, bergemont, camphor, cardamom, carrot, canola, cassia, catnip, cedarwood, citronella, clove, cypress, eucalyptus, frankincense, garlic, ginger, grapefruit, hyssop, jasmine, jojova, lavender, lavandin, lemon, lime, mandarin, marjoram, myrrh, neroli, nutmeg, orange, peppermint, petitgrain, rosemary, rosehip, sage, spearmint, star anise, tea tree, tangerine, thyme vanilla, verbena and white clover;   10 a silicone oil;   11 an oil selected from the group consisting of a polyalkyl siloxane, a polyaryl siloxane, a polyalkylaryl siloxane, a polyether siloxane copolymer, a polydimethylsiloxane and a poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer;   12 a hydrophobic emollient; and   13 an oil selected from the group consisting of isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, cetyl acetate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, octyl dodecanol, sucrose esters of fatty acids and octyl hydroxystearate.   
     
     
         30 . The composition of  claim 3 , wherein the active agent is selected from the group consisting of an anti-infective agent, an antibiotic agent, an antibacterial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, a steroidal anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, an immunosuppressive agent, an immunomodulator, an immunoregulating agent, a hormonal agent, a steroid, a vasoactive agent, a vasoconstructor, a vasodilator, vitamin A, a vitamin A derivative, a retinoid, vitamin B, a vitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, a vitamin D derivative, vitamin E, a vitamin E derivative, vitamin F, a vitamin F derivative, vitamin K, a vitamin K derivative, a wound healing agent, a burn healing agent, a disinfectant, an anesthetic, an antiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a peptide, a neuropeptide, an allergen, an immunogenic substance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylic acid, azelaic acid, sebacic acid, adipic acid, fumaric acid, an insectoside, a retinoid, an antiproliferative agent, an anticancer agent, a photodynamic therapy agent, an anti-wrinkle agent, a radical scavenger, a metal oxide (e.g., titanium dioxide, zinc oxide, zirconium oxide, iron oxide), silicone oxide, talc, an anti-acne agent, a skin whitening agent, a self tanning agent, an anti-cellulite agent, a skin protective agent, a masking agent, an anti-wart agent, a refatting agent, a lubricating agent and mixtures thereof at any proportion or wherein the active agent is selected from the group consisting of acyclovir, azelaic acid, allantoin, ammonium lactate, benzoyl peroxide, caffeine, calcipotriol, calcitriol, nicotinamide, ciclopirox olamine, clindamycin hydrochloride, clindamycin phosphate, clindamycin palmitate hydrochloride, coal tar, cyanocobalamine, diclofenac sodium, gentamycin sulphate, lactic acid, glycyrrhizinic acid, map (magnesium ascorbyl phosphate), minoxidil, mupirocin, salicylic acid, terbinafine, urea, fusidic acid, a hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, a clobetasol, a halobetasol, a batamethsone; halobetasol and clobetasol-17-propionate or 17-butyrate; ketoconazole, lidocaine hydrochloride, metronidazole, tetracycline, tetracycline hydrochloride, meclocycline sulfosalicylate, resorcinol, chloramphenicol, erythromycin, acriflavinium monochloride, ethacridine lactate, dibrompropamidine isetionate, chlorhexidine acetate, chlorhexidine gluconate, chlorhexidine hydrochloride, hexamidine isetionate, phenol, povidone-iodine, dequalinium chloride, hydroxyquinoline sulfate, potassium hydroxyquinoline sulphate, benzalkonium chloride, cetrimonium bromide, cetylpyridinium chloride, cetrimide, phenylmercuric acetate, phenylmercuric borate, mercuric chloride, silver nitrate, potassium permanganate, tosylchloramide sodium, prednisolone sodium phosphate, betamethasone sodium phosphate, betamethasone 17-valerate, betamethasone diproprionate, demeclocycline, demeclocycline hydrochloride, chlortetracycline hydrochloride, oxytetracycline hydrochloride, neomycin sulfate, bacitracin zinc, gentamicin sulphate, amikacin, amikacin sulphate, sulfathiazole sodium, mafenide acetate, idoxuridine, fumaric acid, mepyramine maleate, tripelennamine hydrochloride, promethazine hydrochloride, dimetindene maleate, diphenhydramine hydrochloride, cinchocaine hydrochloride, oxybuprocaine hydrochloride, benzocaine, tetracaine hydrochloride, pramoxine hydrochloride, panthenol, dexpanthenol, calcium pantothenate, hyaluronic acid, trypsin, aminobenzoic acid, methylrosanilinium chloride, sodium butyl hydroxybenzoate, sodium ethyl hydroxybenzoate, sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate, flucytosine and fluconazole. 
     
     
         31 . The composition of  claim 30  wherein the active agent is selected from the group consisting of a nonsteroidal anti-inflammatory drug, an immunosuppressive agent, an immunomodulator, an immunoregulating agent, a hormonal agent, a steroid, a steroidal anti-inflammatory agent, vitamin A, a vitamin A derivative, vitamin D and a vitamin D derivative. 
     
     
         32 . The composition of  claim 30  wherein the active agent is calcipotriol or calcitriol. 
     
     
         33 . The composition of  claim 31  wherein the active agent is a steroid selected from the group consisting of betamethasone diproprionate, a clobetasol, a halobetasol, or derivatives thereof. 
     
     
         34 . The composition of  claim 33  wherein the active agent is a combination of betamethasone diproprionate and calcipotriol. 
     
     
         35 . The composition of  claim 2 , wherein the active agent comprises an extract or tincture comprising one or more beneficial agents selected from the group consisting of proteins, polypeptides, sugars, hyularonic acid herbal extracts and coal tar. 
     
     
         36 . A composition of  claim 23  wherein the composition provides at least two of the following traits:
 a) increased solubility of the active agent;   b) increased delivery of the active agent;   c) enhanced skin barrier build up;   d) increased penetration of the active agent whilst replenishing the skin; or   e) prolonging the delivery of the active agent whilst replenishing the skin.   
     
     
         37 . A composition of  claim 23  wherein the composition provides at least two of the following traits:
 a) the composition is able to at least partially solubilize the active agent;   b) the composition is able to substantially solubilize the active agent;   c) the active agent is at least partially soluble in petrolatum or mixtures thereof;   d) the active agent is at least partially soluble in a solvent substantially miscible in petrolatum or mixtures thereof;   e) the active agent is at least partially soluble in a hydrophilic solvent;   f) the active agent is at least partially soluble in an oil;   g) the active agent is at least partially soluble in a PPG alkyl ether; or   h) the active agent is insoluble or slightly soluble and is distributed uniformly in the composition.   
     
     
         38 . The compositions of  claim 19  wherein the polymeric agent selected from the group consisting of ASOS, an alkyl lactate, C-12 to C-15 alkyl lactate, a cellulose, carboxymethyl cellulose sodium, microcrystalline cellulose, methocel and xantham gum. 
     
     
         39 . The compositions of  claim 20  wherein the polymeric agent selected from the group consisting of ASOS, an alkyl lactate, C-12 to C-15 alkyl lactate, a cellulose, carboxymethyl cellulose sodium, microcrystalline cellulose, methocel and xantham gum. 
     
     
         40 . A low water content, non-alcoholic foamable composition comprising:
 a foamable carrier and at least one liquefied or compressed gas propellant, wherein the foamable carrier comprises:   (1) a petrolatum or mixtures thereof at a concentration of about 25% to about 95% by weight;   (2) a solvent substantially miscible in the petrolatum at a concentration of 0% to about 70% by weight;   (3) at least one foam agent selected from the group consisting of a surfactant, a surfactant system, a foam adjuvant and combinations thereof; at a concentration of about 0.1% to about 20% by weight; and   (4) water at a concentration of up to about 26% by weight   wherein, in the absence of the solvent, the petrolatum is present in the foamable carrier at a concentration of at least about 50% by weight;   wherein, in the presence of the solvent:
 (i) the petrolatum is present in the foamable carrier at a concentration of at least about 25% by weight and the solvent and petrolatum are together present in the foamable carrier at a concentration of least about 55% by weight; or 
 (ii) the amount of petrolatum is about the same as or in excess of the solvent and, together, the solvent and petrolatum are present in the foamable carrier at a concentration of at least about 80%; 
   wherein the ratio of the foamable carrier to the propellant ranges from about 100:10 to about 100:35;   wherein the composition is substantially free of silicone; and   wherein the composition is stored in an aerosol container and upon release expands to form a breakable foam.   
     
     
         41 . A low water content, non-alcoholic foamable carrier composition comprising:
 a foamable carrier and at least one liquefied or compressed gas propellant, wherein the foamable carrier comprises:   (1) a petrolatum or mixtures thereof at a concentration of about 50% to about 95% by weight;   (2) a solvent substantially miscible in the petrolatum at a concentration of about 0% to about 45% by weight;   (3) at least one foam agent selected from the group consisting of a surfactant, a surfactant system; a foam adjuvant and combinations thereof at a concentration of about 0.1% to about 20% by weight; and   (4) an effective amount of an active pharmaceutical agent;   wherein the solvent is water and is present in the carrier at a concentration of about 0.1% to about 26% by weight;   wherein the ratio of the foamable carrier to the propellant ranges from about 100:10 to about 100:35;   wherein the composition is substantially free of silicone; and   wherein the composition is resistant to centrifugation at 1000 rpm for about 10 minutes; wherein the composition is flowable or flowable to a degree and or is shakable or substantially so when stored in an aerosol container and upon release expands to form a breakable foam having no substantial or sustained cooling affect and having a foam hardness in the range of about 5 g to about 100 g.