Topical formulations having enhanced bioavailability

Abstract

The present disclosure provides compositions suitable for delivering lipophilic bioactive agents. The compositions may be utilized to treat numerous diseases and conditions that would benefit from the application of a lipophilic bioactive agent.

1 . A composition comprising:
 a liposomal concentrate comprising a phospholipid selected from the group consisting of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, and combinations thereof;   at least one lipophilic bioactive agent; and   at least one solubilizer;   in combination with at least one pharmaceutically acceptable carrier possessing at least one permeation enhancer in an amount from about 0.5% by weight to about 20% by weight of the composition,   
       wherein the phospholipid is present in the composition in an amount from about 2% to about 20% by weight of the composition and the bioactive agent is present in an amount from about 0.5% to about 20% by weight of the composition. 
     
     
         2 . The composition of  claim 1 , wherein the phospholipid further comprises a solvent selected from the group consisting of water, purified water, deionized water, ethanol, isopropanol, glycols, diglycols, polyglycols, and combinations thereof. 
     
     
         3 . The composition of  claim 1 , wherein the phospholipid is in combination with an additional component selected from the group consisting of absorbents, antifoaming agents, acidifiers, alkalizers, buffers, antimicrobial agents, antioxidants, binders, solubilizing agents, solvents, viscosity modifiers, humectants, thickening agents, and combinations thereof. 
     
     
         4 . The composition of  claim 1 , wherein the at least one lipophilic bioactive agent is selected from the group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β-Blockers, cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastro-intestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2 inhibitors, leucotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and combinations thereof. 
     
     
         5 . The composition of  claim 1 , wherein the at least one lipophilic bioactive agent is selected from the group consisting of acutretin, albendazole, albuterol, aminogluthemide, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, beclomethsone, benezepril, benzonatate, betamethasone, bicalutanide, budesonide, bupropion, busulphan, butenafine, calcifediol, calciprotiene, calcitriol, camptothecan, candesartan, capsaicin, carbamezepine, carotenes, celecoxib, cerivistatin, cetrizine, chlorpheniramine, cholecalciferol, cilostazol, cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin, clemastine, clomiphene, clomipramine, clopidrogel, codeine, coenzyme Q10, cyclobenzaprine, cyclosporine, danazol, dantrolene, dexchlopheniramine, diclofenac, dicoumarol, digoxin, dihydroepiandrosterone, dihydroergotamine, dihydrotachysterol, dirithromycin, donepezil, efavirenz, eposartan, ergocalciferol, ergotamine, essential fatty acid sources, etodolac, etoposide, famotidine, fenofibrate, fentanyl, fexofenadine, finasteride, flucanazole, flurbiprofen, fluvastatin, fosphenylion, frovatriptan, furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide, glyburide, glymepride, griseofulvin, halofantrine, ibuprofen, irbesartan, irinotecan, isosorbide dinitrate isotreinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, lanosprazole, leflunomide, lisinopril, loperamide, loratadine, lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone, mefepristone, mefloquine, megesterol acetate, methadone, methoxsalen, metronidazole, metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone, montelukast, nabumetone, nalbuphine, naratiptan, nelfinavir, nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizatidine, omeprazole, oprevelkin, osteradiol, oxaprozin, paclitaxel, paricalcitol, paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin, prednisolone, probucol, progesterone, pseudo-ephedrine, pyridostigmine, rabeprazole, raloxifene, refocoxib, repaglinide, rifabutine, rifapentine, rimexolone, ritanovir, rizatriptan, rosigiltazone, saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine, terzosin, tetrahydrocannabinol, tiagabine, ticlidopine, tirofibran, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, valsartan, venlafaxine, vertoporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone, and combinations thereof. 
     
     
         6 . The composition of  claim 1 , wherein the pharmaceutically acceptable carrier is selected from the group consisting of solvents, buffers, antioxidants, antibacterial agents, antifungal agents, stabilizing excipients, absorption enhancing agents, absorption delaying agents, hydrophilic polymers, peptides, proteins, monosaccharides, disaccharides, carbohydrates, chelating agents, sugar alcohols, surfactants, and combinations thereof. 
     
     
         7 . The composition of  claim 1 , wherein the at least one permeation enhancer is selected from the group consisting of ethoxydiglycol, 1,3-butylene glycol, isopentyl diol, 1,2-pentane diol, propylene glycol, 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, di(2-hydroxypropyl)ether, pentan-2,4-diol, acetone, polyoxyethylene(2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1,4 dioxane, tetrahydrofuran, butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, polyoxyethylene ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, diisopropyl adipate, diisopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibuyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl salicylate, isopropyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, isopropyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hyroxyoctanoic acid, dimethyl sulphoxide, methyl sulfonyl methane, n,n-dimethyl acetamide, n,n-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, 1-dodecylazacyloheptan-2-one, and combinations thereof. 
     
     
         8 . The composition of  claim 1 , wherein the permeation enhancer is present in an amount from about 3% by weight to about 15% by weight of the composition and the bioactive agent is present in an amount of from about 0.75% by weight to about 10% by weight of the composition. 
     
     
         9 . The composition of  claim 1 , wherein the solubilizer is selected from the group consisting of polyoxyalkylene dextrans, fatty acid esters of saccharose, fatty alcohol ethers of oligoglucosides, fatty acid esters of glycerol, fatty acid esters of polyoxyethylenes, polyethoxylated fatty acid esters of sorbitan, fatty acid esters of poly(ethylene oxide), fatty alcohol ethers of poly(ethylene oxide), alkylphenol ethers of poly(ethylene oxide), polyoxyethylene-polyoxypropylene block copolymers, ethoxylated oils, and combinations thereof. 
     
     
         10 . The composition of  claim 1 , wherein the phospholipid comprises lecithin, the at least one lipophilic bioactive agent comprises coenzyme Q10, and the permeation enhancer comprises propylene glycol in combination with ethoxydiglycol. 
     
     
         11 . A pharmaceutical composition comprising the composition of  claim 1 , wherein the pharmaceutically acceptable carrier includes an oil phase, an optional water phase, and an optional neutralization phase. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the composition is selected from the group consisting of lotions and creams. 
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein the oil phase comprises emollients, fatty alcohols, emulsifiers, and combinations thereof. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the emollient is selected from the group consisting of C12-15 alkyl benzoates, capric-caprylic triglycerides, vegetable derived oils, caprates, linoleates, dilinoleates, isostearates, fumarates, sebacates, lactates, citrates, stearates, palmitates, synthetic medium chain triglycerides, silicone oils, polymers and combinations thereof; the fatty alcohol is selected from the group consisting of cetyl alcohol, stearyl alcohol, cetearyl alcohol, lauryl alcohol and combinations thereof; and the emulsifier is selected from the group consisting of glyceryl stearate, polyethylene glycol 100 stearate, neutralized fatty acids, partially neutralized fatty acids, polyethylene glycol 150 stearate, polyethylene glycol 8 laurate, polyethylene glycol oleate, polyethylene glycol 8 stearate, polyethylene glycol 20 stearate, polyethylene glycol 40 stearate, polyethylene glycol 150 distearate, polyethylene glycol 8 distearate, and combinations thereof. 
     
     
         15 . The pharmaceutical composition of  claim 11 , wherein the optional water phase comprises the permeation enhancer optionally in combination with a viscosity modifier selected from the group consisting of cross linked acrylic acid polymers, pullulan, mannan, scleroglucans, polyvinylpyrrolidone, polyvinyl alcohol, guar gum, hydroxypropyl guar gum, xanthan gum, acacia gum, arabia gum, tragacanth, galactan, carob gum, karaya gum, locust bean gum, carrageenin, pectin, amylopectin, agar, quince seed, rice starch, corn starch, potato starch, wheat starch, algae extract, dextran, succinoglucan, carboxymethyl starch, methylhydroxypropyl starch, sodium alginate, alginic acid propylene glycol esters, sodium polyacrylate, polyethylacrylate, polyacrylamide, polyethyleneimine, bentonite, aluminum magnesium silicate, laponite, hectonite, and anhydrous silicic acid. 
     
     
         16 . The pharmaceutical composition of  claim 11 , wherein the optional water phase comprises water, glycerine, propylene glycol, ethoxydiglycol, phenoxyethanol, and cross linked acrylic acid polymers. 
     
     
         17 . The pharmaceutical composition of  claim 11 , wherein the optional neutralization phase comprises components selected from the group consisting of water, amines, sodium lactate, lactic acid, and combinations thereof. 
     
     
         18 . The pharmaceutical composition of  claim 11 , further comprising a pigment. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the oil phase comprises C12-15 alkyl benzoates, cetyl alcohol, stearyl alcohol, glyceryl stearate and polyethylene glycol stearate; the water phase comprises glycerine, propylene glycol, ethoxydiglycol, phenoxyethanol, purified water, and a cross linked acrylic acid polymer dispersion comprising phenoxyethanol, propylene glycol, water, and a cross linked acrylic acid polymer; the neutralization phase comprised purified water, triethanolamine, sodium lactate, and lactic acid; and the pigment comprises titanium dioxide. 
     
     
         20 . A method for treating cancer comprising applying the composition of  claim 1  to a patient. 
     
     
         21 - 22 . (canceled)