Trans-epithelial membrane drug delivery system
View Patent ↗The present invention relates to trans-epithelial membrane delivery systems, methods and kits that include an agent to penetrate the basement membrane, a membrane of the skin and mucosa previously known to be difficult to penetrate. In particular, the formulation includes a basement membrane disruptor that reversibly denatures or cleaves molecules of the basement membrane of the epithelial membrane. The formulation of the present invention further includes having at least one penetration agent, at least one vaso-modulator, and at least one active ingredient. In an embodiment, the penetration agent includes a solvent, a lipophilic agent, a hydrophilic agent, wherein the basement membrane disruptor, the vaso-modulator, and the active ingredient pass through the outer layers of the epithelial membrane. The basement membrane disruptor allows the vaso-modulator and the active ingredient pass through the basement membrane to smooth muscle. The active ingredient, once at the smooth muscle, is delivered locally to the tissue or systemically to the blood stream.
1. A formulation for trans-epithelial membrane delivery of an active ingredient to a mammal; the formulation comprises:
a) at least one first penetration agent, wherein the at least one first penetration agent is present in an amount ranging from 0.01% w/w to 2.0% w/w, wherein the at least one penetration agent is acetylcysteine, N-acetylcysteine, L-cysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mecysteine, dornase alfa, althea extract, Marshmallow root, bromelain, thyme, salt water, eucalyptol, rosemary extract, cineole, peppermint, frankincense, oregano, bergamot, nutmeg, cypress, camphene, geranium, pelargonium sidoide, cinnamon, lemon, citrus, d-limonene, 1-limonene, lavender, lemon grass, chamomile, basil or a combination thereof;
b) at least one basement membrane disruptor, wherein the at least one basement membrane disruptor is present in an amount ranging from 0.2% w/w to 10% w/w, wherein the at least one basement membrane disruptor is a serine protease, a cysteine protease, a threonine protease, an aspartic protease, a glutamic protease, a lipase, a lactase, an ox bile extract, a phytase, a pancreatin, a pepsin, Chymotrypsin A, α-trypsin, and β-trypsin, papain, papaya, bromelain, pineapple, or a combination thereof;
c) at least one vaso-modulator present in an amount ranging from 0.001% w/w to 15% w/w; and
d) at least one active ingredient;
wherein the formulation has a pH of between about 5.0 and about 6.5; and wherein the formulation allows for penetration of the active ingredient past the basement membrane.
2. The formulation of claim 1 , wherein the formulation allows for penetration of the active ingredient to a smooth muscle.
3. The formulation of claim 1 , wherein the body surface comprises skin, a mucosal membrane and a nail surface.
4. The formulation of claim 1 , wherein the body surface comprises skin, oral mucosa, vaginal mucosa, anal mucosa, throat mucosa, nasal mucosa, ocular tissue, tracheal mucosa, lungs, fingernail surface, or toenail surface.
5. The formulation of claim 1 , further comprising a second penetration agent that comprises a solvent, a lipophilic agent, a hydrophilic agent, or a combination thereof.
6. The formulation of claim 3 , wherein the first penetration agent allows the basement membrane disruptor, the vaso-modulator, and the active ingredient to pass through a stratum corneum layer and an epidermis of the skin or a stratified squamous epithelial layer of the mucosal membrane.
7. The formulation of claim 5 , wherein the second penetration agent comprises the solvent, wherein the solvent is selected from the group consisting of: one or more nonpolar solvents, one or more polar aprotic solvents, one or more polar protic solvents, one or more limonenes, one or more lipophilic agent, one or more fatty acid, and a combination thereof.
8. The formulation of claim 7 , wherein the second penetration agent comprises one or more nonpolar solvents is selected from the group consisting of: carbon tetrachloride, benzene, diethyl ether, hexane, methylene chloride, toluene and a combination thereof.
9. The formulation of claim 7 , wherein the second penetration agent comprises one or more polar aprotic solvents is selected from the group consisting of: propylene carbonate, acetone, ethyl acetate, acetonitrile, dimethylformamide, and a combination thereof.
10. The formulation of claim 7 , wherein the second penetration agent comprises one or more polar protic solvents is selected from the group consisting of: water, methanol, isopropanol, acetic acid, methanol, ethanol, n-propanol, n-butanol and a combination thereof.
11. The formulation of claim 7 , wherein the second penetration agent comprises one or more limonenes is selected from the group consisting of: D-limonene, L-Limonenes and a combination thereof.
12. The formulation of claim 7 , wherein the second penetration agent comprises one or more fatty acids is selected from the group consisting of: linoleic acids, linolenic acids, oleic acids, stearic acids, myristic acids, phosphatidylcholine, and a combination thereof.
13. The formulation of claim 1 , wherein the basement membrane disruptor denatures or cleaves one or more molecules of the basement membrane to allow for passage of the active ingredient.
14. The formulation of claim 1 , wherein the basement membrane disruptor allows the vaso-modulator and the active ingredient pass through the basement membrane.
15. The formulation of claim 1 , wherein the basement membrane disruptor further comprises one or more chaotropic agents.
16. The formulation of claim 1 , wherein basement membrane disruptor is selected from the group consisting of: guanidine hydrochloride, a guanidine salt, guanidine analogs, guanidine conjugates; and a combination thereof.
17. The formulation of claim 1 , wherein the vaso-modulator comprises a vasodilator.
18. The formulation of claim 17 , wherein the vasodilator allows for the active ingredient to be delivered systemically or to local tissue.
19. The formulation of claim 17 , wherein the vasodilator is selected from the group consisting of: amrinone, arginine, bamethan sulphate, bencyclane fumarate, benfurodil hemisuccinate, benzyl nicotinate, buflomedil hydrochloride, buphenine hydrochloride, butalamine hydrochloride, cetiedil citrate, ciclonicate, cinepazide maleate, cyclandelate, di isopropylammonium dichloroacetate, ethyl nicotinate, hepronicate, hexyl nicotinate, ifenprodil tartrate, inositol nicotinate, isoxsuprine hydrochloride, kallidinogenase, methyl nicotinate, naftidrofuryl oxalate, nicametate citrate, niceritrol, nicoboxil, nicofuranose, nicotinyl alcohol, nicotinyl alcohol tartrate, nitric oxide, nonivamide, oxpentifylline, papaverine, papaveroline, pentifylline, peroxynitrite, pinacidil, pipratecol, propentofyltine, raubasine, suloctidil, teasuprine, thymoxamine hydrochloride, tocopherol nicotinate, tolazoline, papaverine, xanthinol nicotinate, diazoxide, hydralazine, minoxidil, and sodium nitroprusside, clonidine, quanaberz, methyl dopa, alpha adrenoceptor, indoramin, phenoxybenzamine, phentolamine, prazosin, PDE-5 inhibitors, sildenafil, tadalafil, adrenergic neuron blocking agents, bedmidine, debrisoquine, guanethidine, ACE inhibitors, benazepril, captopril, cilazapril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril, ganglion blocking agents, pentolinium, trimetaphan, calcium channel blockers, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, verapamil, prostaglandins, prostacyclin, thrombuxane A2, leukotrienes, PGA, PGA1, PGA2, PGE1, PGE2, PGD, PGG, PGH, angiotensin II analogs, saralasin, nitroglycerin, labetalol, thrazide, isosorbide dinitrate, pentaerythritol tetranitrate, digitalis, hydralazine, diazoxide, sodium nitroprusside, and a combination thereof.
20. The formulation of claim 1 , wherein the active ingredient is present in an amount ranging from about 0.001% w/w and about 30% w/w.
21. The formulation of claim 1 , wherein the active ingredient is selected from the group consisting of: acetaminophen, acetohydoxamic acid, acetophenazine, acyclovir, albuterol, allopurinol, amiloride, amoxicillin, amphetamine, ampicillin, antisense polymers, atenolol, baclofen, beclomethasone, benfotiamine, betamethasone, budesonide, bumetanide, butorphanol, carbamazepine, carphenazine, celacoxhib, cefuroxime, cephradine, chloramphenicol, chlorothiazide, chlorzoxazone, cinoxacin, clorazepate, cloxacillin, cyclacillin, dapsone, dicloxacillin, diethylstilbestrol, dopamine, doxorubicin, erythropoietin, estradiol, fenoprofen, gabapentin, human growth hormone, hydralazine, hydrochlorothiazide, ibuprofen, indomethacin, insulin, isoproterenol, ketoprofen, levodopa, levothyroxine, meclofenamate, melphalan, metformin methyl salicylate, metronidazole, minoxidil, morphine, nadolol, nalidixic acid, naproxen, nomifensine, norfloxacin, oxaprozin, oxycontin, paramethasone, peptide fragments, perphenazine, phenylpropanolamine, pregabalin, probenecid, quinethazone, ritodrine, scopolamine, serotonin, sildenafil, tadalafil, terbutaline, terfenadine, tocainide, terbinafine, triamterene, riamterine, trimethoprim, valacyclovir, a sirtuin inhibitor, nicotinamide, AIII, coumarin, sirtinol, alpha-NAD, carbamido-NAD, trichostatin A, suramin sodium, apicidin, BML-210, BML-266, depudecin, HC Toxin, ITSA1, nullscript, phenylbutyrate, sodium, scriptaid, splitomicin, suberoyl bis-hydroxamic acid, a sirtuin activators, resveratrol, isonicotinamide, butein, luteolin, plant extract, hemp, nicotine, hemp derived compounds, terpenes, and a combination thereof.
22. The formulation of claim 1 , further comprising a transpiration barrier, wherein the transpiration barrier includes at least one of a chemical barrier or a physical barrier.
23. A kit for transdermal delivery of an active ingredient to a mammal; the kit comprises
a) at least one first penetration agent, wherein the at least one penetration agent is present in an amount ranging from 0.01% w/w to 2.0% w/w, wherein the at least one penetration agent is acetylcysteine, N-acetylcysteine, L-cysteine, ambroxol, bromhexine, carbocisteine, erdosteine, mecysteine, dornase alfa, althea extract, Marshmallow root, bromelain, thyme, salt water, eucalyptol, rosemary extract, cineole, peppermint, frankincense, oregano, bergamot, nutmeg, cypress, camphene, geranium, pelargonium sidoide, cinnamon, lemon, citrus, d-limonene, 1-limonene, lavender, lemon grass, chamomile, basil or a combination thereof;
b) at least one basement membrane disruptor, wherein the at least one basement membrane disruptor is present in an amount ranging from 0.2% w/w to 10% w/w, wherein the at least one basement membrane disruptor is a serine protease, a cysteine protease, a threonine protease, an aspartic protease, a glutamic protease, a lipase, a lactase, an ox bile extract, a phytase, a pancreatin, a pepsin, Chymotrypsin A, α-trypsin, and β-trypsin, papain, papaya, bromelain, pineapple, or a combination thereof;
c) at least one vaso-modulator present in an amount ranging from 0.001% w/w to 15% w/w; and
d) at least one active ingredient;
wherein the kit creates a formulation that allows for penetration of the active ingredient to a smooth muscle, wherein the formulation has a pH of between about 5.0 and about 6.5; and
wherein the formulation allows for penetration of the active ingredient past the basement membrane.
24. The kit of claim 23 , further comprising a set of written instructions for use, by or on said mammal.