Transdermal drug delivery system
View Patent ↗The present invention relates to transdermal delivery systems, methods and kits that include an agent to penetrate the basement membrane, a membrane of the skin previously known to be difficult to penetrate. In particular, the formulation includes a basement membrane disruptor that reversibly denatures the basement membrane of the skin. 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 stratum corneum and epidermis. The basement membrane disruptor allows the vaso-modulator and the active ingredient pass through the basement membrane to dermis. The active ingredient, once at the dermis, is delivered locally to the tissue or systemically to the blood stream.
1 . A formulation for transdermal delivery of an active ingredient to a mammal having a body surface; the formulation comprises
a) at least one penetration agent;
b) at least one basement membrane disruptor;
c) at least one vaso-modulator; and
d) at least one active ingredient.
2 . The formulation of claim 1 , wherein the formulation allows for penetration of the active ingredient to a dermis layer.
3 . The formulation of claim 1 , wherein the body surface comprises skin, mucosal membranes and nail surfaces.
4 . The formulation of claim 1 , wherein the body surface comprises skin, vaginal mucosa, anal mucosa, throat mucosa, nasal mucosa, ocular tissue, fingernail surface, or toe nail surface.
5 . The formulation of claim 1 , wherein the penetration agent comprises a solvent, a lipophilic agent, a hydrophilic agent, or a combination thereof.
6 . The formulation of claim 1 , wherein the penetration agent is present in an amount ranging from about 1% w/w and about 60% w/w.
7 . The formulation of claim 1 , wherein the penetration agent allows the basement membrane disruptor, the vaso-modulator, and the active ingredient to pass through the stratum corneum layer and the epidermis.
8 . The formulation of claim 5 , wherein the 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, and a combination thereof.
9 . The formulation of claim 8 , wherein the 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.
10 . The formulation of claim 8 , wherein the 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.
11 . The formulation of claim 8 , wherein the 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.
12 . The formulation of claim 8 , wherein the penetration agent comprises one or more limonenes is selected from the group consisting of: D-limonene, L-Limonenes and a combination thereof.
13 . The formulation of claim 1 , wherein the basement membrane disruptor denatures one or more molecules of the basement membrane to allow for passage of the active ingredient, and wherein the one or more molecules of the basement membrane renature once the active ingredient is delivered to the dermis.
14 . The formulation of claim 1 , wherein the basement membrane disruptor is present in an amount ranging from about 0.2% w/w and about 10% w/w.
15 . The formulation of claim 1 , wherein the basement membrane disruptor, when in use, reversibly denatures a basement membrane.
16 . The formulation of claim 1 , wherein the basement membrane disruptor allows the vaso-modulator and the active ingredient pass through the basement membrane.
17 . The formulation of claim 1 , wherein the basement membrane disruptor comprises one or more chaotropic agents.
18 . The formulation of claim 1 , wherein the basement membrane disruptor is selected from the group consisting of: guanidine hydrochloride, a guanidine salt, guanidine analogs, guanidine conjugates; and a combination thereof.
19 . The formulation of claim 1 , wherein the vaso-modulator is present in an amount ranging from about 0.005% w/w and about 15% w/w.
20 . The formulation of claim 1 , wherein the vaso-modulator comprises a vasodilator or vasoconstrictor.
21 . The formulation of claim 20 , wherein the vasodilator allows for the active ingredient to be delivered systemically or to local tissue.
22 . The formulation of claim 20 , 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.
23 . The formulation of claim 20 , wherein the vasoconstrictor allows for the active ingredient to be delivered to the dermis.
24 . The formulation of claim 20 , wherein the vasoconstrictor is selected from the group consisting of: adenosine triphosphate, amphetamine, antazoline, asymmetric dimethylarginine, cocaine, dopamine, endothelin, ephedrine, epinephrine, ergine, hydroxyamphetamine, isoproterenol, levonordefrin, metaraminol, methamphetamine, methoxamine, methylphenidate, neuropeptide Y, naphazoline, norepinephrine, oxymetazoline, phenylephrine, pseudoephedrine, tetrahydozoline, thromboxane, tramazoline, tyramine, and a combination thereof.
25 . 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.
26 . 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, 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, and a combination thereof.
27 . 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.
28 . A method for transdermal delivery of a formulation having an active ingredient to a mammal having a body surface, the method comprises:
a) applying the formulation to the body surface, wherein formulation comprises:
i) at least one penetration agent;
ii) at least one basement membrane disruptor;
iii) at least one vaso-modulator; and
iv) at least one active ingredient;
wherein the formulation allows for penetration of the active ingredient to a dermis layer of the body surface.
29 . A method for transdermal delivery of a formulation having an active ingredient to a mammal, said mammal having a body surface; the method comprises:
a) administering at least one penetration agent to the body surface;
b) administering at least one basement membrane disruptor to the body surface;
c) administering at least one vaso-modulator to the body surface; and
d) administering at least one active ingredient to the body surface;
wherein the formulation allows for penetration of the active ingredient to the dermis.
30 . The method of claim 29 , wherein the penetration agent, basement membrane, vaso-modulator, and active ingredient are applied sequentially.
31 . The method of claim 29 , wherein the penetration agent, basement membrane, vaso-modulator, and active ingredient are applied together.
32 . The method of claim 29 , further comprising applying an occlusive barrier to the body surface.
33 . A kit for transdermal delivery of an active ingredient to a mammal having a body surface; the kit comprises
a) at least one penetration agent;
b) at least one basement membrane disruptor;
c) at least one vaso-modulator; and
d) at least one active ingredient;
wherein the kit creates a formulation that allows for penetration of the active ingredient to a dermis layer of the body surface.
34 . The kit of claim 33 , further comprising a set of written instructions for use, by or on said mammal.