MXPA06006615A - Method of treatment for undesired effect following transdermal or topical drug delivery - Google Patents

Abstract

This invention relates to a method for inhibiting the percutaneous absorption of a physiologically active agent topically applied to a transdermal administration site of a subject, the method including the step of applying to skin of the subject at the transdermal administration site, a device (1, 7) comprising a membrane (8) for contacting the skin of the subject coated on the skin contacting side thereof (11) with a layer of an adhesive (10).

Description

METHOD OF TREATMENT FOR UNWANTED EFFECT AFTER TRANSDERMAL OR TOPICAL APPLICATION OF DRUG Field The present invention deals with a composition and method for reducing the effective transdermal dose of a topically applied drug for treatment or prophylaxis of undesired effects. The invention provides a method for inhibiting the release of a drug in the general system under circumstances such as an overdose or when an adverse reaction is expected or desired after the application. Background All drugs have the potential to be misused, whether they are legally prescribed by a doctor, bought without a prescription at the local pharmacy or purchased illegally. In combination with other drugs or alcohol, drugs that even under normal conditions are considered safe can cause death or serious long-term consequences. Accidental overdose with drugs can be the result of misuse of prescription medicines or commonly used medicines such as analgesics and cold remedies. The symptoms are different depending on the drug taken. Although many victims of unwanted drug effects recover without long-term effects, serious consequences may be possible in the long term.

Some drug overdoses can cause failure of major organs such as the kidneys or liver, or failure of complete devices such as the respiratory system or the circulatory system. The drugs have effects throughout the body.

Normally, in an overdose, the effects of the drug may be a sharper level of the therapeutic effects observed with regular use. In overdoses, the side effects become more pronounced and can lead to other effects that do not occur otherwise. Large overdoses of some drugs cause only minimal effects, although smaller overdoses of other drugs can cause serious effects, possibly death. Some overdoses can worsen a person's chronic illness, for example, an asthma attack or chest pains that can be triggered. Conventional means for administering antidotic agents to a human or animal that experiences an undesired effect is to pump the stomach, to mechanically remove non-absorbed drugs from the stomach or to administer substances such as activated charcoal, which help the drugs to stick and reduce the amount absorbed in the blood. However, these methods are only applicable for the treatment of oral overdose. The administration of therapeutic agents through the skin (transdermal administration of drugs) has received greater attention because it is considered that not only provides a relatively simple administration regime but also provides a relatively slow and controlled way to release an agent in the system the general circulation. Thus, any adverse reaction or error in the application would be traditionally remedied by the removal of the transdermal system. However, with the new transdermal technology, the rate of transdermal absorption has increased dramatically and the risk of error in the application has been amplified along with it. The treatment of non-oral overdose currently requires the administration of other medicines to reverse the effects or to prevent further damage. The removal of drugs from the skin and / or the general circulation offers several inherent clinical and patient advantages over traditional remedies in that it is non-invasive, avoids another reaction of the metabolism thus reducing the impact on the kidneys or liver, and can be self-administered Structurally, the skin consists of two main parts, a relatively thin outer layer (the epidermis) and a thicker inner region (the dermis). The outer layer of the epidermis (the stratum corneum) consists of flattened dead cells that are filled with keratin. The region between the flattened dead cells of the stratum corneum is filled with lipids that form the lamellar phases that are responsible for the natural barrier properties of the skin. The epidermal thickness is remarkably constant throughout the body, except in the soles of the feet and the palms of the hands (Rushmer, and collaborators, 1966, The Skin. Science 154 (3747), 343-348). For the effective transdermal administration of a therapeutic agent that is applied to the surface of the skin (topical application), the agent must first be divided from the vehicle in the stratum corneum, typically it must then be dispersed within the stratum corneum before dividing from the stratum corneum to the viable epidermis and to the dermis and then into the bloodstream. Many transdermal systems currently available are based on rapid absorption in the stratum corneum and subsequent division, thereby creating a deposit of the drug within the skin. Although the patch or transdermal system can be removed, the drug reservoir remains and will continue to be divided into the general circulation. There is a need for simple and effective removal of drugs from the skin and / or the general circulation to reduce or avoid an undesirable effect. Summary The present invention originates from the inventor's studies on transdermal and topical formulations containing penetration enhancers that increase the percutaneous absorption of a physiologically active agent. Studies of the inventor have shown that the release of the physiologically active agent can be inhibited to improve an undesired effect such as that caused by overdose or adverse reaction. The present invention provides a method for inhibiting the percutaneous absorption of the physiologically active agent applied locally at a transdermal delivery site, the method includes the step of applying to the skin at the site of transdermal administration a device comprising a membrane, with a layer adhesive, applied to the side that comes in contact with the skin of the same. The invention usually results in the treated individual receiving a serum concentration of the locally applied drug that is lower than what would otherwise be received. The membrane is preferably an occlusive or semipermeable membrane. According to the method of the invention, the membrane device can be applied to the transdermal administration site to obtain a reduction in the serum profile of the animal drug to reduce or avoid the occurrence of undesired effects of the administration of the transdermal drug. The membrane device is preferably applied to the entire transdermal drug application site and better yet will include the surrounding area. In this way it is possible to inhibit the increase in the profile of the blood serum. In fact, in some cases, we believe that the method of the invention causes the drug to be extracted from the skin to substantially reduce both the increase in the blood level and the total dose of the drug that would otherwise be administered. Furthermore, in many cases these effects of blood level reduction and total administration occur even when the membrane device is applied after a substantial period has elapsed since the topical application of the drug. The present invention also establishes a method for removing physiologically active agent from the drug reservoir within the skin, the method includes the step of applying a membrane to the transdermal drug delivery site to reduce or eliminate the occurrence of the undesired effect, wherein the Application of the membrane to the application site of the transdermal drug is used to extract the physiologically active agent from the drug reservoir into the skin. The invention further stipulates the use of an adhesive in preparation of a membrane compound for the treatment of prophylaxis of the effects of transdermal administration of a drug. Conveniently, the membrane is coated with a layer of an adhesive on the skin contact side of the membrane, which holds the membrane in place and prevents wrinkling of the surface. Preferably the membrane and the adhesive are malleable and move with the body. The membrane is preferably transparent and the free side of the membrane (which is the remote side from the side applied to the body) is resistant to liquids, allowing the person to bathe or wash. DETAILED DESCRIPTION Before describing the present invention in detail, it should be understood that the present invention is not limited to specific drug delivery systems, device structures, enhancers or vehicles, since they may vary. It should also be understood that the terminology used is intended to describe particular embodiments only and is not limiting. To describe the present invention, the following terminology will be used in accordance with the definitions stipulated below. The terms "topical" and "transdermal" are used herein in the broadest sense to refer to the administration of a drug to the surface of the skin or mucous membrane of an animal, including humans, so that the The drug passes through the tissue of the skin and / or into the bloodstream of the animal, thereby providing a local or general effect. The term "transdermal" further includes the administration of transmucosal drug, ie the administration of a drug to the mucosal surface of an animal so that the drug passes through the mucosal tissue and into the bloodstream. Unless otherwise stipulated or implied otherwise, the terms of topical drug administration and transdermal drug administration are used interchangeably. The term "skin deposit" is used herein in the broadest sense to refer to a deposit or store of active agent and dermal penetration enhancer within the epidermis, either intracellular (within the keratinocytes) or intercellular . The term "stratum corneum" is used herein in its broadest sense to refer to the outer layer of the skin, which is comprised of layers (approximately 15) of terminally differentiated keratinocytes formed primarily of the proteinaceous keratin material arranged so as to brick and cement being the cement a matrix of lipids formed mainly of cholesterol, ceramides and long chain fatty acids. The stratum corneum creates the restrictive velocity barrier for the diffusion of the active agent through the skin. As mentioned above, the present invention provides a method for reducing or eliminating the percutaneous absorption of a physiologically active agent thereby preventing high concentrations of the drug in the serum, within the bloodstream of an animal that suffers from an unwanted effect of a transdermally administered drug, the method includes the step of applying an occlusive or semipermeable membrane, coated with a layer of an adhesive, to the transdermal application site. Typically, the membrane will comprise a suitable elastic or semi-permeable layer suitable as polyurethane films and copolymers of ethyl vinyl acetate, hydrocolloids or cellulose. Conveniently the membrane of the present invention comprises an adhesive layer on one side. The adhesive layer will comprise a material that is permeable to the drug to be extracted. Examples of suitable materials for the adhesive layer include acrylics, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, plasticized copolymers of ethylene vinyl acetate, sticky gums such as polyisobutene and the like. The membrane will typically have a thickness of less than 5 mm, preferably less than 2 mm in thickness.

A benefit of the method of the present invention is that, in case of an undesired effect, the systemic or local absorption can be avoided or reduced, thereby diminishing or eliminating the effect and the possible side effects. In contrast to other treatments for overdoses, the method of the present invention can be self-administered safely, quickly and efficiently without experiencing gastrointestinal irritation problems from traditional remedies. The transdermal administration dose of preference is reduced by at least 10% more preferably by at least 20% and better yet by at least 30%. The reduction of the dose can be determined by measuring the proportion of the dose extracted through the membrane. The method of the present invention can be applied to inhibit or reduce any transdermal or topical delivery system comprising a physiologically active agent that can be administered through the skin with or without the assistance of a dermal penetration enhancer. A list of suitable physiologically active agents includes, but is not limited to: Antidiarrheals such as diphenoxylate, loperamide and hyoscyamine. Antihypertensives such as hydralazine, minoxidil, captopril, enalapril, clonidine, prazosin, debrisoquine, diazoxide, guanethidine, methyldopa, reserpine, trimetafan and lacidipine. Calcium channel blockers such as diltiazem, felodopine, amlodipine, nitrendipine, nifedipine and verapamil. Antiarrhythmics such as amiodarone, flecainide, disopyramide, procainamide, mexiletene and quinidine. Anti-angina agents such as glyceryl trinitrate, erythritol tetranitrate, pentaerythritol tretranitrate, mannitol hexanitrate, perhexylene, isosorbide dinitrate and nicorandil. Beta-adrenergic blocking agents, such as alprenolol, atenolol, bupranolol, carteolol, labetolol, metoprolol, nadolol, nadoxolol, oxetazolol, pindolol, propranolol, sotalol, timolol and timolol maleate. Cardiotonic glycosides such as digoxin and other cardiac glycosides and theophylline derivatives. Stimulant adrenergic agents such as epinephrine, ephedrine, fenoterol, isoprenaline, orciprenaline, rimeterol, salbutamol, salmeterol, terbutaline, dobutamine, phenylephrine, phenylpropanolamine, pseudoephedrine and dopamine. Vasodilators such as cycllandelate, isoxsuprine, papaverine, dipyrimadol, isosorbide dinitrate, phentolamine, nicotinyl alcohol, co-dergocrine, nicotinic acid, glyceryl trinitrate, pentaerythritol tetranitrate and xanthinol.

Migraine preparations such as ergotamine, dihydroergotamine, methysergide, pizotifen and sumatriptan. Anticoagulants and thrombolytic agents such as warfarin, dicumarol, low molecular weight heparins such as enoxaparin; streptokinase and its active derivatives.

Hemostatic agents such as aprotinin, tranexamic acid and protamine. Analgesics, antipyretics, which include opioid analgesics such as buprenorphine, destromoramide, destropropoxyphene, butorphanol, fentanyl, ketamine, alfentanil, sufentanil, hydromorphone, methadone, morphine, oxycodone, papaverate, pentazocine, pethidine, phenoperidine, codeine and dihydrocodeine. Others include acetylsalicylic acid (aspirin), paraceta ol, rizatriptin, sumatriptan, zolmitriptan and phenazone. Hypnotics and sedatives such as barbiturates,. amylobarbitone, butobarbitone and pentobarbitone and other hypnotics and sedatives such as ketamine, chloralhydrate, chlormethiazole, hydroxyzine and meprobamate. Anti-anxiety agents such as benzodiazepines, alprazolan, bromazepam, chlordiazepoxide, clobazam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, nitrazepam, buspirone, oxazepam, temazepam, and triazolam. Neuroleptic and antifungal drugs such as phenothiazines, chlorpromazine, flufenazine, periciazine, perphenazine, promazine, thiopropazate, thioridazine and trifluoperazine and the butyrophenones, droperidol and haloperidol and the other antipsychotic drugs such pimozide, thiothixene, olanzapine and lithium. Antidepressants such as tricyclic antidepressants, amitriptyline, clomipramine, desipramine, dotiepin, doxepin and imipramine, nortriptyline, opipramol, protriptyline and trimipramine and tretracyclic antidepressants such as mianserin and monoamine oxidase inhibitors such as isocarboxazid, phenelizine, tranylcypromine and moclobemide and selective inhibitors of resorption of serotonin such as fluoxetine, paroxetine, citalopram, fluvoxamine and sertraline. CNS stimulants such as caffeine and methylphenidate. Anti-Alzheimer agents such as tacrine, zinc chelators such as phenanthrins and their derivatives, such as 1,10-phenanthroline, aryl propionic acids and their derivatives such as ibuprofen and flurbiprofen. Agents against Parkinson's such as apomorphine, amantadine, benserazide, carbidopa, rivastigmine, levodopa, benztropine, biperiden, benzhexol, procyclidine, pergolide, ropinirole and dopamine-2 agonist such as S (-) - 2 ~ (N-propyl) N-2-thienylethylamino) -5-hydroxytetralin (N-0923).

Anticonvulsants such as phenytoin, valproic acid, primidone, phenobarbitone, methylphenobarbitone and carbamazepine, ethosuximide, methsuximide, fensuximide, sultiam and clonazepam. Antiemetics, antinausees such as phenothiazines, procloperazine, thiethylperazine and 5HT-3 receptor antagonists such as ondansetron, tropisetron and granisetron and others such as dimenhydrin, diphenhydramine, metoclopramide, domperidone, hyoscine, hyoscine hydrobromide, hyoscine hydrochloride, clebopride and brompiride. Non-spheroidal anti-inflammatory agents include their racemic mixtures or individual enantiomers when applied, such as ibuprofen, flurbiprofen, ketoprofen, aclofenac, diclofena, aloxiprin, acetone, aspirin, diflunisal, fenoprofen, indometacin, mefenamic acid, natroxene, phenylbutazone, piroxicam, salicylamide silicic acid, sulindac, deoxysulindac, tenoxicam, tramadol and quetoralac, salicylamide, flufenisal, salsalate, triethanolamine salicylate, aminopyrine, antipyrine, oxyphenbutazone, apazone, tapezone, flufenamic acid, clonixeril, clonixin, meclofenamic acid, flunixin, coiquicin, demecolcin, allopurinol, oxypurinol, benzydamine hydrochloride, dimefadane, indoxol, intrazol, mimoban hydrochloride, paraniline hydrochloride, tetridamine, bencidopyrine hydrochloride, fluprofen, ibufenac, naproxol, fenbufen, cincofen, diflumidone sodium, fenamol, flutiazin, metazamide, letimide hydrochloride , nexeridine hydrochloride, octazamide, molinazole, neocincofen, nimazole, proxazole citrate, tesicam, tesimide, tolmetin and triflumidate. Anti-rheumatic agents such as penicillamine, aurothioglucose, sodium aurothiomalate, methotrexate and auranofin. Muscle relaxants such as baclofen, diazepam, cyclobenzaprine hydrochloride, dantrolene, methocarbamol, orfenadrine and quinine. Agents used in gout and hyperuricemia such as allopurinol, colchicine, probenecid and sulfinipirazone. Estrogens such as estradiol, estriol, estrone, ethinyloestradiol, mestranol, stilboestrol, dienoestrol, epiostrol, estropipate and zeranol. Progesterone and other progestagens such as allylstrenol, dirgesterone, linoestrenol, norgestrel, noretindrel, norethisterone, norethisterone acetate, gestodene, levonorgestrel, medroxyprogesterone and megestrol. Antiandrogens such as cyproterone acetate, flutamide and danazol. Antiestrogens such as tamoxifen and epitiostanol and the aromatase inhibitors, exemestane and 4-hydroxy-androstenedione and their derivatives. Androgens and anabolic agents such as calusterone, clotebol acetate, dehydroepiandrostenedione (DHEA), dihydrotestosterone (DHT), propionate of drornostañolona, drostanolona, enanttato, etilestrenol, fluoxymesterone, furazabol, methandriol, methandrostenolone, methyltestosterone, nandrolone decanoate, nandrolone oxandrolone, oxymetholone, nandrolone fenpropionate, stanozol, testolactone, testosterone, cypionate of testosterone, testosterone propionate, trenbolone testosterone acetate, 7-methyl-19-testosterone (MENT), and 17-a-methyl-19-nortestosterone. Antialopecia agents such as minoxidil, cromakalin, pinacidil, naminidil, diphenylcyclopropenone, tricomin and those compounds selected from the classes of S-triazines, benzopyrans, pyridinopyrans and thia-1-oxides. 5-alpha reductase inhibitors such as finasteride, turosteride LY-191704, MK-386 and dutasteride. Corticosteroids such as betamethasone, betamethasone valerate, cortisone, dexamethasone, dexamethasone 21-phosphate, fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide, fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide, halopredone, hydrocortisone, hydrocortisone valerate 17, hydrocortisone butyrate 17 , methylprednisolone hydrocortisone acetate 21, prednisolone, prednisone phosphate 21, prednisone, triamcinolone, triamcinolone acetonide. Other examples of spheroidal anti-inflammatory agents include shortdoxone, fluoracetonide, fludrocortisone, difluorsone diacetate, flurandrenolone acetonide, medrisone, amcinafel, amcinafide, betamethasone and its other esters, chloroprednisone, chlorotellone, descinolone, desonide, dichlorisone, difluprednate, flucloronide, flumethasone, flunisolide, flucortolone, fluorometalone, fluperolone, fluprednisolone , meprednisone, methylmeprednisolone, parametasone, cortisone acetate, hydrocortisone cyclopentyl propionate, shortdoxone, flucetonide, fludrocortisone acetate, flurandrenolone acetonide, medrisone, amcinafal, amcinafide, betamethasone, betamethasone benzoate, chloroprednisone acetate, clocortolone acetate, acetonide descinolone, desoximetasone, dichlorisone acetate, difluprednate, flucloronide, flumethasone pivalate, flunisolide acetate, fluperolone acetate, fluprednisolone valerate, parametasone acetate, prednisolamate, prednival, triamcinolone hexacetonide, cortivazole, formocorthal and nivazole. The pituitary hormones and their active derivatives or analogs such as corticotrophin, thyrotropin, follicle stimulating hormone (FSH), luteinizing hormone and gonadotrophin releasing hormone (GnRH).

Hypoglycemic agents such as insulin, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutide and metformin. Thyroid hormones such as calcitonin, thyroxine and liothyronine and antithyroid agents such as carbimazole and propylthiouracil. Other various hormone agents such as octreotide. Pituitary inhibitors such as bromocriptine. Ovulation inducers such as clomiphene. Antimuscarinic agents that include atropine, beladone alkaloids, benzatropine (benztropine), biperidine, cyclopentolate, dicycloverine (dicyclomine), flavoxate, homatropine, hyoscine, ipratropium, orphenadrine, oxitropium, oxybutynin, procyclidine, propantheline, propiverine, tiotropium, tolterodine, trihexyphenidyl ( benzhexol), tropicamide and trospium. Diuretics such as thiazides, related diuretics and loop diuretics, bendrofluazide, chlorothiazide, chlorthalidone, dopamine, cyclopenthiazide, hydrochlorothiazide, indapamide, mefruside, methoxythiazide, metolazone, kinetazone, bumetanide, ethacrynic acid and frusemide, and moderate potassium diuretics, spironolactone, amiloride, and triamterene. Antidiuretics such as desmopressin, lyserin and vasopressin including their active derivatives or the like. Obstetric drugs that include agents that act on the uterus such as ergometrine, oxytocin and gemeprost. Prostaglandins such as alprostadil (PGE1), prostacycline (PG12), dinoprost (prostaglandin F2-alpha) and misoprostol. Antimicrobials that include cephalosporins such as cephalexin, cefoxitin and cephalothin. Penicillins such as amoxicillin, amoxicillin with clavulanic acid, ampicillin, bacampicillin, penicillin benzathine, benzylpenicillin, carbenicillin, cloxacillin, methicillin, phenoxymethylpenicillin, phenoxymethylpenicillin, flucoxacillin, mezlocillin, piperacillin, ticarcillin and azlocillin. Tetracyclines such as minocycline, chlortetracycline, tetracycline, demeclocycline, doxycycline, metacycline and oxytetracycline and other tetracycline-type antibiotics. Aminoglycosides such as amikacin, gentamicin, kanamycin, neomyinanethylmycin and tobramycin. Antimycotics such as butenafine, butoconazole, clioquinol, itraconazole, lanoconazole, neticonazole, thioconazole, terconazole, cyclopirox olamine, amorolfine, isoconazole, clotrimazole, econazole, miconazole, nystatin, terbinafine, bifonazole, amphotericin, griseofulvin, ketoconazole, fluconazole and flucytosine, salicylic acid , fezationa, ticlatona, tolnaftate, triacetin, zinc, pyrithione, sodium pyrithione. Quinolones such as nalidixic acid, cinoxacin, ciprofloxacin, enoxicin and norfloxacin. Sulfonamides such as phthalylsulfothiazole, sulf doxin, sulfadiazine, sulfametizole and sulfamethoxazole. Sulfones such as dapsone. Other miscellaneous antibiotics such as chloramphenicol, clindamycin, erythromycin, erithromycin ethyl carbonate, erithromycin estolate, erithromycin glucepato, erithromycin ethylsuccinate, erithromycin lactobionate, roxitromicin, lincomicin, natamicin, nitrofurantoin, spectinomycin, vancomycin, aztreonam, colistin IV, metronidazole, tinidazole, fusidic acid and trimethoprim, 2-thiopyridine N-oxide; halogen compounds, particularly iodine and iodine compounds such as PVP iodine complex and diodohydroxyquin; hexachlorophene; chlorhexidine, chloramine compounds, benzoyl peroxide. Drugs against tuberculosis such as ethambutol, isoniazid, pyrazinamide, rifampicin and clofazimine. Antimalaria such as primaquine, pyrimethamine, chloroquine, hydroxychloroquine, quinine mefloquine and halofantrine.

Antiviral agents such as acyclovir and prodrugs of acyclovir, famciclovir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, saquinavir, indinavir, ritonavir, n-docosanol, tromantadine and idoxuridine. Anthelmintics such as mebendazole, thiabendazole, niclosamide, praziquantel, pyrantel embonate and diethylcarbamazine. Cytotoxic agents such as plicamycin, cyclophophamide, dacarbazine, fluorouracil and their prodrugs, methotrexate, procarbazine, 6-mercaptopurine and mucophenolic acid. Anorective and weight-reducing agents that include desfenturamine, fenfluramine, diethylpropion, mazindol and phentermine. Agents used in hypercalcemia such as calcitriol, dihydrotaquisterol and its active derivatives or the like. Antitussives such as ethylmorphine, dextromethorphan and pholcodine. Expectorants such as acetylcysteine, bromhexine, emetine, guaifenesin, ipecacuanha and saponins. Deconfestants such as phenylephrine, phenylpropanolamine and pseudoephedrine. Relaxants bronchospasm such as ephedrine, fenoterol, orciprenaline, rimiterol, salbutamol, sodium cromoglycate, cromoglicic acid and its prodrugs, terbutaline, ipratropium bromide, salmeterol and theophylline and theophylline derivatives. Antihistamines such as meclozine, cyclizine, chlorcyclizine, hydroxyzine, brompheniramine, chlorpheniramine, clemastine, cyproheptadine, chlorpheniramine, diphenhydramine, diphenylamine, diphenylamine, doxylamine, mebdroline, pheniramine, tripolidine, azatadine, diphenylpyraline, metdilazine, terfenadine, astemizole, loratidine and cetirizine. Local anesthetics such as bupivacaine, amethocaine, lignocaine, cincocaine, dibucaine, mepivacaine, prilocaine and etidocaine. Neuromuscular blocking agents such as suxamethonium, alcuronium, pancuronium, atracurium, galamin, tubocuranin and vecuronium. Smoking cessation agents such as nicotine, bupropion and ibogaine. Insecticides and other pesticides that are suitable for local or systemic application. Dermatological agents such as vitamin A and E, vitamin E acetate and vitamin E sorbate. Food agents such as vitamins, essential amino acids and essential fats. Keratolytics such as alpha-hydroxy acids, glycolic acid and salicylic acid. Psychological energizers such as 3- (2-aminopropyl) indole, 3- (2-aminobutyl) indole and the like. Anti-acne agents such as those containing isotretinoin, tretinoin and benzoyl peroxide. Anti-psoriasis agents such as those containing etretinate, cyclosporin and calcipotriol. Anti-itching agents such as capsaicin and its derivatives such as nonivamide (Tsai, et al., Drug, Dev. Ind. Pharm., 20 (4), 719, 1994). Anticholinergic agents that are effective for the inhibition of axillary sweating and for the control of miliary fever. The antiperspirant activity of agents such as metatropine nitrate, propantheline bromide, scopolamine, metscopolamine bromide and the new class antiperspirant soft, acyloxymethyl quaternary ammonium salts. Other physiologically active peptides and proteins, from small to medium-sized peptides, for example, vasopressin and human growth hormone. The membrane may comprise one or more solvent reservoirs. The portion of the membrane between the reservoir and the adhesive layer can be a one-way membrane. The one-way membrane can function so that the drug extracted from the systemic circulation and / or skin layers penetrates through the one-way membrane and into the solvent reservoir. The membrane is preferably administered to the application site within 4 days of the application of the transdermal drug, more preferably within 24 hours of the transdermal drug application and better still within 1 hour of the transdermal drug application. Preferred aspects of the invention are described in more detail with reference to the accompanying drawings. In the accompanying drawings: Figure 1 is a schematic drawing showing a cross section of an occlusive membrane that has been applied to a topically treated area of skin according to a preferred embodiment of the present invention. Figure 2 is a schematic drawing showing a cross section of an occlusive membrane applied to a topically treated skin area according to an alternative but less preferred embodiment of the invention. Figure 3 is a graph that shows the average concentration - time profiles of the serum (+ SEM); n = 5) after the application of treatment A (a single dose of 140 μl of the fentanyl formulation) or treatment B (a single dose of 140 μl of the fentanyl formulation followed by occlusion for 24 hours). Values under the LOQ assay (0.1 ng / ml) have been omitted. Figure 4 is a graph showing the cumulative amount of testosterone diffused through the skin with or without application of the solvent deposit membrane. Figure 5 is a bar graph showing the distribution of fentanyl between the upper stratum corneum and the lower stratum corneum at different times up to 16 hours after the spray application of a fentanyl composition containing dermal penetration enhancer. With reference to the drawings, Figure 1 shows a set of pieces of the membrane (1) according to a preferred embodiment of the invention comprising an occlusive membrane (2) having a skin-side surface (3) which it is to be applied adjacent to a topically treated skin area (4) and a remote free surface (5) thereof. The skin side surface (3) is provided with an adhesive layer (6) formed by a suitable skin-safe adhesive. In the method of the invention the membrane assembly (1) is used in circumstances where it is necessary to terminate or reduce transdermal administration after topical application of the active in a transdermal formulation. The need to terminate or reduce transdermal administration may arise as a result of knowing after the event that an overdose was applied topically or the occurrence of the adverse reaction or some other factor that may lead to it being considered convenient to reduce the dose to another mode would result from the initial topical application. The topical application area (4) is identified and the set of membrane pieces preferably applied with sufficient dimensions to cover to at least substantially cover the area of topical application (4). The set of membrane pieces (1) is applied to the skin in the application area (4) so that the adhesive layer (6) on the side that comes into contact with the skin (3) of the membrane (3) make adherent contact with the skin (4). Pressure, such as the pressure of a firm hand, is preferably applied to the free surface (5) of the occlusive membrane (2) to force the membrane assembly (1) to adhere uniformly in contact with the membrane. the skin (4). With reference to Figure 2 the set of pieces of the alternative membrane (7) comprises a multilayer semi-permeable membrane (8) comprising a skin side layer (9) that is selectively permeable to allow the entry of the topically applied composition. The skin side layer (9) is provided with an adhesive that comes into contact with the skin (10) on the side of the skin thereof (11) and which is attached to a second layer (12) which can be waterproof, on the remote side (13). One or more solvent tanks (14) are provided between the first (9) and second (12) layers. The solvent deposit (14) can provide an absorption of possible osmotic promotion of the topical composition through the first layer (9) (selectively permeable). Preferably, the first membrane layer (9) is substantially impermeable for the discharge of the solvent from the solvent reservoir (14). In this embodiment, the method of the invention includes applying the set of pieces of the membrane to the area of the skin in which the topical application has occurred (15). The assembly of parts (7) is applied so that the adhesive layer (10) comes into contact with the skin (15) and that the adhesion is preferably substantially uniformly carried out by application of pressure (for example hand pressure). ) on the outer side (18) of the membrane assembly. According to one embodiment We provide a method for reducing the effect of overdose through transdermal administration of a physiologically active agent to a skin site of an individual to form a deposit of physiologically active agent in the skin. The method comprises providing a set of membrane pieces. to come into contact with the skin site the membrane assembly comprises (a) selectively permeable membrane so that it comes into contact with the skin and allows the entry of the physiologically active agent and provides an adhesive layer on the side of the skin. skin of it, (b) a backing layer and (c) a solvent deposit between the backing layer and the membrane wherein the physiologically active agent is at least partially soluble in the solvent and preferably (d) an impermeable layer of adjacent solvent next to the remote membrane of the adhesive; and applying the adhesive layer of the membrane piece assembly to the site of transdermal administration wherein the physiologically active agent is extracted from the skin to the membrane assembly. The choice of solvent used in the reservoir can be selected based on the particular drug previously administered in order to obtain the desired extraction effect, since the drug must be at least partially soluble in the selected solvent. Preferably, the solvent is n alcohol, alkane, ether, ketone, chlorinated hydrocarbon or nitrile. Better still, the solvent is aliphatic with 1 to 4 carbon atoms. It is even more preferred that the solvent be selected from the group consisting of ethanol and its derivatives, methanol, chloroform, isopropyl alcohol or a mixture of two or more of the aforementioned solvents. The amount of solvent used will depend on the period that has elapsed after the initial topical application and the physical-chemical properties of the solvent and the drug and the area of application of the drug. The occlusive or semipermeable membrane is applied to the transdermal application site preferably within 4 days, better still within 24 hours and more preferably within 1 hour. The occlusive or semipermeable membrane is applied to the largest possible area of the transdermal drug application site including the surrounding area and remains in place preferably 12 hours, and better still for 24 hours. Conveniently, the occlusive or semipermeable membrane is coated with a layer of an adhesive to achieve a secure and secure positioning on the skin. In another embodiment the invention provides a solvent extraction method by means of which the drug application site can be a swabbed with a solvent mixture and / or the occlusive or semipermeable membrane contains a reservoir solvent. In a particularly preferred form of the invention the solvent is less alcohol, preferably more methanol or chloroform or a mixture thereof. The amount of drug that is to be prevented from being absorbed and / or extracted will depend on the number of factors and will vary from person to person and will depend on the particular drug administered and the length of time prior to the application of the occlusive or semipermeable membrane. The desired effect of the present invention is such that the amount of drug present will not exceed a rate of release reaching levels that provide the undesired effect. The method of the invention can be used to reduce the level of administration of the active agents from a range of transdermal formulations administered via patches, nebulizations or other topical methods. Said formulations will generally comprise an active agent, a vehicle that preferably includes a volatile solvent and optionally a penetration enhancer. The compositions preferably will contain a penetration enhancer. Examples of such compositions are disclosed in U.S. Patent 6229900, the content of which is incorporated herein by reference. Examples of suitable vehicles and penetration enhancers are described in U.S. Patent 6,229,900. Examples of dermal penetration enhancers include fatty acids, fatty acid esters, fatty alcohols, glycols and glycol esters, 1,3-dioxolanes and 1,3-dioxanes, macrocyclic ketones containing at least 12 carbon atoms, oxazolidinones and oxazolidinone derivatives, esters of alkyl-2- (N, N-disubstituted amino) -alkanoate, alkanoates of (N, N-disubstituted amino) -alkanol, esters for sunscreen and mixtures thereof. More preferably the dermal penetration enhancer is selected from the list that includes leic acid, oleyl alcohol, cyclopentadecane (CPE-218 ™), sorbitan monooleate, glycerol monooleate, propylene glycol monolaurate, polyethylene glycol monolaurate, 2-n-nonyl 1,3-dioxolane propionate (SEPA ™), docecyl 2- (N, N-dimethylamino) -propionate (DDAIP) or its salt derivatives, 2-ethylhexyl-2-ethylhexanoate, isopropyl myristate, dimethyl isosorbide, 4-decyloxazolidinon-2-one (SR-38 ™, TCPI , Inc.), 3-methyl-4-decyloxazolidonon-2-one, octyl dimethyl-para-aminobenzoate, octyl para-methoxycinnamate, octyl salicylate and mixtures thereof. Examples of volatile solvents include skin tolerant solvents such as tannol isopropanol and aerosol propellants such as diethyl ether, hydrofluorocarbons and the like. The transdermal formulation can have a fast drying time for example up to 3 minutes. Although the formulations with fast drying time are more effective to drive the composition in the epidermis we have discovered that the method of the invention allows a significant reduction in the dose to be obtained with said compositions. The invention will now be described with reference to the following examples. It should be understood that the examples are provided as an illustration of the invention and that they are not in any way limiting to the scope of the invention. Example 1 The objectives of the pharmacokinetic study were to determine the pharmacokinetics of fentanyl after a single dose in healthy volunteers and to compare with the pharmacokinetic profile of the fentanyl profile with and without occlusion of the application site. Method The study was a parallel design. In the first stage 5 healthy volunteers received treatment A. The second stage 5 healthy volunteers received treatment B. The treatments consisted of a single application of 140 μl of fentanyl formulation applied to the abdomen, with or without occlusion of the application site. The fentanyl concentration profiles in the serum were measured for 72 hours after the administration of the transdermal fentanyl. A validated GC / MS assay was used to analyze the concentrations of fentanyl in the serum samples. Treatment of the Study Treatment A: The formulation of fentanyl (140 μl) containing 7.5% fentanyl and 5.0% octisalate applied to the lateral abdomen. Treatment B: Formulation of fentanyl (140 μl) containing 7.5% fentanyl and 5.0% octisalate applied to the lateral abdomen and then covered by an occlusive gauze to the entire area in 2 minutes (polyurethane membrane coated with a layer of an adhesive acrylic) for 24 hours. Result Treatment B (formulation of fentanyl with occlusion) produced very low levels of fentanyl in the serum (Figure 3). The values below the LOQ of the assay (0.1 ng / ml) were omitted from the graphs. The values were considerably lower than the levels observed after the application of Treatment A (formulation of fentanyl without occlusion). This indicates that the occlusion of the application site with the polyurethane membrane patches, coated with a layer of an acrylic adhesive, considerably reduces the absorption of the skin deposit.

Table 1: Average pharmacokinetic parameters (+ S.E.M.) after the application of Treatments A and B.

Example 2 The occlusive or semipermeable membrane may contain a reservoir solvent. The choice of solvent used in the reservoir can be selected based on the particular drug previously administered in order to achieve the desired extraction effect. The aforementioned examples are not intended to be limiting and it is envisaged that combinations of the solvents could also be used to obtain the desired pharmacological effect, for example on a weight basis. Solvent Ratio (% weight / weight) Methanol: chloroform 20-80: 20-80 Figure 4 describes the in vitro diffusion profile that can be obtained by applying a solvent deposit membrane immediately after the undesirable administration of testosterone. Example 3 This example determines the amount of fentanyl absorbed by an adhesive membrane during the procedure described in Example 1. Materials and Methods HPLC Conditions The following HPLC conditions were used to measure fentanyl content in the membrane. The mobile phase constituted the same components as for the fentanyl diffusion test by HPLC. The flow conditions is 1 ml / min isocratic in 75% A, 25% B. The "Previal C18" brand column of 250 x 4.6 mm, (available from Alltech) was used. The condition was validated. The typical curve had concentrations between 0.1-2 μg / ml of fentanyl. Extraction procedure 1. The patch was placed in glass jar; 2. A known amount (40 ml) of ethanol (100%) was added to the flask; 3. The bottle is sonic for 40 minutes; 4. The solution was filtered with Millipore Millex HN nylon 0. 45 μm filter; and 5. The filtrates were diluted 1 in 5 parts with water MilliQ before injection in HPLC. Additional dilution may be required if the solution is too concentrated.

Outcome and Discussion Two patches of the same individual were obtained and analyzed. The amount of fentanyl obtained from the 2 patches was 5.85 mg. In the assay, 140 μL of 7.5% fentanyl solution administered to each subject, ie 10.2 mg of fentanyl. The amount recovered from the patch was therefore 56.8% of the applied dose. Example 4 The objective of this study was to determine the distribution of fentanyl through the human stratum corneum at various exposure times. The data for the example is taken from PhD of B.T. Traversa 2004, Victorian Collage of Pharmacy. Method Human skin samples of full thickness were prepared by removing subcutaneous tissue from the lower part of the dermal membrane using a stainless steel scalpel. The stratum corneum surface was rinsed with Milli-Q ™ water and gently washed to remove any surface contamination. The skin is placed flat with the stratum corneum up and dissected in sections 1 5 cm (width by length) (n = 5) using a stainless steel scalpel. Each section, with the dermal side up and super-fast drying (Selleys® "Fix'n'Go Supa Glue" Selleys, Australia) was dried on the ventral surface of the dermis. The leather sections were immediately assembled, the stratum corneum upwards, into 1 x 7 cm pieces of cartonboard (the 2 cm excess length to be able to handle the samples). After applying gentle pressure on the skin for approximately 10 seconds to ensure contact with the paperboard. The formulation was prepared by dissolving 5% weight / volume of fentanyl, with 5% weight / volume of octisalate, 95% volume / volume of ethanol and was applied (5 μl / cm2) to the stratum corneum surface of each skin sample . After a predetermined exposure time (5 minutes (0.08 h), 0.5, 2, 6 or 16 hours), the excess formulation was removed from the stratum corneum surface by cleaning with cotton. The cotton is placed in a glass jar and an aliquot of 10 ml of 100% methanol is added. The contents were sealed with a Teflon-lined lid, and vortexed for 30 seconds, then placed in a horizontal roller mixer to gently mix for 16 hours at room temperature (Step 1). At the end of the 16-hour extraction period, the sample was vortexed for 30 seconds, the cotton was then transferred to an empty glass jar and 5 ml of methanol was added. The sample was vortexed for 30 seconds, then placed in a horizontal roller mixer for 8 hours at room temperature (Stage 2). At the end of the 8 hour period, the methanol stratum retained from Step 1 was added to the sample. The sample was then vortexed for 2 minutes and 5 ml of the stratum was centrifuged at 3500 rpm for 15 minutes at 25 ° C. An aliquot of 1 ml of supernatant was diluted to 10 ml with methanol for HPLC / UV analysis. The stratum corneum was progressively removed by removing the sequential adhesive tape. Sections of 1.2 x 5 cm of pieces of polyester adhesive tape were applied to the stratum corneum surface and a constant pressure of 240 g / cm2 was applied to the tape for 5 seconds. After the tape was applied, it was removed from the surface of the stratum corneum. The strip release procedure was repeated 20 times in order to remove much of the stratum corneum. The tape strips were placed with the adhesive side down on the filter paper and the samples were then cut to individual sizes placed in 15 ml glass centrifuge flasks. Aliquots of 100% methanol with HPLC quality were added to the strip strip samples. 10 ml were added to each of the first 10 strips of tape and 5 ml were added to strip strips 11 to 20. The samples were vortexed for 30 seconds and then placed in a water bath with 25 ° agitation. C, where they were continuously agitated in hits / minutes for 24 hours. At the end of the 24-hour period, the samples were removed from the water bath and vortexed for 30 seconds. The ink strips and the filter paper were removed from the bottles and removed. The strata were then centrifuged at 3,500 rpm for 15 seconds at 25 ° C. After centrifugation, a 1 ml aliquot was taken from each of the strata of the tape strips 1 and 2 and diluted with 10 ml with methanol for HPLC / UV analysis. The extracts of the tape strips 3 to 20 were analyzed undiluted. Results In general, fentanyl concentrations were reduced exponentially along the stratum corneum with several times of exposure between 0.08 to 6 hours. After 16 hours of exposure concentrations were distributed more linearly along the stratum corneum. When fentanyl was applied with octyl salicylate, the concentrations within the upper layers of the stratum corneum remained relatively constant during the various exposure times. With reference to Figure 5, fentanyl distribution profiles followed the application of fentanyl with octyl salicylate. The AUC were calculated for the entire stratum corneum (ie stratum corneum removed by tape strips 2-20, AUCx / L2- »20) the upper stratum corneum (i.e., the stratum corneum removed from the tape strips 2-10 , AUCx / L2- »20) and the lower stratum corneum (ie the stratum corneum removed by the tape strips 11-20, AUCx / Lll? 20). As shown in Figure 5, a significant amount of fentanyl remains on the surface of the skin and within the layers of the upper stratum corneum after amplified exposure times. The method of the present invention will continue to exert an important effect on the division of fentanyl after longer exposure times.

Claims (17)

1. CLAIMS 1. A method for inhibiting the percutaneous absorption of a physiologically active agent applied to a transdermal administration site of an individual, the method includes the step of applying to the skin of the individual at the site of transdermal administration, a device comprising a membrane so that it comes into contact with the skin of the individual coated on the contact side of the skin thereof with a layer of an adhesive.
2. 2. A method according to claim 1, wherein the membrane device is applied to the site of transdermal administration of an individual who has received at least (a) an overdose of transdermally applied physiologically active agent, and (b) adverse side effects of the physiologically active agent, wherein the dose of the physiologically active agent transferred to the bloodstream is thereby reduced.
3. 3. A method according to any of the preceding claims, wherein the membrane is applied to the entire transdermal application site.
4. 4. A method according to any of the preceding claims, wherein the physiologically active agent is administered in a manner that forms a deposit of the physiologically active agent in the skin and the application of the membrane device results in the physiologically active agent being extracted from the skin to significantly reduce the total dose of the drug that would otherwise be administered transdermally.
5. 5. A method for physiologically active removal from the reservoir thereof within the skin of an individual after transdermal administration of the agent physiologically to a site on the skin of the individual the method includes the step of applying a device comprising a membrane to the site of transdermal administration of the pharmaceutically active agent.
6. 6. A method according to claim 5, wherein the membrane is covered by a layer of adhesive on the side that comes into contact with the skin of the membrane to adhere the membrane to the transdermal delivery site.
7. A method according to any one of the preceding claims, wherein the membrane device comprises an occlusive or semipermeable elastic layer selected from polyurethane polymers, ethylene vinyl acetate copolymers, hydrocolloidal and cellulose membranes.
8. A method according to claim 1 or 6, wherein the adhesive layer is permeable to the physiologically active agent and is selected from the group consisting of acrylics, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, plasticized copolymers of ethylene vinyl acetate and gums sticky 9.
9. A method according to any of the preceding claims, wherein the membrane is less than 2 ml thick.
10. A method according to any one of the preceding claims, wherein the membrane is applied to the transdermal administration site within 24 hours of transdermal application of the physiologically active agent.
11. A method according to any one of the preceding claims, wherein an overdose of the physiologically active agent was applied locally to the site of the skin prior to application thereto of the membrane.
12. A method according to any one of the preceding claims, wherein the membrane device is a set of parts further comprising at least one layer on the side of the remote membrane on the side applied to the skin and wherein a reservoir of solvent is provided between at least one layer and the membrane wherein the active agent is at least partially soluble in the solvent.
13. 13. A method according to claim 12, wherein the solvent is selected from the group consisting of alcohols, alénes, ethers, ketones, chlorinated hydrocarbons and nitriles.
14. 14. A method according to claim 12, wherein the solvent is selected from the group consisting of ethanol and its derivatives, methanol, chloroform, isopropyl alcohol and mixture of two or more thereof.
15. 15. A method according to claim 12, wherein the membrane remains adhered to the skin at the site of transdermal administration for a period of at least 12 hours.
16. 16. A method for reducing the effect of overdose through transdermal administration of a physiologically active agent to a skin site of a person to form a deposit of the physiologically active agent in the skin, the method comprising supplying a set of pieces of membrane to come into contact with the site of the skin, the set of membrane pieces comprises (a) selectively permeable membrane so that it comes in contact with the skin and allows the entry of the physiologically active agent and that is provided with an adhesive layer on the skin side thereof, (b) a reinforcing layer and (c) a solvent deposit between the reinforcing layer and the membrane wherein the physiologically active agent is at least partially soluble in the solvent and preference (d) an impermeable layer of solvent adjacent to the side of the remote membrane of the adhesive; and applying the adhesive layer of the membrane piece set to the transdermal delivery site where the physiologically active agent is extracted from the skin to the membrane piece set.
17. 17. A method according to any one of the preceding claims, wherein the physiologically active agent comprises at least one of those selected from the group consisting of antidiarrheal agents, antihypertensive agents, calcium channel blockers, antiarrhythmics, antianginal agents, blocking agents. of beta-adrenergic, cardiotonic glycosides, adrenergic stimulants, vasodilators, antimigraine preparations, anticoagulants, thrombolytic agents, analgesics, hypnotics, antianxiety agents, antipsychotics neurolytic agents, antidepressants, CNS stimulants, anti-Alzheimer agents, anti-Parkinson agents, anticonvulsants, anti-emetics, non-spheroidal anti-inflammatory agents, anti-rheumatoid agents, muscle relaxing agents for the treatment of gout, agents for the treatment of hyperuricemia, estrogens, progesterone, antiandrogens, antiestrogens, androgens, anti-alopecia agents, inhibitors of 5-alpha r eductase, carbosteroids, pituitary hormones, hypoglycemic agents, thyroid hormones, pituitary inhibitors, ovulation inducers, anti-muscarinic agents, diuretics, antidiuretics, obstetric drugs, prostaglandins, antimicrobials, anti-tuberculosis drugs, anti-malaria, antivirals , anthelmintics, cytotoxic agents, anorectic agents, agents used in hypocalcemia, antitussives, expectorants, decongestants, bronchospasm relaxants, antihistamines, local anesthetics, neuromuscular blockers, smoking cessation agents, insecticides, dermatological agents, food agents, keratolytics, psychic energizers , anti-acne agents, anti-itch agents and anti-cholinergic agents.