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Home , Buflomedil, Butalamine, Ciclonicate, Oxprenolol, Thonzonium bromide

Europäisches Patentamt *EP001201230A2* (19) European Patent Office

Office européen des brevets (11) EP 1 201 230 A2

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.7: A61K 9/08 02.05.2002 Bulletin 2002/18

(21) Application number: 01125567.6

(22) Date of filing: 25.10.2001

(84) Designated Contracting States: (72) Inventors: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU • Masiz, John, J. MC NL PT SE TR Topsfield, Massachusetts 01983 (US) Designated Extension States: • Carter, Stephen, G. AL LT LV MK RO SI Andover, Massachusetts 01810 (US)

(30) Priority: 27.10.2000 US 698483 (74) Representative: Fuchs Mehler Weiss & Fritzsche, Patentanwälte (71) Applicant: BioChemics, Inc. Naupliastrasse 110 Danvers, Massachusetts 01923 (US) 81545 München (DE)

(54) Solution-based transdermal drug delivery system comprising a vasodilator

(57) An efficient transdermal delivery system for de- need for a polymeric binding agent and thus diminishing livering an active ingredient to the blood supply of a liv- the total molecular weight of the mixture and increasing ing body, comprising a vasodilator, an active ingredient, the penetration and delivery efficiency of the active drug and a permeation enhancer for the active ingredient. molecules. The components of this mixture are combined in a man- ner that dissolves them into solution, eliminating the EP 1 201 230 A2

Printed by Jouve, 75001 PARIS (FR) 1 EP 1 201 230 A2 2

Description mixing certain individual ingredients (penetration en- hancers) with a drug molecule, the ability of the drug BACKGROUND OF THE INVENTION molecule to pass through the skin is increased some- what. For example, U.S. Patent No. 4,933,184 discloses [0001] Transdermal drug delivery offers many advan- 5 the use of menthol as a penetration enhancer; U.S. Pat- tages over other types of drug delivery. These advan- ent No. 5,229,130 discloses the use of vegetable oil tages include improved local, specific drug delivery; (soybean and/or coconut oil) as a penetration enhancer; avoiding the gastrointestinal complications caused by and U.S. Patent No. 4,440,777 discloses the use of eu- oral delivery, and improved efficacy and safety profiles calyptol as a penetration enhancer. for the drugs. While the process of transdermal drug de- 10 [0005] Although mixing a penetration enhancer with livery offers these and other advantages, a system that a drug molecule helps to somewhat increase the speed can quickly, precisely and reliably deliver predictable and efficiency of drug delivery into the skin, problems quantities of a wide spectrum of different drug molecules are still present. First, the aforementioned penetration through the skin has heretofore not been developed. enhancers constitute a passive, not an active, transport [0002] The evolution of transdermal drug delivery has 15 system. Penetration enhancers may improve the trans- centered around patch technology. Patch technology is portation of the drug through the outer layers of skin and based on the ability to hold an active ingredient in con- into the lower skin tissue but they do not significantly stant contact with the epidermis. Over substantial peri- enhance the second stage of transfer through the wall ods of time, certain drug molecules, held in such a state, of the blood vessel and into the bloodstream. Second, will eventually transfer from the patch into the skin and 20 since penetration enhancers are not chemically linked to a small and variable degree, into the bloodstream. to the drug molecule, the transport of the penetration Thus, patch technology relies on the ability of the human enhancer into the skin does not necessarily mean that body to passively pick up drug molecules through the the drug molecule has penetrated into the skin. skin. Transdermal drug delivery using patch technology [0006] U.S. Patent Nos. 5,460,821, 5,645,854 and has recently been applied for delivery of , in an 25 5,853,751 disclose efficient transdermal drug delivery effort to assist smokers in quitting, the delivery of nitro- systems created by combining penetration enhancers, glycerine to sufferers, the delivery of replace- chemical vasodilators, active drug ingredients and a ment hormones (e.g., estrogen, and tes- binding element. These systems function by allowing tosterone) and for the delivery of scopolamine for motion the penetrating enhancers to pass through the barrier sickness. These drug delivery systems comprise a 30 layer of the skin, and in a physically associated complex, patch with an active ingredient such as a drug incorpo- bring all the components of the delivery system into the rated therein, the patch also includes an adhesive for dermal layer of the skin. Once in the dermal layer of the attachment to the skin so as to place the active ingredi- skin, the vasodilators act to expand or dilate the capil- ent in close proximity to the skin. laries and other blood vessels in and beneath the dermal [0003] Problems with patch technology abound. First, 35 layer, resulting in an increase in blood flowing into and most active drug molecules (with the exception of those away from the site of system application. The purpose previously listed) have difficulty passing through the of the polymeric binding element is not only to provide skin, as the skin tissue poses a significant barrier. In fact, a binding agent, but also to function as a delivery vehicle in order for a drug molecule to reach the bloodstream, for the transdermal release of the vasodilator and active it must pass through the stratum corneum (an especially 40 drug molecule, post stratum corneum penetration. dense layer of cells), the dermis tissue layer and finally [0007] However, polymeric binding elements have a through the wall of the blood vessel. Second, real world substantial molecular weight, which may inhibit or retard conditions such as the patient's obesity, metabolism and their ability to penetrate the skin. Secondly, sol- circulatory efficiency can effectively inhibit the efficiency uble vasodilators and alcohol soluble active drug mole- of patch-based transdermal drug delivery. Third, patch 45 cules can be difficult to associate with some binding el- technology can be used only for conditions involving ements in a mixture. Finally, as a result of the physical long, non-acute treatment periods, since the typical and chemical properties of some polymeric binding el- transport rate of drug molecules is typically so slow and ements, they can act as thickening agents in the solu- variable. Finally, patch adhesion to the skin may cause tion, which may not be desirable in certain applications. extensive skin trauma as well as cosmetic problems. 50 [0008] It is therefore an object of the present invention Specifically, most adhesives currently used tend to ag- to provide a transdermal drug transport system that ef- gressively adhere to the skin in a manner that their re- ficiently and easily allows for the effective delivery of a moval may cause irritation and trauma. Indeed, subse- broad range of active drug ingredients through the skin quent patches used by a given individual are often ap- and into the blood supply of a living organism, including plied to a different area of the skin in order to minimize 55 animals and humans, without the use of a polymeric such irritation and trauma to the skin. binding element. [0004] In an effort to enhance the efficiency of transdermal drug delivery, the prior art teaches that by

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SUMMARY OF THE INVENTION llidinogenase, methyl nicotinate, methyl salicylate, naf- tidrofuryl oxalate, nicametate citrate, niceritrol, nicobox- [0009] The problems of the prior art have been over- il, nicofuranose, , nicotinyl alcohol tar- come by the present invention, which provides an effi- trate, nitric oxide, nonivamide, oxpentifylline, papaver- cient, predictable and reliable active ingredient 5 ine, papaveroline, , peroxynitrite, pinacidil, transdermal delivery system for one or more active in- pipratecol, propentofyltine, raubasine, , teasu- gredients. More specifically, the present invention com- prine, thymoxamine hydrochloride, nicotinate, bines functional elements of the transdermal drug deliv- diazoxide, hydralazine, minoxidil and sodium nitroprus- ery system that can perform in more than one functional side. Centrally acting agents include , quana- capacity to achieve the results of delivering a drug or 10 berz and methyl dopa. Alpha-adrenoceptor blocking therapeutic or diagnostic agent through the skin and into agents include , , phen- the bodily fluids. The present invention utilizes the sol- tolamine and . neuron blocking ubility of the active drug molecule and/or the vasodilator agents include bedmidine, debrisoquine and guanethi- and creates a mixture where the active drug molecule dine. ACE inhibitors include benazepril, captopril, cilaz- is dissolved into a solvent, the vasodilator is dissolved 15 april, enalapril, fosinopril, lisinopril, perindopril, quinapril into a solvent which may be the same or different from and ramipril. Ganglion-blocking agents include pentolin- the solvent used for the active drug molecule, and a pen- ium and trimetaphan. Calcium channel blockers include etration enhancer is added to the mixture but is not nec- , diltiazem, , isradipine, nica- essarily bound to either the active ingredient or the va- rdipine, , nimodipine and verapamil. Prosteg- 20 sodilator. The need for a polymeric binding agent is elim- landins include prostacyclin, thrombuxane A2, leukot- inated, thus diminishing the total molecular weight of the rienes, PGA, PGA1, PGA2, PGE1, PGE2, PGD, PGG mixture and increasing the penetration and delivery ef- and PGH. Angiotension II analogs include saralasin. ficiency of selected active ingredients, including but not Other vasodilators include nitroglycerin, , limited to drugs. thrazide, isosorbide dinitrate, pentaerythritol tetrani- 25 trate, digitalis, and diazoxide. This element may serve DETAILED DESCRIPTION OF THE INVENTION exclusively as the agent or it may also serve another function to the delivery complex such as the [0010] The invention comprises the creation of a mo- penetration agent or the active drug agent. One or more lecular transdermal complex that performs the following vasodilators or chemically modified vasodilators may be functions: 1) dermal penetration; 2) vasodilation and 3) 30 used in the delivery complex at any one time for one delivery of the active drug molecule or agent into the formulation for the purpose of transdermally delivering bodily fluids (e.g., into the blood or into the skin tissue). an active drug molecule or agent. The delivery complex The functional characteristics of the component molec- may contain one or more different vasodilators in the ular parts of the complex can be shared within any one same complex to achieve varying and different degrees or more of the component molecular parts of the com- 35 and modes of vasodilation. plex with the eventual result being the transdermal de- [0012] The second element of the delivery complex is livery of an active drug molecule or agent into the bodily an ingredient that functions as a permeation or penetra- fluids or tissues of a living organism. The functional tion enhancer. Suitable enhancers include but are not sharing between the delivery complex components may limited to vegetable oil, oleic acid, aliphatic chained lip- result from a naturally diverse molecule or it may result 40 ids, cholesterol, a vegetable oil/alcohol mix, or combi- from a physical modification of an existing molecule to nations thereof including, but not limited to, various com- intentionally incorporate the desired traits into a compo- positions and preparations of liposomes. Suitable veg- nent molecule. Examples of this functional sharing in- etable oils include hamamelis, peanut oil, olive oil, sun- clude, but are not limited to, a vasodilator compound flower oil, soybean oil, monoi oil and macadamia oil, with serving also as an active drug molecule, a vasodilator 45 olive oil being preferred. Suitable alcohols for the vege- serving also as a penetration agent, a vasodilator serv- table oil/alcohol mix include ethyl alcohol, isopropyl al- ing also as a binding agent, a penetrating agent serving cohol and methanol. Olive oil mixed with isopropyl alco- also as an active drug agent, and a penetrating agent hol is a preferred vegetable oil/alcohol mix. Eucalyptol serving also as a binding agent. is a further suitable example of a vegetable oil/alcohol [0011] Examples of chemical vasodilators include, 50 mix. Suitable ratios of vegetable oil:alcohol range from and are not limited to, acetylcholine, amrinone, bame- about 5:1 to about 1:10, preferably 1:2. Suitable than sulphate, fumarate, benfurodil hemis- amounts of vegetable oil or vegetable oil/alcohol mix in uccinate, benzyl nicotinate, hydrochloride, the delivery complex range from about 1% to about 66% hydrochloride, hydrochloride, by weight, more preferably from about 10% to about citrate, , maleate, cyclan- 55 33.3% by weight. This component may serve exclusive- delate, di-isopropylammonium dichloroacetate, ethyl ly as the penetrating agent or it may also serve another nicotinate, hepronicate, hexyl nicotinate, tar- function to the delivery complex such as the vasodilator trate, , hydrochloride, ka- or as the active drug agent. One or more penetrating

3 5 EP 1 201 230 A2 6 agents or chemically modified penetrating agents may hydrinate, dimethindene, , diphenidol, be used in varying quantities or ratios with respect to the diphenoxylate & atrophive, diphenylopyraline, dipyrad- other component parts in the drug delivery complex at amole, dirithromycin, disopyramide, disulfiram, divalpo- any one time. The third element of the delivery complex rex, calcium, docusate potassium, docusate is the active ingredient. The term "active ingredient" is 5 sodium, , domiphen bromide, , - used herein to indicate any material or composition de- orubicin, doxylamine, dronabinol, enzymes, enalaprilat, sired to be delivered transdermally, especially therapeu- , epinephrine, ergoloidmesylates, ergono- tic drugs and molecules and diagnostic agents. This el- vine, , , erythropoietin, conju- ement may serve exclusively as the active drug agent gated estrogens, estradiol, estrogen, estrone, estropi- or it may also serve another function to the delivery com- 10 pute, etbarynic acid, ethchlorvynol, ethinyl estradiol, plex such as vasodilation or penetration. Examples of ethopropazine, ethosaximide, ethotoin, etidronate sodi- active ingredients that can be used in accordance with um, etodolac, famotidine, felodipine SR, fenoprofen, the present invention include, but are not limited to, ace- , , ferrous fumarate, ferrous gluconate, butolol, acetaminophen, acetohydoxamic acid, ace- ferrous sulfate, fexofenadine, finasteride, flavoxate, fle- tophenazine, acyclovir, adrenocorticoids, albuterol, al- 15 caimide, fluconazole, , , flupred- endronate, allopurinol, alprazolam, alpha hydroxylipids, nisolone, flurazepam, fluticasone, fluticasone propion- aluminum hydroxide, amantadine, ambenonium, amilo- ate, fluvastin, fluvoxamine maleate, fuma- ride, amino acids and amino acid polymers, aminoben- rate, folic acid, fosinopril, furosemide, gabapentin, gan- zoate potassium, HCl, , amo- ciclovir, gemfibrozil, glimepiride, glipizide, glyburide, barbital, amlodipine, amoxicillin, , ampicil- 20 glycopyrrolate, gold compounds, granstron HCl, grise- lin, , androgens, anesthetics, antibody mol- ofuwin, growth hormones, guaifenesin, ac- ecules, anticoagulants, anticonvulsants-dione type, an- etate, guanadrel, , , tisense molecules, antithyroid medicine, appetite sup- halazepam, , heparin, , hexobarbi- pressants, aspirin, astemizole, , atorvastatin; at- tal, hydralazine, hydrochlorothiazide, hydrocodone with ropine, azatadine, azithromycin, bacampicillin, ba- 25 APAP, hydrocortisone (cortisol), hydroflunethiazide, hy- clofen, beclomethasone, belladonna, benzazepril, droxychloroquine, , hyoscyamine, ibupro- bendroflumethiazide, benzoyl peroxide, benzthiazide, fen, , idebenone, indapamide, indomethacin, benztropine, betamethasone, betha nechol, isradipine, insulin, interferon, ipratropium bromide, iofo- HCl, biperiden, bisacodyl, /HCTZ, bleomycin, quinol, iron-polysaccharide, isoetharine, isoniazid, iso- botulism toxin, , bromodiphenhydramine, 30 propamide, isoproterenol, isosorbide mononitrate S.A, brompheniramine, buclizine, budesonide, bumetanide, isotretinoin, isoxsuprine, isradipine, itraconazole, iver- HCl, , busulfan, butabarbital, buta- mectin, kaolin & pectin, , ketoprofen, nol, , butoconazole nitrate, butorphanol, ketorolac-tromethamine, lactulose, lansoprazole, latan- caffeine, calcitonin, calcium carbonate, camptothecin, oprost, levodopa, levaflozacin, levonogestrel levothy- capsaicin, captopril, , carbenicillin, car- 35 roxine, lidocaine, lincomycin, liothyronine, liotrix, lisino- bidopa & levodopa, carbinoxamine inhibitors, carbonic pril, lithium, lomefloxacin HCl, loperamide, loracarbef, anhydrase, carboplatin, carisoprodol, carotene, car- , lorazepam, losartan, losartan/HCTZ, lovas- phenazine, HCl, cascara, cefaclor, cefproxil, tatin, succinate, lymphokines, magnesium hy- cefuroxime, cephalexin, cephradine, cetirizine, chlo- droxide, magnesium sulfate, magnesium trisilicate, phedianol, chloral hydrate, chlorambucil, chloramphen- 40 , , meclofenamate, medroxypro- icol, chlordiazepoxide, chloroquine, chlorothiazide, gesterone, mefloquine HCl, melatonin, melenamic acid, chlorotrianisene, chlorpheniramine, , meloxicam, melphalan, menthol, mephenytoin, mepho- chlorpropamide, , chlorthalidone, chlo- barbital, meprobanate, mercaptopurine, , rzoxazone, cholestyramine, cimetidine, cinoxacin, cip- metaproterenol, metaxalone, metformin hydrochloride, rofloxacin, , cis-platin, clarithromycin, clemas- 45 methadone, methamphetamine, methaqualone, meth- tine, clidinium, , clofibrate, clomiphere, clon- arbital, methenamine, methicillin, methocarbamol, azepam, clonidine, clorazepate, clotrimoxazole, cloxa- methotrexate, methsuximide, methylchlothinzide, meth- cillin, cloxapine, codeine, colchicine, collagen, ylcellulose, , methylergonovine, methylphe- coloestipol, conjugated estrogen, contraceptives, corti- nidate, , methylsergide, methyl sal- costerone, cortisone, crornolyn, cyclacillin, cyclande- 50 icylate, metformin HCl, , metolazone, late, cyclizine, , , cy- , metronidazole, mexiletine, miconazole ni- clothiazide, cycrimine, , cytokines, dan- trate, minoxidil, misoprostol, mitotane, moclobemide, azol, darithron, dantrolene, dapsone, daunorubicin, de- moexipril HCl, mometasone, monamine oxidase inhibi- oxyribonucleic acid, -HCl, desloratadine, tors, morphine, mupirocin, nabumetone, , na- desogestrel, dextroamphetamine, , 55 fazodone, , nalidixic acid, naproxen, narcotic an- dexchlorpheniramine, dextromethorphan, diazepan, di- algesics, nedocromil sodium, nefazodpne HCl, neomy- clofenac sodium, , dicyclomine, diethyl- cin, neostigmine, , , nicotine, nifed- stilbestrol, diflunisal, digitalis, digoxin, diltiazen, dimen- ipine, nimodipine, nitrazoxanide, nitrates, nitrofurantoin,

4 7 EP 1 201 230 A2 8 nitroglycerin, nizatidine, nomifensine, norethindrone, For example, if the active drug molecule or molecules norethindrone acetate, norfloxacin, norgestimate, norg- to be used are soluble in alcohol, water or oil (lipid), it estrel, nylidrin, nystatin, oflaxacin, omeprazol, orphen- or they are dissolved in the suitable respective solvent. adrine, oxacillin, oxaprozin, oxazepam, , ox- Similarly, if the vasodilator to be used is alcohol, water ycodone, , oxyphenbutazone, pancreli- 5 or oil soluble, it is dissolved in the suitable solvent, which pase, pantothenic acid, papaverine, para-aminosalicylic can be the same or different from the solvent used to acid, paramethasone, paregoric, paroxetine, pemoline, dissolve the active drug molecule(s). Suitable alcohol penicillamine, penicillin, penicillin-v, pentazocine HCl, solvents include but are not limited to isopropanol, eth- pentobarbital, , peptides and peptide frag- anol, methanol, or mixtures thereof. Suitable oil solvents ments, pergolid mesylate, , pethidine, 10 include but are not limited to vegetable oils, such as olive phenacetin, phenazopyridine, pheniramine, phenobar- oil, peanut oil, soybean oil, monoi oil, macadamia oil and bital, phenolphthalein, phenprocoumon, phensuximide, sunflower oil; glycerin; cetyl alcohol and propylene gly- mesylate, phenylbutazone, phenyle- col. The amount of solvent used may range from about phrine, , phenyl toloxamine, 1% to 60% by weight. The two are then combined, and , pilocarpine, , piper acetazine, pirox- 15 a penetration enhancer, which is preferably lipid-based, icum, poloxamer, polycarbophil-calcium, polythiazide, is then added to the mixture (the penetration enhancer potassium supplements, pravastatin, prazosin, pred- may or may not be soluble). The order of the addition of nisolone, prednisone, primidone, probenecid, probucol, the complex components may also change, depending procainamide, procarbazine, , procyc- on the desired formulation. For example, the water-sol- lidine, progesterone, , , pro- 20 uble phase may be combined with the oil phase into an pantheline, propofol, propoxyphene, , pro- emulsion, then the alcohol phase added to the water-oil teins and protein fragments, pruzepam, pseudoephe- phases. drine, psoralens, psyllium, pyrazinamide, pyridostig- [0014] It is not necessary that the active ingredient (s) mine, pyrodoxine, pyrilamine, pyrvinium, quinapril, and vasodilator both be soluble in the same solvent. For quinestrol, quinethazone, , quinine, rabepra- 25 example, if an active ingredient is used that is alcohol zole, ramipril, ranitidine, rauwolfia alkaloids, riboflavin, soluble, a vasodilator that is water soluble can be used. ribonucleic acid, , , , sali- Each is dissolved in its respective solvent and then com- cylates, , sannosides a & b, scopolamine, bined. Similarly, if the active ingredient is water soluble secobarbital, senna, , sertraline, sildenafil cit- and the vasodilator is alcohol soluble, again each is dis- rate, simethicone, , sodium bicarbonate, so- 30 solved in its respective solvent and combined. The pen- dium phosphate, sodium fluoride, sodium nitrate, etration enhancer is then added. Other ingredients may , sucrulfate, sulfacytine, sulfamethoxa- be added to the mixture to achieve maximum delivery zole, sulfasalazine, sulfinpyrazone, sulfisoxazole, sulin- efficiency or other effects if desired. dac, , talbutal, tamoxifen, tamazepam, ten- [0015] The order of addition of the various compo- oxicam, , terbinafine, , terconzaole, 35 nents may be variable for each different formulation and terfenadine, terphinhydrate, , testosterone delivery objective. The penetration enhancer/solvent and analogs, thiabendazole, thiamine, , thi- mix may be added to the water and water soluble com- othixene, thonzonium bromide, thyroglobulin, thyroid, ponents (or vice versa), and then the alcohol soluble thyroxine, tibolone, ticarcillin, , tioconazole, to- components may be added to the resulting mixture (or bramycin, tocainide, , tolazamide, tolbuta- 40 vice versa). mide, tolmetin, , , tretinoin, triamci- [0016] Although the described delivery complex nolone, triamterine, triazolam, trichlormethiazide, tricy- transports drug molecules efficiently without any patch- clic , trihexethyl, , triflu- like device, in some instances a patch may be desirable. promazine, trihexyphenidyl, trimeprazine, trimethoben- Patches, pre-impregnated with one or more compo- zamine, trimethoprim, , tripclennamine, 45 nents of the delivery complex or with the complete de- triprolidine, , trolamine salicylate, tumor livery complex may be preferable for the delivery of necrosis factor, valacyclovir, valproic acid, valsartan, some active drugs to facilitate delivery efficiency or to venlafaxine, verapamil, vitamin A, vitamin B-12, vitamin alter delivery kinetics or dynamics. If a patch is used in C, vitamin D, vitamin E, vitamin K, voltarin, warfarin so- conjunction with the delivery complex of the present in- dium, xanthine, zidovudine, zopiclone and zolpidem. 50 vention, preferably the patch is a non-breathable layer One or more active ingredients may be used in the same into which the complex components or the complex is formulation for delivery. The active ingredient may serve placed or integrated. Suitable non-breathable layers in- exclusively as the active drug molecule or it may also clude sheets of plastic, polyethylene, polyvinyl chloride, serve as the vasodilator or the penetrating agent where wax paper, foil, latex, etc., and combinations thereof. the active drug molecule exhibits both functions in the 55 Those skilled in the art will recognize that any non- drug delivery complex. breathable substance (defined as a substance that does [0013] The drug delivery complex is in part created by not allow the exchange of gases through its membrane) predetermining the solubility of the various components. that is not deleterious to the particular active ingredient

5 9 EP 1 201 230 A2 10

(s) or to the other delivery system components and that site by applying a vasodilator to said site; does not cause any irritation to the skin may be used. b. placing said active ingredient on the skin at The patch-like device may function to create and control said transport site after said blood supply has a suitable microenvironment at the drug delivery site to been enhanced; facilitate the delivery of drugs across the skin and into 5 c. enhancing the permeation of said active in- the bodily fluids. Environmental conditions which can be gredient through said skin by applying a perme- deleterious to transdermal drug delivery and which may ation enhancer to said skin. be enhanced when the delivery system is combined with or applied by a patch-like device include: cold, heat, ex- 2. The method of claim 1, wherein the temperature cessive humidity, dry skin or arid conditions. The patch- 10 and humidity at said transport site are controlled. like device may potentially maintain more stable and more favorable conditions (e.g., temperature, humidity, 3. The method of claim 2, wherein said temperature skin pore size, enhanced localized blood flow) for the and humidity are controlled by covering said trans- optimization of transdermal drug transportation at the port site with a non-breathable material. drug delivery site. The patch-like device may be secured 15 to the skin by any suitable means, such as with a band- 4. The method of claim 1, wherein said active ingredi- age having adhesive or fasteners. In the preferred em- ent is dissolved in a solvent. bodiment, no adhesive is used, instead compression is used as discussed in detail below. 5. The method of claim 4, wherein said solvent is an 20 alcohol or water. FORMULATION EXAMPLE 1 6. The method of claim 1, wherein said vasodilator is [0017] Separately, propylene glycol and water are dissolved in a solvent. combined and then mixed with olive oil. Ethanol, men- thol and Loratadine are combined and added to the wa- 25 7. The method of claim 6, wherein said solvent is an ter/propylene glycol/olive oil mix. The amount of each alcohol or water. component in the final formulation is as follows: 8. The method of claim 1, wherein step (c) is carried Olive oil - 9% out simultaneously with step (b). Propylene glycol - 2.5% 30 Water - 38.5% 9. The method of claim 1, wherein step (c) is carried Ethanol - 30% out after step (b). menthol - 10% Loratadine - 10% 10. A method of delivering an active ingredient at a 35 transport site through the skin of a living body, con- FORMULATION EXAMPLE 2 sisting essentially of:

[0018] Propylene glycol and water are combined and a. enhancing the blood supply at said transport then mixed with oleic acid. To that mixture is added a site by applying a vasodilator to said site; mixture of isopropanol, menthol and ketoprofen. The 40 b. applying a penetration enhancer to said amount of each component in the final formulation is as transport site; follows: c. placing said active ingredient on the skin at said transport site after said blood supply has Oleic acid - 15% been enhanced; and Propylene glycol - 5% 45 d. causing said active ingredient to penetrate Water - 20% said skin. Isopropanol - 30% menthol - 10% 11. A transdermal delivery system for delivering an ac- Ketoprofen - 20% tive ingredient through the skin of a living body, con- 50 sisting essentially of:

Claims a. an active ingredient; b. a vasodilator; and 1. A method of delivering an active ingredient at a c. means for enhancing the permeation of said transport site through the skin of a living body, con- 55 active ingredient through said skin. sisting essentially of: 12. The transdermal delivery system of claim 11, a. enhancing the blood supply at said transport wherein said active ingredient is dissolved in a sol-

6 11 EP 1 201 230 A2 12

vent.

13. The transdermal delivery system of claim 12, wherein said solvent is an alcohol or water. 5 14. The transdermal delivery system of claim 11, wherein said vasodilator is dissolved in a solvent.

15. The transdermal delivery system of claim 14, wherein said solvent is an alcohol or water. 10

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