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 nicotine, 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 angina sufferers, the delivery of replace- chemical vasodilators, active drug ingredients and a ment hormones (e.g., estrogen, progesterone 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, alcohol 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 2 3 EP 1 201 230 A2 4 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, 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, pentifylline, peroxynitrite, pinacidil, transdermal delivery system for one or more active in- pipratecol, propentofyltine, raubasine, suloctidil, teasu- gredients. More specifically, the present invention com- prine, thymoxamine hydrochloride, xanthinol 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 clonidine, 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 indoramin, phenoxybenzamine, phen- the bodily fluids. The present invention utilizes the sol- tolamine and prazosin. Adrenergic 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- amlodipine, diltiazem, felodipine, isradipine, nica- essarily bound to either the active ingredient or the va- rdipine, nifedipine, nimodipine and verapamil. Prosteg-