AU597618B2

AU597618B2 - Dermal and transdermal patches having a discontinuous pattern adhesive layer

Info

Publication number: AU597618B2
Application number: AU68798/87A
Authority: AU
Inventors: Frederic D. Loveland
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1986-02-14
Filing date: 1987-02-13
Publication date: 1990-06-07
Anticipated expiration: 2007-02-13
Also published as: HU196133B; IL81540A0; FI870557A; EP0236266B1; KR870007701A; DK72787D0; NO870576D0; ZA871060B; MY100784A; CA1277564C; FI870557A0; JPH081679U; EP0236266A1; DK72787A; JPS62215521A; PT84278B; HUT43959A; ATE64539T1; DD270246A5; NO870576L

Abstract

The system is in the form of a plaster (1) consisting of a cover layer (2) impermeable to the components of the active substance formulation, a reservoir (3) for the active substance formulation, an adhesive layer (4) and a pull-off protective layer (6). On this system, a discontinuous adhesive pattern is applied to the outer side of the active substance reservoir (3) facing towards the patient, and, if appropriate, a discontinuous or continuous adhesive border (7) is applied as a limit to the adhesive pattern. <IMAGE>

Description

I

COMMONWEALTH OF AUSTRALIA51U 7 PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class I t. Class Application Number: Lodged: 9 7 lql(5 -7 Complete Specification Lodged: Accepted: Published- Priority: Tb is document contains the amendments mnade under Section 49 and is correct for Printing. 'elted Art 0 010 Name of Applicant: 0 Ad~ress of Applicant 0 .0 o4 0 0 ilct~al Inventor: CIBA-GEIGY AG.

Klyheckstrasse 141, 4002 Basle, Switzerland.

FREDERIC D. LOVELAND.

EDWD. WATERS 8, SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000. A 6 o Address for Service: Complete Specification for the invention entitled: DERMAL AND TRANSDERMAL PATCHES HAVING A DISCONTINUOUS PATTERN ADHESIVE LAYER The following statement is a full description of this Invention, including the best metthod of performing it known to us I 4 1 a 4 -1 5750 /=/CGC 1179 Dermal and Transdermal Patches Having a Discontinuous Pattern Adhesive Layer In recent years medicated bandages have become increasingly important for the administration of systemically active drugs. These 0 80 patches have also been used to deliver drugs for topical admini- 0 a 0 stration.

009 o a The patches can be classified in two general groups. The first group has the drug contained in an adhesive or has the drug formulation in 0 00 a reservoir which is completely coated with an adhesive. The second group includes those patches in which the drug or drug formulation is within a reservoir in which the drug is soluble or is contained 4 066 o in a "sponge"-like material through which it is freely transferable 0 00 and an adhesive surrounds, but does not cover, the contact area ao. between the reservoir and the patient. Such patches are described in U.S. Patent specifications 3,598,122; 3,598,123; 3,731,683; 3,734,097; 3,742,951; and 3,797,494.

3. These patches have defects. In the first group mentioned above (those with continuous adhesive layers over the reservoir or with the active'substance dispersed therein), only a limited number of adhesives can be advantageously employed, since the drug must pass through the adhesive to reach the patient's skin.

If the active drug is soluble in the adhesive, the drug redistributes itself, from the reservoir into the adhesive, during storage.

This results in an initial "burst" of drug exposed to the skin, yielding an initial higher dose. This also means that the dose which -2is delivered later in time is much less than that desired. Graphically, the dose-time curve approximates the shape of that obtained with a typical single oral dose of a drug rather than the desired sustained release curve. When the drug in the reservoir must pass through the adhesive, an occlusive type adhesive is also ruled out.

Hence, only a very limited range of adhesives have been compatible, with this mode of drug administration.

In the case where the adhesive surrounds the drug compartmentpatient contact area of the patch, problems are encountered with the integrity of the compartment surface-skin surface contact area (buckling of the patch away from the skin in the course of a normal movement) and the need for excessively large patches 4' relative to the amount of active agent being administered. When smaller sizes are needed (due to the limited application area or for .15 cosmetic reasons) a high percentage of the application area is o°oreserved for the adhesive. If this adhesive covered area is to be reduced, the adhesive used must hold stronger to the skin than would ctherwise be acceptable or desirable. Strong adhesives result in problems of their own. Primarily, patches employing strong adhesives o, 20 are difficult to remove and patients requiring frequent replacement a a aof the patches are not likely to use them as regularly as recommended. Hence, proper treatment is compromised.

It is an object of the invention to provide a patch for administering medication which is free of the above defects and has improved release properties.

o a Another object is to provide a patch for administering medication which is compatible with a large number of alternative adhesives.

A further object of the invention is to provide a patch for administering medication which assures proper patch-skin contact over the patch's entire surface.

3 Surprisingly, it has now been found that all of these objects, and others, are realized by applying a discontinuous pattern of adhesive over the external surface of an active-agent containing compartment, which adhesive will contact the patient's skin when the S patch is applied.

Brief description of the drawings Fig. 1 illustrates a top view of a typical patch of the invention absent a protective overlayer.

Fig. 2 (membrane system with overlayer) and Fig. 6 (matrix system with overlayer) are cross sectional views of Fig. 1.

0 00 0O 04 Fig. 3 represents an alternative embodiment of the invention absent o 0 o a protective overlayer.

0 0 0 00 0o,' Fig. 4 represents an alternative printing pattern on a reservoir o o compartment.

Fig. 5 (membrane system with overlayer) and Fig. 7 (matrix system oa oa with overlayer) are cross sectional views of Fig. 3.

o co 0 04 Detailed Description of the Invention o o0 0 o0 Prior art patches 1 comprise various parts of different or identical sizes and consist of an occlusive backing layer 2, a drug resera 20 voir 3, an adhesive layer 4 and a removable protective overlayer 6.

0*0*00 The drug reservoir 3 consists of the drug or the drug formulation which are either embedded within a matrix polymer material (matrix system) or are contained within a membrane (membrane system) through which the drug can migrate. The occlusive backing layer 2 consists of impermeable material and covers the external side of the drug reservoir 3 which is directed away from the skin of the patient. When the backing layer has the same size as the reservoir, only this external side of the drug reservoir is covered, whereas 4the perimetric edges are open, see Fig. 6 and 7. When the backing layer is larger and extends over the drug reservoir, the surmounting part of the backing layer is connected at the edges with the adhesive layer 4 or the membrane 5, see Fig. 2 and 5. For example, the backing layer 2 and the membrane layer 5 define an occluded reservoir compartment 3 therebetween. Patches wherein the perimetric edges or the entire drug reservoir are covered with adhesive are described in U.S. Patent specification 3,797,494.

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0 00 0 00 0 *0 6° o o a 0 0o o«0 According to the invention, the external side of the drug reservoir 3 which is directed toward the site of application, e.g. the skin of the patient, especially the membrane material, is provided with an adhesive layer consisting of a discrete, discontinuous pattern. This pattern can be surrounded by a discontinuous or, perferably, continuous band of adhesive. In a preferred embodiment 15 of the invention the membrane is covered with a discrete, discontinuous pattern. This pattern may be surrounded with a continuous band of adhesive covering the peripheral edge of the membrane or matrix. The shape of the patch itself, the shape of the reservoir and its content are not limited to the embodiments shown in the 20 drawings. They can be of any shape and number as desired. e( o o -o 0 0*0 0 00B 0 0 0 9 0o 0 00 oi o o o p 0 6* 1 7 Essentially any pattern of adhesive (such as the adhesive pattern 4' in Fig. 4) covering the surface of reservoir 3 is suitable. However, 4 series of adhesive dots of uniform or regular size and spacing is most convenient. While any means of applying the adhesive pattern will suffice, pattern printing is the most preferred.

0 4 ar At least 20 preferably at least 30 more preferably about 40 of the entire patch-patient, preferably the reservoir-patient contact area should be covered with adhesive to assure proper adhesion. Preferably, not more than 80 most preferably less than about 60 most preferably about 40 of the reservoir external surface distal to the backing layer is covered by the adhesive.

5 The adhesive material may also form the edge or surround the discontinuous pattern printed on the reservoir and may, therefore, be printed as a discontinuous or, preferably, continuous band around the external side of the reservoir, see Fig. 3. In these patches, the coverage pattern of adhesive is a combination of a discontinuous pattern over the drug reservoir and a continuous surrounding band.

The form of the surrounding band is derived from the geometry of the patch and may be circular or rectangular. The continuous band, especially when an occlusive type of adhesive is employed, is an extremely advantageous embodiment of the invention in that a seal is formed to prevent the leakage of the drug or components of the drug formulation. When a continuous surrounding band is present, a minimum of 10 of the reservoir surface area which forms the contact area between the drug and the patient, has to be covered 1 5 with adhesive material.

V.

4 1 The surrounding continuous or discontinuous bands of adhesive are of optional width. Thin or broad bands are present depending on 4 So,, particular needs or desires.

The adhesives useful in the instant invention are virtually any S°0 medically acceptable adhesives. The only limitations thereon are S 0o 0 aro *that the adhesive does not interact with the patch reservoir or a backing material and does not adversely affect the drug being i *administered. Such adhesives are known to those of ordinary skill.

j The adhesives can be classified as one of three types on the basis 25 of the drug solubility therein: a" t occlusive, highly soluble, and slightly or sparingly soluble. For nitroglycerin, typical occlusive adhesives include: natural or synthetic rubber based compounds such as styrenebutadiene, polyisobutylene, polybutadiene, polyisoprene, and block copolymers. Adhesives in which nitroglycerin is highly soluble include: acrylic and methacrylic resins, polyurethanes, vinyl polymers, silicon, and ethylene vinyl acetate compounds containing high levels of tackifying resins (which serve as solubilizers). Of 1 Y-lil I-ilYIL PI 6 course, the sparingly solubilizing adhesives can also be utilized in the instant invention. The above classification depends on the solubility of the particular drug in the adhesive, but those of ordinary skill are able to determine which class of a particular adhesive is suitable for the preparation of the transdermal therapeutic system intended.

Preferred are adhesives consisting of polystyrene, e.g. Kraton® (Shell) copolymers, ethylene vinyl acetate compounds, e.g. Elvax® (Du Pont) or Vynathene chemicals) types, polybutadiene, e.g.

Indopol® (Amoco), polyisobutylene, e.g. Oppanol® (BASF) or acrylic or methacrylic, e.g. Acronal® homopolymers, silicon rabber, e.g. DC medical adhesive (Dow), vinylpolymers or polyurethane, e.g. Vondic i (Dainippon).

f C a €Ci, 0 I S o a 00Cr Sooe €,4 00 0 000 o 00 0 0 The adhesives mentioned above are of varying composition wherein the base polymer is the principal component.

One may employ any of those adhesive types on the basis of compatibility with other patch materials and the skin.

0o 0 0 0 o 00 0 0

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ft« Generally, the patches are prepared by printing a pattern of adhesive onto an adhesive releasing substrate, such as a foil or "24 film, which substrate acts as a removable protective overcoat for the finished patch. The drug reservoir is then laid down on the adhesive layer, a backing layer applied on the reservoir, and the i& 0' entire patch punched from the sheet material. The reservoir is fixed IC: to the backing layer by applying an additional suitable adhesive on top of the'reservoir and applying the backing layer. The reservoir can also be heat sealed to the backing layer. In "pouch" type reservoirs a drug-permeable membrane is placed on the first applied adhesive layer and then the drug is applied. Alternatively the "pouch" containing the drug can be applied to the adhesive layer as a prefabricated unit. Other alternative means of making the patches of the invention are known to those of ordinary skill and are described in U.S. patent specification 3,797,494.

_1 i 7- As should be apparent from the above, the instant invention is suitable for use with any active ingredient which is to be delivered to the skin.

In practicing this invention one can employ any systemically active drug which will be absorbed by the body surface to which the bandage is applied, consistent with their known dosages and uses. Of course, the amount of drug necessary to obtain the desired therapeutic effect will vary depending on the particular drug used. Suitable systemic drugs include, without limitation, anti-microbial agents such as penicillin, tetracycline, oxytetracycline, chlortetraoa cycline, chloramphenicol, and sulfonamides; sedatives and hypnotics ,0 such as pentabarbital sodium, codeine, (bromoisovaleryl) urea, °o carbromal, and sodium phenobarbital; psychic energizers such as 0 0 0 o 90 3-(2-amino-propyl) indole acetate and 3-(2-aminobutyl) indole a V°5 acetate; tranquilizers such as reserpine, chlorpromazine hydro- 0 0o chloride, and thiopropazate hydrochloride; hormones such as adrenocorticosteroids, for example methylprednisolone; androgenic steroids, for example, methyltestosterone, and fluoxymesterone; 0o S0 estrogenic steroids, for example, estrone, 17B-estradiol and ethinyl estradiol; progestational steroids, for example, 17a-acetoxy-proa gesterone, medroxyprogesterone acetate, 19-norprogesterone, norethindrone and thyroxine, antipyretics such as aspirin, salicylamide, and sodium salixylate; morphine and other narcotic analgeo* sics; antidiabetics, insulin; cardiovascular agents, e.g. nitroglycerin, beta-blockers such as metoprolol or oxprenolol 9 0 and cardiac glycosides such as digitoxin, digoxin, ouabain; antispasmodic such as atropine, scopolamine hydrobromide, methscopolamine bromide, methscopolamine bromide with phenobarbital; antimalarials such as the 4-aminoquinolines, 9-amino-quinolines, and pyrimethamine; nutritional agents such as vitamins, essential amino acids, and essential fats; and arecoline.

'1 8 Additionally, in practicing this invention one can employ a wide variety of topically active drugs consistent with their known dosages and uses. Suitable drugs include, without limitation: antiperspirants, aluminum chloride; deodorants, e.g. triclosan or methylbenzethonium chloride; astringents, tannic acid; irritants, methyl salicylate, camphor, cantharides; keratolytics, benzoic acid, salicylic acid, resorcinol iodochlorhydroxyquin; antifungal agents, such as tolnaftate, griseofulvin, nystatin and amphotericin; anti-inflammatory agents, such as orticosteroids, hydrocortisone, hydrocortisone acetate, prednisolone, methylprednisolone, triamcinolone acetonide, fludrocortisone, flurandrenolone, flumethasone, dexamethasone sodium phosphate, bethamethasone valerate, fluocinolone acetonide; fluoro- S metholone; and pramoxine HC1; anti-neoplastic agents, e.g. metho- 15 trexate; and antibacterial agents such as bacitracin, neomycin, S erythromycin, tetracycline HC1 chlortetracycline HC1, chloramphenicol, oxytetracycline, polymyxin B, nitrofuraxone, mafenide (a-aminoo p-toluenesulfonamide), hexachlorophene, benzalkonium chloride, cetalkonium chloride, methylbenzethonium chloride, and neomycin 20 sulfate.

o t 99 B 0 S4

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00 00 9 a €v Q 0 o o o 99t 99y 9 9 9 *4 do ra 0 9 996 94 9 Of the above drugs, nitroglycerin, scopolamine hydrobromide, 178estradiol and arecholine are especially useful.

It will be appreciated, with regard to the aforesaid list of drugs, that designation of the drug as either "systemically or topically" active is done for purposes of classification only. Further, a given drug can be both systemically and topically active depending upon its manner'of use, variation of which will be apparent to those of ordinary skill. For example, subtherapeutic systemic levels of drugs can still be utilized for a topical effect. This is especially so when systemic dosing is rate limited by the skin and acting as a barrier, a flux enhancer is advantageously used to obtain a proper systemic dose.

9 In addition to the aforementioned drugs, simple pharmacologically acceptable derivatives of the drugs, such as ethers, esters, amides, acetals, salts, etc.as well as the corresponding free acids or bases or formulations of these drugs having the desired polymeric permeability or transport properties can be prepared and used in practicing the invention. Drugs mentioned above can be used alone or in combination with others and each other. Of course, the derivatives should be such as to convert to the active drugs within the body through the action of body enzyme assisted transformations, pH, etc.

00 0 000 4, Ot Q *0 oc 0 00 oo 0o 0 00 %0 2 00 The instant invention will be more clearly understood from the following example, which is of an exemplary nature only and does not limit the scope of the invention.

Example 1: Transdermal patches having nitroglycerin as the active agent are prepared as follows: The adhesive is pattern printed (this means coverage of the adhesive is less than 100 with a series of dots of uniform sizes and spacing.

Samples differ only in terms of the adhesive used and degree of coverage of the reservoir-patent contact area. 100 coverage shows prior art patches. Other patches are illustrating the invention. As a control, Transderm® Nitro-5 (CIBA-GEIGY), a patch with 100 coverage currently being marketed, is presented. The cumulative release rates of the drug in each sample are set forth in Table I below.

sl 0 0 0 0i 000 10 TRANSDERM NITRO RELEASE RATE TESTING Cumulative Nitroglycerin Release (hig/cm 2 1 Hr 4 Hr 8 lir 12 Hr 16 Hr 20 Hr 24 Hr Material Control TN-5 Systems (Average of 3 production lots) Medical Adhesive Modified 100 Coverage Coverage Coverage 303 532 748 960 1160 1348 101 290 521 103 266 469 81 260 486 398 609 800 373 746 1004 181 439 690 961 1156 862 1052 886 1059 1354 1230 1234 1358 1701 1454 Century CA-1028 (Acrylic*), 100 Coverage Coverage Coverage Fuller HM-6677 (Kraton* 100 Coverage Coverage Coverage 971 1200 906 1082 1378 1109 1275 1546 1289 Century 100 GI-1 (Kraton*) Coverage Coverage Coverage 63 241 224 9 196 271 83 110 131 149 167 4+36 620 793 963 1118 420 604 783 948 1106 17 23 29 350 498 637 500 712 918 34 772 1113 34 902 1301 *base polymer 0 jO 0009 0 4 4 0 0 4 00 00 4 0 00 ~00 4 9* 00.. 0

Claims

1. A dermal or transdermal drug delivery system in the form of a patch comprising succesively a drug occlusive backing layer, a drug reservoir, contained within a matrix material or membrane, an adhesive layer covering the matrix or membrane, and a removable protective overlayer, characterised in that said adhesive layer is in the form of a discrete and discontinuous geometrical pattern of bands of adhesive optionally surrounded with a band of more adhesive which may be continuous or discontinuous.

2. A dermal or transdermal drug delivery system according to claim 1 wherein the discrete and discontinuous geometrical pattern of bands of adhesive covering the matrix or membrane material is surrounded with a continuous band of adhesive.

3. A dermal or transdermal drug delivery system according to claim 1 wherein the drug reservoir is contained within a membrane and this membrane is covered with a discrete and discontinuous geometrical pattern of bands of adhesive surrounded with a continuous band of adhesive.

4. A dermal or transdermal drug delivery system according to claim 1 wherein the continuous band of adhesive is circular.

A dermal or transdermal drug delivery system according to any one of claims 1 4, wherein the discrete and discontinuous geometrical pattern 00o of bands of adhesive consists of an equidistant arrangement of stripes or of diamonds.

6. A dermal or transdermal drug delivery system substantially as herein described with reference to any one of the figures 2 and 5-7. 12

7. A dermal or transdermal drug delivery system substantially as herein described with reference to Example 1, excluding the control and prior art examples. DATED this 27th day o: February, 1990. CIBA-GEIGY AG By Its Patent Attorneys ARTHUR S. CAVE CO. a#,s 00 0 00 0 0 0 00 0 0 00 0 00