CA1277564C - Dermal and transdermal patches having a discontinuous pattern adhesive layer - Google Patents

Abstract

Dermal and Transdermal Patches Having a Discontinuous Pattern Adhesive Layer Abstract of the Disclosure Disclosed is a dermal or transdermal drug delivery system in form of a patch consisting of a drug occlusive backing layer, a drug reservoir, an adhesive layer and a removable protective overlayer.
The improvement comprises a discrete and discontinuous pattern of the adhesive covering the external side of the drug reservoir directed towards the site of application, and which pattern is optionally surrounded with a continuous or discontinuous band of adhesive.

Description

12~ 4 4-15750t=/CGC 1179 Dermal and Transdermal Patches Having a Discontinuous Pattern Adhe~ive Layer In recent years medicated bandages have become increasingly impor-tant for the administration of systemically active drugs. These patches have also been used to deliver drugs for topical admini-~tration.

The patches can be cla~sified in two general groups. The first group has the drug contained in an adhesive or has the drug formulation in a re~ervoir which i8 completely coated with an adhe~ive. The second group includes tho~e patches in which the drug or drug formulation is within a reservoir in which the drug is soluble or is contained in a "sponge"-like msterial through which it i8 freely transferable snd an adhesive surrounds, but does not cover, the contact area 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.

The~e 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 nul~ber of adhe~ives can be advantageously employed, since the drug must pass through the adhesive to reach the patient' 8 skin.

If the active drug is ~oluble in the adhesive, the drug red~stri-butes itself, from the reservoir into the adhesive, during storage.
This results in an initial "burst" of drug expo~ed to the skin, yielding an initial higher dose. This also means that the dose which ~ ~ J ,:
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~ms~4 is dellvered later in time i~ much les~ than that desired. ~raphi-cally, the dose-time curve approximates the ~hape of that obtsined with a typlcal 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 i9 also ruled out.
Hence, only a very limited range of adhesives have been compat-lble, with thi~ mode of drug administration.

In the case where the adhesive surrounds the drug compartment-patient contact area of the patch, problems are encountered with (1) the integrity of the compartment surface-skin surface contact area (buckling of the patch away from the skin in the cour~e oE
Dormal movement) and ~2) the need for excessively large patches relative to the amount of active agent being administered. When smaller slzes are needed (due to the limited application area or for co~metic reasons) a high percentage of the application area is reserved for the adhesive. If this adhesive covered area is to be reduced, the adhesive used must hold stronger to the skin than would otherwise be acceptable or desirable. Strong adhesives result in problems of their own. ~rimarily, patches employing ~trong adhesives are difficult to rPmove and patients requiring frequent replacement of the patches are not likely to uYe them as regularly as recom-mended. Hence, proper treatment i8 compromised.

It is an object of the invention to provlde a yatcb for administer-ing medication which is free of the above defects and has improved release properties.

Another ob~ect is to provlde a patch for administering medication which is compatible with a large number oE alternative adhesives.

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

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Surprisingly, it has now been found that all of these object~, and other~, are reallzed by applying a discontinuous pattern of sdhesive over the external surface of an active-agent contain-tng compartment, which adhesive will contact the patient's skin when the pstch is applied.

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

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

~ig. 3 represents an alternative embodiment of the invention absent a protective overlayer.

Fig. 4 represents an alternative printing pattern on a reservoir compartment.

Fig. 5 (membrsne sy~tem with overlayer) and Fig. 7 (matrix system with overlayer) are cross sectional views of Fig. 3.

Detailed Descrlptlon of the Invention Prior art pstches 1 comprise variou~ parts of tifferent or identical sizes and consist of an occlu#ive backing layer 2, a drug reser-voir 3, an adhe~ive layer 4 and a removable protective overlayer 6.
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 bac~ing layer 2 con~ists of impermeable material and covers the e~ternal side of the drug re~ervoir 3 which ls 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 re~ervoir is covered, wherea~

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the perimetric edges are open, see Fig. 6 snd 7. When the backlnglayer is larger and extends over the drug reservoir, the sur-mounting 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 ex~mple, 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.

According to the invention, the external side of the drug reser-voir 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 of the invention the membrane is covered with a discrete, dls-continuous pattern. This pattern may be surrounded ~ith 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 limlted to the embodiments shown in the dra~ings. Thsy can be of any shape and number a~ desired.

~ssentially any pattern of adhesive (such as the adhesive pattern 4' in Fig. 4) covering the surface of reservoir 3 i9 suitable. However, a series of adhesive dots of uniform or regular slze and Ypacing is most convenient. ~hile any mean~ of applying the adhesive pattern will suffice, pattern printing ls the most preferred.

At least 20 %, preferably at least 30 %, more preferably about 40 æ~
of the entlre patch-patient, preferably the reservoir-patient contact area should be covered with adhesive to assure proper adhesion. Preferably, not more than 80 %, most preferably le~s than about 60 %, most preferably about 40 %, of the reservoir external surface distal to the backing layer ls covered by the adhesive.

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-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 thege patches, the coverage pattern oE adhesiv~ is a combination of a discontinuous pattern over the drug reservoir and a continuous surrounding band.
The form of the surrounding band i6 derived from the geometry of the patch and may be circular or rectangular. The continuous band, especially when an occlusive type oE adhesive is employed, i8 an extremely advantigeous 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 % oE the reservoir surface area which forms the contact area between the drug and the patient, has to be covered with adhesive material.

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

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

The adhesives can be classified as one of three types on the basis of the drug solubility therein:
(1) occlusive, (2~ highly soluble, and (3) slightly or sparingly soluble. ~or nitroglycerin, typical occlusive adhesives include:
natural or synthetic rubber based compounds such as styrenebuta-diene, polyisobutylene, polybutadiene, polyisoprene, ànd block copolymers. Adhesives in which nitroglycerin is highly soluble include: acrylic and methacrylic resins, polyurethanes, vinyl polymer~, silicon, and ethylene vinyl acetate compounds containing high levels of tackifying resins (which serve as solubili2ers~. Of ~2775~g course, the sparingly ~olubilizlng adhesives can also be utilized in the instsnt invention. The above ~lassification depends on the 901u-b~lity of the particular drug ln the adhesive, but those oE ordinary skill are able ~o determine which class of a particular adhesive is suitable for the preparation of the transderl1lal therapeutic system intended.

Preferred are adllesives consisting of polystyrene, e.g. Kraton~
(~hell) copolymers, ethylene vinyl acetate compounds, e.g. Elvax~
~Du Pont) or Vynathene (U.S.J. 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 (Dainippon).

The adhesives mentioned above are of varying composition wherein the base polymer is the p}incipal component.

e may employ any of those adheslve types on the basis of compa-tibility with other patch materlals and the skin.

Generally, the patches are prepared by printing a pattern of adhesive onto an adhesive releasing substrate, such as a foil or film, whlch substrate acts as a removable protective overcoat for the finished patch. The drug reservoir i9 then laid down on the adhesive layer, a backing layer applied on the re#ervolr, and the entire patch punched from the sheet materisl. The reservoir i8 fixed to the backing layer by applying an additional suitable adhesive on top of the reservoir and apply~ng 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.

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~277564 As sl~auld ~e apparent Erom the above, the instant invention is suitable for use wlth any active ingredient which is to be delivered to the Ykin.

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, con~istent with their known dosages and uses. Of course, the amount of drug necessary to obtain the desired therapeutlc effect will vary depending on the particular drug used. Suitable systemic drugs include, without limitation, anti-microbial agents such as penicillill, tetracycline, oxytetracycline, chlortetra-cycline, chloramphenicol, Hnd sulfonamides sedatives and hypnotics such as pentabarbital sodiuul, codeinej (bromoisovaleryl) urea, carbromal, and sodium phenobarbital; psychic energizers such as 3-(2-amino-propyl) indole acetate and 3-(2-aminobutyl) indole acetate; tranquilizers such as reserpine, chlorproma~ine hydro-chloride, and thiopropazate hydrochloride; hormones such a~ adreno-corticosteroids, for example methylprednisolone; androgenic steroids, for example, methylte~to~terone, and fluoxymesterone;
estrogenic steroids, for example, estrone, 17e-estradiol and ethinyl e~tradiol; progestation~l steraids, ~or example, 17a-acetoxy-pro-gesterone, medroxyprogesterone acetate, 19-norprogesterone, nor-ethindrolle and thyroxine, antipyretics such as aspirin, salicyl-amide, and ~odium salixylate; morphine and other narcotic analge-8iC~; antidiabetics, e.g., insulin; cardiovascular agents, e.g. nitroglycerin, beta-blockers such as metoprolol or oxprenolol and cardiac glycosides such as digitoxin, digoxin, ouabain; anti-spasmodic ~uch as atropine, scopolamine hydrobromide, methscopol-amine broulide, methscopolamine bromide with phenobarbital; anti-malarials such as the 4-aminoquinolines, 9-amino-quinolines, and pyrimethamiDe; nutritional agents such as vitamins, es~ential amino acids, and essential fats; and arecoline.

12~75~;4, Additionally, in practicing this invention one can employ a wide variety of topically active drugR consistent with their known do~ages and uses. Suitable drugs include, without limitation:
alltiper6pirants, e.g., aluminum chloride; deodorants, e.g. triclosan or methylbenzethonium chloride; astringents, e.g., tannic acid:
irritants, e.g., methyl salicylate, camphor, cantharides; kerato-lytics, e.g., benzoic acid, salicylic acid, resorcinol iodochlor-hydroxyquin; antifungal agents, such as tolnaftate, griseofulvin, nystatin and amphotericin anti-inflammatory agents, such as orticostsroids, e.g., hydrocortisone, hydrocorti~one acetate, prednisolone, methylprednisolone, triamcinolone acetonide, fludro-cortisone, flurandrenolone, flumethasone, dexamethasone sodium phosphate, bethamethasone valerate, fluocinolone acetonide; fluoro-metholone; and pramoxine HCl; anti-neoplastic agents, e.g. metho-trexate; and antibacterial agents such as bacitracin, neomycin, erythromycin, tetracycline HCl chlortetracycli~le HCl, chlorampheni-col, oxytetracycline, polymyxin B, nitrofuraxone, mafenide (~-amino-p-toluenesulfonamide), hexachlorophene, benzalkonium chloride, cetalkonium chloride, methylbenzethonium chloride, and neomycin sulfate.

Of the aoove drugs, nitroglycerin, scopolamine hydrobromide, 17B-estradiol and arecholine are especially useful.

lt will be appreciated, with regard to the aforesaid llYt of drugs, that designation of the drug as either "systemically or topically"
active 18 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 Drdinary skill. For example, subtherapeutic systemic levels of drugs can still be utilized for a topical effect. This iY egpecially gO
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.

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_ 9 _ In addition to the aforementioned drugs, simple pharmacologically accepta'ole derivativea of the drugs, such as ethers, esters, amides, acetals, salts, etc.as well as the corresponding free aclds or bases or formulations of these drug~ having the desired polymeric per-n~eability or transport proper~ies can be prepared and used in practiclng the invention. Drugs mentioned above can be used alone or in combination with others and each other. Of course, the deri-vatives should be such as to convert to the active drugs within the body through the action of body enzyme assisted transformations, pH, etc.

The instant invention will be more clearly under~tood from the following example, which is of an exemplary nature only and does not limit the scope of the invention.

Exam~le 1: Transdermal patches having nitroglycerin as the active agent are prepared as follows:

The adhesiYe is pattern printed (this 1neans coverage of the adhesive is less than 100 %) with a series of dots of uniform sizes and spacing.

Samples differ only in tenDs of the adhesive used and degree of coverage of the reservoir-patent contact area. 100 % coverage show3 prior art patches. Other patches are illustratlng the invention. A~
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.

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Claims (28)

1. In a dermal or transdermal drug delivery system comprising a drug occlusive backing layer, a drug reservoir thereon and a first adhesive to affix (1) said drug reservoir and occlusive backing layer to (2) a patient such that drug contained in said reservoir can be delivered by said system to said patient, and a removable drug occlusive layer on said adhesive, the improvement comprising said first adhesive being in a discrete, discontinuous pattern in a region which, when said patch is applied to said patient, constitutes a reservoir-patient contact area, said first adhesive being present in said region to a degree which results in at least 10 % of said region to no more than about 60 % of said region having said first adhesive thereon, such that at least 20 %
of the entire surface area which will contact said patient once said patch is applied to said patient has an adhesive thereon; said drug being insoluble in said adhesive.

2. The improvement of claim 1 wherein said reservoir-patient contact area having said first adhesive thereon has a continuous border around the perimeter of said first adhesive of a second adhesive.

3. The improvement of claim 2 wherein said second adhesive is different than said first adhesive.

4. The improvement of claim 3 wherein said second adhesive is selected from those in which said drug is readily soluble.

5. The improvement of claim 3 wherein said second adhesive is selected from those in which said drug is insoluble.

6. The improvement of claim 2 wherein said first adhesive and said second adhesive are the same.

7. The improvement of claim 1 wherein at least 20 % to about 60 % of said region has said first adhesive thereon.

8. The improvement of claim 1 wherein at least about 40 % to about 60 %
of said region has said first adhesive thereon.

9. The improvement of claim 1 wherein about 40 % of said region has said first adhesive thereon.

10. The improvement of claim 1 wherein said discontinuous pattern is a series of dots.

11. The improvement of claim 1 wherein said reservoir is a matrix having said drug dispersed therein.

12. The improvement of claim 1 wherein said reservoir is a volume defined by said backing layer and a drug permeable porous membrane fused thereto along the periphery thereof, said drug being contained within said volume so defined.

13. The improvement of claim 1 wherein said reservoir is a volume defined by a drug-permeable porous membrane and a secondary membrane, said reservoir being oriented such that when said patch is applied to said patient, said porous membrane is closer to said patient than said secondary membrane, said drug being within said volume so defined.

14. The improvement of claim 1 wherein said discontinuous pattern is a series of crosses.

15. In a dermal or transdermal drug delivery system comprising a drug occlusive backing layer, a drug reservoir thereon and a first adhesive to affix (1) said drug reservoir and occlusive backing layer to (2) a patient such that drug contained in said reservoir can be delivered by said system to said patient, and a removable drug occlusive layer on said adhesive, the improvement comprising said first adhesive being in a discrete, discontinuous pattern in a region which, when said patch is applied to said patient, constitutes a reservoir-patient contact area, said first adhesive being present in said region to a degree which results in at least 10 % of said region to no more than about 60 % of said region having said first adhesive thereon, such that at least 20 %
of the entire surface area which will contact said patient once said patch is applied to said patient has an adhesive thereon; said drug being soluble in said adhesive.

16. The improvement of claim 15 wherein said reservoir-patient contact area having said first adhesive thereon has a continuous border around the perimeter of said first adhesive of a second adhesive.

17. The improvement of claim 16 wherein said first adhesive and said second adhesive are the same.

18. The improvement of claim 15 wherein at least 20 % to about 60 % of said region has said first adhesive thereon.

19. The improvement of claim 15 wherein at least about 40 % to about 60 %
of said region has said first adhesive thereon.

20. The improvement of claim 15 wherein about 40 % of said region has said first adhesive thereon.

21. The improvement of claim 16 wherein said second adhesive is selected from those in which said drug is insoluble.

22. The improvement of claim 15 wherein said discontinuous pattern is a series of dots.

23. The improvement of claim 15 wherein said reservoir is a matrix having said drug dispersed therein.

24. The improvement of claim 15 wherein said reservoir is a volume defined by said backing layer and a drug permeable porous membrane fused thereto along the periphery thereof, said drug being contained within said volume so defined.

25. The improvement of claim 15 wherein said reservoir is a volume defined by a drug-permeable porous membrane and a secondary membrane, said reservoir being oriented such that when said patch is applied to said patient, said porous membrane is closer to said patient than said secondary membrane, said drug being within said solume so defined.

26. The improvement of claim 15 wherein said second adhesive is different than said first adhesive.

27. The improvement of claim 15 wherein said second adhesive is selected from those in which said drug is readily soluble.

28. The improvement of claim 15 wherein said discontinuous pattern is a series of crosses.

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