US 3734097 A
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United States Patent 1191 Zaffaroni 1451 *May 22, 1973  THERAPEUTIC ADHESIVE TAPE  References Cited  Inventor: Alejandro Zaffaroni, Atherton, UNITED STATES PATENTS Calif. 3,339,546 9/1967 Chen ..l28/268  Ass1gnee: Alza Corporation, Palo Alto, Calif. 3,551,556 12/1970 Klimem et a1... "424/22 3,598,122 8/1971 Zaffaroni ..l28/268 [*1 The 3,598,123 8/1971 Zaffaroni ..l28/268 t f= 10,1938 3,632,740 1 1972 Robinson etal ..424 2s has been d1scla1med.
 Filed; AP 23, 7 Primary Examiner-Charles F. Rosenbaum Att0rney-Steven D. Godlby, Edward L. Mandel] and 1 1 PP Paul L. Sabatine Related U.S. Application Data  ABSTRACT [63 Continuation-inart of Ser. No. 812,116, A r'l 1, 1
1 1969, Pat 598,122, and a continuatiomgblpan Adhes1ve lammate tape for the topical admmistration f Sen 812,117, April 1 1969, pat of controlled therapeutically effectwe quantities of 3,598,123. drug selected from the group consisting of antineoplastic agents, folic acid antagonists and anit-  U.S.Cl ..l28/268, 424/22 mitotic agents for the treatment of Skin lesions, 51 1m. (:1. ..A6lf 7/02 prising a backing member bearing a Pressure-Sensitive 58 Field of Search ..128/260, 268, 271, adhesive, the adhesive having distributed therein 8 means for metering the flow of a therapeutically effective amount of the drug to the lesions over a prolonged period of time.
16 Claims, 5 Drawing Figures PATENTEflLL-KYZZISB 3,734,097
INVENTOR. Alejandro Zaffaroni BYM/Q 1 THERAPEUTIC ADHESIVE TAPE RELATED APPLICATIONS This application is a continuation-in-part of Ser. No. 812,116, now U.S. Pat. No. 3,598,122, filed Apr. 1, 1969, entitled Bandage for Administering Drugs and Ser. No. 812,117, filed Apr. 1, 1969, entitled Bandage now U.S. Pat. No. 3,598,123, both applications of Alejandro Zaffaroni and both issued on Aug. 10, 1971, as U.S. Pat. Nos. 3,598,122 and 3,598,123 respectively.
BACKGROUND OF THE INVENTION This invention relates to a therapeutic adhesive tape and more especially, to a therapeutic adhesive tape for the treatment of skin lesions, such as psoriatic lesions.
Severe skin lesions, such as psoriatic lesions, are conventionally treated with anti-inflammatory steroids administered systemically or topically. With systemic administration of anti-inflammatory steroids, as by injection or through the gastrointenstinal tract, severe sideeffects have been reported. Theseinclude death, steroid-induced diabetes, severe bacterial infection, severe osteoporosis, severe cutaneous atrophy, myopathy, pituitary failure, and others. While these sideeffects are generally not experienced with topical steroid therapy, many severe skin lesions, including many psoriatic lesions, do not respond favorably to topical steroid therapy. As a result, the medical profession has looked to alternative therapeutic regimes for the treatment of skin lesions.
It has long been recognized that many skin lesions, including psoriatic lesions, are caused by rapid or runaway growth of skin cells. To slow the cell growth rate to a more normal one, treatment with various antimetabolites has been proposed. Severe cases of psoriasis have been effectively treated by systemic administration of folic acid antagonists, such as methotrexate, and by anti-neoplastic agents, such as 5-fluorouracil. However, when administering these agents systemically, massive doses must be employed and this has led to some significant toxic side-effects. Although these agents have also been found to be topically active in the treatment of severe skin lesions, substantial problems have been encountered in their effective topical application. Due perhaps to instability of the compounds themselves and their instability or unavailability from creams and solutions, many studies using topical creams and ointments containing these agents have been found them to be topically inactive in the treatment of skin lesions. There is a significant need for a reliable preparation for the topical application of folic acid antagonists and anti-neoplastic agents in the treatment of severe skin lesions.
SUMMARY OF THE INVENTION Accordingly, one object of this invention is to provide a dosage unit for the topical treatment of severe skin lesions, such as psoriatic lesions.
Another object of this invention is to provide a stable, topical preparation for reliably applying folic acid antagnosists or anti-neoplastic agents to severe skin lesions in a convenient and sanitary manner.
In accomplishing these objects, one feature of this invention resides in a therapeutic adhesive tape for treatment of skin lesions by direct application to the skin lesions. The tape has a backing member and a surface having a pressure-sensitive adhesive coating, the tape containing an amount of a therapeutic agent selected from an anti-neoplastic agent and a folic acid antagonist sufficient to release a therapeutically effective amount of the therapeutic agent to the skin lesions.
Another feature of this invention resides in a therapeutic adhesive tape as described above wherein the anti-neoplastic agent or folic acid antagonist is uniformly distributed throughout the pressure-sensitive adhesive coating.
Still another feature of this invention resides in a therapeutic adhesive tape as described above wherein the anti-neoplastic agent or folic acid antagonist is encapsulated with a material permeable to passage of the therapeutic agent and the microcapsules are uniformly distributed throughout the pressure-sensitive adhesive.
A further feature of this invention resides in an adhesive tape as described above wherein the backing member has on one surface thereof a reservoir containing the anti-neoplastic agent or folic acid antagonist and permeable to passage of those therapeutic agents, the reservoir bearing on its surface remote from the backing member a coating of the pressure-sensitive adhesive.
Still a further feature of this invention resides in a method for treatment of skin lesions, such as psoriatic lesions, by directly applying to the lesions an adhesive tape releasing a therapeutically effective amount of an anti-neoplastic agent or folic acid antagonist to the lesions.
Other objects, features and advantages of the invention will become more apparent from the following description when taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS In the drawings:
FIG. 1 is a perspective view of the therapeutic adhesive tape of the invention having the folic acid antagonist or anti-neoplastic agent uniformly distributed throughout the pressuresensitive adhesive coating;
FIG. 2 is a cross-sectional view of a modified adhesive tape of the invention wherein the folic acid antagonist or anti-neoplastic agent is microencapsulated with a material permeable to passage of those therapeutic agents and the microcapsules are uniformly distributed throughout the pressure-sensitive adhesive coating;
FIG. 3 is a cross-sectional view of another embodiment of the invention wherein the anti-neoplastic agent or folic acid antagonist is uniformly distributed throughout a matrix laminated to the backing member and bearing a coating of the pressure-sensitive adhesive;
FIG. 4 is a cross-sectional view of another embodiment of the invention wherein a solubility membrane is interposed between the reservoir layer and the pressure-sensitive adhesive coating; and
FIG. 5 is a cross-sectional view of still another embodiment of the invention wherein the reservoir laminated to the backing member is a hollow container permeable to passage of the folic acid antagonist or antineoplastic agent and having the drug within an interior chamber thereof.
DETAILED DESCRIPTION OF THE INVENTION In accordance with this invention, there is provided a therapeutic adhesive tape containing an antineoplastic agent or folic acid antagonist.
As illustrated in FIG. 1, the adhesive tape 10 of the invention has a backing member 1 1 bearing a pressuresensitive adhesive coating 12. Dispersed throughout pressure-sensitive adhesive coating 12 is an antineoplastic agent or folic acid antagonist. Folic acid antagonists suitable for use in the adhesive tape of the invention include methotrexate, aminopterin, 3- chloromethotrexate and 3, 5'-dichloromethotrexate, with methotrexate being the preferred folic acid antagonist. Anti-neoplastic agents for use in the invention include vincristine, vinblastine, S-fluorouracil, 5- fluorodeoxyuridine, and 6-mercaptopurine, with use of S-fluorouracil being preferred. Antimitotic agents, such as colchicine and podophyllum, can also be used alone or in conjunction with the folic acid antagonist or anti-neoplastic agent to enhance their properties. In addition to the aforementioned compounds, simple pharmacologically acceptable derivatives of the drugs, such as ethers, esters, amides, acetals, salts, etc., having the desired skin penetration and stability properties can be prepared and used in practicing the invention. Drugs mentioned above can be used alone or in combination with each other.
Anti-neoplastic agent or folic acid antagonist is incorporated in the adhesive tape in an amount sufficient to release a therapeutically effective amount of the drug to skin lesions to which applied. Usually, the drug is incorporated in the adhesive tape in a concentration of 0.01 to 100 micrograms of drug per square centimeter of surface of the pressure-sensitive adhesive coating. However, with some drugs such as 5- fluorodeoxyuridine and podophyllum, the concentration can range as high as 1,000 micrograms per sq. cm. There is no benefit in exceeding these limits.
Any of the well-known dermatologically acceptable pressure-sensitive adhesives which permit drug migration can be used in practicing this invention. Exemplary adhesives include acrylic or methacrylic resins such as polymers of esters of acrylic or methacrylic acid with alcohols such as n-butanol, n-pentanol, isopentanol, 2- methyl butanol, l-methyl butanol, l-methyl pentanol, 2-methyl pentanol, 3-methyl pentanol, 2-ethyl butanol, isooctanol, n-decanol, or n-dodecanol, alone or copolymerized with ethylenically unsaturated monomers such as acrylic acid, methacrylic acid, acrylamide, methacrylamide, N-alkoxymethyl acrylamides, N- alkoxymethyl methacrylamides, N-tert. butylacrylamide, itaconic acid, .vinylacetate, N-branched alkyl maleamic acids wherein the alkyl group has 10 to 24 carbon atoms, glycol diacrylates, or mixtures of these; natural or synthetic rubbers such as silicon rubber, styrene-butadiene, butyl-ether, neoprene, nitrite, polyisobutylene, polybutadiene, and polyisoprene; polyurethane elastomers; vinyl polymers, such as polyvinyla1 cohol, polyvinyl ethers, polyvinyl pyrrolidone, and polyvinylacetate; ureaformaldehyde resins; phenolformaldehyde resins; resorcinol formaldehyde resins; cellulose derivatives such as ethyl cellulose, methyl cellulose, nitrocellulose, cellulose acetatebutyrate, and carboxymethyl cellulose; and natural gums such as guar, acacia, pectins, starch, dextrin, albumin, gelatin,
casein, etc. The adhesives may be compounded with tackifiers and stabilizers as is well known in the art.
Various occlusive and non-occlusive, flexible or nonflexible backing members can be used in the adhesive tape of the invention. Suitable backings include cellophane, cellulose acetate, ethylcellulose, plasticized vinylacetate-vinylchloride copolymers, polyethylene terephthalate, nylon, polyethylene, polypropylene, polyvinylidenechloride, paper, cloth, and aluminum foil. Preferably, a flexible occlusive backing is employed to conform to the shape of the body member to which the adhesive tape is applied and to enhance absorption of the folic acid antagonist or anti-neoplastic agent by the skin.
To prepare the therapeutic adhesive tape, an antineoplastic agent or folic acid antagonist is mixed with the pressure-sensitive adhesive and the mixture coated onto the backing member, usually to provide an adhesive layer 0.01 to 7 millimeters thick, although these limits can be exceeded if more or less drug is required. Alternatively, a solution or suspension of the antineoplastic agent or folic acid antagonist can be sprayed on the adhesive surface of the tape, one of whose sides is already coated with the pressure-sensitive adhesive.
To prevent passage of the drug away from the exposed surface of the pressure-sensitive adhesive prior to use, the adhesive surface of the tape generally is covered with a protective release film or foil, such as waxed paper. Alternatively, the exposed rear surface of the backing member can be coated with a low-adhesion backsize and the bandage rolled about itself. To enhance stability of the active compounds, the therapeutic bandage usually is packaged between hermetically sealed polyethylene terephthalate films under an inert atmosphere, such as gaseous nitrogen.
To use the adhesive tape of the invention, it is applied directly to skin lesions, to release a therapeutically effective amount of the anti-neoplastic agent or folic acid antagonist to the lesion. By use of this invention, one ensures that an accurately measured quantity of the active drug is available when the adhesive tape is applied to the lesion, since the drug is uniformly distributed over the pressure-sensitive adhesive face surface of the tape. The tape is effective to maintain the active agent in contact with the lesion and to enhance subcutaneous penetration of the drug. Uncertainties previously encountered in application of these agents from creams or ointments are avoided and a reliable, stable topical preparation is provided.
FIG. 2 illustrates a modified adhesive tape 20 of the invention including a backing member 21 hearing a pressure-sensitive adhesive coating 22 on one surface thereof. Adhesive coating 22 has uniformly distributed therethrough microcapsules 23 of folic acid antagonist or anti-neoplastic agent encapsulated with a material permeable to passage of the drug.
Materials used to encapsulate the drug and form the microcapsules to be distributed throughout the adhesive must be permeable to the drug to permit passage of the drug, as by diffusion, through the walls of the microcapsules at a relatively low rate. Normally, the rate of passage of the drug through the walls of the microcapsules is dependent on the solubility of the drug therein, as well as on the microcapsule wall thickness. This means that selection of appropriate encapsulating materials will be dependent on the particular drug used in the adhesive tape. By varying the encapsulating material and the wall thickness, the dosage rate per area of bandage can be controlled and movement of drug to the adhesive regulated.
Suitable materials for use in encapsulating the drug include hydrophobic polymers such as polyvinylchloride either unplasticized or plasticized with long-chain fatty amides or other plasticizer, plasticized nylon, unplasticized soft nylon, silicon rubber, polyethylene, and polyethylene terephthalate', and hydrophilic polymers such as esters of acrylic and methacrylic acid (as described in US. Pat. Nos. 2,976,576 and 3,220,960 and Belgian Pat. No. 701,813), modified collagen, crosslinked hydrophilic polyether gels (as described in US. Pat. No. 3,419,006) cross-linked polyvinylalcohol, cross-linked partially hydrolyzed polyvinylacetate, cellulosics such as methylcellulose, ethylcellulose, and hydroxyethylcellulose, and gums such as acacia, carboxymethylcellulose, and carageenan alone or combined with gelatin.
To provide the microcapsules, the encapsulating material can be uniformly impregnated with the drug to form microcapsules which are a matrixhaving the drug distributed therethrough. Alternatively, particles of drug can be encapsulated with thin coatings of the encapsulating material to form microcapsules having an interior chamber containing the drug. If desired, particles of a matrix, such as starch, gum acacia, gum tragacanth, and polyvinylchloride, can be impregnated with the drug and encapsulated with other materials such as the encapsulating materials previously described which function as a solubility membrane to meter the flow of drug to the adhesives; use of 'a matrix and a different solubility membrane coating can slow the passage of the drug from the microcapsules which is desirable with drugs that are released too rapidly from available encapsulating materials.
Anyof the encapsulation or impregnation techniques known in the art can be used to prepare the microcapsules to be incorporated into the pressure-sensitive adhesive in accord with the embodiment of FIG. 2. Thus, the drug can be added to the encapsulating material in liquid form and uniformly distributed therethrough by mixing and subsequently converting to a solid by curing or cooling; or solid encapsulating material can be impregnated with a drug by immersion in a bath of the drug to cause the drug to diffuse into the material. Subsequently, the solid material can be reduced to fine microcapsules by grinding, each of the microcapsules comprising drug coated with and distributed throughout the encapsulating material. Alternatively, fine particles of the drug can be encapsulated with the coating. One suitable technique comprises suspending dry particles of the drug in an air stream and contacting that stream with a stream containing the encapsulating material to coat the drug particles. Usually, the microcapsules have an average particle size of from 1 to 1,000 microns, although this is not critical to the invention. The microcapsules, however made, are then mixed with any of .the previously described pressure-sensitive adhesives and the mixture coated onto the backing member to provide the therapeutic adhesive tape.
Further embodiments of the therapeutic adhesive tape of the invention are illustrated in FIGS. 3,4 and 5. As illustrated in FIG. 3, the adhesive tape 30 of the invention is comprised of a backing member 31 having a reservoir 32 on one surface thereof. One wall of reservoir 32 remote from backing member 31 bears a pressure-sensitive adhesive coating 33. Reservoir 32 contains folic acid antagonist or anti-neoplastic agent 34 dispersed therethrough. In the embodiment of FIG. 3, reservoir 32 is a polymeric matrix having the drug distributed therethrough. It is permeable to passage of drug 34, as by diffusion, to gradually release drug to adhesive layer 33 over a prolonged period of time.
FIG. 4 illustrates a further modified form of the invention in which a solubility membrane 35 is interposed between reservoir 32 and pressure-sensitive adhesive layer 33.
FIG. 5 illustrates a further form of the therapeutic adhesive tape 40 including a backing member 41 and a reservoir 42 in the form of a hollow container having an interior chamber 43 containing particles of folic acid antagonist or anti-neoplastic agent 44. Wall 45 of reservoir 42, remote from backing; member 41, is permeable to passage of drug 44, as by diffusion, to meter the flow of drug to pressure-sensitive adhesive layer 46 on the outer surface thereof. This form of the therapeutic adhesive tape is less preferred since it cannot conveniently be cut to fit precisely the size of skin lesions to which applied. However, it is satisfactory for application to large areas of skin lesions.
Suitable materials for forming the reservoir, whether of the matrix or hollow container type, are those materials permeable to passage of the drug previously described as suitable encapsulating materials. The reservoir can be formed by molding into the form of a hollow container with the drug trapped therein. Alternatively, the reservoir can be in the form of an envelope formed from sheets of polymeric material permeable to passage of the drug and enclosing the drug. While the walls of the reservoir can be of any convenient thickness, usually they have a thickness of from 0.01 to 7 millimeters. When the reservoir comprises a matrix with the drug distributed therethrough, it can be prepared by adding the drug to the matrix material in liquid form or solvent solution form and subsequently converting the matrix to a solid by curing, cooling or evaporation of solvent; or by immersing the solid matrix in the drug to effect diffusion of the drug into the matrix.
Thus, the reservoir of the therapeutic adhesive tape is a hollow drug container or a solid matrix. Drug is metered from the reservoir to the adhesive layer, at a rate controlled by the composition and thickness of the reservoir or of the reservoir wall. From the adhesive layer, drug is directly transmitted to the skin lesion to which the therapeutic adhesive tape is applied.
In the embodiment of the invention illustrated in FIG. 4, metering of the drug from the reservoir to the adhesive is further controlled by :interposing a further solubility membrane therebetween. The solubility membrane, as with the walls of the reservoir, usually is formed of a material in which the drug is soluble and capable of diffusing through. Any of the materials previously mentioned for use in microencapsulation may be used as the solubility membrane. Of course, in each instance, the solubility membrane will have different characteristics than the reservoir wall of the particular device. This use of a pair of solubility membranes, that is, the reservoir wall and the further solubility membrane, allows for precise metering of drug to the adhesive layer; for the thickness and composition of both membranes can be varied to provide for wide range of dosage levels for a given area of bandage. It will be appreciated that this solubility membrane can be used with either the matrix or container. type of reservoir.
The following examples will serve to illustrate the invention without in any way being limiting thereon.
Example 1 Pressure-sensitive adhesive composition is prepared by adding to 100 milliliters of hexane the following:
20 grams of polyvinylethyl ether (reduced viscosity=5.0 i 0.5) 4 grams of polyvinylethylether cosity=0.3 0.1) 4 grams of glycerol ester of hydrogenated rosin and 2 grams polyethylene glycol 400 To the resulting solution are added 10 milligrams of methotrexate and the solution stirred for 60 minutes. The resulting methotrexate containing solution is applied to a 100 by 100 centimeter polyethylene sheet to a uniform thickness and the solvent removed by drying to give about 3 milligrams of adhesive per centimeter square of polyethylene. The methotrexate present in the adhesive layer is at a concentration of about 1 microgram per square centimeter. The resulting therapeutic adhesive tape is effective in the treatment of psoriatic lesions when applied directly to the lesions. It can be stored for prolonged periods under an inert atmosphere and is packaged between hermetically sealed polyethylene terephthalate sheets prior to use.
(reduced vis- Example 2 Pressure-sensitive adhesive is prepared by mixing together, 90 grams of polyacrylate solution (ethylacetate: hexane/:1) containing 25 percent non-volatile matter, (obtained by the catalylic polymerization of isoamylacrylate and acrylic acid in the ratio of 95:5 in ethylacetate and then diluting with hexane), 5 grams polyvinylethylether (reduced viscosity=0.3 i 0.1), 1 gram castor oil (USP) and 4 grams polyethyleneglycol 400.
To the resulting solution are added 32 milligrams of 5-fluorouracil and the solution is coated onto a polyvinylchloride sheet. After removing the solvent by evaporation, it is found that the sheet has an adhesive coating of a thickness of about 0.05 millimeter and contains about 4 micrograms of 5-fluorouracil per square centimeter of adhesive face surface.
Example 3 To 100 milliliter of solvent naptha are added the following components of a pressuresensitive adhesive formulation: 15 grams polyisobutylene having approximate average molecular weight of about 80,000; 2 grams polyisobutylene having average molecular weight approximately 10,000; 5 grams hydroabietyl alcohol; 3 grams fumed silica (SiO and 4 grams mineral oil. 16 milligrams of aminopterin are added to the resulting solvent naphtha solution which is then coated onto a rayon acetate cloth sheet. The solvent free adhesive coating of a thickness of about 0.05 millimeter contains about 2 micrograms of aminopterin per square centimeter of adhesive face surface.
Example 4 In a manner similar to that of Example 1, therapeutic adhesive tapes are prepared containing, respectively, 3 '-chloromethotrexate, 3 5 '-dichloromethotrexate, vincristine, vinblastine, S-fluorodeoxyuridine, and 6- mercaptopurine. These tapes are also effective in the treatment of skin lesions, such as psoriatic lesions.
In some instances, it is found that when the therapeutic adhesive tape is applied, the normal skin surrounding the lesion which makes contact with the adhesive tape can be slightly inflamed, as evidence by a reddening of the skin. To prevent such reddening, a small amount of an anti-inflammatory steroid can be incorporated into the adhesive tape of the invention. Suitable anti-inflammatory steroids include cortisone, hy drocortisone, prednisolone, mecrol, florandrenolone, flumethasone, B-methasone, dexamethasone, and triamcinolone. When these are employed, they are incorporated in a concentration of between 0.5 and 10 micrograms of steroid per square centimeter of pressuresensitive adhesive face surface. Normally, the antiinflammatory steroid is dispersed throughout the pressure-sensitive adhesive coating regardless of whether the folic acid antagonist or anti-neoplastic agent is microencapsulated or incorporated in a reservoir. How ever, the steroid too can be microencapsulated or incorporated in the reservoir, in the same manner as the primary drugs.
Thus, this invention provides a reliable and easy to use device for administering folic acid antagonists or anti-neoplastic agents directly to skin lesions. Detrimental side-effects encountered when these agents are systemically administered are avoided. Uncertainties resulting from topical application of these agents, from creams and solutions, are not encountered; and a precisely determined amount of the drug is applied in a controlled manner.
Although the product of this invention has been referred to as an adhesive tape, those skilled in the art will appreciate that the term adhesive tape as used herein includes any product having a backing member and a pressure-sensitive adhesive face surface. Such products can be provided in various sizes and configurations, including tapes, bandages, sheets, plasters, and the like.
While there have been shown and described and pointed out the fundamental novel features of the invention as applied to the preferred embodiment, it will be understood that various omissions and substitutions and changes in the form and details of the adhesive tape illustrated may be made by those skilled in the art without departing from the spirit of the invention. It is the invention, therefore, to be limited only as indicated by the scope of the following claims.
What is claimed is:
l. A therapeutic adhesive tape for the topical administration of controlled quantities of drug for the treatment of skin lesions, said tape comprising a laminate of (l) a backing member bearing (2) a pressure-sensitive adhesive on one surface thereof adapted for contact with the skin, said pressure-sensitive adhesive having distributed therethrough (3) a plurality of discreet microcapsules, each of which microcapsules comprise a therapeutic agent selected from the group consisting of an anti-neoplastic agent and a folic acid antagonist confined within a wall member, the wall member being formed from drug release rate controlling material to continuously meter the flow of a therapeutically effective amount of the therapeutic agent to the skin lesions from the microcapsules at a controlled and predetermined rate over a period of time.
2. The therapeutic adhesive tape of claim 1 wherein said microcapsules (3) comprise a matrix of the drug release rate controlling wall material, said matrix having the therapeutic agent distributed therethrough.
3. The therapeutic adhesive tape of claim 1 wherein said microcapsules (3) comprise the therapeutic agent microencapsulated within the drug release rate controlling wall material.
4. The therapeutic adhesive tape of claim 1 wherein said folic acid antagonist is selected from the group consisting of methotrexate, aminopterin, 3'- chloromethotrexate and 3, 5-dichloromethotrexate.
5. The therapeutic adhesive tape of claim 1 wherein said anti-neoplastic agent is selected from the group consisting of vincristine, vinblastine, S-fluorouracil, 5- fluorodeoxyuridine and fi-mercotopurine.
6. The therapeutic adhesive tape of claim 1 wherein said therapeutic agent is methotrexate present at a concentration of 0.01 to 100 micrograms of methotrexate per sq. cm. of surface of pressure-sensitive adhesive coating.
7. The therapeutic adhesive tape of claim 1 further containing an anti-inflammatory steroid.
8. A therapeutic adhesive tape for the topical administration of controlled quantities of drug for the treatment of skin lesions, said tape comprising a laminate of (l) a backing member; (2) a discrete middle reservoir layer containing a therapeutic agent selected from the group consisting of an anti-neoplastic agent and a folic acid antagonist confined within a wall member, said wall member being formed from drug release rate controlling material to continuously meter the flow of a therapeutically effective amount of the therapeutic agent to the skin lesions from the reservoir at a controlled and predetermined rate over a period of time; and (3) a pressure-sensitive adhesive surface adapted for contact with the skin and positioned on one wall of the reservoir remote from the backing member.
9. The therapeutic adhesive tape of claim 8 where the reservoir layer (2) comprises a walled container having an interior chamber containing the therapeutic agent.
10. The therapeutic adhesive tape of claim 8 wherein the reservoir layer (2) comprises :a matrix of the drug release rate controlling wall material, said matrix having the therapeutic agent distributed therethrough.
11. The therapeutic adhesive tape of claim 8 further including a solubility membrane interposed between said reservoir and said pressure-sensitive adhesive coatmg.
12. The therapeutic adhesive tape of claim 8 wherein said folic acid antagonist is selected from the group consisting of methotrexate, aminopterine, 3'- chloromethotrexate and 3, 5'-dichloromethotrexate.
13. The pressure-sensitive adhesive tape of claim 8 wherein said anti-neoplastic agent is selected from the group consisting of vincristine, vinblastine, 5- fluorouracil, S-fluorodexyuridine, and 6- mercoptopurine.
14. The therapeutic adhesive tape of claim 8 wherein said therapeutic agent is methotrexate.
15. The therapeutic adhesive tape of claim 8 wherein said therapeutic agent is methotrexate present at a concentration of 0.01 to micrograms of methotrexate per sq. cm. of surface of pressure-sensitive adhesive coating.
16. The therapeutic adhesive tape of claim 8 further including an anti-inflammatory steroid.