United States Patent (19) [11] 3,797,494 Zaffaroni (45*Mar. 19, 1974

(54) BANDAGE FOR THE ADMINISTRATION OF 3,598,123 8/1971 Zaffaroni...... 128/268 DRUGBY CONTROLLED METERING 3,426,754 2/1969 Bierenbaum...... 128/268 X THROUGH MICROPOROUS MATERIALS 3,053,255 9/1962 Meyer...... 128/268 3,464,413 9/1969 Goldfarb et al...... 128/268 75 Inventor: Alejandro Zaffaroni, Atherton, 3,512,997 5/1970 Cohly et al...... 28/296 X Calif. (73) Assignee: Alza Corporation, Palo Alto, Calif. Primary Examiner-Dalton L. Truluck Assistant Examiner-J. C. McGowan * Notice: The portion of the term of this patent subsequent to Aug. 10, 1988, has been disclaimed. (57) ABSTRACT 22 Filed: Aug. 9, 1971 A bandage for use in the continuous administration of drugs to the skin or mucosa, comprising a backing 21 ) Appl. No.: 169,976 member defining one exterior surface, a surface of Related U.S. Application Data pressure-sensitive adhesive defining a second exterior 63) Continuation-in-part of Ser. Nos. 812, 1 16, April 1, surface, and disposed therebetween a reservoir con 1969, Pat. No. 3,598, 122, and Ser. No. 8 12,1 17, taining drug formulation confined therein. The reser April 1, 1969, Pat. No. 3,598,123, and Ser. No. voir can comprise a distinct layer of the bandage or a 150,085, June 4, 1971, Pat. No. 3,731,683. plurality of microcapsules distributed throughout the adhesive surface, and in either case the drug can be (52) U.S. Cl...... 128/268 confined within an interior chamber of the reservoir (51) Int. Cl...... A61 15/06 or distributed throughout a reservoir matrix. The drug 58) Field of Search ...... 128/260,268, 156, 155, passes through drug release rate controlling micropo 128/296; 424/19, 20, 28 rous material which continuously meters the flow of drug by viscous or diffusive transfer to the skin or mu (56) References Cited cosa at a controlled and predetermined rate over a pe UNITED STATES PATENTS riod of time. 3,598,122 8/1971 Zaffaroni...... 128/268 7 Claims, 5 Drawing Figures

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g P 9. o Z77 - INVENTOR. ?/ BY Alejandro Zaffaroni solubility of the drug in the diffu achieve the desired release rate of drug. Additionally, sive medium and the thickness and porosity of the ma the material must have the appropriate chemical resis terial properly modified by a tortuosity factor. For drug 20 tance to the drug used and be non-toxic when used as transfer mechanism (2), i.e., flow of drug through the an element of the bandage of the invention. pores of the microporous rate controlling material, the Materials useful in forming the microporous rate pressure differential, the thickness of the membrane, controlling materials used in this invention include, but the viscosity of the permeant drug, the size of the per are not limited to the following. meant molecule relative to the pore size, the absolute 25 Polycarbonates, i.e., linear polyesters of carbonic value of the pore size, and the number of pores or per acids in which carbonate groups recur in the polymer cent voids in the material are the controlling factors chain, by phosgenation of a dihydroxy aromatic such as governing permeability. For the simplest type of flow bisphenol A. Such materials are sold under the trade mechanism of this type, e.g., viscous flow, the amount designation Lexan by the General Electric Company. of drug passing through the porous structure is given by Polyvinylchlorides; one such material is sold under Poiseuille's equation for viscous flow. the trade designation Geon 121 by B. G. Goodrich Therefore, the selection of appropriate materials for Chemical Company. fabricating the microporous rate controlling membrane Polyamides such as polyhexamethylene adipamide or matrix material will be dependent on the particular and other such polyamides popularly known as "ny drug to be used in the bandage. Both organic and inor 35 lon'. One particularly advantageous material is that ganic polymeric materials can be shaped into a wide va sold under the trade name “NOMEX' by E. I. DuPont riety of forms with tailored morphology and a wide de Nemours & Co. range of chemical and physical properties to advanta Modacrylic copolymers, such as that sold under the geously control release of a wide variety of drugs, in trade designation DYNEL and formed of polyvinyl cluding those with large molecular structures such as 40 chloride (60 percent) and acrylonitrile (40 percent), insulin, and over a large dosage range rate appropriate styrene-acrylic acid copolymers, and the like. pore size selection. Additionally, by impregnating the Polysulfones such as those of the type characterized interconnected pores of the microporous structure with by diphenylene sulfone groups in the linear chain a diffusive medium for the drug to be administered, a thereof are useful. Such materials are available from given microporous membrane or matrix material can 45 Union Carbide Corporation under the trade designa be adapted to control the release of drugs having a wide tion P-1700. range of chemical properties by diffusive permeability. Halogenated polymers such as polyvinylidene fluo Thus, by varying the composition, pore size, and effec ride sold under the trade designation Kynar by Pennsalt tive thickness of the microporous rate controlling ma Chemical Corporation, polyvinylfluoride sold under terial, the viscosity of the drug to be administered by 50 the trade name Tedlar by E. I. DuPont de Nemours & appropriate formulation or by impregnating the mate Co., and the polyfluorohalocarbon sold under the trade rial with suitable solvent, the dosage rate per area of name Aclar by Allied Chemical Corporation. bandage can be controlled since the material functions Polychloroethers such as that sold under the trade to meter the flow of drug from the device. Therefore, name Penton by Hercules Incorporated, and other such bandages of the same surface area can provide differ 55 thermoplastic polyethers. ent dosages of a drug by varying the above discussed Acetal polymers such as the polyformaldehyde sold parameters, under the trade nambe Delrin by E. I. DuPont de Ne The microporous rate controlling materials of this in mours & Co., and the like. vention are known in the art and can be visualized as Acrylic resins such as polyacrylonitrile, polymethyl a plurality of sponge-like fused polymer particles which 60 methacrylate, poly n-butyl methacrylate and the like. provide a supporting structure having therethrough a Other polymers such as polyurethanes, polyimides, dispersion of microscopic sized interconnecting voids polybenzimidazoles, polyvinyl acetate, aromatic and or pores. The rate controlling structures formed from aliphatic, polyethers, cellulose esters, e.g., cellulose tri the materials can be isotropic, wherein the structure is acetate; cellulose; collodion (cellulose nitrate with 11% homogeneous throughout the cross-section of the ma 65 nitrogen); epoxy resins, olefins, e.g., polyethylene poly trix or membrane material, or anisotropic wherein the propylene; porous rubber; cross-linked poly (ethylene structure is non-homogenous. These rate controlling oxide); cross-linked polyvinylpyrrolidone; cross-linked 3,797,494 7 8 poly (vinyl alcohol); polyelectrolyte structures formed such as plasticized or unplasticized polyvinylchloride, of two ionically associated polymers of the type as set plasticized nylon, plasticized soft nylon, plasticized forth in U.S. Pat. Nos. 3,549,016 and 3,546,142; deriv polyethyleneterephthalate, natural rubber, Ca-C atives of polystyrene such as poly (sodium styrenesul olefins, e.g., polyethylene, polyisoprene, polyisobutyl fonate) and polyvinylbenzyltrimethyl-ammonium 5 ene, polybutadiene; silicone rubbers, especially the chloride); poly(hydroxyethyl methacrylate); medical grade polydimethylsiloxanes, as described in poly(isobutyl vinyl ether), and the like, may also be uti U.S. Pat. No. 3,279,996, hydrophilic polymers such as lized. A large number of copolymers which can be the hydrophilic hydrogels of esters of acrylic and neth formed by reacting various proportions of monomers acrylic acid (as described in U.S. Pat. Nos. 2,967,576 from the aforesaid list of polymers are also useful for O and 3,220,960, and Belgian Patent No. 701,813), mod preparing rate controlling structures useful in the in ified collagen, cross-linked polyvinylalcohol, and cross vention. linked partially hydrolyzed polyvinylacetate. Of course, As illustrated in FIG. 1, the bandage 20 of the inven these materials used to form the matrix must be perme tion is comprised of drug 24 uniformly distributed in able to passage of the drug, as by diffusion. Accord the interstices of the microporous matrix material 15 ingly, selection of appropriate materials will, in each forming reservoir 22. The matrix material is laminated instance, be dependent on the particular drug to be ad to backing member 21 and bears a pressure-sensitive ministered. adhesive coating 23 thereon. The microporous matrix FIG. 3 illustrates a further form of the invention material 22 functions to control the release rate of the wherein bandage 40 includes a backing member 21 and drug impregnated therein. The reservoir can be pre a reservoir 42 in the form of a hollow container having pared by employing any of the known impregnating an interior chamber 43 containing drug 34. Wall or sur techniques. Thus, the drug can be added to the rate face 45 of reservoir 42, remote from backing member controlling material in liquid form and uniformly dis 21, is of a microporous membrane structure permeable tributed therethrough by mixing, and subsequently to passage of drug 34, to meter the flow of drug to pres converted to a microporous structure by the various 25 sure-sensitive adhesive layer 23 on the outer surface methods known to the art. One such method calls for thereof. The sides of the reservoir 42, other than rate dissolving a natural or synthetic polymer in a suitable controlling microporous membrane 45, preferably are solvent in which it has sufficient solubility to permit the preparation of a solution that is sufficiently viscous for impermeable to passage of the drug, and can be made conventional film casting. The preferred method is to of the same materials used to make the backing mem cast a film of a polymer solution having the drug ber as hereinafter described. As discussed, one face therein, and, shortly after casting, to immerse it in a surface of the drug reservoir bears a backing member non-solvent or "diluent,' a medium which is compati 21. The purpose of the backing is to prevent passage of ble with the solvent, but not a solvent for the polymer. the drug through the surface of the reservoir distant The original solution then forms two phases, one 35 from the adhesive layer. An ancillary purpose of the polymer-rich and one polymer-poor. Under the proper backing is to provide support for the bandage where conditions, both of these phases are physically continu needed. When the outer surface of the reservoir 33 is ous, so that the resulting polymer membrane is me impermeable to the drug and strong enough, the back chanically reasonably strong, but it is completely inter ing becomes unnecessary. The other surface of the res laced with continuous pores. The size and uniformity of 40 ervoir bears a coating of a pressure-sensitive adhesive. the pores depend on the conditions of preparation. Al If desired, additional microporous rate controlling ternatively, preformed microporous materials can be membranes can be juxtaposed on top of membrane 45 impregnated with drug by immersion in a bath of the to further tailor the rate of flow of drug. Of course, in drug to diffuse the drug into the material. While the each instance, the membrane will have different cha matrix material can be of any convenient thickness, 45 racteristics than the reservoir membrane 45 of the par typically a thickness of from 20 to 200 microns is em ticular device. This use of a pair of multiplicity of mem ployed. branes, that is, the reservoir wall and the further mem FIG. 2 illustrates a further modified form of the in brane, allows for precise metering of drug out of the vention wherein the adhesive bandage 30 of the inven reservoir; for the thickness, porosity and composition tion is comprised of a backing member 21 having a res SO of both membranes can be varied to provide for wide ervoir 32 on one surface thereof. A microporous rate range of dosage levels for a given area of bandage. It controlling membrane 35 is interposed between the will be appreciated that this type of membrane can be reservoir 32 and a pressure-sensitive adhesive coating used with either the matrix (FIGS. 1 or 2) or container 23. Drug 24 is confined in polymeric matrix material 32 type (FIG. 3) of reservoir. To provide additional me which acts as the reservoir for the drug. Matrix material 55 chanical strength, if necessary, the rate controlling mi 32 can be solid material as illustrated, or microporous croporous membrane 45 can be supported by an appro as illustrated for reservoir 22 in FIG. 1. If desired, addi priate mesh or screen having a greater release rate to tional membranes can be juxtaposed next to membrane drug than does membrane 45. 35 in order to achieve optimum rate release properties. The reservoir of the embodiment in FIG. 3 can be The matrix material 32 when solid or microporous 60 formed by molding into the form of a hollow container should have a release rate to drug which is higher than with the drug trapped therein. While the non-rate con that of the rate controlling microporous membrane 35, trolling walls of the reservoir can be of any convenient such that passage through the latter is the rate control thickness, usually they have a thickness of from 0.01 to ling step. Materials used to form the matrix reservoir 32 7 millimeters. The rate controlling membranes 35 and of FIG. 2, when solid, can be those heretofore exempli 65 45, in FIGS. 2 and 3, respectively, can have varying fied for preparing the microporous rate controllingma thickness depending upon the nature of the membrane, terial and, in addition, include hydrophobic polymers its porosity and the number of membranes used in com 3,797,494 9 O bination. Typically, a thickness of from 20 to 200 mi rous coating of the encapsulating material to form mi crons is employed. crocapsules having an interior chamber containing the It will, of course, be appreciated that the pressure drug. If desired, particles of a matrix, such as starch, sensitive adhesive surface need not form a continuous gum acacia, gum tragacanth, and polyvinylchloride, layer on the subject bandage. Particularly in the case of 5 can be impregnated with the drug and encapsulated a bandage having a distinct reservoir layer, equally ad with other materials such as the microporous rate con vantageous results are obtained by providing an annu trolling materials previously described, which function lar surface of adhesive around the periphery of the ban to meter the flow of drug to the adhesives, use of a ni dage face. In this manner a liquid tight adhesive seal be croporous matrix and a different rate controlling mem tween the bandage and the patient's skin or mucosa is 10 brane coating to slow the passage of the drug from the maintained, and at the same time, drug may be directly microcapsules, which is desirable with drugs that are absorbed by the skin from the exposed surface of the released too rapidly from available encapsulating mate drug reservoir layer without first migrating through an rials, is therefore also contemplated herein. adhesive layer. As a further alternative, in the embodi Any of the encapsulation or impregnation techniques ment of the invention employing a distinct reservoir s known in the art can be used to prepare the microcap layer, to prevent passage of the drug into the adhesive sules to be incorporated into the pressure-sensitive ad layer prior to use, the adhesive can be supplied sepa hesive in accord with the embodiment of FIGS. 4 and rately from the reservoir and backing, with the device 5. The porous microcapsules can be made by tech assembled at the point of use. For example, the adhe niques as set forth in U.S. Ser. No. 751,251, corre sive in sheet form can have both surfaces protected 20 sponding to German Patent No. 1,939,066, entitled with a release film and the wall of the reservoir can be "Microcapsules with Anisotropic Microporous Liquid similarly protected. At the point of use, the release Permeable Polymeric Outer Skin and Internal Macro films can be removed from the reservoir and one sur porous Support Partitions or Structure,' Bixler, Mi face of the adhesive, the adhesive sheet applied to the chaels, and Sternberg, or by standard coacervation reservoir wall to complete assemblage of the bandage, 25 methods. The coacervation method of fabrication, as the remaining release film then removed from the ad conventionally employed, consists essentially of the hesive, and the bandage then applied to the patient. formation of three immiscible phases, a liquid manu As previously discussed, one type of drug transfer facturing phase, a core material phase and a coating mechanism is that of flow through the pores or pinholes phase with deposition of the liquid polymer coating on in microporous rate controlling material. A driving the core material and rigidizing the coating, usually by force, i.e., a pressure differential across the micropo thermal, cross-linking or desolvation techniques to rous material, is necessary to cause the flow of drug by form microcapsules. Usually, the microcapsules made this mode. The bandage of the type illustrated in FIG. by the above techniques have an average particle size 3, wherein the reservoir is a hollow container, can be of from several tenths of a micron to 5,000 microns, al conveniently adapted to meter the flow of drug by a mi 35 though this feature is not critical to the practice of the croporous hydrodynamic mechanism by pressurizing invention. Techniques for prepairing microcapsules, the container. This can suitably be accomplished by ad such as the classic Bungenberg de Jong and Kass mixing with the drug a solid particulate material which method are reported in Biochem. Z, Vol. 232, Pg.338 liberates gas on contact with the drug formulation. For to 345, 1931; Colloid Science, Vol. 11, “Reversible Sys example, in the case wherein the formulation is of an 40 tem', edited by H. R. Kruyt, 1949, Elsevier Publishing aqueous nature, a conventional effervescent powder Company, Inc., New York; J. Pharm. Sci., Vol. 59, No. such as a mixture of citric acid and sodium bicarbonate 10, Pg 1367 to 1376, 1970; and, Remington's Pharma can be inserted immediately prior to use through an ceutical Science, Vol. XIV, Pg. 1676 to 1677, 1970, opening in the reservoir wall so provide for this pur Mack Publishing Company, Easton, Pennsylvania. pose. After insertion of the effervescent material, the 45 Thus, the drug can be added to the encapsulating mate opening is sealed, for example, by means of an adhesive rial in liquid form and uniformly distributed there tape. The pressure can be controlled by adjusting the through by mixing and then forming the microcapsules particle size of the effervescent powder composition by any of the above set forth methods. Alternatively, and the quantity thereof. Pressure in an amount of from the porous microparticles can be made by the above 1 mm to 50 mm of mercury can be satisfactorily em 50 techniques and impregnated with drug. Still another ployed, with the actual amount depending upon the de method is to impregnate a porous solid encapsulating sired release rate and the other parameters previously material with a drug by immersion in a bath of the drug discussed regarding viscous flow. to diffuse the drug into the material, and subsequently FIGS. 4 and 5 illustrate an adhesive bandage 10 of 55 the solid material can be reduced to fine microcapsules the invention including a backing member 11 bearing by grinding, each of the microcapsules comprising drug a pressure-sensitive adhesive coating 12 on one surface coated with and distributed throughout the encapsulat thereof. Adhesive coating 12 has uniformly distributed ing material. Further, drug can be encapsulated with a therethrough microcapsules 13 comprising drug encap microporous coating by suspending dry particles of the sulated with a microporous rate controlling material drug in an air stream and contacting that stream with permeable to passage of the drug. Thus, in the embodi 60 a stream containing the encapsulating material to coat ment illustrated herein, porous microcapsules 13 con the drug particles. Usually, the micro-capsules have an stitute the drug reservoir. average particle size of form 1 to 1000 microns, al To provide the microcapsules, the encapsulating ma though this is not critical to the invention. The micro terial can be uniformly impregnated with the drug to capsules, however made, are then mixed by conven form microcapsules which are a porous matrix having 65 tional methods, e.g., stirring, ballmilling, and the like, the drug distributed therethrough. Alternatively, parti with a pressure-sensitive adhesive. The mixture of mi cles of drug can be encapsulated with a thin micropo crocapsules and pressure-sensitive adhesive is then 3,797,494 11 12 coated onto a backing member, usually to provide an plasticizers known to the art can be employed, such as adhesive layer 0.01 to 7 millimeters thick, although long-chain fatty amides, higher alcohols, and high boil these limits can be exceeded if more or less drug is re ing esters such as di(isooctyl) sebacate or di(2-ethyl quired. The purpose of the backing is to provide sup hexyl) phthalate. port for the bandage and to prevent passage of the drug 5 It is preferred that the diffusive medium also be in through the adhesive surface away from the body sur corporated in the reservoir in combination with the face to which the bandage is applied. drug in the form of a pharmaceutically acceptable car As above discussed, the microporous rate controlling rier as hereinafter described. materials can be adapted to control the release of drug In practicing this invention one can employ any sys by diffusive permeation wherein the micropores are im 10 temically active drug which will be absorbed by the pregnated or otherwise filled with a diffusive medium body surface to which the bandage is applied, consis for the drug to be administered. The material can be tent with their known dosages and uses. Of course, the impregnated with the diffusive medium by methods amount of drug necessary to obtain the desired thera well known to the art, e.g., as by immersion in a bath peutic effect will vary depending on the particular drug of the material to permit the diffusive medium material 15 used. Suitable systemic drugs include, without limita to fully saturate the micropores. The impregnation tion, Anti-microbial Agents such as penicillin, tetracy technique can be employed with any of the embodi cline, oxytetracycline, chlortetracycline, chloramphen ments represented herein. In embodiments illustrated icol, and sulfonamides; Sedatives and Hypnotics such in FIGS. 1, 4 and 5 the micropores can be concurrently as pentabarbital sodium, phenobarbital, secobarbital impregnated with both drug and diffusive medium ma sodium, codeine, (a-bromoisovalery) urea, carbromal, terial. and sodium pheno-barbital; Psychic Energizers such as In cases where the pressure-sensitive adhesive and 3-(2-aminopropyl) indole acetate and 3-(2- microporous rate controlling material employed are aminobutyl) indole acetate; Tranquilizers such as re water permeable, body fluids will self-migrate into the serpine, chlorpromazine hydrochloride, and thiopropa microporous material after the bandage has been in 25 zate hydrochloride; Hormones such as adrenocor contact with the skin for a suitable period of time to ticosteroids, for example, 6cy-methylprednisolone; an provide the diffusive medium, as hereinafter described, without the necessity of carrying out a separate impreg drogenic steroids, for example, methyltestosterone, nation step. Additionally, the pores can be self-filled by and fluoxymesterone; estrogenic steroids, for example, 30 estrone, 173-estradiol and ethinyl estradiol, progesta migration of the diffusive medium by contact with the tional steroids, for example, 17a-hydroxyprogesterone composition employed to prepare the drug formula acetate, medroxyprogesterone acetate, 19-norprogest tion, as later described. The diffusive medium is one which enables the drug erone, and norethindrone; and thyroxine; Antipyretics to dissolve therein and flow by diffusion at the desired such as aspirin, salicylamide, and sodium salicylate; rate. It can be either of a liquid or solid nature and be 35 morphine and other narcotic analgesics; Antidiabetics, a poor or good solvent for the drug. A medium with e.g., insulin; Cardiovascular Agents, e.g., nitroglycerin, poor solvent properties for the drug is desired when the and cardiac glycosides such as digitoxin, digoxin, oua required release rate is low and of course the converse bain; Anti-spasmodics such as atropine, methscopola is true when the desired release rate is high. mine bromide, methscopolamine bromide with pheno The art provides many useful approaches to enable 40 barbital; Anti-malarials such as the 4-aminoquinolines, selection of particular solvent-drug systems. Specific 9-amino-quinolines, and pyrimethamine; and Nutri attention is called to Rennington's Pharmaceutical Sci tional Agents such as vitamins, essential amino acids, ences, Chapters 19 and 71. The solvent selected must and essential fats. be non-toxic and one in which the rate controlling mi Additionally, in practicing this invention one can em croporous material has the required solubility. The ma 45 ploy a wide variety of topically active drugs consistent terials which are useful for impregnating the micro with their known dosages and uses. Suitable drugs in pores can be polar, semi-polar or non-polar. Exemplary clude, without limitation: Antiperspirants, e.g., alumi are any of the pharmaceutically acceptable solvents num chloride; Deodorants, e.g., hexachlorophene, such as water, alcohols containing 2 to 10 carbon methylbenzethonium chloride; Astringents, e.g., tannic atoms, such as hexanol, cyclohexanol, benzylalcohol, SO acid; Irritants, e.g., methyl salicylate, camphor, can 1,2-butanediol, glycerol, and amyl alcohol; hydrocar tharidin; Keratolytics, e.g., benzoic acid, salicylic acid, bons having 5 to 12 carbon atoms such as n-hexane, cy resorcinol, iodochlorhydroxyquin; Antifungal Agents, clohexane, and ethyl benzene; aldehydes and ketones such as tolnaftate, griseofulvin, nystatin and amphoteri having 4 to 10 carbon atoms such as heptyl aldehyde, cin; Anti-inflammatory Agents, such as corticosteroids, cyclohexanone, and benzaldehyde; esters having 4 to 55 e.g., hydrocortisone, hydrocortisone-acetate, predniso 10 carbon atoms such as amyl acetate and benzyl pro lone, methylprednisolone, triamcinolone acetonide, pionate; etheral oils such as oil of eucalyptus, oil of rue, fludrocortisone, flurandrenolone, flumethasone, dexa cumin oil, limonene, thymol, and 1-pinene; haloge methasone sodium phosphate, bethamethasone valer nated hydrocarbons having 2 to 8 carbon atoms such ate, fluocinolone acetonide; fluorometholone; and as n-hexyl chloride, n-hexyl bromide, and cyclohexyl 60 pramoxine HCl; Anti-neoplastic Agents, e.g., metho chloride; or mixtures of any of the foregoing materials. trexate, and Antibacterial Agents, such as bacitracin, Also suitable are many of the conventional non-toxic neomycin, erythromycin, tetracycline HCl, chlortetra plasticizers used in the fabrication of microporous rate cycline HCl, chloramphenicol, oxytetracycline, poly controlling material, e.g., octyl diphenyl phosphate. myxin B, nitrofuraxone, mafenide (a-amino-p- When these plasticizers are suitable diffusive materials 65 toluenesulfonamide), hexachlorophene, benzalkonium for the drug used, advantageously, the necessity for fill chloride, cetalkonium chloride, methylbenzethonium ing the pores by a separate step is thus obviated. Other chloride, and neomycin sulfate. 3,797,494 13 14 It will be appreciated, with regard to the aforesaid list bons; salicylates; polyalkylene glycol silicates, mixtures of drugs, that characterization of the drug as either thereof; and the like. "systemically or topically' active is done for purposes The amount of active agent to be incorporated in the of convenience only. Further, a given drug can be both bandage to obtain the desired therapeutic effect will systemically and topically active depending upon its 5 vary depending upon the desired dosage, the perme manner of use. ability of the rate controlling materials of the bandage In addition to the aforementioned drugs, simple phar which are employed to the particular agent to be used, macologically acceptable derivatives of the drugs, such and the length of time the bandage is to remain on the as ethers, esters, amides, acetals, salts, etc., or formula skin or body mucosa. Since the bandage of this inven tions of these drugs, having the desired polymeric per- 10 tion is designed to control drug administration for an meability or transport properties can be prepared and extended period of time, such as 1 day or more, there used in practicing the invention. Drugs mentioned is no critical upper limit on the amount of agent incor above can be used alone or in combination with others porated into the bandage. The lower limit is deter and each other. Of course, the derivatives should be mined by the fact that sufficient amounts of the agent such as to convert to the active drugs within the body 15 must remain in the bandage to maintain the desired through the action of body enzyme assisted transforma dosage. In order to achieve a therapeutic effect in a tions, pH, etc. human adult, the daily release dosage of atropine The above drugs and other drugs can be present in should be in the range of between 200 and 600 micro the reservoir alone or in combination form with phar grams per day. Thus, for example, using atropine and maceutical carriers. The pharmaceutical carriers ac with a bandage intended to remain in place for 1 week, ceptable for the purpose of this invention are the art and with a release rate of 500 micrograms of atropine known carriers that do not adversely affect the drug, per day, at least 3.5 mg of atropine would be incorpo the host, or the material comprising the drug delivery rated in the bandage. Generally, the drug delivery ban dages made according to the invention can release at device. Suitable pharmaceutical carriers include sterile 25 water, saline, dextrose; dextrose in water or saline; con a controlled rate about 25 nanograms to about 1 gram densation products of castor oil and ethylene oxide of drug or larger amounts per day. Of course, other de combining about 30 to about 35 moles of ethylene vices for use for different time periods such as week or month are also readily made by the invention. oxide per mole of castor oil; liquid glyceryl triester of The effective rate of release of the active agent to the a lower molecular weight fatty acid; lower alkanols; oils 30 skin or mucosa can be in the range of from 0.5 to 1000 such as corn oil; peanut oil, sesame oil and the like, micrograms per square centimeter of bandage per day. with emulsifiers such as mono-or di-glyceride of a fatty The exact amount will depend on the desired dosage as acid, or a phosphatide, e.g., lecithin, and the like; gly well as the condition to be treated. The desired effec cols; polyalkylene glycols; aqueous media in the pres tive rate of release of active agent can be obtained by ence of a suspending agent, for example, sodium car- 35 altering the earlier discussed parameters affecting the boxymethylcellulose; sodium alginate; poly(vinylpyr release rate controlling barrier. In the case of the mi rolidone); and the like, alone, or with suitable dispens cro-encapsulated active agent, the release rate can also ing agents such as lecithin; polyoxyethylene stearate; be controlled by varying the number of microcapsules and the like. The carrier may also contain adjuvants present in a given volume of the matrix of the device. such as preserving, stabilizing, wetting, emulsifying 40 This is a particularly desirable feature of this aspect of agents, and the like. the invention. Additionally, the duration of action of The drug can also be mixed in the reservoir with a the device can be altered by controlling the amount of transporting agent, that is, a material that aids or assists active agent initially incorporated consistent with the the drug delivery device to achieve the administration release rate. Further, the release rate of drug, as well of a drug to a drug receptor, for example, by enhancing 45 as the duration of release of the drug from the device, penetration through the skin. The transporting aids can be predetermined to be in consonance with the op suitable for the purpose of the invention are the thera timum therapeutic values. Once this dosage level in mi peutically acceptable transporting aids that do not ad crograms per square centimeter of bandage has been versely affect the host, the drug, or alter or adversely determined, the total amount of drug to be incorpo affect the materials forming the drug delivery device. 50 rated in the bandage can be established by obtaining The transporting aids can be used alone or they can be the release rate of the agent in the particular material admixed with acceptable carriers and the like. Exem or materials which are to be used. Those skilled in the plary of transporting aids include manovalent, satu art can readily determine the rate of permeation of rated and unsaturated aliphatic cycloaliphatic and aro agent through the porous rate controlling material or matic alcohols having 4 to 12 carbon atoms, such as 55 selected combinations of rate controlling materials. hexanol, cyclohexane and the like; aliphatic cycloali Standard techniques are described in Encyl. Polymer phatic and aromatic hydrocarbons having from 5 to 12 Science and Technology, Vo. 5 and 9, Pg. 65 to 85 and carbon atoms such as hexane, cyclohexane, isopropyl 795 to 807, 1968; and the references cited therein. benzene and the like; cycloaliphatic and aromatic alde Any of the well-known dermatologically acceptable hydes and ketones having from 4 to 10 carbon atoms 60 pressure-sensitive adhesives can be used in practicing such as cyclohexanone; acetamide; N,N-di(lower) this invention. Exemplary adhesives include acrylic or alkyl acetamides such as N,N-diethyl acetamide, N,N- methacrylic resins such as polymers of esters of acrylic dimethyl acetamide, N-(2-hydroxyethyl) acetamide, or methacrylic acid with alcohols such as n-butanol, n and the like; and other transporting agents such as ali- 65 pentanol, isopentanol, 2-methylbutanol, 1-methyl bu phatic, cycloaliphatic and aromatic esters; N,N-di tanol, 1-methyl pentanol, 2-methyl pentanol, 3-methyl lower alkylsulfoxides; essential oils; halogenated or ni pentanol, 2-ethylbutanol, isooctanol, n-decanol, or n trated aliphatic, cycloaliphatic and aromatic hydrocar dodecanol, alone or copolymerized with ethylenically 3,797,494 5 16 unsaturated monomers such as acrylic acid, meth the oral mucosa. Although obtaining a liquid tight ad acrylic acid, acrylamide, methacrylamide, N hesive seal between the skin and bandage is important, alkoxymethyl acrylamides, N-alkoxymethyl metha it becomes critical in the mouth. Without such a seal, crylamides, N-tert, butylacrylamide, itaconic acid, vi irrigation of the oral mucosa by saliva will transfer the nylacetate, N-branched alkyl maleamic acids wherein drug to the gastrointestinal tract, rather than to circula the alkyl group has 10 to 24 carbon atoms, glycol diac tion through the oral mucosa. In addition, the bandage rylates, or mixtures of these; natural or synthetic rub of the invention can be used to administer drugs to bers such as silicone rubber, styrenebutadiene, butyl other mucosa of the body, for example, it can be ap ether, neoprene, polyisobutylene, polybutadiene, and plied to the vaginal mucosa, rectal mucosa, etc. By use polyisoprene; polyurethane elastomers; vinyl polymers, 10 of this invention, one ensures that an accurately mea such as polyvinylalcohol, polyvinyl ethers, polyvinyl sured quantity of the active drug is available to the site pyrrolidone, and polyvinylacetate; ureaformaldehyde of application. resins; phenolformaldehyde resins; resorcinol formal The following examples are merely illustrative to the dehyde resins, cellulose derivatives such as ethyl cellu present invention and should not be construed as limit lose, methyl cellulose, nitrocellulose, cellulose acetate 15 ing the scope of the invention in any way, as these ex butyrate, and carboxymethyl cellulose; and natural amples and other equivalents thereof will become ap gums such as guar, acacia, pectins, starch, dextrin, al parent to those versed in the art in light of the present bumin, gelatin, casein, etc. The adhesives may be com disclosure, drawings and accompanying claims. pounded with tackifiers and stabilizers as is well know in the art. EXAMPLE 1. When the adhesive layer covers one face surface of Porous, discrete particles of polymerized poly(vinyl the bandage or when the reservoir is in the form of mi chloride) of about 100 microns in diameter are pre crocapsules distributed throughout the adhesive, the pared by mixing 100 grams of suspension grade poly(- adhesive must be permeable to passage of the drug to vinyl chloride) resin with 50 grams of octyl diphenyl allow drug released from the reservoir to reach the 25 phosphate and 10 grams of nitroglycerin. These ingre outer surface of the bandage in contact with the pa dients are mixed at room temperature into a sticky, wet tient. In such cases, the rate of release of drug from the mass. Next, the solvent is allowed to escape to form adhesive should exceed the rate of release of drug from dry, free flowing, discrete micro-capsules. 10 grams of the reservoir so that release from the reservoir by pas sage through the drug release controlling microporous 30 the resulting microcapsules of poiyvinylchloride/nitro material is the rate limiting step for drug administration glycerin are mixed with 100 grams of a 22 percent solu by the device of the invention. Of course, when the ad tion in hexane: isopropyl-acetate (70:30) of a visco hesive is disposed only about the periphery of the ban elastic copolymer of isooctyl acrylate and acrylic acid dage face, the adhesive need not be permeable to pas (94:6) adhesive to uniformly distribute the microcap sage of the drug. 35 sules throughout the adhesive solution. The resulting Various occlusive and non-occlusive, flexible or non slurry is coated onto a cellophane sheet 10 centimeters flexible backing members can be used in the adhesive in width by 100 centimeters in length and the solvent bandage of the invention. Suitable backings include removed from the coated film. cellophane, cellulose acetate, ethylcellulose, plasti When a 5 centimeter by 5 centimeter section is cut cized vinylacetate-vinylchloride copolymers, polyethyl 40 from the above sheet and applied to the skin of a ene terephthalate, nylon, polyethylene, polypropylene, human adult, the resulting bandage is effective to con polyvinylidenechloride, paper, cloth, and aluminum trol the continuous administration of a daily therapeuti foil. Preferably, a flexible occlusive backing is em cally effective dosage of nitroglycerin for the prophy lactic treatment of angina pectoris. ployed to conform to the shape of the body member to 45 which the adhesive tape is applied and to enhance ad EXAMPLE 2 ministration of the agent to the skin. To prevent passage of the drug away from the ex Dry crystalline powdered megesterol acetate (0.3 posed surface of the pressure-sensitive adhesive prior gram) in 10 ml. ethanol is mixed with 25 parts by to use, the adhesive surface of the tape generally is cov weight of polydimethylsiloxane, 5 parts by weight of sil ered with a protective release film or foil such as waxed 50 icone oil and 0.25 parts by weight of stannous octoate paper. Alternatively, the exposed rear surface of the catalyst. The ingredients are mixed until a homogenous backing member can be coated with a low-adhesion mixture is produced. The mixture is then cast into a backsize and the bandage rolled about itself. To en mold and allowed to cure to prepare a matrix having a hance stability of the active compounds, the therapeu surface area of 10 square centimeters and 9 mils thick. tic bandage usually is packaged between hermetically 55 One face surface of the matrix is bonded to a sheet of sealed polyethylene terephthalate films under an inert cellophane. On the other face surface is placed an etha atmosphere, such as gaseous nitrogen. nol impregnated microporous membrane of the same To use the adhesive bandage of the invention, external surface area as the matrix. The membrane is wherein the drug is topical, it is applied directly to the sold by Millipore Corporation and designated to the area of skin to be treated, to release a therapeutically trade as HA, and is characterized by a porosity of 60 effective amount of the agent to the affected area. For percent, a pore size of 0.45 microns, and a thickness of administration of systemic drugs the bandage can be 4 mils. Dimethyl silicone rubber adhesive is coated to applied to any area of the patient's skin, with the lower a thickness of 2 mils on the membrane. The adhesive back and buttocks being the areas of choice. In like face surface of the completed bandage has an area of manner, the bandage can be applied to the mucosa of 10 square centimeters. The bandage is effective to the mouth, for example, by application to the palate or slowly release megesterol acetate, and when applied to the buccal mucosa, to obtain absorption of the drug by the female skin, is useful for fertility control. 3,797,494 17 8 circulation can be obtained. Treatment is begun by ap EXAMPLE 3 plying the bandage to the skin or mucosa and termi 10 milligrams of betamethasone in 10 ml, of propy nated by removing it therefrom. The bandage can con lene glycol is placed on a sheet of dimethyl silicone rub tain and administer the complete dosage requirements ber having a thickness of 10 mils. The sheet is folded for a particular time period, for example, 24 hours. In tervention by the patient is required only to apply and to provide a surface area of 10 square centimeters on remove the bandage, so that uncertainties through pa each face and the flaps sealed with silicone adhesive to tient error are eliminated. provide a thin envelope containing the drug. The top Moreover, this invention provides a reliable and easy face of the envelope is removed and replaced with a to use device for administering topically active drugs propylene glycol impregnated microporous membrane O directly to the affected areas of skin or mucosa. Uncer sold by Amicon Corporation under the designation of tainties resulting from topical application of these PM 30. The membrane is secured to the envelope by agents, from creams and solutions, are not encoun means of adhesive to form a tight seal therewith. The tered; and a precisely determined amount of the drug membrane is characterized by having an anisotropic is applied in a controlled manner. structure, with a minimum pore size of 70 angstrom 15 Although the product of this invention has been re units, an overall porosity of 70 percent, and a thickness ferred to as an adhesive bandage, those skilled in the of 4 units. art will appreciate that the term "adhesive bandage' as Pressure-sensitive adhesive is prepared by mixingto used herein includes any product having a backing gether 90 grams of polyacrylate solution (ethylacetate: member and a pressure-sensitive adhesive face surface. Such products can be provided in various sizes and hexane/5:1) containing 25 percent non-volatile matter 20 configurations, including tapes, bandages, sheets, plas (obtained by the catalytic polymerization of isomyla ters, and the like. crylate and acrylic acid in the ratio of 95:5 in ethylace What is claimed is: tate and then diluting with hexane), 5 grams 1. A medical bandage for the continuous administra polyvinylethylether (reduced viscosity= 0.3 - 0.1), 1 tion of controlled quantities of drug to the skin or mu gram castor oil (USP) and 4 grams polyethyleneglycol 25 cosa, comprised of a laminate of: (1) a backing mem 400. ber; bearing (2) a discrete middle reservoir layer con One face surface of the envelope is bonded to a sheet taining a drug confined within a body, the body being of cellophane while the external membrane surface is comprised of drug release rate controlling microporous coated with adhesive prepared above to a thickness of material permeable to the passage of drug, to continu 2 millimeters. The adhesive face surface of the bandage 30 ously meter the flow of a therapeutically effective has an area of 100 square centimeters. The bandage is amount of the drug to the skin or mucosa from the res effective to release a therapeutically effective daily ervoir at a controlled and predetermined rate over a dosage of the drug when applied to the skin for control period of time; and (3) a pressure-sensitive adhesive of psoriasis. surface adapted for contact with the skin or mucosa 35 and postitioned on one surface of the reservoir remote EXAMPLE 4 from the backing member. 2. The bandage as defined by claim 1 wherein the 3 grams of a polyacrylonitrile fiber sold under the pores of the microporous rate controlling material are trade designation Orlon by E. I. DuPont de Nemours & filled with a medium to permit controlled diffusion of Co. was dissolved in 30 grams of an aqueous solution the drug from the reservoir. comprising 70 percent by weight of zinc chloride. After 40 3. A medical bandage for the continuous administra the solution was cooled to about 25°C, 0.250 grams of tion of controlled quantities of drug to the skin or mu DIGOXIN was added to the solution. Thereupon, the cosa, comprised of a laminate of: (1) a backing mem solution was added drop-wise through a No. 21 hypo ber; bearing (2) a discrete middle reservoir containing dermic needle into an acetone bath whereupon parti a drug confined therein, the reservoir being formed of 45 material permeable to passage of the drug, and (3) a cles were formed. After being stirred for about thirty pressure-sensitive adhesive surface adapted for contact minutes in the acetone, the particles were removed and with the skin or mucosa and positioned on one surface placed in a water bath for four hours at room tempera of the reservoir remote from the backing member and ture to leach our residual acetone and salt. wherein one or more drug release rate controlling mi 20 grams of polyvinylethylether (reduced visosity croporous membranes are interposed between the sur 5.0 - 0.5) face of the reservoir and pressure-sensitive adhesive so 4 grams of polyvinylethylether (reduced viscosity= as to continuously meter the flow of a therapeutically 0.3-0.1) - effective amount of the drug from the reservoir at a 4 grams of glycerol ester of hydrogenated rosin and controlled and predetermined rate over a period of 2 grams polyethyleneglycol 400 time. The resulting DIGOXIN capsules are mixed with 55 4. The bandage as defined by claim3 wherein the res pressure-sensitive adhesive prepared above to uni ervoir is a container having the drug confined therein. formly distribute the microcapsules throughout the ad hesive. Immediately thereafter, the adhesive mixture is 5. The bandage as defined by claim 4 wherein the res coated onto one surface of a 1000 square centimeter ervoir is pressurized to permit controlled microporous 60 flow of the drug from the reservoir. Mylar sheet. A 5 centimeter by 5 centimeter area of the 6. The bandage as defined by claim 3 wherein the res resulting bandage can be used for control of cardiac ervoir is a solid or microporous matrix having the drug disorders. dispersed therein. Thus, this invention provides an easy to use device 7. The bandage as defined by claim. 3 wherein the for administering systemically active drugs through the 65 pores of the microporous rate controlling material are skin or oral mucosa and other body mucosa. Uncertain filled with a medium to permit controlled diffusion of ties of administration through the gastrointestinal tract the drug from the reservoir. are avoided and a controlled constant level of drug in k s: xk : k