US005656286A United States Patent (19) 11) Patent Number: 5,656,286 Miranda et al. 45) Date of Patent: Aug. 12, 1997

54 SOLUBLITY PARAMETER BASED DRUG FOREIGN PATENT DOCUMENTS DELVERY SYSTEMAND METHOD FOR 2027053 4/1991 Canada. ALTERNG DRUG SATURATION 0201828 11/1986 European Pat. Off.. CONCENTRATION 208395 1/1987 European Pat. Off.. 0272045 6/1988 European Pat. Off.. 75 Inventors: Jesus Miranda; Steven Sablotsky, O343807 11/1989 European Pat. Off.. both of Miami, Fla. O 371. 496 6/1990 European Pat. Off.. 046842 3/1991 European Pat. Off.. (73) Assignee: Noven Pharmaceuticals, Inc., Miami, 0529123 3/1993 European Pat. Off. . Fla. 54-89.017 7/1979 Japan. 58-225010 12/1983 Japan. 2 105990 4/1983 United Kingdom. 21 Appl. No.: 178,558 91/05529 5/1991 WIPO 22 Filed: Jan. 7, 1994 93/08795 5/1993 WPO. Related U.S. Application Data OTHER PUBLICATIONS Yu et al., “Transdermal Dual-Controlled Delivery of Test 63) Continuation-in-part of Ser. No. 722,342, Jun. 27, 1991, Pat. No. 5,474,783, which is a continuation-in-part of PCT/ osterone and Estradiol: (1) Impact of System Design,” Drug US90/01750, Mar. 28, 1990, which is a continuation-in-part Devel. Indust. Pharm. 17(14): 1883-1904 (1991). of Ser. No. 671,709, Apr. 2, 1991, Pat No. 5,300,291, which Ziller et al., "Control of Crystal Growth in Drug Suspen is a continuation-in-part of Ser. No. 295,847, Jan. 11, 1989, Pat. No. 4,994,267, which is a continuation-in-part of Ser. sions.” Pharm. Ind. 52(8): 1017-1022 (1990). No. 164,482, Mar. 4, 1988, Pat No. 4,814,168. English translation of Japanese patent application No. 2-48859, filed Feb. 27, 1990. 51 Int, C. m. A61F 13/02 Sloan, K. B. et al., “Use of Solubility Parameters of Drug 52) U.S. Cl...... 424/449; 424/448 and Vehicle to Predict FluxThrough Skin". The Journal of 58) Field of Search ...... 424/448, 449 Investigative Dermatology, vol. 87 (No. 2) pp. 244-252 (Aug. 1986). 56) References Cited Primary Examiner-Jyothsna Venkat U.S. PATENT DOCUMENTS Attorney, Agent, or Firm-Foley & Lardner 3,969,308 7/1976 Penneck ...... 260/37 SB 57 ABSTRACT 3,972,995 8/1976 Tsuk et al...... 424/28 4,291,015 9/1981 Keith et al...... 424/28 Ablend of at least two polymers, or at least one polymer and 4,292,301 9/1981 Keith et al...... 424/28 4,390,520 6/1983 Nagai et al...... 424/28 a soluble polyvinylpyrrolidone, in combination with a drug 4,438,139 3/1984 Keith et al...... 424/28 provides a pressure-sensitive adhesive composition for a 4,542,013 9/1985 Keith ...... 424/28 transdermal drug delivery system in which the drug is 4,585,452 4/1986 Sablotsky ...... 604/896 delivered from the pressure-sensitive adhesive composition 4,593,053 6/1986 Jevne et al...... 523/11 and through dermis when the pressure-sensitive adhesive 4,668,232 5/1987 Cordes et al...... 604/897 composition is in contact with human skin. According to the 4,690,683 9/1987 Chien et al...... 604/896 invention, soluble polyvinylpyrrolidone can be used to pre 4,693,887 9/1987 Shah ...... 424/19 vent crystallization of the drug, without affecting the rate of 4,696,821 9/1987 Belsole ...... 424/448 drug delivery from the pressure-sensitive adhesive compo 4,699,146 10/1987 Sieverding . ... 128/640 4,750,482 6/1988 Sieverding ...... 128/156 sition. (List continued on next page.) 73 Claims, 19 Drawing Sheets

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U.S. PATENT DOCUMENTS 5,122,543 6/1992 Khanna ...... 514/772.5

4,769,013 9/1988 Lorenz et al...... 604/265 3. CE Play ...... : 4,845,0814,814,168 3/19897/1989 SablotskySloan ..... et al...... 514/232.2 424/78 5,151.151271 9/19921992 otsukaOtsuka etet al.al...O...... 424/443 4,883,669 11/1989 Chien et al. ... 424/448 5,154,922 10/1992 Govil et al...... 424/448 4,906,169 3/1990 Chien et al. ... 424/448 5,230,896 7/1993 Yeh et al...... 424/443 4,911,916 3/1990 Cleary ...... 424/449 5,230,898 7/1993 Horstmann et al...... 424/449 4,931,281 6/1990 Kim et al. ... 424/448 5,232,702 8/1993 Pfister et al...... 424/448 4,987,893 1/1991 Salamone et al. ... 128/156 5,232,703 8/1993 Blank --0-0 0000 - - - - - O - O 424/449 4,994,267 2/1991 Sablotsky ...... 424/78 5,252,334 10/1993 Chiang et al...... 424/448 5,032,403 7/1991 Sinnreich ...... 424/448 5,260,064 11/1993 Nakagawa et al...... 424/448 5,059,189 10/1991 Cilento et al...... 604/307 5,262,165 11/1993 Govil et al...... 424/448 5,071,656 12/1991 Lee et al...... 424/448 5,393,529 2/1995 Hoffmann et al...... 424/445 U.S. Patent Aug. 12, 1997 Sheet 1 of 19 5,656,286

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0,7%)/-/ 96Z/977Z0 (SI?)HWIL X[\THTOÏCIWHILSE (J?/Zyuuofiri) 5,656.286 1. 2 SOLUBLITY PARAMETER BASED DRUG an adequate and controlled rate or incorporate high concen DELIVERY SYSTEMAND METHOD FOR trations of drugs while retaining good physical adhesive ALTERING DRUGSATURATION properties. CONCENTRATION In transdermal drug delivery systems, the presence of crystals (drugs and/or additives) is generally undesirable. If CROSS-REFERENCE TO RELATED the drug is presentin crystalline form, it is not available for APPLICATION release from the system, and therefore not available for This application is a continuation-in-part of Ser. No. delivery. Moreover, although drug crystals can first dissolve 07/722.342 filed Jun. 27, 1991, now U.S. Pat. No. 5,474,783, and then release from the system, such a process is usually which application is a continuation-in-part of PCT applica 10 rate-limiting and tends to reduce delivery. tion PCT/US90/01750 filed Mar. 28, 1990, and filed nation Crystal size and distribution thus become important ally as U.S. Ser. No. 671,709 on Apr. 2, 1991, now U.S. Pat. parameters which must be controlled in order to control No. 5,300,291; which in turn is a continuation-in-part of delivery. These parameters are, however, usually difficult to U.S. patent application Ser. No. 295.847, filed Jan. 11, 1989, control. Failure to control crystal size and distribution can now U.S. Pat. No. 4,994.267 issued Feb. 19, 1991; which is 15 resultin products whose appearance suggests that the manu a continuation-in-part of U.S. patent application Ser. No. facturing process by which they are produced is not under 164482, filed Mar. 4, 1988 now U.S. Pat. No. 4,814,168, control. More importantly, the presence of large crystals, granted Mar. 21, 1989 all of which patents and applications particularly in excessive amounts, can be detrimental to are hereby incorporated by reference. All applications and adhesive-type transdermals. Crystals on the surface of the patents are assigned to Noven Pharmaceuticals, Inc. of 20 adhesive system can result in loss of tack. Furthermore, Miami, Fla. surface crystals can come into direct contact with the skin, and could cause skin irritation. BACKGROUND OF THE INVENTION There is a need in the art for an adhesive composition for This invention relates generally to transdermal drug deliv transdermal delivery systems which can prevent or suppress ery systems, and more particularly, to a transdermal drug 25 crystallization of drugs therein. delivery composition wherein a blend of polymers is utilized It is, therefore, an object of this invention to provide a to affect the rate of drug delivery from the composition. transdermal drug delivery system wherein the rate of drug More specifically, a plurality of polymers including a soluble delivery from the transdermal composition may be select polyvinylpyrrollidone having differing solubility parameters, 30 ably modulated. preferably immiscible with each other, adjusts the solubility It is another object of this invention to provide a trans of the drug in a polymeric adhesive system formed by the dermal drug delivery system wherein the rate of drug blend, affects the maximum concentration of the drug in the delivery from the transdermal composition may be select system, and modulates the delivery of the drug from the ably modulated by adjusting the solubility and/or diffusivity composition and through the dermis. 35 of the drug in the multiple polymer adhesive system. The use of a transdermal composition, for example a pressure-sensitive adhesive containing a medicament, It is also an object of this invention to provide a trans namely, a drug, as a means of controlling drug delivery dermal drug delivery system wherein the multiple polymer through the skin at essentially a constant rate, is well known. adhesive system is simple to manufacture. It is a further object of this invention to provide a Such known delivery systems involve incorporation of a 40 medicament into a carrier such as a polymeric matrix and/or transdermal drug delivery system wherein drug-loading of a a pressure-sensitive adhesive formulation. The pressure multiple polymer adhesive system may be selectably varied sensitive adhesive must adhere effectively to the skin and without adverse effects on drug delivery rate and adhesive permit migration of the medicament from the carrierthrough properties, such as adhesion, tack, and shear resistance. the skin and into the bloodstream of the patient. 45 It is additionally an object of this invention to provide a Drug concentration in a monolithic transdermal delivery transdermal drug delivery system wherein a novel multiple system can vary widely depending on the drug and polymers polymer adhesive system is provided which has desirable used. For example, certain drugs are effective in low doses physical properties. and therefore the transdermal formulation may involve low SUMMARY OF THE INVENTION concentrations, illustratively 5% or less by weight of the 50 medicament in an adhesive. Other drugs, such as The foregoing and other objects are achieved by this nitroglycerin, require large doses to be effective and the invention which provides a transdermal drug delivery sys transdermal formulation therefore may involve high drug tem wherein a blend of at least two polymers, or at least one concentrations, approximately between 5 to 40% or more by polymer and a soluble polyvinylpyrrollidone permits weight in an adhesive. Low concentrations of medicament 55 increased loading of a drug and adjusts the solubility of a typically do not critically affect the adhesion, tack, and shear drug in the blend and thereby modulates the delivery of the resistance properties of the adhesive. However, low drug drug from the system and through the dermis. concentrations in the adhesive can result in difficulties in In accordance with one aspect of the invention, an achieving an acceptable delivery rate of the medicament. improved pressure-sensitive adhesive composition of the High concentrations, on the other hand, frequently affect the 60 type which is suitable as a matrix for controlled release of a adhesion properties of the adhesives. The deleterious effects drug therefrom comprises a blend of a rubber-based are particularly exacerbated by drugs which also act as pressure-sensitive adhesive and a soluble polyvinylpyrroli plasticizers or solvents for the polymeric adhesive (e.g., done (PVP). nitroglycerin in polyacrylates). The term “polyvinylpyrrolidone,” or “PVP" refers to a There is a need in the art for an adhesive composition for 65 polymer, either a homopolymer or copolymer, containing transdermal drug delivery systems which can selectably N-vinylpyrrolidone as the monomeric unit. Typical PVP incorporate low concentrations of drug and deliver same at polymers are homopolymeric PVPs and the copolymer vinyl 5,656,286 3 4 acetate vinylpyrrolidone. The homopolymeric PVPs are while the polyacrylate polymer is preferably present in an known to the pharmaceutical industry under a variety of amountranging from about 5% to about 85%. Preferably, the designations including Povidone, Polyvidone, ratio of the polyacrylate polymer to the rubber-based Polyvidonum, Polyvidonum solubile, and Poly(1-vinyl-2- pressure-sensitive adhesive is from about 2:98 to about 96:4, pyrrollidone). The copolymer vinyl acetate vinylpyrrolidone and more preferably from about 2.98 to about 086:14 by is known to the pharmaceutical industry as Copolyvidon, weight. Copolyvidone, and Copoly Vidonum. In both binary and ternary blends, soluble PVP is prefer The term “Soluble' when used with reference to PVP ably present in the pressure-sensitive adhesive composition means that the polymer is soluble in water and generally is in an amount ranging from about 1% to about 20% by not substantially cross-linked, and has a molecular weight of 10 weight of the total pressure-sensitive adhesive composition. less than about 2,000,000. See, generally, Bihler, KOLLI The pressure-sensitive adhesive compositions may further DONGR): POLYVINYLPRYRROLIDONE FOR THE include enhancers, fillers, co-solvents, and excipients as are PHARMACEUTICAL INDUSTRY, BASF Aktiengesell known in the art for use in Such compositions. schaft (1992). In a dermal adhesive composition embodiment of the It has been surprisingly found that use of a soluble PVP 15 invention, a multiple polymer adhesive system comprises a results in the ability to form a film that does not contain blend of 14–94% by weight of a rubber-based pressure particles of insoluble PVP and in the ability to employ sensitive adhesive, 5-85% by weight of a polyacrylate higher concentrations of drug without resulting in increased polymer, and 2-10% by weight of a soluble PVP, and the crystallization of the drug. multiple polymer adhesive system comprises about 50-99% In accordance with another embodiment of the invention, by weight of the dermal adhesive composition. This multiple an improved pressure-sensitive adhesive composition of the polymer adhesive system is combined with a drug in the type which is suitable as a matrix for controlled release of a amount of 0.1-50% by weight of the total dermal adhesive drug therefrom comprises a blend of a rubber-based composition. Optional additives, such as co-solvent for the pressure-sensitive adhesive having a first solubility drug (up to 30% by weight) and enhancers (up to 20% by parameter, a polyacrylate polymer having a second solubil 25 weight) may be included in the dermal adhesive composi ity parameter, and a soluble PVP, the first and second tion. solubility parameters preferably being different from one In transdermal drug delivery system embodiments, incor another by an increment of at least 2 (J/cm)'. The blend, porating a drug in the improved pressure-sensitive adhesive therefore, has a characteristic net solubility parameter. 30 composition, the characteristic net solubility parameter can In accordance with further embodiment of the invention, be preselected to adjust the saturation concentration of the an improved pressure-sensitive adhesive composition of the drug in the composition and thereby control the release of type which is suitable as a matrix for controlled release of a the drug. The saturation concentration of the drug may be drug therefrom comprises a blend of a rubber-based adjusted either upward or downward depending upon pressure-sensitive adhesive having a first solubility 35 whether the rate of release is to be enhanced or retarded. parameter, and a polyacrylate polymer having a second In particularly preferred embodiments, the drug is solubility parameter, the first and second solubility param asteroid, such as an estrogen or a progestational agent, or eters preferably being different from one another by an combination thereof. In other preferred embodiments, the increment of at least 2 (J/cm)'. The blend, therefore, has drug may be a B-adrenergic agonist, such as albuterol, or a a characteristic net solubility parameter. 40 cardioactive agent, such as nitroglycerin. In still other Particularly preferred embodiments include binary blends embodiments, the drug is a cholinergic agent, such as comprising a rubber-based pressure-sensitive adhesive and a pilocarpine, or an antipsychotic Such as haloperidol or a soluble PVP, wherein the rubber-based pressure-sensitive tranquilizer/sedative such as alprazolam. adhesive is a polysiloxane. Polysiloxane is preferably The transdermal drug delivery system may comprise a present in the pressure-sensitive adhesive composition in an 45 monolithic adhesive matrix device in some embodiments. amount ranging from about 9% to about 97% by weight of The transdermal drug delivery system may further include a the total pressure-sensitive adhesive composition. backing material and a release liner as is known in the art. Other particularly preferred embodiments include ternary The saturation concentration of a drug in a transdermal blends comprising a rubber-based pressure-sensitive drug delivery system of the type having a drug-containing adhesive, a polyacrylate polymer, and a soluble PVP, 50 pressure-sensitive adhesive diffusion matrix is adjusted in wherein the rubber-based pressure-sensitive adhesive is a accordance with an aspect of the present invention by polysiloxane. Polysiloxane is preferably present in the blending at least two polymers having differing solubility pressure-sensitive adhesive composition in an amount rang parameters as defined above to form a pressure-sensitive ing from about 9% to about 97% by weight of the total adhesive diffusion matrix having a net solubility parameter pressure-sensitive adhesive composition, while the poly 55 acrylate polymer is preferably present in an amount ranging which modifies the delivery rate of the drug from the from about 5% to about 85%. Preferably, the ratio of the pressure-sensitive adhesive diffusion matrix and through the polyacrylate polymer to the rubber-based pressure-sensitive dermis. adhesive is from about 2:98 to about 96:4, and more BRIEF EDESCRIPTION OF THE DRAWINGS preferably from about 2:98 to about 86:14 by weight. 60 Other particularly preferred embodiments include blends Comprehension of the invention is facilitated by reading comprising a rubber-based pressure-sensitive adhesive and a the following detailed description, in conjunction with the polyacrylate polymer, wherein the rubber-based pressure annexed drawing, in which: sensitive adhesive is a polysiloxane. Polysiloxane is prefer FIG. 1 is a schematic illustration of a monolithic trans ably present in the pressure-sensitive adhesive composition 65 dermal drug delivery device of the present invention; in an amount ranging from about 9% to about 97% by FIG. 2 is a graphic representation of the steady-state weight of the total pressure-sensitive adhesive composition, nitroglycerinflux rates through cadaver skin in vitro from a 5,656,286 5 6 transdermal drug delivery composition of the present inven calculated using a weighted average of the solubility param tion (formulation of Example 1) and two commercially eters of the individual polymers comprising the matrix: available nitroglycerin-containing transdermal delivery devices: Transderm-Nitro® (a trademark of Ciba-Geigy SP-2SP+2 SP, Corporation, Summit, N.J.), and Nitro-Durš (a trademark of where Øis the weight percentage of polysiloxane and SP. Key Pharmaceuticals, Inc., Kenilworth, N.J.); is the solubility parameter of polysiloxane. The subscript FIG. 3 is a graphical representation which summarizes in "pa" refers to the polyacrylate; vitro nitroglycerinflux results through cadaver skin for the FIG. 15 is a plot of diffusion coefficient versus net polymeric systems of Examples 2-5. The composition of solubility parameter; Example 2 (polyacrylate-only adhesive) is compared to the 10 FIG. 16 shows the average flux of estradiol for two multiple polymer compositions of Examples 3, 4, and 5, in compositions of this invention containing a soluble PVP; which the polyacrylate is blended with an ethylene vinyl FIG. 17 shows estradiol flux through the human epidermis acetate, a polyisobutylene, and a polysiloxane, respectively; from a PVP-containing compositions of this invention; FIG. 4 is a graphical representation of the steady-state FIG. 18 shows norethindrone flux through human epider nitroglycerin flux through cadaver skin in vitro from a 15 mis in a composition of this invention containing estradiol multiple polymer transdermal adhesive system of Example and soluble PVP: 6 comprising various weight ratios of polyacrylate and FIG. 19 shows average estradiol and norethindrone polysiloxane; acetate flux from a composition of this invention containing FIG. 5 is a graphical representation of steady-state estra varying concentrations of soluble PVP; and diol flux through cadaver skin invitro from the drug delivery 20 FIG. 20 shows the effect of soluble PVP on estradiol flux systems of the prior art, specifically single polymeric adhe through human epidermis. sives of silicone and acrylic, as compared to a multiple polymer transdermal adhesive system (polyacrylate/ DETALED DESCRIPTION OF PREFERRED EMBODIMENTS polysiloxane) of the present invention; 25 FIG. 6 is a graphical representation of average estradiol In one aspect of the presentinvention, a pressure-sensitive flux through cadaver skin in vitro from 0 to 22 hours and adhesive composition is provided which comprises a blend from 22 to 99 hours for a multiple polymer transdermal of at least two polymers and a soluble PVP, and a drug. The adhesive system comprising various weight ratios of poly blend of at least two polymers is herein referred to as a acrylate and polysiloxane; 30 multiple polymer adhesive system. The term “blend” is used FIG. 7 is a graphical representation of steady-state nore herein to mean that there is no, or substantially no, chemical thindrone acetate flux through cadaver skin in vitro from the reaction or cross-linking (other than simple H-bonding) drug delivery systems of the prior art, specifically single between the different polymers in the multiple polymer polymeric adhesives of silicone and acrylic, as compared to adhesive system. a multiple polymer transdermal adhesive system 35 As used herein, the term "pressure-sensitive adhesive” (polyacrylate/polysiloxane) of the present invention; refers to a viscoelastic material which adheres instanta neously to most substrates with the application of very slight FIG. 8 is a graphical representation of average estradiol pressure and remains permanently tacky. A polymer is a and norethindrone acetate flux through cadaver skin in vitro pressure-sensitive adhesive within the meaning of the term for a multiple polymer transdermal adhesive system com as used herein if it has the properties of a pressure-sensitive prising both drugs and various weight ratios of polyacrylate 40 adhesive perse or functions as a pressure-sensitive adhesive and polysiloxane; by admixture with tackifiers, plasticizers or other additives. FIG. 9 is a graphical representation showing the ratio of The term pressure-sensitive adhesive also includes mix average estradiol to norethindrone acetate flux (estradiol flux tures of different polymers and mixtures of polymers, such divided by norethindrone acetate flux) through cadaver skin as polyisobutylenes (PIB), of different molecular weights, in vitro for a multiple polymer transdermal adhesive system 45 wherein each resultant mixture is a pressure-sensitive. In the comprising various weight ratios of polyacrylate and pol last case, the polymers of lower molecular weight in the ysiloxane; mixture are not considered to be "tackifiers,” said term being FIG. 10 is a graphical representation of steady-state flux reserved for additives which differ other than in molecular of pilocarpine through cadaver skin in vitro from the drug weight from the polymers to which they are added. delivery systems of the prior art, specifically single poly 50 As used herein, the term "rubber-based pressure-sensitive meric adhesives of silicone and acrylic, as compared to a adhesive' refers to a viscoelastic material which has the multiple polymer transdermal adhesive system properties of a pressure-sensitive adhesive and which con (polyacrylate/polysiloxane) of the present invention; tains at least one natural or synthetic elastomeric polymer. FIG. 11 is a graphical representation of steady-state As used herein, the term "drug,” and its equivalent, 55 “bioactive agent,” is intended to have its broadest interpre albuterol and nitroglycerinflux through cadaver skin in vitro tation as any therapeutically, prophylactically and/or phar from multiple polymer transdermal adhesive systems macologically or physiologically beneficial active (polyacrylate/polysiloxane) of the present invention substance, or mixture thereof, which is delivered to a living (Examples 24-27), and Nitro-Dur?), respectively; organism to produce a desired, usually beneficial, effect. FIG. 12 is a graphical representation of steady-state More specifically, any drug which is capable of producing estradiol flux through cadaver skin in vitro from two differ a pharmacological response, localized or systemic, irrespec ent multiple polymer transdermal adhesive systems tive of whether therapeutic, diagnostic, or prophylactic in polyacrylate/polysiloxane and polyacrylate/polybutylene; nature, in plants or animals is within the contemplation of FIGS. 13 and 14 show the relationship of flux rate (J) the invention. Also within the contemplation of the inven plotted against apparent diffusion coefficient (D) and net 65 tion are such bioactive agents as pesticides, insectrepellents, solubility parameter (SP), respectively, for Compositions sun screens, cosmetic agents, etc. It should be noted that the I-VI of Example 6. The net solubility parameter, SP was drugs and/or bioactive agents may be used singly or as a 5,656,286 7 8 mixture of two or more such agents, and in amounts suffi Table I-A below sets forth solubility parameters of some cient to prevent, cure, diagnose or treat a disease or other exemplary adhesive polymers which would be useful in the condition, as the case may be. practice of the invention and shows the variation of SP with The multiple polymer adhesive not only functions as a molecular weight, free -OH and -COOH groups, the carrier matrix for the drug, but enhances the rate of release degree of cross-linking. Table LA is in (cal/cm)' and of the drug, and hence the transdermal permeation rate. In (j/cm)' as calculated by Small's method. some embodiments of the invention, however, the multiple polymer adhesive system will function to retard the trans TABLE LA dermal permeation rate. Solubility Parameter A soluble PVP is blended with one or more other poly O mers in order to further modulate the transdermal perme Polymers (cal/cm)/2 (J/cm)/2 ation rate of the drug. Addition polymers of An important aspect of the present invention is the unsaturated esters discovery that the transdermal permeation rate of a drug from the multiple polymer adhesive system can be selec 15 Polymethyl methacrylate 9.3 19.0 Polyethylmethacrylate 9.1 8.6 tively modulated by adjusting the solubility of the drug in Polymethylacrylate 9.7 9.8 the device. As used herein, the term “transdermal perme Polyethylacrylate 9.2 8.8 ation rate” means the rate of passage of the drug through the Hydrocarbon polymers skin; which, as known in the art, may or may not be affected Polyethylene 8. 16.6 by the rate of release of the drug from the carrier. 20 Polystyrene 9. 18.6 The polymers comprising the multiple polymer adhesive Polyisobutylene 7.7 15.7 system are preferably inert to the drug, and are preferably Polyisoprene 8.1 16.6 immiscible with each other, as can be surmised by their Polybutadiene 8.4 16.6 different solubility parameters. Forming a blend of multiple Polyethylene/butylene 7.9 16.2 Halogen-containing polymers polymers results in an adhesive system having a character 25 istic "net solubility parameter,” the selection of which Polytetrafluoroethylene 6.2 12.7 advantageously permits a selectable modulation of the deliv Polyvinylchloride 9.5 19.4 ery rate of the drug by adjusting the solubility of the drug in Polyvinylidene chloride 12.2 249 the multiple polymer adhesive system. Polychloroprene 9.4 19.2 Polyacrylonitrile 12.7 26.0 Solubility parameter, also referred to herein as “SP” has 30 Condensation polymers been defined as the sum of all the intermolecular attractive forces, which are empirically related to the extent of mutual Nylon-66 3.6 27.8 solubility of many chemical species. A general discussion of Epon resin 1004 (epoxy) 9.7 9.8 solubility parameters is found in an article by Vaughan, Polysiloxanes “Using Solubility Parameters in Cosmetics Formulation,” J. Polydimethylsiloxane 7.3 14.9 Soc. Cosmet. Chem. Vol.36, pages 319-333 (1985). Many 35 Copolymers methods have been developed for the determination of solubility parameters, ranging from theoretical calculations Polybutadiene-co-acrylonitrile: 75.125 to 70/30 9.25 18.9 to totally empirical correlations. The most convenient Polybutadiene-co-styrene: method is Hildebrand's method, which computes the solu 75/25 to 7228 8.5 17.4 bility parameter from molecular weight, boiling point and 40 density data, which are commonly available for many mate excerpted from Kraton (EThermoplastic Rubber Shell Chemical Co. Product rials and which yields values which are usually within the Brochure Number SC: 198-89 range of other methods of calculation: Table I-B below sets forth solubility parameters calcu 45 lated by Fedors' method and are expressed in units of where V=molecular weight/density and AE=energy of (J/cm)/?. Vaporization. Alternatively written, SP=(AH/V-RT/V)' where AH TABLE I-B heat of vaporization, R=gas constant, and T is the absolute Solubility Parameter temperature, K. For materials, such as high molecular 50 Components (J7cm)? weight polymers, which have vapor pressures too low to ethylene/vinyl acetate 20.9 detect, and thus for which AH is not available, several (404 VAc) methods have been developed which use the Summation of polydimethylsiloxane 15.1 atomic and group contributions to AH. polyisobutylene 17.6 polyethylene 17.6 55 polyethyl methacrylate 19.8 polyethyl acrylate 20.9 where Ah, is the contribution of the ith atom or group to the polymethyl acrylate 21.7 molar heat of vaporization. One convenient method has been polymethyl methacrylate 22.3 polystyrene 22.5 proposed by R. F. Fedors, Polymer Engineering and nitroglycerin 27.0 Science, Vol. 14, p. 147 (1974). In this method AE,and Vare 60 estradiol 24.5 be obtained by simply assuming that norethindrone acetate 21.3 AEv-XAe, and VeXu, where Ae and v are the additive pilocarpine 22.9 atomic and group contributions for the energy of vapor albuferol 26.1 ization and molar volume, respectively. Yet another method of calculating the solubility parameter 65 In accordance with the principles of the invention, the of a material is described by Small, J. Applied Chem. Vol. 3, transdermal permeation rate is controlled by varying the p. 71 (1953). polymer components of a ternary multiple polymer adhesive 5,656.286 9 10 system so as to alter the difference in the solubility param solubility parameter, for example a polysiloxane (SP about eter of the multiple polymer adhesive system relative to that 15 (J/cm)"). By reducing the "net" solubility parameter of of the drug (see Examples 2-5, or 28 and 29, hereinbelow). the multiple polymer transdermal adhesive system, the dif The solubility parameters of a rubber-based pressure ference between the solubility parameter of nitroglycerin and the multiple polymer adhesive system is modified. This sensitive adhesive and a polyacrylate polymer are different solubility parameter difference results in a lower saturation from one another by an increment of at least 2 (J/cm)". concentration for nitroglycerin, and thereby a greater ther Most preferably they differ by at least 4 (J/cm)'. modynamic driving force. Conversely, the composition of The transdermal permeation rate is also controlled by the multiple polymer adhesive system can be selected so that varying the relative proportions of the polymers comprising the saturation concentration of the drug in the system is the multiple polymer adhesive system (see Example 6 O modified, so the rate of delivery is retarded, such as would hereinbelow). be desirable for administration of scopolamine or nicotine. The multiple polymer adhesive system is preferably for Advantageously, the method and composition of the mulated so that it is a pressure-sensitive adhesive at room present invention permit selectable loading of the drug in the temperature and has other desirable characteristics for adhe transdermal drug delivery system. The concentration by sives used in the transdermal drug delivery art. Such char 15 weight of the drug in the transdermal drug delivery system acteristics include good adherence to skin, ability to be is preferably about 0.1 to about 50 percent, more preferably peeled or otherwise removed without substantial trauma to about 0.1 to about 40 percent, and even more preferably the skin, retention of tack with aging, etc. In general, the about 0.3 to about 30 percent, said percentages being based multiple polymer adhesive should have a glass transition on the total weight of the transdermal drug delivery system. temperature (T), measured using a differential scanning 20 Irrespective of whether there is high-loading or low-loading calorimeter, of between about -70° C. and 0° C. of the drug into the transdermal drug delivery system, the Selection of the particular polymer composition is gov pressure-sensitive adhesive composition of the present erned in large part by the drug to be incorporated in the invention can be formulated to maintain acceptable shear, device, as well as the desired rate of delivery of the drug. tack, and peel adhesive properties. Those skilled in the art can readily determine the rate of 25 Although not wishing to be bound by theory, particularly delivery of drugs from the multiple polymer adhesive sys in this case where the structure of the composition has not temin order to select suitable combinations of polymers and been analyzed, it is postulated that the polymers of varying drug for a particular application. Various techniques can be solubility parameters, for example, the polysiloxane and the used to determine the rate of delivery of the drug from the polyacrylate, result in a heterogenous mix, with the com polymer. Illustratively, the rate of delivery can be deter 30 ponents of the polymeric mixture performing as a mutually mined by measuring the transfer of drug from one chamber interpenetrating polymeric network in the composition. In to another through cadaver skin over time, and calculating, other words, the multiple polymer adhesive system is a from the obtained data, the drug delivery or flux rate. mixture of essentially mutually insoluble or immiscible In a particularly preferred embodiment of the invention, polymers, in contradistinction to the typical prior art trans the multiple polymer adhesive system comprises a pressure 35 dermal drug delivery systems derived from a single polymer sensitive adhesive blend of an acrylic polymer, a silicone or a solution of mutually soluble polymers. polymer, and a soluble PVP. The term "acrylic polymer" is In the practice of preferred embodiments of the invention, used here as in the art interchangeably with "polyacrylate.” the polyacrylate polymer can be any of the homopolymers, "polyacrylic polymer,” and "acrylic adhesive.” The acrylic copolymers, terpolymers, and the like of various acrylic based polymer and silicone-based polymer are preferably in acids. In such preferred embodiments, the polyacrylate a ratio by weight, respectively, from about 2:98 to about polymer constitutes preferably from about 2% to about 95% 96:4, more preferably from about 2:98 to about 90:10, and of the total weight of the total polymer blend, and preferably even more preferably about 2:98 to about 86:14. The amount about 3% to about 90%, and more preferably about 5% to of acrylic-based (hereinafter referred to broadly as a about 85%, the amount of polyacrylate polymer being polyarylate) polymer and silicone-based polymer 45 dependent on the amount and type of drug used. (hereinafter referred to broadly as a polysiloxane) is adjusted The acrylate polymers useful in practicing the invention so as to modify the saturation concentration of the drug in are polymers of one or more monomers of acrylic acids and the ternary multiple polymer adhesive system in order to other copolymerizable monomers. The acrylate polymers affect the rate of delivery of the drug from the system and also include copolymers of alkyl acrylates and/or methacry through the skin. 50 lates and/or copolymerizable secondary monomers or mono In other particularly improved embodiments of the mers with functional groups. By varying the amount of each invention, the polyacrylate polymer is present in an amount type of monomer added, the cohesive properties of the ranging from about 5-85% by weight of the composition resulting acrylate polymer can be changed as is known in the and polyisobutylene is present in an amount ranging from art. In general, the acrylate polymer is composed of at least about 14-94% by weight of the composition. In yet another 55 50% by weight of an acrylate or alkyl acrylate monomer, preferred embodiment, the polyisobutylene is present in an from 0 to 20% of a functional monomer copolymerizable amount ranging from about 10-90% by weight of said with the acrylate, and from 0 to 40% of other monomers. composition and the polysiloxane is present in an amount Acrylate monomers which can be used include acrylic ranging from about 5-95% by weight of said composition. acid, methacrylic acid, butyl acrylate, butyl methacrylate, The adjustment to the saturation concentration of the drug hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, in the multiple polymer adhesive system can either be an 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl increase or a decrease. It has been found that when a methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl polyacrylate having a solubility parameter SP of about 21 methacrylate, decyl acrylate, decyl methacrylate, dodecyl (J/cm)" is used as the principal polymer of a nitroglycerin acrylate, dodecyl methacrylate, tridecyl acrylate, and tride (SP about 27 (J/cm)") monolithic system, a significant 65 cyl methacrylate. increase in the transdermal permeation rate of nitroglycerin Functional monomers, copolymerizable with the above can be achieved by the addition of a polymer having a lower alkyl acrylates or methacrylates, which can be used include 5,656,286 11 12 acrylic acid, methacrylic acid, maleic acid, maleic Ephedrine, Epinephrine, Fenoxazoline, Guanabenz, anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, Guanfacine, Hydroxyamphetamine, Ibopamine, acrylamide, dimethylacrylamide, acrylonitrile, dimethy Indianazoline, Isometh eptene, Mephen termine, laminoethyl acrylate, dimethylaminoethyl methacrylate, Metaraminol, Methoxamine Hydrochloride, tert-butylaminoethyl acrylate, tert-butylaminoethyl Methylhexaneamine, Metizolene, Midodrine, Naphazoline, methacrylate, methoxyethyl acrylate and methoxyethyl Norepinephrine, Norfenefrine, Octodrine, Octopamine, methacrylate. Oxymetazoline, Phenylephrine Hydrochloride, Phenylpro Further details and examples of acrylic adhesives which panolamine Hydrochloride, Phenylpropylmethylamine, are suitable in the practice of the invention are described in Pholedrine, Propylhexedrine. Pseudoephedrine, Satas, "Acrylic Adhesives.” Handbook of Pressure-Sensitive 10 Rilmenidine, Synephrine, Tetrahydrozoline, Tiamenidine, Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Tramazoline, Tuaminoheptane, Tymazoline, Tyramine and Van Nostrand Reinhold, N.Y. (1989). Xylometazoline. Suitable acrylic adhesives are commercially available and 2. B-Adrenergic agonists such as Albuterol, Bambuterol, include the polyacrylate adhesives sold under the trademarks Bitolterol, Carbuterol, Clenbuterol. Clorprenaline, Duro-Tak 80-1194, Duro-Tak 80-1196, and Duro-Tak 15 Denopamine, Dioxethedrine, Dopexamine, Ephedrine, 80-1197 by National Starch and Chemical Corporation, Epinephrine, Etafedrine, Ethylnorepinephrine, Fenoterol. Bridgewater, N.J. Other suitable acrylic adhesives are those Formoterol, Hexoprenaline, Ibopamine, Isoetharine, sold under the trademarks Gelva-Multipolymer Solution Isoproter enal, Mabuterol, Metaprote renol. (GMS) 737 or 788 (Monsanto; St. Louis, Mo.). Methoxyphenamine, Oxyfedrine, Pirbuterol, Prenalterol, The rubber-based pressure-sensitive adhesives useful in 20 Procaterol, Protokylol, Reproterol, Rimiterol, Ritodrine, practicing the invention include hydrocarbon polymers such Soterenol, Terbuterol and Xamoterol. as natural and synthetic polyisoprene, polybutylene and 3. O-Adrenergic blockers such as Amosulalol, Arotinolol, polyisobutylene, styrene/butadiene polymers, styrene Dapiprazole, Doxazosin, Ergoloid Mesylates, Fenspiride, isoprene-styrene block copolymers, hydrocarbon polymers Indoramin, Labetalol, Nicergoline, Prazosin, Terazosin, Such as butyl rubber, halogen-containing polymers such as 25 Tolazoline, Trimazosin and Yohimbine. polyacrylic-nitrile, polytetrafluoroethylene, 4. B-Adrenergic blockers such as Acebutolol, Alprenolol, polyvinylchloride, polyvinylidene chloride, and Amosulalol, Arotinolol, Atenolol, Befunolol, Betaxolol, polychlorodiene, and polysiloxanes and other copolymers Bevantolol, Bisoprolol, Bopindolol, Bucumolol. Befetolol, thereof. Bufuralol, Bunitrolol, Bupranolol, Butidrine Hydrochloride. Suitable polysiloxanes include silicone pressure-sensitive 30 Butofilolol, Carazolol, Carteolol, Carvedilol, Celiprolol, adhesives which are based on two major components: a Cetamolol, Cloranolol, Dilevalol, Epanolol, Esmolol, polymer, or gum, and a tackifying resin. The polysiloxane In denolol, Labetalol, Levobunolol, Mepindolol, adhesive is usually prepared by cross-linking the gum, Metipranalol, Metoprolol, Moprolol, Nadoxolol, Nifenalol, typically a high molecular weight polydiorganosiloxane, Nipradillol, Oxprenolol, Penbutolol, Pindolol, Practolol, with the resin, to produce a three-dimensional silicate 35 Pronethalol, Propranolol, Sotalol, Sulfinalol, Talinolol, Structure, via a condensation reaction in an appropriate Tertatolol, Timolol, Toliprolol and Xibenolol. organic solvent. The ratio of resin to polymer is the most 5. Alcohol deterrents such as Calcium Cyanamide important factor which can be adjusted in order to modify Citrated, Disulfiram, Nadide and Nitrefazole. the physical properties of polysiloxane adhesives. Sobieski, 6. Aldose reductase inhibitors such as Epal restat, et al., "Silicone Pressure Sensitive Adhesives," Handbook of 40 Ponalrestat, Sorbinil and Tolrestat. Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 7. Anabolics such as Androisoxazole, Androstenediol, 508-517 (D. Satas, ed.), Van Nostrand Reinhold, N.Y. Bolandiol, Bolasterone, Clostebol, Ethylestrenol. (1989). Formyldienolone, 4-Hydroxy-19-nortestosterone, Further details and examples of silicone pressure sensitive Methandriol, Methenolone, Methyltrienolone, Nandrolone, adhesives which are useful in the practice of this invention 45 Nandrolone Decanoate, Nandrolone are described in the following U.S. Pats. Nos. : 4,591,622; p-Hexyloxyphenylpropionate, Nandrolone Phenpropionate, 4.584,355; 4,585,836; and 4,655,767. Norbolethone, Oxymesterone, Pizotyline, Quinbolone, Suitable silicone pressure-sensitive adhesives are com Stenbolone and Trenbolone. mercially available and include the silicone adhesives sold 8. Analgesics (dental) such as Chlorobutanol, Clove and under the trademarks BIO-PSA X7-3027, BIO-PSA 50 Eugenol. X7-4503, BIO-PSAX7-4603, BIO-PSAX7-4301, BIO-PSA 9. Analgesics (narcotic) such as Alfentanil, Allylprodine, X7-4303, BIO-PSAX7-4919, BIO-PSAX7-2685, and BIO Alphaprodine, Anileridine, Benzylmorphine, Bezitramide, PSA X7-3122 by Dow Corning Corporation, Medical Buprenorphine, Butorphanol, Clonitazene, Codeine. Products, Midland, Mich. BIO-PSA-3027 is particularly Codeine Methyl Bromide, Codeine Phosphate, Codeine Suitable for use in formulations containing amine-functional 55 Sulfate, Desomorphine, Dextromoramide, Dezocine, drugs, Such as albuterol. Diampromide, Dihydrocodeine, Dihydrocodeinone Enol In the practice of preferred embodiments of the invention, Acetate, Dihydromorphine, Dimenoxadol, Dimepheptanol, the polysiloxane constitutes preferably from about 9% to Dimethylthiambutene, Dioxaphetyl Butyrate, Dipipanone, about 97% of the total weight of the total polymer blend, and Eptazocine, Ethoheptazine, Ethylmethlythiambutene, preferably about 8% to about 97%, and more preferably 60 Ethylmorphine, Etonitazene, Fentanyl, Hydrocodone, about 14% to about 94%. Hydromorphone, Hydroxypethidine, Isomethadone, Exemplary of drugs that can be administered by the novel Ketobemidone, Levorphanol, Lofentanil, Meperidine, transdermal drug delivery system of this invention include, Meptazinol, Metazocine, Methadone Hydrochloride, but are not limited to: Metopon, Morphine, Morphine Derivatives, Myrophine, 1. O-Adrenergic agonists such as Adrafinil, Adrenolone. 65 Nalbuphine, Narceline, Nicomorphine, Norlevorphanol, Amidephrine, Apraclonidine, Budralazine, Cionidine, Normethadone, Normorphine, Norpipanone, Opium, Cyclopentamine, Detomidine, Dimetofrine, Dipivefrin. Oxycodone, Oxymorphone, Papaveretum, Pentazocine, 5,656.286 13 14 Phenadoxone, Phenazocine, Pheoperidine, Piminodine, Chloride, Midazolam, Myrtecaine, Naepaine, Octacaine, Piritramide, Proheptazine, Promedol, Properidine, Orthocaine, Oxethazaine, Parethoxycaine, Phenacaine Propiram, Propoxyphene, Sufentanil and Tilidine. Hydrochloride, Phencyclidine, Phenol, Piperocaine, 10. Analgesics (non-narcotic) such as Acetaminophen, Piridocaine, Polidocanol, Pramoxine, Prilocaine, Procaine, Acetaminosalol, Acetanilide, Acetylsalicylsalicylic Acid, Propanidid, Propanocaine, Proparacaine, Propipocaine, Propofol, Propoxycaine Hydrochloride, Pseudococaine, Alclofenac, Alminoprofen, Aloxiprin, Aluminum Bis Pyrrocaine, Quinine Urea Hydochloride, Risocaine, Salicyl (acetylsalicylate), Aminochlorthenoxazin, 2-Amino-4- Alcohol, Tetracaine Hydrochloride, Thialbarbital, Thimylal, picoline, Aminopropylon, Aminopyrine, Ammonium Thiobutabarbital, Thiopental Sodium, Tolycaine, Tri Salicylate, Antipyrine, Antipyrine Salicylate, Antrafenine, mecaine and Zolamine. Apazone, Aspirin, Benorylate, Benoxaprofen, 10 13. Anorectics such as Aminorex, Amphecloral, Benzpiperylon, Benzydamine, p-Bromoacetanilide, Amphetamine, Benzaphetamine, Chlorphentermine, 5-Bromosalicylic Acid Acetate, Bucetin, Bufexamac, Clobenzorex, Cloforex, Cortermine, Cyclexedrine, Destro Bumadizon, Butacetin, Calcium Acetylsalicylate, amphetamine Sulfate, Diethylpropion, Diphemethoxidine, Carbamazepine, Carbetidine, Carbiphene, Carsalam, N-Ethylamphetamine, Fenbutrazate, Fenfluramine, Chloralantipyrine, Chlorthenoxazin(e), Choline Salicylate, 15 Fen proporex, Furfurylmethylamphetamine, Cinchophen, Ciramadol, Clometacin, Cropropamide, Lev ophacet operate, Ma Zindol, Mefe norex, Crotethamide, Dexoxadrol, Difenamizole, Diflunisal, Dihy Metamfe pro amone, Methamphetamine, droxyaluminum Acetylsalicylate, Dipyrocetyl, Dipyrone, Norpseudoephedrine, Phendimetrazine, Phenmetrazine, Emorfazone, Enfenamic Acid, Epirizole, Etersalate, Phenpentermine, Phenylpropanolamine Hydrochloride and Ethenzamide, Ethoxazene, Etodolac, Felbinac, Fenoprofen, 20 Picilorex. Floctafenine, Flufenamic Acid, Fluoresone, Flupirtine, 14. Anthelmintics (Cestodes) such as Arecoline, Aspidin, Fluproquazone, Flurbiprofen, Fosfosal, Gentisic Acid, Aspidinol, Dichlorophen(e), Embelin, Kosin, Napthalene, Glafenine, Ibufenac, Imidazole Salicylate, Indomethacin, Niclosamide, Pellertierine, Pellertierine Tannate and Quina Indoprofen, Isofezolac, Isoladol, Isonixin, Ketoprofen, C. Ketorolac, p-Lactophenetide, Lefetamine, Loxoprofen, 25 15. Anthelmintics (Nematodes) such as Alantolactone, Lysine Acetylsalicylate, Magnesium Acetylsalicylate, Amoscanate, Ascaridole, Bephenium, Bitoscanate, Carbon Tetrachloride, Carvacrol, Cyclob endazole, Methotrimeprazine, Metofoline, Miroprofen, Morazone, Diethylcarbamazine, Diphenane, Dithiazanine Iodide, Morpholine Salicylate, Naproxen, Nefopam, Nifenazone, 5' Dymanthine, Gentian Violet, 4-Hexylresorcinol, Kainic Nitro-2' propoxyacetanilide, Parsalmide, Perisoxal, Acid, Mebendazole, 2-Napthol, Oxantel, Papain, Piperazine, Phenacetin. Phenazopyridine Hydrochloride, Phenocoll, 30 Piperazine Adipate, Piperazine Citrate, Piperazine Edetate Phenopyrazone, PhenylAcetylsalicylate, Phenyl Salicylate, Calcium, Piperazine Tartrate, Pyrantel, Pyrvinium Pamoate, Phenyramidol, Pipebuzone, Piperylone, Prodilidine, o-Santonin, Stilbazium Iodide, Tetrachloroethylene, Propacetamol, Propyphenazone, Proxazole, Quinine Tetramisole, thiabendazole, Thymol, Thymyl Salicylate, Ramifenazone, Rimazolium Metilsulfate, N-Isoamylcarbamate, Triclofenol Piperazine and Urea Salacetamide, Salicin, Salicylamide, Salicylamide O-Acetic 35 Stibamine. Acid, Salicylsulfuric Acid, Salsalte, Salverine, Simetride, 16. Anthelmintics (Onchocerca) such as Ivermectin and Sodium Salicylate, Sulfamipyrine, Suprofen, Talniflumate, Suramin Sodium. Tenoxicam, Terofenamate, Tetradrine, Tinoridine, Tolfe 17. Anthelmintics (Schistosoma) such as Amoscanate, namic Acid, Tolpronine, Tramadol, Viminol, Xenbucin and Amphotalide, Antimony Potassium Tartrate, Antimony Zomepirac. 40 Sodium Gluconate, Antimony Sodium Tartrate, Antimony 11. Androgens such as Boldenone, Fluoxymesterone, Sodium. Thioglycollate, Antimony Thioglycollamide, Mestanolone, Mesterolone, Methandrostenolone, Becanthone, Hycanthone, Lucanthone Hydrochloride, 17-Methyltestosterone, Methyltestosterone, 170 Niridazole, Oxamniquine, Praziquantel, Stibocaptate, Sti Methyl testosterone 3-Cyclopentyl Enol Ether, bophen and Urea Stibamine. Norethandrolone, Normethandrone, Oxandrolone, 45 18. Anthelmintic (Trematodes) such as Anthiolimine and Oxymesterone, Oxymetholone, Prasterone, Stanlolone, Tetrachloroethylene. Stanozool, Testosterone, Testosterone 17-Chloral 19. Antiacne drugs such as Algestone Acetophenide, Hemiacetal, Testosterone 17B-Cypionate, Testosterone Azelaic Acid, Benzoyl Peroxide, Cyoctol, Cyproterone, Enanthate, Testosterone Nicotinate, Testosterone Motretinide, Resorcinol, Retinoic Acid and Tetroquinone. Pheynylacetate, Testosterone Propionate and Tiomesterone. 50 20. Antiallergics such as Amlexanox, Astemizole, 12. Anesthetics (intravenous) such as Acetamidoeugenol, Azelastine, Cromolyn, Fenpiprane, Histamine, budilast, Alfadolone Acetate, Alfaxalone, Amucaine, Amolanone, Nedocromil, Oxatomide, Pentigetide, Poison Ivy Extract, Amylocaine Hydrochloride, Benoxinate, Betoxycaine, Poison Oak Extract, Poison Sumac Extract, Repirinast, Biphenamine, Bupivacaine, Butacaine, Butaben, Tranilast, Traxanox and Urushiol. Butanilicaine, Burethamine, Buthalital Sodium, 55 21. Antiamebics such as Arsthinol, Bialamicol, Butoxycaine, Carticaine, 2-Chloroprocaine Hydrochloride, Carbarsone, Cephaeline, Chlorbetamide, Chloroquine, Coca ethylene, Cocaine, Cyclomethy caine. Chlorphenoxamide, Chlortetracycline, Dehydroemetine, DibucaineHydrochloride, Dimethisoquin, Dimethocaine, Dibromopropamidine, Diloxanide, DephetarSone, Emetine, Diperadon Hydrochloride, Dyclonine, Ecgonidine, Fumagillin, Glaucarubin, Glycobiarsol, 8-Hydroxy-7-iodo Ecgonine, Ethyl Aminobenzoate, Ethyl Chloride, 5-quinoline sulfonic Acid, Iodochlorhydroxyquin, Etidocaine, Etoxadrol, B-Eucaine, Euprocin, Fenalcomine, Iodoquinol, Paronomycin, Phanquinone, Phearsone Fomocaine, Hexobarbital, Hexylcaine Hydrochloride, Sulfoxylate, Polybenzarsol, Propamidine, Quinfamide, Hydroxydione Sodium, Hydroxyprocaine, Secnidazole, Sulfarside, Teclozan, Tetracycline, Hydroxytetracaine, Isobutyl p-Aminobenzoate, Kentamine, Thiocarbamizine, Thiocarbarisone and Tinidazole. Leucinocaine Mesylate, Levoxadrol, Lidocaine, 65 22. Antiandrogens such as Bifuranol, Cyoctol, Mepivacaine, Meprylcaine Hydrochloride, Metabutox Cyproterone, Delmadinone Acetate, Flutimide, Nilutamide ycaine Hydrochloride, Methohexital Sodium, Methyl and Oxendolone. 5,656,286 15 16 23. Antianginals such as Acebutolol, Alprenolol, Aspoxicillin, AZidocillan, AZlocillan, Bacampicillin, Amiodarone, Amlodipine, Arotinolol, Atenolol, Bepridil, Benzylpenicillinic Acid, Benzylpenicillin Sodium, Bevantolol, Bucumolol, Bufetolol, Bufuralol, Bunitrolol, Carbenicilin, Carfecillin Sodium, Carindacillin, Bupranolol, Carozolol, Carteolol, Carvedilol, Celiprolol, Clometocillin, Cloxacillin, Cyclacillin, Cinepazet Maleate, Diltiazem, Epanolol, Felodipine, Dicloxacillin, Diphenicillin Sodium, Epicillin, Gallopamil, Imolamine, Indenolol, Isosorbide Dinitrate, Isradipine, Limaprost, Mepindolol, Metoprolol, Fenbenicillin, Floxicillin, Hetacillin, Lenampicillin, Molsidomine, Nadolol, Nicardipine, Nifedipine, Nifenalol, Metampicillin, Methicillin Sodium, Mezlocillin, Nilvadipine, Nipradillol, Nisoldipine, Nitroglycerin, Nafcillin Sodium, Oxacillin, Penamecillin, Peneth Oxprenolol, Oxyfedrine, Ozagrel, Penbutolol, Pentaerythri amate Hydriodide, Penicillin G Benethamine, Peni tol Tetranitrate, Pindolol, Pronethalol, Propranolol, Sotaiol, 10 cillin G Benzathine, Penicillin G Benzhydrylamine, Terodiline, Timolol, Toliprolol and Verapamil. Penicillin G Calcium, Penicillin G Hydrabamine, 24. Antiarrhythmics such as Acebutol, Acecaine, Penicillin G Potassium, Penicillin G Procaine, Peni Adenosine, Ajmaline, Alprenolol, Amiodarone, Amoproxan, cillen N, Peniciliin O, Penicillin V, Penicilin V Aprindine, Arotinolol, Atenolol, Bevantolol, Bretylium Benzathine, Penicillin V Hydrabamine, Tosylate, Bubumolol, Bufetolol, Bunaftine, Bunitrolol, 15 Penimepicycline, Phenethicillin Potassium, Bupranolol. Butidrine Hydrochloride, Butobendine, Piperacillin, Pivapicillin, Propicillin, Quinacillin, Capobenic Acid. Carazolol, Carteolol, Cifenline, Sulbenicillin, Talampicillin, Temocillin and Ticarcil Cloranolol, Disopyramide, Encainide, Esmolol, Flecainide, lin; Gallopamil, Hydroquinidine, Indecainide, Indenolol, prat Lincosamides such as Clindamycin and Lincomycin; ropium Bromide, Lidocaine, Lorajmine, Lorcainide, Macrollides such as Azithromycin, Carbomycin, Meobentine, Metipranolol, Mexiletine, Moricizine, Clarithromycin, Erythromycin, Erythromycin Nadoxolol, Nifenalol, Oxprenolol, Penbutolol, Pindolol, Acistrate, Erythromycin Estolate, Erythromycin Pirmenol, Practolol, Prajmaline, Procainamide Glucoheptonate, Erythromycin Lactobionate, Erythro Hydrochloride, Pronethalol, Propafenone, Propranolol, mycin Propionate, Erythromycin Stearate, Josamycin, Pyrinoline, Quinidine Sulfate, Quinidine, Sotalol, Talinolol, 25 Leucomycins, Midecamycins, Miokamycin, Timolol, Tocainide, Verapamil, Viquidil and Xibenolol. 25. Antiarteriosclerotics such as Pyridinol Carbamate. Oleandomycin, Primycin, Rokitamycin, Rosaramicin, 26. Antiarthritic/Antirheumatics such as Allocupreide Roxithromycin, Spiramycin and Troleandomycin; Sodium, Auranofin, Aurothioglucose, Aurothioglycanide, Polypeptides such as Amphomycin, Bacitracin, Azathioprine, Calcium 3-Aurothio-2-propanol-1-sulfonate, Capreomycin, Colistin, Enduracidin, Enviomycin, Chloroquine, Clobuzarit, Cuproxoline, Diacerein, 30 Fusafungine, Gramicidin(s), Gramicidin S, Glucosamine, Gold Sodium. Thiomalate, Gold Sodium Mikamycin, Polymyxin, Polymyxin Thiosulfate, Hydroxychloroquine, KebuZone, Lobenzarit, B-Methanesulfonic Acid, Pristinamycin, Ristocetin, Melittin, Methotrexate, Myoral and Penicillamine. Teicoplanin, Thiostrepton, Tuberactinomycin, 27. Antibacterial (antibiotic) drugs including: Tyrocidine, Tyrothricin, Vancomycin, Viomycin, Vio Aminoglycosides such as Amikacin, Apramycin, 35 mycin Pantothenate, Virginiamycin and Zinc Bacitra Arbekacin, Bambermycins, Butirosin, Dibekacin, Cl Dihdrostreptomycin, Fortimicin(s), Gentamicin, Tetracyclines such as Apicycline, Chlortetracycline, Ispamicin, Kanamycin, Micronomicin, Neomycin, Clomocycline, Demeclocycline, Doxycycline, Neomycin Undecylenate, Netilmicin, Paromomycin, Guamecycline, Lyme cycline. Meclocycline, Ribostamycin, Sisomicin, Spectinomycin, 40 Methacycline, Minocycline, Oxytetracycline, Streptomycin, Streptonicozid and Tobramycin; Penimepicycline, Pipacycline, Rolitetracycline, Amphenicols such as Azidamfenicol, Chloramphenicol, Sancycline, Senociclin and Tetracycline; and Chloramphenicol Palmitate, Chloramphenicol other antibiotics such as Cycloserine, Mupirocin and Pantothenate, Florfenicol and Thiamphenicol; 45 Tuberin. Ansamycins such as Rifamide, Rifampin. Rifamycin and 28. Antibacterial drugs (synthetic), including: Rifaximin; 2,4-Diaminopyrimidines such as Brodimoprim, TetroX B-Lactams, including: oprim and Trimethoprim; Carbapenems such as Imipenem; Nitrofurans such as Furaltadone, Furazolium Chloride, Cephalosporins such as Cefactor, Cefadroxil, 50 Nifuradene, Nifuratel, Nifurfoline, Nifurpirinol, Cefamandole, Cefatrizine, Cefazedone, Cefazolin, Nifurprazine, Nifurtoinol and Nitrofurantoin: Cefixime, Cefnenoxime, Cefodizime, Cefonicid, Quinolones and Analogs such as Amifloxacin, Cinoxacin, Cefoperazone, Ceforanide, Cefotaxime, Cefotiam, Ciprofloxacin, Difloxacin, Enoxacin, Feroxacin, Cefpimizole, Ce?pirimide, Cefpodoxime Proxetil, Fiumequine, nomefloxacin, Miloxacin, Nalidixic Acid, Cefroxadine, Cefsulodin, Ceftazidime, Cefteram, 55 Norfloxacin, Ofloxacin, Oxolinic Acid, Pefloxacin, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Pipemidic Acid, Piromidic Acid, Rosoxacin, Tema Cefuroxime, Cefuzonam, Cephacetrile Sodium, floxacin and Tosufloxacin; Cephalexin, Cephaloglycin, Cephaloridie, Sulfonamides such as Acetyl Sulfamethoxypyrazine, Cephalosporin. Cephalothin, Cephapirin Sodium, Acetyl Sulfisoxazole, Azosulfamide, Benzylsulfamide, Cephradine and Piveefalexin; 60 Chloramine-B, Chloramine-T, Dichloramine T, Cephamycins such as Cefbuperazone, Cefnetazole, Formosulfathiazole, N°Formylsulfisomidine, N°-B-D- Cefninox, Cefetan and Cefoxiitin; Glucosylsulfanilamide, Mafenide, 4'- Monobactams Such as Aztreonam, Carumonam and (Methylsulfamoyl) sulfanilanilide, Tigemonam; p-Nitrosulfathiazole, Noprylsulfamide, Oxacephems such as Flomoxef and Moxolactam; 65 Phthalylsulfacetamide, Phthalylsulfathiazole, Penicillins such as Amidinocillin, Amdinocillin Salazosulfadimidine. Succinylsulfathiazole, Pivoxil, Amoxicillin, Ampicillan, Apacilin, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine, 5,656,286 17 18 Sulfachrysoidine, Sulfacytine, Sulfadiazine, sium Bromide, Magnesium Sulfate, Mephenytoin, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Mephobarbital, Metharbital, Methetoin, Methsuximide, Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, 5-Methyl-5-(3-phenanthry1)hydantoin, 3-Methyl-5- Sulfaloxic Acid, Sulfamerazine, Sulfameter, phenylhydantoin, Narcobarbital, Nimetazepam, Sulfamethazine, Sulfamethizole, Sulfamethomidine, Nitrazepam, Paramethadione, Phenacemide, Phenetharbital, Sulfamethoxazole, Sulfamethoxypyridazine, Pheneturide, Phenobarbital, Phenobarbital Sodium, Sulfametrole, Sulfamidochrysoidine. Sulfamoxole, Phensuximide, Phenylmethylbarbituric Acid, Phenytoin, Sulfanilamide, Sulfanilamidomethanesulfonic Acid Phethenylate Sodium, Potassium Bromide, Primidone, Triethanolamine Salt, 4-Sulfanilamidosalicylic Acid, Progabide, Sodium Bromide, Solanum, Strontium Bromide, N'-Sulfanilylsulfanilamide, Sulfamily lurea, 10 Suclofenide, Sulthiame, Tetrantoin, Trimethadione, Valproic N-Sulfanillyl-3,4-xylamide, Sulfanitran, Sulfaperine, Acid, Valpromide, Vigabatirin and Zonisamide. Sulfaphenazole. Sulfaproxyline, Sulfapyrazine, 31. Antidepressants, including: Sulfapyridine, Sulfasomizole, Sulfasymazine, Bicyclics such as Binedaline, Caroxazone, Citalopram, Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfisomi Dimethazan, Indalpine, Fencamine, Indeloxazine dine and Sullfisoxazole; 15 Hydrochcloride, Nefopam, Nomifensine, Oxitriptan, Sulfones such as Acedapsone, Acediasulfone, Acetosul Oxypertine, Paroxetine, Sertraline, Thiazesim, Traz fone Sodium, Dapsone, Diathymosulfone, Glucosul odone and Zometapine; fone Sodium, Solasulfone, Succisulfone, Sulfanilic Hydrazides/Hydrazines such as Benmoxine, proclozide, Acid, p-Sulfanilylbenzylamine, pp-Sulfonyldianiline Iproniazid, Isocarboxazid, Nialamide, Octamoxin and N.N'digalactoside, Sulfoxone Sodium and Thiazolsul Phenelzine; fone; and Pyrrollidones such as Cotinine, Rolicyprine and Rolipram; others such as Clofoctol, Hexedine, Methenamine, Meth Tetracyclics such as Maprotiline, Metralindole, Mianserin enamine Anhydromethylene-citrate, Methenamine and Oxaprotiline. Hippurate, Methenamine Mandelate, Methenamine Tricyclics such as Adinazolam, Amitriptyline, Sulfosalicylate, Nitroxoline and Xibornol. Amitriptylinoxide, Amoxapine, Butriptyline, 29. Anticholinergics such as Adiphenine Hydrochloride, Clomipramine, Demexiptiline, Desipramine, Alverine, Ambutonomium Bromide, Aminopentamide, Dibenzepin, Dimetracrine, Dothiepin, Doxepin, Amixetrine, Amprotropine Phosphate, Anisotropine Fluacizine, Imipramine. Imipramine N-Oxide, Methylbromide, Apoatropine, Atropine, Atropine N-Oxide, prindole, Lofepramine, Melitracen, Metapramine, Benactyzine, Benapryzine, Benzetimide, Benzilonium 30 Nortriptyline. Noxiptilin, Opipramol, Pizotyline, Bromide, Benztropine Mesylate, Bevonium Methyl Sulfate, Biperiden, Butropium Bromide, N-Butylscopolammonium Propizepine, Protriptyline, Quinupramine, Tianeptine Bromide, Buzepide, Camylofine, Caramiphen and Trimipramine; and Hydrochloride, Chlorbenzoxamine, Chlorphenoxamine, others such as Adrafinil, Benactyzine. Bupropion, Cimetropium Bromide, Clidinium Bromide, Cyclodrine, 35 Butacetin, Deanol, Deanol Aceglumate, Deanol Cyclonium Iodide, Cycrimine Hydrochloride, Deptropine, Acetamidobenzoate, Dioxadrol, Etoperidone, Dexetimide, Dibutoline Sulfate, Dicyclomine Febarbamate, Femoxetine, Fenpentadiol, Fluoxetine, Hydrochloride, Diethaz ine, Difemerine, Dihexyverine, Fluvoxamine, Hematoporphyrin, Hypercinin, Diphemanil Methylsulfate, N-(1,2-Diphenylethyl) Levophacetoperane, Medifoxamine, Minaprine, nicotinamide, Dipiproverine, Diponium Bromide, Emepro 40 Moclobemide, Oxaflozane, Piberaline, Prolintane, nium Bromide, Endobenzyline Bromide, Ethopropazine, Pyrisuccideanol, Rubidium Chloride, Sulpiride, Ethybenztropine, Ethylbenzhydramine, Etomidoline, Sultopride, Teniloxazine, Thozalinone, Tofenacin, Eucatropine, Fenpiverinium Bromide, Fentonium Bromide, Toloxatone, Tranylcypromine, L-Tryptophan, Vilox Flutropium Bromide, Glycopyrrolate, Heteronium Bromide, azine and Zimeldine. Hexocyclium Methyl Sulfate, Homatropine, Hyoscyamine, 45 32. Antidiabetics, including: pratropium Bromide, Isopropamide, Levomepate, Biguanides such as Buformin, Metformin and Phen Mecloxamine, Mepenzolate Bromide, Metcaraphen, Meth formin; antheline Bromide, Methixene, Methscopolamine Bromide, Hormones such as Glucagon, Insulin, Insulin Injection, Octamylamine, Oxybutynin Chloride, Oxyphencyclimine, Insulin Zinc Suspension, Isophane Insulin Suspension, Oxyphenonium Bromide, Pentapiperide, Penthienate 50 Protamine Zinc insulin Suspension and Zinc Insulin Bromide, Phencarbamide, Phenglutarimide, Pipenzolate Crystals; Bromide, Piperidolate, Piperilate, Poldine Methysulfate, Sulfonylurea derivatives such as Acetohexamide, Pridinol, Prifinium Bromide, Procyclidine, Propanthel ine 1-Butyl-3-metanily lure a, Carbutamide, Bromide, Propenzolate, Propyromazine, Scopolamine, Sco Chlorpropamide, Glibornuride, Gliclazide, Glipizide, polamine N-Oxide. Stilonium Iodide, Stramonium, 55 Gliquidone, Glisoxepid, Glyburide, Glybuthiazol(e), Sultroponium, Thihexinol, Thiphenamil, Tiemonium iodide, Glybuzole, Glyhexamide, Glymidine, Glypinamide, Timepidium Bromide, Tiquizium Bromide, Tridihexethyl Phenbutamide, Tolazamide, Tolbutamide and Tolcycla Iodide, Trihexyphenidyl Hydrochloride, Tropacine, mide; and Tropenzile, Tropicamide, Trospium Chloride, Valethamate others such as Acarbose, Calcium Mesoxalate and Migli Bromide and Xenytropium Bromide. tol. 30. Anticonvulsants such as Acetylpheneturide, Albutoin, 33. Antidiarrheal drugs such as Acetyltannic Acid, Albu Aloxidone, Aminoglutethimide, 4-Amino-3-hydroxybutyric min Tannate, Alkofanone, Aluminum Salicylates-Basic, Acid, Atrolactamide, Beclamide, Buramate, Calcium Catechin, Difenoxin, Diphenoxylate, Lidamidine, Bromide, Carbamazepine, Cinromide, Clomethiazole, Loperamide, Mebiquine, Trillium and Uzarin. Clonazepam, Decinemide, Diethadione, Dimethadione, 65 34. Antidiuretics such as Desmopressin, Felypressin, Doxenitoin, Eterobarb, Ethadione, Ethosuximide, Ethotoin, Lypressin, Ornipressin, Oxycinchophen, Pituitary-Posterior, Fluoresone, 5-Hydroxytryptophan, Lamotrigine, Magne Terlipressin and Vasopressin. 5,656,286 19 20 35. Antiestrogens such as Delmadinone Acetate, other antihistamines such as Antazoline, Astemizole, Ethamoxytriphetol, Tamoxifen and Toremifene. Azelastine, Cetoxime, Clemizole, Clobenztropine, 36. Antifungal drugs (antibiotics), including: Diphenazoline, Diphenhydramine, Mebhydroline, Polyenes such as Amphotericin-B, Candicidin, Phenindamine, Terfenadine and Tritoqualine. Dermostatin, Filipin, Fungichromin, Hachimycin, 5 42. Antihyperlipoproteinemics, including: Hamycin, Lucensomycin, Mepartricin, Natamycin, Aryloxyalkanoic acid derivatives such as Beclorbrate, Nystatin, Pecilocin and Perimycin; and Bazafibrate, Binifibrate, Ciprofibrate, Clinofibrate, others such as AZaserine, Griseofulvin, Oligomycins, Clofibrate, Clofibric Acid, Etonfibrate, Fenofibrate, Neomycin Undecylenate, Pyrrolnitrin, Siccanin, Tuber Gemfibrozil, Nicofibrate, Pirifibrate, Ronifibrate, Simfibrate cidin and Viridin. 37. Antifungal drugs (synthetic), including: 10 and Theofibrate; Allylamines such as Naftifine and Terbinafine; Bile acid sequesterants such as Cholestyramine Resin, Imidazoles such as Bifonazole. Butoconazole, Colestipol and Polidexide; Chloridantoin, Chlormidazole, Cloconazole, HMG CoA reductase inhibitors such as Lovastatin, Prav astatin Sodium and Simvastatin; Clotrimazole, Econazole, Eniconazole, Fenticonazole, 15 Isoconazole, Ketoconazole, Miconazole, Nicotinic acid derivatives Aluminum Nicotinate, Omoconazole, Oxiconazole, Nitrate, Sulconazole and Acipinox, Niceritrol, Nicoclonate, Nicomol and Tioconazole; Oxiniacic Acid; Triazoles such as Fluconazole, Itraconazole and Tercona Thyroid hormones and analogs such as Etiroxate, Thyro Zole; and propic Acid and Thyroxine; and others such as Acrisorcin, Amorolfine, Biphenamine, 20 Bromosalicylchloranilide, Bucosamide, Calcium others such as Acifran, AZacosterol, Benfluorex, Propionate, Chlophenesin, Ciclopirox, Cloxyquin, B-Benzabutyramide, Carnitine, Chondroitin Sulfate, Coparafinate, Diamthazole, Dihydrochloride, Comestone, Detaxtran, Dextran Sulfate Sodium, 5,8, Exalamide, Flucytosine, Halethazole, Hexetidine, 11, 14,17-Eicosapentaenoic Acid, Eritadenine, Loflucarban, Nifuratel, Potassium Iodide, Propionic 25 Furazbol, Meglutol, Melinamide, Mytatrienediol, Acid, Pyrithione, Salicylanilide, Sodium Propionate, Ornithine, y-Oryzanol, Pantethine, Penataerythritol Sulbentine, Tenonitrozole, Tolciclate, Tolindate, Tetraacetate, O-Phenylbutyramide, Pirozadil, Probucol, Tolnaftate, Tricetin, Ujothion, Undecylenic Acid and O-Sitosterol, Sultosilic Acid, Piperazine Salt, Tiadenol, Zinc Propionate. Triparanol and Xenbucin. 30 43. Antihypertensive drugs, including: 38. Antiglaucoma drugs such as Acetazolamide, Befunolol. Betaxolol, Bupranolol, Carteolol, Dapiprazoke, Arylethanolamine derivatives such as Amosulalol, Dichlorphenamide, Dipivefrin, Epinephrine, Levobunolol, Bufuralol, Dilevalol, Labetalol, Pronethalol, Sotalol Methazolamide, Metipranolol, Pilocarpine, Pindolol and and Sulfinalol; Timolol. Aryloxypropanolamine derivatives such as Acebutolol, 39. Antigonadotropins such as Danazol, Gestrinone and 35 Alprenolol, Arotinolol, Atenolol, Betaxolol. Paroxypropione. Bevantolol, Bisoprolol, Bopindolol, Bunitrolol. 40. Antigout drugs such as Allopurinol, Carprofen, Bupranolol, Butofilolol, Carazolol. Cartezolol. Colchicine. Probenecid and Sulfinpyrazone. Carvedilol, Celiprolol, Cetamolol, Epanolol, Indenolol, 41. Antihistamines, including: Mepindolol, Metipranolol, Metoprolol, Moprolol. Alkylamine derivatives such as Acrivastine, Bamipine, 40 Nadolol, Nipradillol, Oxprenolol, Penbutolol, Pindolol, Brompheniramine, Chlorpheniramine, Dimethindene, Propranolol, Talinolol, Tetraolol, Timolol and Tolip Metton S. Pheniramine, Pyrrobutamine, Thenaldine, rool: Tolpropamine and Triprolidine; Benzothiadiazine derivatives such as Althiazide, Amino alkyl ethers such as Bietan autine, 45 Ben droflume thiazide, Ben Zthiazide, Bromodiphenhydramine, Carbinoxamine, Clemastine, Ben Zylhydrochlorothiazide, Buthiazide, Diphenlypyraline, Doxylamine, Embrammine, Chlorothiazide, Chlorthalidone, Cyclopenthiazide, Me dry lamine, Mephenphy dramine, Cyclothiazide, Diazoxide, Epithiazide, Ethiazide, p-Methyldiphenhydramine, Orphena drine, Fen quizone, Hydrochlor othiazide, Hydroflumethiazide, Methyclothiazide, Meticrane, Phenyltoloxamine, Piprinhydrinate and Setasine; 50 Ethylenediamine derivatives such as Alloclamide. Metolazone, Parafutizide, Polythiazide, Tetrachlorme p-Bromtripelennamine, Chloropyramine, Chlorothen, thiazide and Trichlorimethiazide; Histapyrrodine, Methafurylene, Methaphenilene, N-Carboxyalkyl (petide/lactam) derivatives such as Methapyrilene, Phenbenzamine, Pyrilamine. Talastine, Alacepril, Captopril, Cilazapril, Delapril, Enalapril, Thenyldiamine, Thonzylamine Hydrochloride, Tripe 55 Enalaprilat, Fosinopril, Lisinopril, Moveltipril, lennamine and Zolamine; Perindopril, Quinapril and Ramipril; Piperazines such as Cetirizine, Chlorcyclizine, Dihydropyridine derivatives such as Amlodipine, Cinnarizine, Clocinizine and Hydroxyzine; Felodipine, Isradipine, Nicardipine, Nifedipine, Tricyclics, including: Nilvadipine, Nisoldipine and Nitrendipine; Phenothiazines such as Ahistan. Etymemazine, 60 Guanidine derivatives such as Bethanidine, Debrisoquin, Hydroxyazine, N-Hydroxyethylpromethazine Guanabenz, Guanacline, Guanadrel, GuanaZodine, Chloride, Isopromethazine, Mequitazine, Guanethidine, Guanfacine, Guanochlor, Guanoxabenz Promethazine, Pyrathiazine and Thiazinamium and Guanoxan; Methyl Sulfate; and Hydrazines and phthalazines such as Budralazine, others Such as AZatadine, Clobenzepam, 65 Cadralazine, Dihydralazine, Endralazine, Cyproheptadine, Deptropine, Isothipendyl, Lorata Hydracarbazine, Hydralazine, Pheniprazine, Pildrala dine and Prothipendyl; and Zine and Todralazine; 5,656.286 21 22 Imidazole derivatives such as Clonidine, Lofexidine, Salicylic acid derivatives such as Acetaminosalol, Phentolamine, Tiamenidine and Tolonidine; Aspirin, Benorylate, Bromosaligenin, Calcium Quaternary ammonium compounds Azamethonium Acetylsalicylate, Diflunisal, Etersalate, Fendosal, Gen Bromide, Chlorisondamine Chloride, Hexamethonium, tisic Acid, Glycol Salicylate, Imidazole Salicylate, Pentacynium Bis(methyl sulfate), Pentamethonium Lysine Acetylsalicylate, Mesalamine, Morpholine Bromide, Pentolinium Tartate, Phenactopinium Chlo Salicylate, 1-Naphthyl Salicylate, Olsalazine, ride and TrimethidiunumMethosulfate; Parsalmide, PhenylAcetylsalicylate, Phenyl Salicylate, Quinazoline derivatives such as Alfuzosin, Bunazosin, Salacetamide, Salicylamine O-Acetic Acid, Salicylsul Doxazosin, Prasosin, Terazosin and Trimazosin; furic Acid, Salsalate and Sulfasalazine; Reserpine derivatives such as Bietaserpine, Deserpidine, 10 Thiazinecarboxamides Such as Droxicam, Isoxican, Rescinnamine, Reserpine and Syrosingopine; Piroxicam and Tenoxicam; and Sulfonamide derivatives such as Ambuside, Clopamide, others such as e-Acetamidocaproic Acid, Furosemide, Indapamide, Quinethazone, Tripamide S-Adenosylmethionine, 3-Amino-4-hydroxybutyric and Xipamide; and Acid, Amixetrine, Bendazac, Benzydamine, Bucolome, others such as Ajmaline, Y-AminobutYric Acid, 15 Difenpiramide, Ditazol, Emorfazone, Guaiazulene, Bufeniode, Chlorthalidone, Cicletaine, Ciclosidomine, Nabumetone, Nimesulide, Orgotein, Oxaceprol, Cryptenamine Tannates, Fenoldopam, Flosequinan, Paranyline, Perisoxal, Pifoxime, Proquazone, Prox Indoramin, Ketanserin, Metbutamate, Mecamylamine, azole and Tenidap. Methyldopa, Methyl 4-Pyridyl Ketone 48. Antimalarial drugs such as Acedapsone. Amodiaquin, Thiosemicarbarzone, Metolazone, Minoxidil, 20 Arteether, Artemether, Artemisinin, Artesunate, Bebeerine, Muzolimine, Pargyline, Pempidine, Pinacidil, Berberine, Chirata, Chlorguanide, Chloroquine, Piperoxan, Primaperone, Protoveratrines, Raubasine, Chlorproguanil, Cinchona, Cinchonidine, Cinchonine, Rescimetol, Rilmenidene, Saralasin, Sodium Cycloguanil, Gentiopicrin, Halofantrine, Nitroprusside, Ticrynafen, Trimethaphan Camsylate, Hydroxychloroquine, Mefloquine Hydrochloride, Tyrosinase and Urapidil. 25 3-Methylarsacetin, Pamaquine, Plasmocid, Primaquine, 44. Antihyperthyroids such as 2-Amino-4-methylthiazole, Pyrimethamine, Quinacrine, Quinine, Quinine Bisulfate, 2-Aminothiazole, Carbimazole, 3,5-Dibromo-L-tyrosine, Quinine Carbonate, Quinine Dihydrobromide, Quinine 3,5-Diiodotyrosine, Hinderin. Iodine, Iothiouracil, Dihydrochloride, Quinine Ethylcarbonate, Quinine Formate, Methimazole, Methylthiouracil, propylthiouracil, Sodium Quinine Gluconate, Quinine Hydriodide, Quinine Perchlorate, Thibenzazoline, Thiobarbital and 2-Thiouracil. 30 Hydrochloride, Quinine Salicylate, Quinine Sulfate, Qui 45. Antihypotensive drugs such as Amezinium Methyl nine Tannate, Quinine Urea Hydrochloride, Quinocide, Sulfate, Angiotensin Amide, Dimetofrine, Dopamine, Quinoline and Sodium Arsenate Diabasic. Etifelmin, Etilefrin, Gepefrine, Metaraminol, Midodrine, 49. Antimigraine drugs such as Alpiropride, Norepinephrine, Pholedrinead and Synephrine. Dihydroergotamine, Ergocornine, Ergocorninine, 46. Antihypothyroid drugs such as Levothyroxine 35 Ergocryptine, Ergot, Ergotamine, Flumedroxone acetate, Sodium, Liothyronine, Thyroid, Thyroidin, Thyroxine, Fonazine, Lisuride, Methysergid(e), Oxetorone, Pizotyline Tiratricol and TSH. and Sumatriptan. 47. Anti-Inflammatory (non-steroidal) drugs, including: 50. Antinauseant drugs such as Acetyleucine Aminoarylcarboxylic acid derivatives such as Enfenamic Monoethanolamine, Alizapride, Benzquinamide, 40 Bietanautine, Bromopride, Buclizine, Chlorpromazine, Acid, Etofenamate, Flufenamic Acid, Isonixin, Clebopride, Cyclizine, Dimenhydrinate, Dipheniodol, Meclofenamic Acid, Mefanamic Acid, Niflumic Acid, Domperidone, Granisetron, Meclizine, Methalltal, Talniflumate, Terofenamate and Tolfenamic Acid; Metoclopramide, Metopimazine, Nabilone, Ondansteron, Arylacetic acid derivatives such as Acemetacin, Oxypendyl, Pipamazine, Piprinhydrinate, Prochlorperazine, Alclofenac, Amfenac, Bufexamac, Cinmetacin, 45 Scopolamine, Tetrahydrocannabinols, Thiethylperazine, Clopirac, Diclofenac Sodium, Etodolac, Felbinac, Thioproperzaine and Trimethobenzamide. Fenclofenac, Fenclorac, Fenclozic Acid, Fentiazac, 51. Antineoplastic drugs, including: Glucametacin, Ibufenac, Indomethacin, Isofezolac, Alkylating agents, including: Isoxepac, Lonazolac, Metiazinic Acid, Oxametacine, Alkyl sulfonates such as Busulfan, Improsulfan and Proglu metacin, Sulindac, Tiaramide, Tolimetin and 50 Piposulfan; Zomepirac; Aziridines such as Benzodepa, Carboquone, Meture Arylbutyric acid derivatives such as Bumadizon, depa and Uredepa; Butibufen, Fenbufen and Xenbucin; Ethylenimines and methylmelamines such as Arylcarboxylic acids such as Clidanac, Ketorolac and Altre tamine, Triethylene melamine, Tinoridine; 55 Triethylenephosphoramide, Triethylenethiophos Arylpropionic acid derivatives such as Alminoprofen, phoramide and Trimethylolomelamine; Benoxaprofen, Bucloxic Acid, Carprofen, Fenoprofen, Nitrogen mustards such as Chlorambucil, Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Chlornaphazine, Chclophosphamide, Estramustine, Indoprofen, Ketoprofen, Loxoprofen, Miroprofen, fosfamide, Mechlorethamine, Mechlorethamine Naproxen, Oxaprozin, Piketoprofen, Pirprofen, Oxide Hydrochloride, Melphalan, Novembichin, Pranoprofen, Protizinic Acid, Suprofen and Tiaprofenic Phenesterine, Prednimustine, Trofosfamide and Acid; Uracil Mustard; Pyrazoles such as Difenamizole and Epirizole; Nitrosoureas such as Carmustine. Chlorozotocin, Pyrazolones such as Apazone, Benzpiperylon, Feprazone, Foremustine, Lomustine, Nimustine and Ranimus Mofebutazone, Morazone, Oxyphenbutazone, 65 tine; and Phenylbutazone, Pipebuzone, Propyphenazone, others such as Dacarbazine, Mannomustine, Ramifenazone, Suxibuzone and Thiazolinobutazone; Mitobronitol, Mitolactol and Pipobroman; 5,656,286 23 24 Antibiotics such as Aclacinomycins, Actinomycin F, 60. Antiprotozoal drugs (Trypanosma) such as Anthramycin, AZas erine, Bleomycins, Benznidazole, Eflornithine, Melarsoprol, Nifurtimox, Cactinomycin, Carubicin, Carzinophilin, Oxophenarsine, Hydrochloride, Pentamidine, Propamidine, Chromomycins, Dactinomycin, Daunorubicin, Puromycin, Quinapyramine, Stilbamidine, Suramin 6-DiaZo-5-oxo-L-norleucine, Doxorubicin, Sodium, Trypan Red and Tryparasmide. Epirubicin, Mitomycins, Mycophenolic Acid, Nogalamycin, Olivomycins, Peplomycin, 61. Antipuritics such as Camphor, Cyproheptadine, Plicamycin, Porfiromycin, Puromycin, Dichlorisone, Glycine, Halometasone, 3-Hydroxycamphor, Streptonigrin, Streptozocin, Tubercidin, Ubenimex, Menthol, Mesulphen, Methdilazine, Phenol, Polidocanol, Zinostatin and Zorubicin; Risocaine, Spirit of Camphor, Thenaldine, Tolpropamine Antimetabolites, including: 10 and Trimeprazine. Folic acid analogs such as Denopterin, Methotrexate, 62. Antipsoriatic drugs such as Acitretin, Ammonium Pteropterin and Trimetrexate; Salicylate, Anthralin, 6-AZauridine, Bergapten(e), Purine analogs such as Fudarabine, Chrysarobin, Etretinate and Pyrogallol. 6-Mercaptopurine, Thiamiprine and Thiogua 63. Antipsychotic drugs, including: naine; and 15 Butyrophenones such as Benperidol, Bromperidol, Pyrimidine analogs such as Ancitabine, Azacitidine, Droperidol, Fluanisone, Haloperidol, Melperone, 6-AZauridine, Carmofur, Cytarabine, Moperone, Pipamperone, Sniperone, Timiperone and Doxifluridine, Enocitabine, Floxuridine, Fluroou Trifluperidol; racil and Tegafur; Enzymes such as Phenothiazines such as Acetophenazine, Butaperazine, L-Asparaginase; and 20 Carphenazine, Chlorproethazine, Chlorpromazine, otherS Such as Aceglatone, Amsacrine, Bestrabucil, Clo Spirazine, Cyame mazine, Dixyrazine, Bisantrene, Carboplatin, Cisplatin, Defofamide, Fluphenazine, Imiclopazine, Mepazine, Mesoridazine, Demecolcine, Diaziquone, Elfornithine, Ellip Methoxypromazine, Metofenazate, Oxaflumazine, tinium Acetate, Etoglucid, Etoposide, Gallium Perazine, Pericyazine, Perimethazine, Perphenazine, Nitrate, Hydroxyurea, Interferon-O, Interferon-B, 25 Interferon-Y, Interleukine-2, Lentinan, Piperacetazine, Pipotiazine, Prochlorperazine, Lonidamine, Mitoguazone, Mitoxantrone, Promazine, Sulforidazine, Thiopropazate, Mopidamol, Nitracrine, Pentostatin, Phenamet, Thioridazine, Trifluoperazine and Triflupromazine; Pirarubicin, Podophyllinic c Acid, Thioxanthenes such as Chlorprothixene, Clopenthixol, 2-Ethythydrazide, Procarbazine, PSKCE), Flupentixol and Thiothixene; Razoxane, Sizofiran, Spirogermanium, Taxol, 30 other tricyclics such as Benzquinamide, Carpipramine, Teniposide, Tenuazonic Acid, Triaziquone, Clocapramine, Clomacran, Clothiapine, Clozapine, 2.2'.2"-Trichlorotriethylamine, Urethan, Opipramol, Prothipendyl, Tetrabenazine, and Winblastine, Vincristine and Vindesine; Zotepine; and 52. Antineoplastic (hormonal) drugs, including: 35 others such as Alizapride, Amisulpride, Buramate, Androgens such as Calusterone, Dromostanolone Fluspirilene, Molindone, Penfuridol, Pimozide, Propionate, Epitiostanol, Mepitiostane and Testolac Spirilene and Sulpiride. tOne, 64. Antipyretics such as Acetaminophen, Acetaminosalol, Antiadrenals such as Aminoglutethimide, Mitotane and Acetanilide, Aconine, Aconite, Aconitine, Alclofenac, Alu Trilostane; 40 minum Bis(acetylsalicylate), Aminochlorthenoxazin, Antiandrogens such as Flutamide and Nilutamide; and Aminopyrine, Aspirin, Benorylate, Benzydamine, Antiestrogens such as Tamoxifen and Toremifene. Berberine, p-Bromoacetanilide, Bufexamac, Bumadizon, 53. Antineoplastic adjuncts including folic acid replen Calcium Acetysalicylate, Chlorthenoxazin(e), Choline ishers such as Frolinic Acid. Salicylate, Clidanac, Dihydroxyaluminum Acetylsalicylate, 54. Antiparkinsonian drugs such as Amantadine, 45 Dipyrocetyl, Dipyrone, Epirizole, Etersalate, Imidazole Benserazide, Bietanautine, Biperiden, Bromocriptine, Salicylate, Indomethacin, Isofezolac, p-Lactophenetide, Budipine. Carbidopa, Deprenyl, Dexetimide, Diethazine, Lysine Acetylsalicylate, Magnesium Acetylsalicylate, Droxidopa, Ethopropazine, Ethylbenzhydramine, Meclofenamic Acid, Morazone, Morpholine Salicylate, Levodopa, Naxagolide, Pergolide, Piroheptine, Pridinol, Naproxen, NifenaZone, 5'-Nitro-2'propoxyacetanilide, Prodipine, Terguride, Tigloidine and Trihexyphenidyl 50 propoxyacetanilide, Phenacetin, Phenicarbazide, Phenocol, Hydrochloride. Phenopyrazone, PhenylAcetylsalicylate, Phenyl Salicylate, 55. Antipheochromocytoma drugs such as Metyrosine, Pipebu Zone, Prop acetamol, Propyphenazone, Phenoxybenzamine and Phentolamine. Ramifenazone, Salacetamide, Salicylamide O-Acetic Acid, Sodium Salicylate, Sulfamipyrine, Tetrandrine and Tinori 56. Antipneumocystis drugs such as Effornithine, Penta dine. midine and Sulfamethoxazole. 55 57. Antiprostatic hypertrophy drugs such as Gestonorone 65. Antirickettsial drugs such as p-Aminobenzoic Acid, Caproate, Mepartricin, Oxendolone and Proscar(E). Chloramphenicol, Chloramphenicol Palmitate, Chloram 58. Antiprotozoal drugs (Leshmania) such as Antimony phenicol Pantothenate and Tetracycline. Sodium. Gluconate, Ethylstibamine, Hydroxystifbamidine, 66. Antiseborrheic drugs such as Chloroxine, 3-O- N-Methylglucamine, Pentamidine, Stilbamidine and Urea 60 Lauroylpyridoxol Diacetate, Piroctone, Pyrithione, Stibamine. Resorcinol, Selenium Sulfides and Tioxolone. 59. Antiprotozoal drugs (Trichomonas) such as 67. Antiseptics, including: AcetarSone, Aminitrozole, Anisomycin, Azanidazole, Guanidines Such as Alexidine, Ambazone, Chlorhexidine Forminitrazole, Furazolidone, Hachimycin, Lauroguadine, and Picloxydine; Mepartricin, Metronidazole, Nifuratel, Nifuroxime, 65 Halogens and halogen compounds such as Bismuth Nimorazole, Secnidazole, Silver Picrate, Tenonitrozole and Iodide Oxide, Bismuth Iodosubgallate, Bismuth Tinidazole. Tribromophenate, Bornyl Chloride, Calcium Iodate, 5,656.286 25 26 Chlorinated Lime, Cloflucarban, Flurosalan, Iodic Bromide, Codeine N-Oxide, Codeine Phosphate, Codeine Acid, Iodine, Iodine Monochloride, Iodine Trichloride, Sulfate, Cyclexanone, Dextromethorphan, Dibunate Iodoform, Methenamine Tetraiodine, Oxychlorosene, Sodium, Dihydrocodeine, Dihydrocodeinone Enol Acetate, Povidone-Iodine, Sodium Hypochlorite, Sodium Dimemorfan, Dimethoxanate, O.O.-Diphenyl-2- Iodate, Symclosene, Thymol Iodide, Triclocarban, Tri piperidinepropanol, Dropropizine, Drotebanol, Eprazinone, closan and Troclosene Potassium; Ethyl Dibunate, Ethylmorphine, Fominoben, Guiaiapate, Mercurial compounds such as Hydragaphen, Meralein Hydrocodone, Isoaminile, Levopropoxyphene, Morclofone, Sodium, Merbromin, Mercuric Chloride, Mercuric Narceline, Normethadone, Noscapine, Oxeladin, Oxolamine, Chloride, Ammoniated, Mercuric Sodium Pholcodine, Picoperine, Pipazethate, Piperidione, Prenoxdi p-Phenolsulfonate, Mercuric Succinimide, Mercuric 10 azine Hydrochloride, Racemethorphan, Taziprinone Sulfide, Red, Mercurophen, Mercurous Acetate, Mer Hydrochloride, Tipepidine and Zipeprol. curous Chloride, Mercurous Iodide, Nitromersol, 71. Antiulcerative drugs such as Aceglutamide Aluminum Potassium Tetraiodomercurate(II), Potassium Complex, e-Acetamidocaproic Acid Zinc Salt, Acetoxolone, Triiodomercurate(II) Solution, Thimerfonate Sodium Arbaprostil, BenexateHydrochloride, Bismuth Subcitrate and Thimerosal; 15 Sol (Dried), Carbenoxolone, Cetraxate, Cimetidine, Enprostil, Esaprazole, Famotidine, Ftaxilide, Gefarnate, Nitrofurans such as Furazolidone, 2-(Methoxymethyl)-5- Guaiazulene, Irsogladine, Misoprostol, Nizatidine, nitrofuran, Nidroxyzone, Nifuroxime, Nifurzide and Omeprazole, Ornoprostil, Y-Oryzanol, Pifarnine, Nitrofurazone; Pirenzepine, Plaunotol, Ranitidine, Rioprostil, Rosaprostol, Phenols such as Acetomeroctol, Bithionol, Cadmium 20 Rotraxate, Roxatidine Acetate, Sofalicone, Spizofurone, Salicylate, Carvacrol, Chloroxylenol, Clorophene, Sucralfate, Teprenone, Trimoprostil, Thrithiozine, Troxipide Cresote, Cresol(s), p-Cresol, Fenticlorn, and Zolimidine. Hexachlorophene, 1-Napthyl Salicylate, 2-Napthyl 72. Antiurolithic drugs such as Acetohydroxamic Acid, Salicylate, 2,4,6-Tribromo-m-cresol, and 3',4',5- Allopurinol, Potassium Citrate and Succinimide. Trichlorosalicylanilide; 25 73. Antivenin drugs such as Lyovac(8 Antivenin. Quinolines such as Aminoquinuride, BenZoxiquine, 74. Antiviral drugs, including: Broxyquinoline, Chloroxine, Chlorquinaldol, Purines and pyrimidinones such as Acyclovir, Cytarabine, Cloxyquin, Ethylhydrocupreine, Euprocin, Halquinol, Dideoxyadenosine, Dideoxycytidine, Dideoxyinosine, Hydrastine, 8-Hydroxquinoline, 8-Hydroxquinoline Edoxudine, Floxuridine, Ganciclovir, Idoxuridine, Sulfate and Iodochlorhydroxyquin; and 30 Inosine Pranobex, MADU, Trifluridine, Vidrarbine and others such as Aluminum Acetate Solution, Aluminum Zidovudine; and Subacetate Solution, Aluminum Sulfate, 3-Amino-4- others such as Acetylleucine Monoethanolamine, hydroxybutyric Acid, Boric Acid, Chlorhexidine, Amantadine, Amidinomycin, Cuminaldehyde Chloroazodin, m-Cresyl Acetate, Cupric Sulfate, Thiosemicarbzone, Foscarnet Sodium, Interferon-O, Dibromopropamidine, Ichthammol, Negatol(8), 35 Interferon-B, Interferon-Y, Kethoxal, Lysozyme, Noxytiolin, Ornidazole, B-Propiolactone, O-Terpineol. Methisazone, Moroxydine, Podophyllotoxin, 68. Antispasmodic drugs such as Alibendol, Ribavirin, Rimantadine, Stallimycin, Statolon, Tro Ambucetamide, Aminopromazine, Apoatropine, Bevonium mantadine and Xenazoic Acid. Methyl Sulfate, Bietamiverine, Butaverine, Butropium 75. Anxiolytic drugs, including: Bromide, N-Butylscopolammonium Bromide, Caroverine, Arylpiperaz ines such as Buspirone, Gepirone and Ipsa Cimetropium Bromide, Cinnamedrine, Clebopride, Conine Hydrobromide, Coniine Hydrochloride, Cyclonium Iodide, pirone; Difemerine, Diisopromine, Dioxaphetyl Butyrate, Dipo Benzodiazepine derivatives such as Alprazolam, nium Bromide, Drofenine, Emepronium Bromide, Bromazepam, Camazepam, Chlordiazepoxide, Ethaverine, Feclemine, Fenalamide, Fenoverine, 45 Clobazam, Clorazepate, Chotiazepam, Cloxazolam, Fenpiprane, Fenpiverinium Bromide, Fentonium Bromide, Diazepam, Ethyl Loflazepate, Etizolam, Fluidazepam, Flavoxate, Flopropione, Gluconic Acid, Guaiactamine, Flutazolam, Flutoprazepam, Halazepam, Ketazolam, Hydramitrazine. Hymecromone, Leiopyrrole, Mebeverine, Lorazepam, Loxapine, Medazepam, Metaclazepam, Moxaverine, Nafiverine, Octamylamine, Octaverine, Mexazolam, Nordazepam, Oxazepam, Oxazolam, Pentapiperide, Phenamacide Hydrochloride, Phloroglucinol, 50 Pinazepam, Prazepam and Tofisopam; Pinaverium Bromide, Piperilate, Pipoxolanhydrochloride, Carbamates such as Cyclarbamate, Emylcamate, Pramiverin, Prifiinium Bromide, Properidine, Propivane, Hydroxyphenamate, Meprobamate, Phenprobamate Propyromazine, Prozapine, Racefemine, Rociverine, and Tybamate; and Spasmolytol, Stilonium Iodide, Sultroponium, Tiemonium others such as Alpidem, Benzoctamine, Captodiamine, Iodide, Tiquizium Bromide, Tiropramide, Trepibutone, 55 Chlormezanone, Etifoxine, Fluoresone, Glutamic Acid, Tricromyl. Trifolium, Trimebutine, N,N-1Trimethyl-33 Hydroxyzine, Mecloraliurea, Mephenoxalone, diphenyl-propylamine, Tropenzile, Trospium Chloride and Oxanamide, Phenaglycodol, Suriclone. Xenytropium Bromide. 76. Benzodiazepine antagonists such as Flumazenil. 69. Antithrombotic drugs such as Anagrelide, Argatroban, 77. Bronchodilators, including: Cilostazol, Daltroban, Defibrotide, Enoxaparin, Ephedrine derivatives such as Albuterol, Bambuterol, Fraxiparine(s). Indobufen, Lamoparan, OZagrel, Picotamide, Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, Plafibride, Tedelparin, Ticlopidine and Trifusal. Dioxethedrine, Ephedrine, Epiniphrine, Eprozinol, 70. Antitussive drugs such as Allocamide, Amicibone, Etafedrine, Ethylnorepinephrine, Fenoterol, Benproperine, Benzonatate, Bibenzonium Bromide, Hexoprenaline, Isoetharine, Isoproterenol, Mabuterol, Bromoform, Butamirate, Butethamate, Caramiphen 65 Metaproterenol, N-Methylephedrine, Pirbuterol, Ethanedisulfonate, Carbetapentane, Chlophedianol, Procaterol, Protokylol, Reproterol, Rimiterol, Clobutinol, Cloperastine, Codeine, Codeine Methyl Soterenol, Terbutaline and Tulobuterol; 5,656.286 27 28 Quaternary ammonium compounds such as Bevonium Benzphetamine, Brucine, Caffeine, Chlorphentermine, Methyl Sulfate, Clutropium Bromide, pratropium Bro Clofenciclan, Clortermine, Coca, Demanyl Phosphate, mide and Oxitropium Bromide; Dexoxadrol, Dextroamphetamine Sulfate, Diethlpropion, Xanthine derivatives such as Acefylline. Acefylline N-Ethytlamphetamine, Ethamivan, Etifelmin, Etryptamine, Piperazine, Ambu phylline, Aminophylline, Fencamfamine, Fenethylline, Fenosolone, Flurothyl, Bamifylline, choline Theophyllinate, Doxofylline, Hexacyclonate Sodium. Homocamfin, Mazindol, Dyphylline, Enprofylline, Etamiphyllin, Etofylline, Megexamide, Methamphetamine, Methylphenidate, Guaithylline, Proxyphylline, Theobromine, Nikethamide, Pemoline, Pentylenetetrazole, 1-Theobromineacetic Acid and Theophylline; and Phenidimetrazine, Phenmetrazine, Phentermine, Picrotoxin, others such as Fenspiride, Medibazine, Methoxyphe 10 Pipradrol, Prolintane and Pyrovalerone. nanime and Tretoquinol. 89. Decongestants such as Amidephrine, Cafaminol, 78. Calcium channel blockers, including: Cyclopentamine, Ephedrine, Epinephrine, Fenoxazoline, Arylalkylamines such as Bepridil, Ditiazem, Fendiline, Indianazoline, Metizoline, Naphazoline, Nordefrin Gallopanil, Prenylamine, Terodiline and Verapamil; Hydrochloride, Octodrine, Oxymetazoline, Phenylephrine Dihydropyridine derivatives such as Felodipine, 15 Hydrochloride, Phenylpropanolamine Hydrochloride, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Phenylpropylmethylamine, Propylhexe drine, Nimodipine, Nisoldipine and Nitrendipine; Pseudoephedrine, Tetrahydrozoline, Tymazoline and Piperazine derivatives such as Cinnarizine, Flunarisine Xylometazoline. and Lidoflazine; and 90. Dental carries prophylactics such as Sodium Fluoride. others such as Bencyclane, Etafenone and Perhexiline. 91. Depigmentors such as Hydroquinine, Hydroquinone 79. Calcium regulators such as Calcifediol, Calcitonin, and Monobenzone. Calcitriol, Clodronic Acid, Dihydrotachysterol, Elcatonin, 92. Diuretics, including: Etidronic Acid, priflavone, Pamidronic Acid, Parathyroid Organomercurials such as Chlormerodrin, Meralluride, Hormone and Teriparatide Acetate. Mercamphamide, Mercaptomerin Sodium, Mercumal 80. Cardiotonics such as Acefylline, Acetyldigititoxins, 25 lylic Acid, Mercumatilin Sodium, Mercurous Chloride 2-Amino-4-picoline, Amrinone, Benfurodil Hemisuccinate, and Mersalyl; Buclasdesine, Cerberoside, Camphotamide, Convallatoxin, Cymarin, Denopamine, Deslanoside, Ditalin, Digitalis, Pteridines such as Furterene and Triamterene; Digitoxin, , Digoxin, Dobutamine, Dopamine, Dopexamine, Purines such S Acefylline, Enoximone, Erythrophleine, Fenalcomine, Gitalin, Gitoxin, 30 7-Morpholinomethyltheophylline, Pamabrom, Pro Glycocyamine, Heptaminol. Hydrastinine, Ibopamine, theobromine and Theobromine; Lanotodises, Metamivam, Miirinone, Neriifolin, Oleandrin, Steroids such as Canrenone, Oleandrin and Spironolac Ouabain, Oxyfedrine, Prenalterol, Proscillaridin, tOne. Resibufogenin, Scillaren, Scillarenin, Strophanthin, Sulfonamide derivatives such as Acetazolmide, Sulmazole, Theobromine and Xamoterol. 35 Ambuside, AZosemide, Bumetamide, Butazolamide, 81. Chelating agents such as Deferozmine, Ditiocarb Chloraminophenamide, Clofenamide, Clopamide, Sodium, Edetate Calcium Disodium, Edetate Disodium, Clorexolene, Diphenylmethane-4.4'-disulfonamide, Edeate Sodium, Edetate Trisodium, Penicillamine, Pentetate Disulfamide, EthoXzolamide, Furosemide, Calcium Trisodium, Pentectic Acid, Succimer and Trientine; Indapamide, Mefruside, Methazolamide, Piretanide, 82. Cholecystokinin antagonists such as Proglumide. 40 Quinethazone, Torasemide, Tripamide and Xipamide; 83. Cholelitholytic agents such as Chenodiol, Methyl Uracils such as Aminometradine and Amisometradine; tert-Butyl Ether. Monooctanoin and Ursodiol others such as Amanozine, Amiloride, Arbutin, 84. Choleretics such as Alibendol, Anethole Trithion, Chlorazanil, Ethacrynic Acid, Etozolin, AZintamide, Cholic Acid, Cicrotoic Acid, Clanobutin, Hydracarbazine, Isosorbide, Mannitol, Metochalcone, Cyclobutyrol, Cyclovalone, Cynarin(e), Dehydrocholic 45 Muzolimine, Perhexiline, Ticrynafen and Urea. Acid, Deoxycholic Acid, Dimecrotic Acid, O.-Ethylbenzyl 93. Dopamine receptor agonists such as Bromocriptine, Alcohol, Exiproben, Feguprol, Fencibutirol, Fenipentol, Dopexamine, Fenoldopam, Ibopamine, Lisuride, Nax Florantyrone, Hymecromone, Menbutone, 3-(o- agolide and Pergolide. Methoxyphenyl)-2-phenylacrylic Acid, Metochalcone, 94. Ectoparasiticides such as Amitraz, Benzyl Benzoate, Moquizone, Osalmid, Ox Bile Extract, 4.4'-Oxydi-2- 50 Carbaryl, Crotamiton, DDT, Dixanthogen, isobornyl butanol, Piprozolin, Prozapine, 4-Salicyloylmorpholine, Thiocyanoacetate-Technical, Lime Sulfurated Solution, Sincalide, Taurocholic Acid, Timonacic, Tocamphyl, LIndane, Malathion, Mercuric Oleate, Mesulphen and Trepibutone and Vanitioide. Sulphur-Pharmaceutical. 85. Cholinergic agents such as Aceclidine, Acetylcholine 95. Enzymes, including: Bromide, Acetylcholide Chloride, Aclatonium Napadisilate, 55 Digestive enzymes such as C.-Amylase (Swine Pancreas), Benzpyrinium Bromide, Bethanechol chloride, Carbachol, Lipase, Pancrelipase, Pepsin and Rennin; Carpronium chloride, Demecarium Bromide, Dexpanthenol, Diisopropyl Paraoxon, Echothiophate Iodide, Edrophomium Mucolytic enzymes such as Lysozyme; chloride, Eseridine. Furtrethonium, Isoflurophate, Metha Penicillin inactivating enzymes such as Penicillinase; and choline chloride, Muscarine. Neostigmine, Oxapropanium 60 Proteolytic enzymes such as Collagenase, Chymopapain, Iodide, Physostigmine and Pyridostigmine Bromide. Chymotrypsins, Papain and Trypsin. 86. Cholinesterase inhibitors such as Ambenonium 96. Enzyme inducers (hepatic) such as Flumecinol. Chloride, Distigmine Bromide and Galanthamine. 97. Estrogens, including: 87. Cholinesterase reactivators such as Obidoximine Nonsteroidal estrogens such as Benzestrol, Broparoestrol, Chloride and Pralidoxime Chloride. 65 Chlorotrianisene, Dienestrol, Diethylstilbestrol, Dieth 88. Central nervous system stimulants and agents such as ylstilbestrol Diproprionate, Dimestrol. Fosfestrol, Amineptine, Amphetimine, Amphetaminil, Bemegride, Hexestrol, Methallenestri and Methestrol; and 5,656,286 29 30 Steroidal estrogens such as Colpormon, Conjugated 115. Mineralcorticoids such as Aldosterone, Estrogenic Hormones, Equilenin, Equilin, Estradiol, Deoxycorticosterone, Deoxycorticosterone Acetate and Estradiol Benzoate, Estradiol 17B-Cypionate, Estriol, Fludrocortisone. Estrone, Ethinyl Estradiol, Mestranol, Moxestrol, 116. Miotic drugs such as Carbachol, Physostigmine, Mytatrienediol, Quinestradiol and Quinestrol. Pilocarpine and Pilocarpus. 98. Gastric secretion inhibitors such as Enterogastrone 117. Monoamine oxidase inhibitors such as Deprenyl, and Octreotide. proclozide, Iproniazid, Isocarboxazid, Moclobemide, 99. Glucocorticoids such as 21-Acetoxyprefnenolone, Octomoxin, Pargyline, Phenelzine, Phenoxypropazine, Aalclometasone, Algestone, Amicinomide, Beclomethasone, Pivalylbenzhydrazine, Prodipine, Toloxatone and Tranyl Betamethasone, Budesonide, Chloroprednisone, Clobetasol, cypromine. Blovetasone, Clocortolone, Cloprednol, Corticosterone, 10 118. Mucolytic agents such as Acetylcysteine, Cortisone, Cortivazol, Deflazacort, De Sonide, Bromhexine, Carbocysteine, Domiodol, Letosteine, Desoximetas one, Dexamethas one, Difloras one, Lysozyme, Mecysteine Hydrochloride, Mesna, Sobrerol, Difiucortolone, Difluprednate, Enoxolone, Fluazacort, Stepronin, Tiopronin and Tyloxapol. Flucoronide, Flumehtasone, Flunisolide, Fluocinolone 119. Muscle relaxants (skeletal) such as Afloqualone, Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone, 15 Alcuronium, Atracurium Besylate, Baclofen, BenZoctamine, Fluorometholone, Fluperolone Acetate, Fluprednidene Benzoquinonium Chloride, C-Calebassine, Carisoprodol, Acetate, Fluprednisolone, Flurandrenolide, Formocortal, Chlorime Zanone, Chlorphene Sin Carb amate, Halcinonide, Halometas one, Hallopredone Acetate, Chlorproethazine, Chlozoxaz one, Curare, Cyclarbamate, Hydrocortamate, Hydrocortisone, Hydrocortisone Acetate, Cyclobenzaprine, Dantrolene, Decamethonium Bromide, ydrocortisone Phosphate, Hydrocortisone 21-Sodium 20 Diazepam, Eperisone, Fazadinium Bromide, Flumetramide, Succinate, Hydrocortisone Tebutate, Mazipredone, Gallamine Triethiodide, Hexacarbacholine Bromide, Medrysone, Meprednisone, Methyolprednisolone, Mometa Hexafluorenium Bromide, Idrocilamide, Lauexium Methyl sone Furoate, Paramethasone, Prednicarbate, Prednisolone, Sulfate, Leptodactyline, Memantine, Mephenes in, Prednisolone 21-Diethylaminoacetate, Prednisone Sodium Mephenoxalone, Metaxalone, Methocarbamol, Metocurine Phosphate, Prednisolone Sodium. Succinate, Prednisolone 25 Iodide, Nimetazepam, Orphenadrine, Pancuronium Sodium 21-m-Sulfobenzoate, Prednisolone Bromide, Phenprobamate, Phenyramidol, Pipecurium 21-Stearoylglycolate, Prednisolone Tebutate, Prednisolone Bromide, Promoxolane, Quinine Sulfate, Styramate, Succi 21-Trimethylacetate, Prednisone, Prednival, Prednylidene, nylcholine Bromide, Succinylcholine Chloride, Succinyl Prednylidene 21-Diethylaminoacetate, Tixocortal, choline Iodine, Suxethonium Bromide, Tetrazepam, Triamcinolone, Triamcinolone Acetonide, Triamcinolone 30 Thiocolchicoside, Tizanidine, Tolperisone, Tubocurarine Benetonide and Triamcinolone Hexacetonide. Chloride, Vecuronium Bromide and Zoxolamine. 100. Gonad-Stimulating principles such as Buserelin, 120. Narcotic antagonists such as Amiphenazole, Clomiphene, Cyclofenil, Epimestrol, FSH, HCG and Cyclazocine, Levallorphan, Nadide, Nalmfene, Nalorphine, LH-RH. Nalorphine Dinicotinate, Naloxone and Naltrexone. 101. Gonadotropic hormones such as LH and PMSG. 35 121. Neuroprotective agents such as Dizocilpine. 102. Growth hormone inhibitors such as Octreotide and 122. Nootropic agents such as Aceglutamide, Somatostatin. Acetylcarnitine, Aniracetam, Bifematiane, Exifone, 103. Growth hormone releasing factors such as Semore Fipexide, Idebenone, Indeloxazune Hydrochloride, lin. Nizofenone, Oxiracetam, Piracetam, Propentofylline, Pyriti 104. Growth stimulants such as Somatotropin. 40 nol and Tacrine. 105. Hemolytic agents such as Phenylhydrazine and Phe 123. Ophthalmic agents such as 15-ketoprostaglandins. nylhydrazine Hydrochloride. 124. Ovarian hormone such as relaxin. 106. Heparin antagonists such as Hexadimethrine Bro 125. Oxytocic drugs such as Carboprost, Cargutocin, mide and Protamines. Deamino oxytocin, Ergono vine, Geme prost, 107. Hepatoprotectants such as S-Adenosylmethionine, 45 Methylergonovine, Oxytocin, Pituitary (Posterior), Prostag Betaine, Catechin, Citolone, Malotilate, Orazamide, landin E, Prostaglandin F and Sparteine. Phosphorylcholine, Protoporphyrin DX, Silymarin-Group, 126. Pepsin inhibitors such as Sodium Amylosulfate. Thiotic Acid and Tiopronin. 127. Peristaltic stimulants such as Cisapride. 108. Immunomodulators such as Amiprilose, 128. Progestogens such as Allylestrenol, Anagestone, Bucillamine, Ditiocarb Sodium, Inosine Pranobex, 50 Chlormadinone Acetate, Delma dinone Acetate, Interferon-y, Interleukin-2, Lentinan, Muroctasin, Platonin, Demege stone, Desoge strel, Dime this terone, Procodazole, Tetramisole, Thymomodulin, Thymopentin Dydrogesterone, Ethisterone, Ethynodiol, Flurogestone and Ubenimex. Acetate, Gestodene, Geston.orone Caproate, 109. Immunosuppressants such as Azathioprine, Haloprogesterone, 17-Hydroxy-16-methylene Cyclosporins and Mizoribine. 55 progesterone, 17 O.-Hydroxyprogesterone, 17 O.- 110. Ion exchange resins such as Carbacrylic Resins, Hydroxygesterone Caproate, Lynestrenol, Medrogestone, Cholestyramine Resin, Colestipol, Polidexide, Resodec and Medroxyprogesterone, Megestrol Acetate, Melengestrol, Sodium Polystyrene Sulfonate. Norethindrone, Norethynodrel, Norgesterone, Norgestimate, 111. Lactation stimulating hormone such as Prolactin. Norgestrel, Norgestrienone, Norvinisterone, Pentagestrone, 112. LH-RH agonists such as Buserelin, Goserelin, Progesterone, Promegestone, Quingestrone and Trenge Leuprolide, Nafarelin, and Triptorelin. StOne. 113. Lipotropic agents such as N-Acetylmethionine, Cho 129. Prolactin inhibitors such as Metergoline. line Chloride, Choline Dehydrocholate, Choline Dihydrogen 130. Prostaglandins and prostaglandin analogs such as Citrate, Inositol, Lecithin and Methionine. Arbaprostil, Carboprost, Enprostil, Bemeprost, Limaprost, 114. Lupus erythematosus suppressants such as Bismuth 65 Misoprostol, Ornoprostil, Prostacyclin, Prostaglandin E, Sodium Triglycollamate, Bismuth Subsalicylate, Chloro Prostaglandin E, Prostagland in F2, Rioprostil, quine and Hydroxychloroquine. Rosaprostol, Sulprostone and Trimoprostil. 5,656,286 31 32 131. Protease inhibitors such as Aprotinin, Camostat, 135. Thrombolytic agents such as APSAC, Plasmin, Pro Gabexate and Nafamostat. Urokinase, Streptokinase, Tissue Plasminogen Activator and 132. Respiratory stimulants such as Almitrine, Urokinase; Bemegride, Carbon Dioxide, Cropropamide, Crotethamide, 136. Thyrotropic hormones such as TRH and TSH. Dimefline, Dimorpholamine, Doxapram, Ethamivan, 137. UricoSurics such as Benzbromarone, Ethelbenecid, Fominoben, Lobeline, Mepixanox. Metamivam, Orotic Acid, Oxycinchophen, Probenecid, Sulfinpyrazone, Ticrynafen and Zoxazolamine. Nikethamide, Picrotoxin, Pimeclone, Pyridofylline, Sodium 138. Vasodilators (cerebral) such as Bencyclane, Succinate and Tacrine. Cinnarizine, Citicoline. Cyclandelate, Ciclonicate, Diiso 133. Sclerosing agents such as Ethanolamine, propylamine Dichloractetate, Eburnamonine, Fenoxedil, Ethylamine, 2-Hexyldecanoic Acid, Polidocanol, Quinine 10 Flunarizine, Ibudilast, Ifenprodil, Nafronyl, Nicametate, Bisulfate, Quinine Urea Hydrochloride, Sodium Nicergoline, Nimodipine, Papaverine, Pentifylline, Ricinoleate, Sodium Tetradecyl Sulfate and Tribenoside. Tinofedrine, Vincamine, Vinpocetine and Viquidil. 134. Sedatives and hypnotics, including: 139. Vasodilators (coronary) such as Amotriphene, Acyclic ureides such as Acecarbromal, Apronalide, Bendazol, Benfurodil Hemisuccinate, BenZiodarone, Bomisovalum, Capuride, Carbromal and Ectylurea; 15 Chloacizine, Chromonar, Cobenfurol, Clonitrate, Dilazep, Alcohols such as Chlorhexadol, Ethchlorvynol, Dipyridamole, Droprenilamine, Efloxate, Erythritol, Eryth Mepartynol, 4-Methyl-5-thiazoleethanol, tert-Pentyl rityl Tetranitrate, Etafenone, Fendiline, Floredil, Alcohol and 2.2.2-Trichloroethanol; Ganglefene, Hexestrol Bis(B-diethylaminoethyl ether), Hexobendine, tramin Tosylate, Khellin, Lidoflazine, Man Amides such as Butoctamide, Diethylbronoacetamide, nitol Hexanitrate, Medibazine, Nicorandil, Nitroglycerin, Ibrotamide, Isovaleryl Diethylamide, Niaprazine, Pentaerythritol Tetranitrate, Pentrinitrol, Perhexiline, Tricetamide, Trimetozine, Zolpidem and Zopiclone; Pimefylline, Prenylamine, Propatyl Nitrate, Pyridofylline, Barbituric acid derivatives such as Allobarbital, Trapidil, Tricromyl, Trimetazidine, Trolnitrate Phosphate Amobarbital, Aprobarbital, Barbital, Brallabarbital, and Visnadine. Butabarbital Sodium, Butalbital, Butallylonal, 25 140. Vasodiliators (peripheral) such as Aluminum But ethal, Carbubarb, Cyclobarbital, Nicotinate, Bamethan, Bencyclane, Betahistine, Bradykinin, Cyclopentobarbital, Enallylpropymal, 5-Ethyl-5-(1- Brovincamine, Bufoniode, Buflomedil, Butalamine, piperidyl) barbituric Acid, 5-Furfuryl-5- Cetiedil, Ciconicate, Cinepazide, Cinnarizine, isopropylbarbituric Acid, Heptabarbital, Hexethal Cyclandelate, Diisopropylamine Dichloracetate, Eledoisin, Sodium, Hexobarbital, Mephobarbital, Methitural, 30 Fenoxidil, Flunarisine, Heronicate, Ifenprodil, Inositol Narcobarbital, Nealbarbital, Pentobarbital Sodium, Niacinate, IsoxSuprine, Kallidin, Kallikrein, Moxisylyte, Phenallymal, Phenobarbital, Phenobarbital Sodium, Nafronyl, Nicametate, Nicergoline, Nicofuranose, Nicotinyl Phenylmethylbarbituric Acid, Probarbital, Alcohol, Nylidrin, Pentifylline, Pentoxifylline, Piribedil, Propallylonal, Proxibarbal, Reposal, Secobarbital Protaglandin E, Suloctidil and Xanthinal Niacinate. Sodium, Talbutal, Tetrabarbital, Vinbarbital Sodium 35 141. Vasoprotectants such as Benzarone. Bioflavonoids, and Vinylbital; Chromocarb, Clobeoside, Diosmin, Dobesilate Calcium, Benzodiazepine derivatives such as Brotizolam, Escin, Rolescutol, Leucocyanidin, Metescufylline, Doxefazepam. Estazolam, Flumitrazepam, Flurazepam, Quercetin, Rutin and Troxerutin. Haloxazolam, Loprazolam, Lorimetazepam, 142. Vitamins, vitamin sources, and vitamin extracts such Nitrazepam, Quazepam, Temasepam and Triazolam; 40 as Vitamins A, B, C, D, E, and K and derivatives thereof, Bromides such as Ammonium Bromide, Calcium Calciferols, Glycyrrhiza and Mecobalamin. Bromide, Calcium Bromolactobionate, Lithium 143. Vulnerary agents such as Acetylcysteine, Allantoin, Bromide, Magnesium Bromide, Potassium Bromide Asiaticoside, Cadexomer Iodine, Chitin, Dextranomer and and Sodium Bromide: Oxaceprol. Carbamates such as Amyl Carbamate-Tertiary, 45 The drugs can be present in the composition in different Ethinamate, Hexaprpymate, Meparfynol Carbamate, forms, depending on which form yields the optimum deliv Novonal and Tricholorourethan; ery characteristics. Thus, in the case of drugs, the drug can be in its free base or acid form, or in the form of salts, esters, Chloral derivatives such as Carbocloral, Chloral Betaine, or any other pharmacologically acceptable derivatives, or as Chloral Formamide, Chloral Hydrate, 50 components of molecular complexes. Chloralantipyrine, Dichloralphenazone, Pentaerythritol The amount of drug to be incorporated in the composition Chloral and Triclofos; varies depending on the particular drug, the desired thera Piperidinediones such as Glutehimide, Methyprylon, peutic effect, and the time span for which the device is to Piperidione, Pyrithyldione, Taglutimide and Thalido provide therapy. For most drugs, the passage of the drugs mide; 55 through the skin will be the rate-limiting step in delivery. Quinazolone derivatives such as Etaqualone, Mecloqua Thus, the amount of drug and the rate of release is typically lone and Methaqualone; and adjusted so as to provide transdermal delivery characterized others such as Acetal, Acetophenone, Aldol, Ammonium by a zero order time dependency for a prolonged period of Valerate. Amphenidone, d-Bornyl O-Bromoisovalerate, time. The minimum amount of drug in the system is selected d-Bornyl Isovalerate, Bromoform, Calcium 60 based on the amount of drug which passes through the skin 2-Ethylbutanoate, Carfinate, O.-Chlorolose, in the time span for which the device is to provide therapy. Clomethiazole, Cypripedium, Doxylamine, Normally, the amount of drug in the system can vary from Etodroxizine, Etomidate, Fenadiazole, Homofenazine, about 0.1% to about 50% by weight, and preferably, for the Hydrobromic Acid, Mecloxamine, Menthyl Valerate, lower drug doses permitted by this invention, from about Opium, Paraldehyde, Perlapine. Propiomazine, 65 0.3% to about 30%. Rilmazafone, Sodium. Oxybate, Sulfonethylmethane Of course, the composition of the transdermal drug deliv and Sulfonmethane. ery system can also contain agents known to accelerate the 5,656,286 33 34 delivery of the drug through the skin. These agents have To summarize, the preferred and optimum compositions been referred to as skin-penetration enhancers, accelerants, for the polyacrylate and polysiloxane embodiments are as adjuvants, and sorption promoters, and are collectively follows: referred to herein as "enhancers.” This class of agents includes those with diverse mechanisms of action including TABLE I those which have the function of improving the solubility PERCENT BY WEIGHT and diffusibility of the drug within the multiple polymer and those which improve percutaneous absorption, for example, Component Preferred Range Optimum Range by changing the ability of the stratum corneumto retain First 97-9 94-14 moisture, softening the skin, improving the skin's 10 Polymer Second 0-95 5-85 permeability, acting as penetration assistants or hair-follicle Polymer openers or changing the state of the skin including the Polyvinyl- 1-20 5-15 boundary layer. Some of these agents have more than one pyrrolidone Co-solvent(s) 0-30 0-20 mechanism of action, but in essence they serve to enhance 15 Enhancer(s) 0-20 0-15 the delivery of the drug. Drug(s) 0.1-50 0.3-30 Some examples of enhancers are polyhydric alcohols such as dipropylene glycol, propylene glycol, and polyethylene The compositions of this invention may further be pro glycol which enhance drug solubility; oils such as olive oil, vided with various thickeners, fillers and other additives squalene, and lanolin; fatty ethers such as cetyl ether and known for use with transdermal drug delivery systems. oleyl ether; fatty acid esters such as isopropyl myristate Where the composition tends to absorb water, for example, which enhance drug diffusibility; urea and urea derivatives when lecithin is used as a co-solvent, hydrophilic substances such as allantoin which affect the ability of keratin to retain are especially useful. One type of hydrophilic substance moisture; polar solvents such as dimethyldecylphosphoxide, which has been successfully employed is clay. The addition methyloctylsulfoxide, dimethyllaurylamide, 25 of clay has been found to improve adhesiveness in trans dodecylpyrrollidone, isosorbitol, dimethylacetonide, dermal formulations without reducing the rate of drug dimethylsulfoxide, decylmethylsulfoxide, and dimethylfor delivery. Suitable clays include aluminum silicate clay, mamide which affect keratin permeability; salicylic acid kaolinite, montmorillonite, atapulgite, illite, bentonite, hal which softens the keratin; amino acids which are penetration loysite and the like. assistants; benzyl nicotinate which is a hair follicle opener; In a device aspect of the invention, the pressure-sensitive and higher molecular weight aliphatic surfactants such as adhesive composition can be used as an adhesive portion of laurylsulfate salts which change the surface state of the skin any transdermal drug delivery system (e.g., a reservoir and drugs administered. Other agents include oleic and device) or it can comprise an adhesive monolithic device. Of linoleic acids, ascorbic acid, panthenol, butylated course, the principles of the invention would still apply to hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl 35 embodiments where the dermal composition is not a linoleate, propyl oleate, and isopropyl palmitate. pressure-sensitive adhesive and comprises the drug reser In certain embodiments of the invention a plasticizer or WO. tackifying agent is incorporated into the formulation to Reference to FIG. 1 shows a schematic illustration of an improve the adhesive characteristics of the pressure adhesive monolithic device embodiment of the invention 10. sensitive adhesive composition. A tackifying agent is par The transdermal drug delivery system comprises a mono ticularly useful in those embodiments in which the drug does lithic body 11 of a defined geometric shape with a protective not plasticize the polymer. Suitable tackifying agents are release liner 12 on one side of monolithic body 11 and a those known in the art including: (1) aliphatic hydrocarbons; backing layer 13 on the other side. Removal of the release (2) mixed aliphatic and aromatic hydrocarbons; (3) aromatic liner 12 exposes the pressure-sensitive multiple polymer hydrocarbons; (4) substituted aromatic hydrocarbons; (5) 45 adhesive composition which functions both as the drug hydrogenated esters; (6) polyterpenes; and (7) hydrogenated carrier matrix and as the means of applying the system to the wood rosins. The tackifying agent employed is preferably patient. compatible with the blend of polymers. In preferred A device, or individual dosage unit, of the present inven embodiments, the tackifying agentis silicone fluid (e.g., 360 tion can be produced in any manner known to those of skill Medical Fluid, available from Dow Corning Corporation, 50 in the art. After the dermal composition is formed, it may be Midland, Mich.) or mineral oil. Silicone fluid is useful for brought into contact with the backing layer in any manner blends comprising polysiloxane as a major component. In known to those of skill in the art. Such techniques include other embodiments, where a synthetic rubber, for example, calender coating, hot melt coating, solution coating, etc. Of is a major component, mineral oil is a preferred tackifying course, backing materials are well known in the art and can agent. 55 comprise plastic films of polyethylene, vinyl acetate resins, Some drugs, such as the vasodilator nitroglycerin, func ethylene/vinyl acetate copolymers, polyvinyl chloride, tion as plasticizers in the composition because they are polyurethane, and the like, metal foils, non-woven fabric, soluble to a certain degree in the polymers comprising the cloth and commercially available laminates. The backing system. For drug molecules which are not readily soluble in material generally has a thickness in the range of 2 to 1000 the polymer system, a co-solvent for the drug and polymer micrometers and the dermal composition is generally dis can be added. Co-solvents, such as lecithin, retinol posed on backing mararial in a thickness ranging from about derivatives, tocopherol, dipropylene glycol, triacetin, pro 12 to 250 micrometers thick. pylene glycol, saturated and unsaturated fatty acids, mineral Suitable release liners are also well known in the art and oil, silicone fluid, alcohols, butylbenzyl phthalate, and the include the commercially available products of Dow Corn like are useful in the practice of the instant invention 65 ing Corporation designated Bio-Release(8) liner and Syl depending on the solubility of the drug in the multiple off& 7610 liner. For preferred embodiments in which a polymer adhesive system. polysiloxane is part of the multiple polymeric adhesive 5,656,286 35 36 System, the release liner must be compatible with the sili 6. Appropriate size and shape “systems” are die-cut from cone adhesive. An example of a suitable commercially the roll material and then pouched. available liner is 3M's 1022 Scotch Pak. The order of steps, the amount of the ingredients, and the The configuration of the transdermal delivery system of amount and time of agitation or mixing may be importance the present invention can be in any shape or size as is process variables which will depend on the specific necessary or desirable. Illustratively, a single dosage unit polymers, drug, co-solvents, and enhancers used in the may have a surface area in the range of 1 to 200 cm. formulation. These factors can be adjusted by those skilled Preferred sizes are from 5 to 60 cm. in the art, while keeping in mind the object of providing a In a method aspect of the invention, a plurality of poly uniform product. It is believed that a number of other mers having differing solubility parameters are blended (but methods, including changing some of the order of steps, can not chemically reacted or cross-linked) with soluble PVP to 10 be carried out and will give desirable results. In addition to result in a pressure-sensitive adhesive composition, or trans having various shapes, the dosage units produces may come dermal drug delivery system adhesive system (with incor in various sizes. A Surface area in the range of 1 to 200 porated drug), which controls delivery of an incorporated square centimeters is contemplated, and the presently pre drug into and through the epidermis. The blending of ferred sizes are: 5, 10, 15, 20, 30, 30 and 60 square polymers results in an adjustment of the saturation concen 15 centimeters. tration of the drug in the polymeric system and therefore Said PVP preferably has a molecular weight of about permits selective modulation of the transdermal drug deliv 2,000 to 1,100,000, more preferably 5,000 to 100,000, and ery rate. The term “blending” of course, incorporates choos most preferably 7,000 to 54,000. ing the appropriate polymeric components, and the propor Preferred embodiments comprise a soluble PVP with a tions thereof, to achieve the desired effect. rubber-based pressure-sensitive adhesive and a polyacrylate In a preferred embodiment of the invention, a transdermal polymer. Particularly preferred blends include blends of a drug delivery system is prepared by mixing a soluble PVP, polyacrylate, a polysiloxane and a soluble PVP. polyacrylate, polysiloxane, drug, co-solvent(s), and tackify Solution PVP has been found to be highly effective in ing agent, if needed, in an appropriate volatile solvent(s), preventing crystallization of drugs, in adhesive-type trans then casting the mixture and removing the solvent(s) by 25 dermal drug delivery systems according to the invention. In evaporation to form a film. particular, soluble PVP has proved useful in maintaining a norethindrone acetate (NETA) system and an NETA/ Suitable volatile solvents include, but are not limited to, estradiol system substantially crystal-free. Other specific alcohols such as isopropanol and ethanol; aromatics such as drugs for which soluble PVP is particularly usefully Xylenes and toluene; aliphatics such as hexane, cyclohexane, employed according to the invention include albuterol, and heptane; and alkanoic acid esters such as ethyl acetate 30 estradiol, haloperidol and alprazolam. and butyl acetate. The amount and type of soluble PVP required in the An exemplary general method for the preparation of an foregoing preferred embodiment will depend on the quantity embodiment that contains a soluble PVP is as follows: and type of drug present in the adhesive, as well as the type 1. Appropriate amounts of soluble PVP, solvent(s), of adhesive, but can be readily determined through routine enhancer(s), and organic solvent(s) (for example toluene) 35 experimentation. Typically, the PVP is present in an amount are combined and thoroughly mixed together in a vessel. from about 1% to about 20% by weight, preferably from 2. The drug is then added to the mixture and agitation is about 5% to about 15% by weight. However, the amount of carried out until the drug is uniformly mixed in. PVP can be higher than 20% for example, up to 40%, 3. Appropriate amounts of polysiloxane with or without depending on the particular drug used and on the desired polyacrylate are then added to the drug mixture, and thor 40 properties of the blend. Oughly mixed. For example, when the drug is norethindrone acetate 4. The formulation is then transferred to a coating opera (NETA), an optimum concentration of about 10% by weight tion where it is coated onto a protective release liner at a PVP has been found to inhibit NETA crystal formation controlled specified thickness. The coated product is then without adversely affecting NETA flux from a multiple passed through an oven in order to drive off all volatile 45 polymer adhesive system (polyacrylate/polysiloxane). processing solvents. When the drug is estradiol, the inclusion of 5-10% of 5. The dried product on the release liner is then joined to soluble PVP in the formulation not only increases the the backing material and wound into rolls for storage. estradiol flux, but increases the total amount of estradiol 6. Appropriate size and shape “systems” are die-cut from through the skin. When the drug is albuterol, an optimum the roll material and then pouched. 50 concentration has been found to be about 5% by weight. An exemplary general method for the preparation of an Large amounts of soluble PVPcan cause a decrease in the embodiment that does not contain a soluble PVP is as flux of drug. For example, when the PVP is present in follows: amounts exceeding about 20% by weight, NETAflux begins 1. Appropriate amounts of polysiloxane and polyacrylate, to decrease. dissolved in a solvent(s), are combined and thoroughly 55 The PVP employed according to the invention is dis mixed together in a vessel. solved together with one or more of the additional polymeric 2. The drug is then added to the polymer mixture and materials of the inventive blend, agitation is carried out until the drug is uniformly mixed in. The type and quantity of soluble PVP also can have 3. Co-solvents and enhancers, if necessary, can then be significant effects on the adhesive properties of the finished added to the drug-polymer mixture, and thoroughly mixed. 60 product. In adhesives with higher shear properties, it is 4. The formulation is then transferred to a coating opera advantageous to include a lower molecular weight soluble tion where it is coated onto a protective release liner at a PVP, whereas in low shear adhesives, the higher molecular controlled specified thickness. The coated product is then weight soluble PVP's are preferred. passed throughan oven in order to drive off all volatile processing Solvents. 65 EXAMPLES 5. The dried product on the release liner is then joined to The following specific examples are included as illustra the backing material and wound into rolls for storage. tive of pressure-sensitive adhesive compositions and trans 5,656.286 37 38 dermal drug delivery systems, and methods of making same, Example 1 within the contemplation of the invention. These examples are in no way intended to be limiting of the scope of the A nitroglycerin-polymer mixture was prepared by com invention. bining 22.0 parts of nitroglycerin, 1.0 part of dipropylene The following commercially available adhesives were glycol, 1.3 parts of lecithin, 0.8 parts of propylene glycol, used in the blends comprising the multiple polymer adhesive 2.5 parts of 360 Medial Fluid (1000 cs), 1.0 part of system of the examples: bentonite, 63.6 parts of polyacrylate as ethanol, toluene, and “Duro-Tak 80-1194, 80-1196, 80-1054, 80-1074, propylene glycol from ICI (Duro-Tak 80-1194), and 85.6 80-1058, 80-2434, 80-1070, 80-6172, and 80-1197" are parts of polysiloxane (BIO-PSAX7-4919), and mixed well trademarks of National Starch and Chemical Corporation, 10 in an appropriate container. Nitroglycerin is available as a Bridgewater, N.J. for acrylic adhesives (polyacrylates) in solution in solvents such as ethanol, toluene, and propylene organic solutions. glycol from ICI Americas Inc., Wilmington, Del. In this “BIO-PSA X7-3027, X7-4919, X7-2685, X7-3122, instance, the nitroglycerin was added as a solution intoluene X7-4603, X7-4301, X7-4301, X7-4303 and X7-4503" are mixed together with the polyacrylate. The resulting compo trademarks of Dow Corning Corporation, Medical Products, 15 sition had the ingredient concentrations on a "dry"basis, that Midland, Mich. for silicone adhesives (polysiloxanes) in is, after removal of volatile process solvents, shown below. organic solutions. BIO-PSA-3027 is particularly suitable for use in formulations containing aminefunctional drugs, such COMPONENT as albuterol and pilocarpine, in the following examples. WEIGHT PERCENT BY "Gelva-Multipolymer Solution (GMS) 737, 788, and 20 2480” are trademarks of Monsanto Company, St. Louis, Polysiloxane 42.8 (Dow Corning Silicone Adhesive BIO-PSAX7-4919) Mo., for an acrylic adhesive in organic solution. Polyacrylate 28.6 "VistanexLM-LS-LC' is a trademark of Exxon Chemical (National Starch Acrylic Adhesive, Company, Houston, Tex., for a polyisobutylene polymer Duro-Tak 80-1194) Polydimethylsiloxane fluid 2.5 with a Flory molecular weight of 42,600 to 46,100. 25 (Dow Corning 360 Medical Fluid) "Elvax 40-W" is a trademark of Du Pont Company, Lecithin 1.3 Wilmington, Del., for a polyethylene/vinyl acetate copoly Propylene glycol 0.8 Dipropylene glycol 10 mer (40% vinyl acetate content). Bentonite 1.0 Kraton D 1101, Kraton D 1107 and Kraton G 1657 are Nitroglycerin 22.0 trademarks of the Shell Chemical Company, Houston,Tex., 30 for styrene-butadiene-styrene (S-B-S), styrene-isoprene 1000 styrene (S-I-S) and styrene-ethylene/butylene-styrene (S-EB-S), respectively, block copolymer rubbers Nitroglycerin flux results through cadaver skin in vitro Nitroglycerin is available as a solution in a solvent such from the formulation of Example 1, Transderm-Nitro(8) (a as ethanol, toluene, and propylene glycol from ICI 35 trademark of Ciba-Geigy Corporation, Summit, N.J.), and Americas, Inc., Wilmington, Del. Nitro-Dur?8) (a trademark of Key Pharmaceuticals, Inc., The aforementioned polymeric adhesives are supplied, or Kenilworth, N.J.) are summarized in FIG. 2. As shown in prepared, as solutions wherein the percent solids by weight FIG. 2, nitroglycerin flux from the dermal composition of are as follows: Example 1 (20.8 g/cmhr) was approximately twice that 40 from Transderm-Nitro® (9.5 pg/cmhr) and about 1.5 times Ingredient Percent Solids that from Nitro-Dur(8) (13.4 pg/cmhr). BIO-PSAX7-3027 50 Examples 2-5 BIO-PSAX7-3122 65 BIO-PSAX7.4301. 60 45 In the following examples (2-5), the method of Example BIO-PSAX74303 60 1 was used with the appropriate amounts of starting mate BIO-PSAX7-4503 60 BIO-PSAX7-4603 60 rials to yield compositions having the following ingredient BIO-PSAX7-4919 50 concentrations set forth in tabular form in TABLE III. BIO-PSAX7-2685 50 Example 2 is presented for comparative purposes and its Duro-Tak 80-1194 45 50 formulation is not within the scope of the present invention. Duro-Tak 80-196 45 Duro-Tak 80-1197 45 Example 3 and 5 are adhesive compositions comprising Evax 40-W 30 blends of polyacrylate and a second poller selected to GMS 737 32 illustrate the principles of the invention. All other Kraton D 1101 30 components, such as excipients or fillers, remain constantin Kraton D 1107 30 55 Kraton G 1657 composition and amount from Examples 2 to 5. Vistanex LM-MS-LC 30 TABLE II "360 Medical Fluid” is a trademark of Dow Corning Ingredient Corporation for a polydimethylsiloxane fluid. In certain (SP, J/cm3/2 Ex. 2 Ex. 3 Ex. 4 Ex. 5 embodiments of the invention, 360 Medical Fluid is added Polyacrylate (21) 73.2 33.1 33.1 33. as a tackifier to improve the adhesive characteristics of the Ethylene/vinyl acetate - 40.1 - m end product. (21) Polyisobutylene (17) --- - 40.1 "Kollidon” is a trademark of BASF AG, Ludwigshafen, Polysiloxane (15) - - 40,1 Germany, for a polyvinylpyrrolidone (PVP) polymer. Pre 65 Nitroglycerine (27) 20.8 20.8 20.8 20.8 ferred are “Kollidon 17PF,” “Kollidon 25,” and “Kollidon Oleic acid 20 2.0 20 20 30.’ 5,656,286 40 The composition of the blend of polymers is preferably TABLE III-continued chosen so that the flux rate of drug from the blend is at a maximum. Studies similar to those reported herein may be Ingredient employed to assist in selecting the appropriate components (SP, J/cm?? Ex. 2 Ex. 3 Ex. 4 Ex. 5 of the biend and the weight ratios thereof. In alternative Propylene glycol 0.8 O.8 0.8 O.8 embodiments, it may be desirable to select a composition in Lecithin 1.2 1.2 1.2 1.2 which the flux rate will be retarded. Dipropylene glycol 10 O 10 10 Bentonite O 10 10 1.0 Examples 7-9 10 FIG. 3 graphically Summarizes the in vitro nitroglycerin An estradiol-polymer mixture (Example 7) was prepared flux results through cadaver epidermis from the dermal by combining 2.0 parts of 170-estradiol, 2.0 parts of pro compositions of Examples 2 to 5. As seen in FIG. 3, addition pylene glycol. 3.0 parts of lecithin, 5.0 parts of oleic acid, of either polyisobutylene (Example 4) or polysiloxane 5.0 parts of dipropylene glycol, 93.3 parts of polyacrylate (Example 5)-both with SPs lower than polyacrylate (Duro-Tak 80-1196), and 63.1 parts of polysiloxane (BIO resulted in doubling of the nitroglycerinflux as compared to 5 PSAX7-3122), and mixing well in an appropriate container. an all polyacrylate system (Example 2). However, addition The resulting composition had the ingredient concentrations of ethylene/vinyl acetate (Example 3)-with an SP value on a “dry” basis, that is, after removal of volatile process similar to the polyacrylate-resulted in little effect on nitro solvents, given below in TABLE VI. glycerinflux as compared to the system of Example 2. Thus, Examples 8 and 9 were made in accordance with the the formulation of Example 3 is not within the scope of the 20 method of Example 7. The compositions of Examples 8 and present invention. 9 have the same drug and additional components, such as the Example 6 co-solvents, as Example 7, but are not within the scope of A series of nitroglycerin-containing compositions (I-VI) this invention inasmuch as the resulting adhesive matrices were prepared in which the polyacrylate (Duro-Tak 25 are single polymer systems. Examples 8 and 9 are given for 80-1194) to polysiloxane (X7-3122) ratio was varied from comparative purposes only. 100.0:0.0 (all polyacrylate) to 0.0:100.0 (all siloxane) by weight. Nitroglycerin concentration was held at 20% for all TABLE VI compositions. The ingredient concentrations of these com Ingredient 7 8 9 positions are shown below in TABLE IV. 30 Polyacrylate 42.0 83.0 TABLE IV Polysiloxane 40 83.0 Estradiol 20 2.0 20 Ingredient I I V W V Oleic acid 50 5.0 50 Propylene glycol 20 2.0 2.0 Polysiloxane 14.4 28.8 43.2 57.6 72.6 35 Lecithin 3.0 3.0 3.0 Silicone ww. 1.6 3.2 4.8 6.4 8.0 Dipropylene glycol 5.0 SO 5.0 Fluid Polyacrylate 8O.O 640 48.0 32.8 16.0 Nitroglycerin 2O.O. 2O.O 2O.O 2O.O 20.0 200 Estradiol flux in vitro from the systems of Examples 7, 8, and 9 is shown in FIG. 5. As seen in FIG. 5, delivery from In vitro skin flux was determined for these compositions 40 the system of this invention utilizing the multiple polymer and the results are summarized in Table V and graphically adhesive (polyacrylate/polysiloxane) of Example 7 was sub depicted in FIG. 4. stantially greater than delivery from the prior art systems comprising single polymer adhesives (Examples 8 and 9). TABLE V 45 Examples 10-13 Polyacrylate Polysiloxane GN Flux Tlag % 2. (ug/cm/hr) (hr) In the following examples (10-13), the method of Example 7 was used with the appropriate amounts of I 1OOO O 1.6 0.0 I 81.6 18.4 3.2 1.5 starting materials to yield compositions having the ingredi 62.5 37.5 4.2 2.0 50 ent concentrations set forth in TABLE VII. V 43.2 56.8 4.5 2.3 W 217 78.3 5.2 2.3 TABLE VII VI O 100 49 2.4 Nitro-Our (R) -- wo- 3.0 2.5 Ingredient 10 1. 12 13

55 Polysiloxane 18.0 33.5 39.5 58.0 As shown, nitroglycerin (GTN) flux increased as the Polyacrylate 65.0 39.5 33.5 15.0 concentration of polysiloxane in the multiple polymer adhe Estradiol 2.0 2.0 2.0 2.O Oleic acid 5.0 5.0 5.0 5.0 sive matrix increased up to a maximum, at around 80% Propylene 2O 2.0 2O 2.0 polysiloxane, after which no more increase influx was seen. glycol It appears that beyond a certain concentration of siloxane 60 Lecithin 3.0 3.0 3.0 3.0 polymer, the nitroglycerin activity ceases to increase (unit Silicone 5.0 5.0 50 15.0 activity is reached), and the flux no longer increases. The attainment of saturation concentration (unit activity) is fur ther verified by the fact that Composition VI had nitroglyc FIG. 6 shows estradiol flux results for the compositions of erin exudate; that is, the surface of the adhesive was "wet' Examples 10-13; average flux was calculated for each with excess nitroglycerin. Of course, Composition VI, 65 composition from 0 to 22 hours and from 22 to 99 hours which is all polysiloxane, is not within the contemplation of from the start of the study. As seen in FIG. 6, estradiol flux the invention. progressively increased with increased silicone polymer 5,656,286 41 42 content during the first 22 hours of delivery, but was affected to a much lesser degree during the remainder of the study TABLE X-continued (22 to 99 hours). Thus, significant adjustment of the estradiol delivery rate during the initial phase of delivery was ingredient 17 18 19 2O accomplished, with minor effects on the later delivery phase, acetate by modulating the polysiloxane to polyacrylate polymer Oleic Acid 2.0 20 2.0 2.0 Butylene 2.0 2.0 20 2.0 ratio. FIG. 6 also illustrates that the delivery characteristics glycol over time can be adjusted by the appropriate choice of Lecithin 5.0 5.0 50 5.0 polymers and respective weight ratios. For example, the Silicone 150 14.0 120 10.0 formulation of Example 10 delivers drug at approximately 10 fluid the same rate over time whereas the formulation of Example 13 delivers more quickly in the early phase than the latter. Flux results for the compositions of Examples 17-20 are shown in FIG. 8. As shown in FIG. 8, the flux of both Examples 14-16 estradiol (E2) and norethindrone acetate (NAc) varied as the 15 polysiloxane to polyacrylate polymer ratio was adjusted; A norethindrone acetate-polymer mixture was prepared estradiol flux gradually increased and then decreased with a by combining 0.6 parts of norethindrone acetate, 1.0 parts of maximum at about 15% acrylate, and the norethindrone butylene glycol, and 40.9 parts of polyacrylate (Duro-Tak acetate flux continuously decreased with increasing acrylate 80-1194), and mixing well in an appropriate container. The content as would be expected from the data of FIG. 7. A resulting composition had the ingredient concentrations on a further effect of varying the polysiloxane/polyacrylate poly “dry” basis, that is, after removal of volatile process mer ratio is exhibited by a plot of estradiol flux relative to solvents, given below in TABLE VIII. The same method was norethindrone acetate flux (estradiol flux divided by nore employed to make Examples 15 and 16. thindrone acetate flux) as shown in FIG. 9. By adjusting the silicone to acrylate polymer ratio, it was possible to modul TABLE VI 25 late the relative delivery of two drugs (estradiol and nore Ingredient 14 15 16 thindrone acetate) from the systems of this invention. Examples 21-23 Polyacrylate 92.0 46.0 Polysiloxane 92.0 46.0 A pilocarpine-polymer mixture was prepared by combin Norethindrone 3.0 3.0 3.0 ing 5.0 parts of pilocarpine base, 1.2 parts of lecithin, 0.8 acetate 30 parts of propylene glycol, 2.0 parts of oleic acid, 2.5 parts of Butylene glycol 5.0 50 5.0 silicone fluid (polydimethylsiloxane. Dow Corning 360 Medical Fluid, 100 cs), and 77.0 parts of polysiloxane (BIO-PSA X7-3027), and mixing well in an appropriate Norethindrone acetate flux in vitro from the systems of container. Example 22 incorporated pilocarpine into a poly Examples 14, 15, and 16 is shown in FIG.7. As seen in FIG. 35 acrylate comprising National Starch Acrylic Adhesive, 7, norethindrone acetate delivery from the polyacrylate/ Duro-Tak 80-1196. Example 23 employed a blend of pol polysiloxane systems of this invention (Example 16) was ysiloxane and polyacrylate in accordance with the principles intermediate to delivery from the single polymer Systems not of the invention. The resulting compositions had the ingre of this invention (Example 14 and 15). Thus, blending the dient concentrations on a "dry" basis, that is, after removal polyacrylate and polysiloxane results in modulation of the 40 of volatile process solvents, given below in TABLE X. norethindrone acetate flux. TABLE X Examples 17–20 Ingredient 21 22 23 As estradiol/norethindrone acetate combination-polymer 45 Polyacrylate s 820 4.0 mixture was prepared by combining 0.6 parts of 173 Polysiloxane 770 410 estradiol, 0.6 parts of norethindrone acetate, 0.6 parts of Silicone 50 --- butylene glycol, 0.6 parts of oleic acid, 1.5 parts of lecithin, fluid 4.5 parts of silicone fluid (polydimethylsiloxane fluid, Dow Pilocarpine 10.0 10.O 10,0 Oleic acid 40 40 4.0 Corning 360 Medical Fluid, 100 cs), and 43.2 parts of 50 Propylene 1.6 1.6 1.6 polysiloxane (BIO-PSA X7-4919), and mixing well in an glycol appropriate container. The method of Example 7 was used Lecithin 2.4 2.4 2.4 with the appropriate amounts of starting materials to yield fluid the compositions of Example 18, 19 and 20. The polyacry late used in Examples 18-20 was National Starch Acrylic 55 Pilocarpinefluxin vitrofrom the systems of Examples 21, Adhesive, Duro-Tak 80-1197. The resulting compositions 22, and 23 is shown in FIG. 10. As seen in FIG. 10, the had the ingredient concentrations on a "dry" basis, that is, delivery rate from the system of this invention utilizing the after removal of volatile process solvents, given below in multiple polymer adhesive (polyacrylate/polysiloxane) of TABLE IX. Example 23, was intermediate of the delivery rates from single polymer compositions (Examples 21 and 22) which TABLE IX are not of this invention. In this embodiment of the invention, the combination of polyacrylate and polysiloxane Ingredient 17 18 19 20 polymers adjusted the delivery of rate of pilocarpine within Polysiloxane 720 8.0 60.0 470 the ranges established by single polymer compositions. Polyacrylate 5.0 150 300 Estradiol 2.0 2.0 20 2.0 65 Examples 24-27 Norethindrone 20 2.0 2.0 2.0 An albuterol-polymer mixture was prepared by combin ing 10.2 parts of albuterol base, 1.5 parts of lecithin, 1.0 part 5,656.286 43 of propylene glycol, 4.1 parts of oleic acid, 2.6 parts of dipropylene glycol, 1.5 parts of butylene glycol, 1.5 parts of TABLE XII-continued vitamin E acetate (tocoperyl acetate), 25.5 parts of poly acrylate (Duro-Tak 80-1196), 11.9 parts of polysiloxane A Ingredient 28 29 (BIO-PSA X7-3122), 20.1 parts of polysiloxane B (BIO Estradiol 20 2.0 PSA X7-3027), and 20.1 parts of isopropyl alcohol, and Oleic acid 5.0 50 mixing well in an appropriate container. The resulting com Lecithin 3.0 3.0 position had the ingredient concentrations on a “dry” basis, that is, after removal of volatile process solvents, given below in Table XI. Estradiol flux in vitro from the systems of Examples 28 10 The method of Example 24 was used with the appropriate and 29 are shown in FIG. 12. As seen in FIG. 12, delivery amounts of starting materials to yield the compositions of from the multiple polymer adhesive system of Example 28 Examples 25, 26, and 27. is comparable to delivery from Example 29. Example 30 TABLE X 15 In addition to flux measurements, the apparent diffusion Ingredient 24 25 26 27 coefficient, D, was calculated from release data for nitro Polysiloxane A 140 13.8 4.O 140 glycerin from matrices of Compositions Ito VI (Example 6) Polysiloxane B 19.6 19.2 28O 9.6 into an infinite sink. The method of D. R. Paul, Controlled Polyacrylate 22.4 22.0 2O.O 22.4 Release Polymeric Formulations, ACS Symposium Series Abuterol 20.0 2O.O 2O.O 200 20 Oleic acid 8.0 8O 8.0 80 No. 33, Chapter 1 (1976) was used wherein the initial Propylene glycol 2O 2.0 2.0 2.0 concentration of nitroglycerin in the matrix, Co., was deter Dipropylene 5.0 50 5.0 5.0 mined (assuming a density of 1.0) and the relationship of the glycol amount released, M., by a matrix of area, A, and the Butylene glycol 3.0 3.0 3.0 diffusion coefficient is defined by: Vitamin E acetate 3.0 3.0 --- 25 Vitamin E 1.0 m Vitamin E - - 3.0 inoleate Plotting, M/A against t', results in a graph having a Lecithin 3. 3.0 3.0 3.0 slope, m, defined by: 30 Albuterol flux results through human cadaver skin in vitro from the formulations of Examples 24, 25, 26, and 27, are summarized in FIG. 11; nitroglycerinflux from Nitro-Duro) The value of m can be ascertained by linear regression to through the same skin specimen is shown as a control. Flux get the slope of the best fit line. The diffusion coefficient is values for the albuterol compositions of Example 24 to 27 calculated as: ranged from about 17 ug/cm/hr to about 22 ug/cm/hr. The 35 nitroglycerinflux value of about 28 pg/cm/hr was slightly higher than the literature delivery rate for this product (20 ug/cm/hr, based on Nitro-Dur?) product label of 0.1 mg/hr The results of these calculations for Compositions Ito VI from a 5 cm system). In order to adjust for the apparent are shown below in Table XI. higher permeability of the skin specimen, albuterol flux 40 results can be multiplied by an adjustment factor of 0.714 TABLE X (20/28); this would result influx values of about 12 g/cm?/ hr to about 16 ug/cm/hr. Composition Co(mg/cm) mcmg/cmh') D (cm/sec) D(x 10) Therapeutic albuterol plasma concentrations are in the I 2410 O.8728 2.861 x 0° 2.86 45 233.3 09483 3,605 x 10° 36.05 range of about 4 to 8 ng/mL, and are produced by delivery 231.3 10834 4.786 x 108 47.86 rates of about 115 to 230 ug/hr. The flux rates (12 to 16 V 2197 1.25O2 7.065 x 108 70.65 g/cm/hr) obtained from the compositions of this invention V 21.0 1.5920 1.174 x 107 117.4 therefore would produce the necessary albuterol plasma V 215.0 2.4551. 2.845 x 107 284.5 levels (4 to 8 ng/mL) for the treatment of asthma from Nitro-Dur 380.0 14680 3.256 x 10 32.56 system sizes of about 10 to 20 cm. 50 FIGS. 13 and 14 show the relationship of flux rate (J) Examples 28-29 plotted against apparent diffusion coefficient (D) and net Estradiol-polymer mixtures were prepared in accordance solubility parameter (SP), respectively, for Compositions with the method of Example 7. Example 28 is illustrative of I-VI. The net solubility parameter, SP, was calculated a multiple polymer adhesive system where polyacrylate is 55 using a weighted average of the solubility parameters of the blended with polyisobutylene (Vistanex LM-LS-LC). The individual polymers comprising the matrix: resulting compositions had the ingredient concentrations on a “dry” basis, that is, after removal of volatile process SP-2SP+2 SP, solvents, given below in TABLE XII. 60 where 2 is the weight percentage of polysiloxane and SP TABLE X is the solubility parameter of polysiloxane. The subscript “pa” refers to the polyacrylate. FIG. 15 is a plot of diffusion Ingredient 28 29 coefficient versus net solubility parameter. Polyacrylate 450 45.0 Tables XTV-A and XIV-B list additional preferred Polyisobutylene 450 65 embodiments, which are prepared according to the proce Polysiloxane w 45.0 dure of Example 7 in the same manner as the preceding preferred embodiments. Table XIV-Alists the polymers and 5,656,286 45 46 drugs utilized in each embodiment, while Table XIV-B lists additives so utilized.

TABLE XIV. A Ingredient (SP, J/cm2) Ex. 31 Ex. 32 Ex. 33 Ex. 34 Ex. 35 Ex. 36 Ex. 37 Ex. 38 Ex. 39 Ex. 40 Ex. 41 Ex. 42 Polyacrylate (21) 33.1, 33. 42.0 42.0 5.0 15.0 Polyethylene (16.6) 40. Polyisoprene (16.6) 40. Polybutadiene (15) 410 Polyethylene?butylene (15) 410 Polytetrafluoroethylene (12.7) 600 Polybutadienelstyrene (174) 60.0 Polysiloxane (15) 46.0 46.0 410 41.0 42.0 420 Polystyrene (18.6) 46.0 Polyvinyl chloride (19.4) 46.0 Polyvinylidene chloride (24.9) 410 Polychloroprene (19.2) 40 Polyacrylonitrile (26.0) 20.0 Butadienefacrylonitrile (18.9) 20,0 Nitroglycerine (27) 20.8 20.8 178-estradiol (24.5) 20 2.0 2.0 2.0 Norethindrone acetate (21.3) 2.0 20 3.0 3.0 Pilocarpine (22.9) 10.0 10.0 Albuterol (26.7) 20.0 2O.O Oleic acid 20 20 50 50 2.0 2.0 40 40 8.0 8.0 Propylene glycol 0.8 0.8 2.0 2.0 1.6 1.6 2.0 2.0 Dipropylene glycol 10 10 50 50 5.0 5.0 Butylene glycol 20 2.0 50 S.O Bentonite 10 1.0 Lecithin 1.2 1.2 3.0 3.0 5.0 5.0 2.4 2.4 3.0 3.0 Silicone fluid 12.0 120

3O Example 43

EXAMPLE 44 An estradiol-polymer mixture was prepared by combining 35 COMPONENT PERCENT BY WEIGHT 1.0 part of estradiol, 6.0 parts of dipropylene glycol, 8.0 Regie 39.0 parts of oleic acid, 35.0 parts of toluene, 5.0 parts of Polyacrylate Adhesive 400 polyvinylpyrrolidone (Kollidon 30), and 129.03 parts of S. GMS 737) polyacrylate adhesive (GMS 737) in an appropriate 40 OleicDipropylene Aci Glycol 6.08.0 container, and mixing well until the mixture was completely Polyvinylpyrrolidone 5.0 homogeneous. Then 66.67 parts of silicone adhesive (X7- Solic 30) 2.0 4503) were added, and the blend was thoroughly mixed. The Stacic - Yola resulting composition has the ingredient concentrations on a 100.0 “dry” basis, that is, after removal of volatile process 45 solvents, given below.

EXAMPLE 45 COMPONENT PERCENT BY WEIGHT 50 COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 40.0 (BIO-PSAX7-4503) Polysiloxane Adhesive 48.0 Polyacrylate Adhesive 400 (BIO-PSAX7-4503) (Monsanto GMS 737) Polyacrylate Adhesive 30.0 Oleic Acid 8.0 (Monsanto GMS 737) Dipropylene Glycol 60 Oleic Acid 6.0 Polyvinylpyrrollidone 50 55 Dipropylene Glycol 40 (Kollidon 30) Polyvinylpyrrollidone 10.0 Estradiol 10 (Kollidon 30) Estradiol 2.0 1000 100.0 60

Estradiol permeation throughhuman epidermis in vitro In the following examples the method of Example 43 was from systems of Examples 44 and 45 are shown in FIG. 16. used with the appropriate amounts of starting materials to 65 This graph illustrates how the formulas of this invention yield compositions having the following ingredient concen delivered significantly greater estradiol than EstradermTM, trations. the commercially available estradiol product. 5,656,286 47 Example 46 -continued

An estradiol/norethindrone acetate-polymer mixture was EXAMPLE 48 prepared by combining 0.04 parts of estradiol, 2.48 parts of 5 norethindrone acetate, 3.31 parts of dipropylene glycol, 4.96 COMPONENT PERCENT BY WEIGHT parts of oleic acid, 49.62 parts of toluene, 8.27 parts of polyvinylpyrrolidone (Kollidon 30), 0.83 parts of butylated Norethindrone Acetate 3.00 hydroxyanisole, and 53.36 parts of polyacrylate adhesive Estradio 0.20 (GMS 737) in an appropriate container, and mixing well 10 until the mixture was completely homogeneous. Then 77.12 1OOO parts of polysiloxane adhesive (X74503) were added, and the blend was thoroughly mixed. The resulting composition has the ingredient concentrations on a “dry” basis, that is, 15 after removal of volatile process solvents, given below. EXAMPLE 49

COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 55.95 20 Polysiloxane Adhesive 55.60 (BIO-PSAX7-4503) (BIO-PSAX7-4503) Polyacrylate Adhesive 2O.OO Polyacrylate Adhesive 20.00 (Monsanto GMS 737) Oleic Acid 600 (Monsanto GMS 737) Dipropylene Glycol 4.00 Oleic Acid 6.00 Polyvinylpyrrolidone 10.00 25 Dipropylene Glycol 4.00 (Kollidon 30) Polyvinylpyrrollidone 1O.OO Butylated Hydroxyanisole 100 (Kollidon 30) Norethindrone Acetate 3.00 Butylated Hydroxyanisole 1.00 Estradiol 0.05 Norethindrone Acetate 3.00 Estradio 0.40 100.0 30 1OO.O

In the following examples the method of Example 46 was used with the appropriate amounts of starting materials to 35 yield compositions having the following ingredient concen EXAMPLE SO trations. COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 55.50 EXAMPLE 47 (BIO-PSAX7-4503) 40 Polyacrylate Adhesive 2O.OO COMPONENT PERCENT BY WEIGHT (Monsanto GMS 737) Oleic Acid 6.00 Polysiloxane Adhesive 55.90 Dipropylene Glycol 4.00 (BIO-PSAX7-4503) Polyvinylpyrrollidone O.OO Polyacrylate Adhesive 2O.OO (Kollidon 30) (Monsanto GMS 737) 45 Butylatea Hydroxyanisole 1.OO Oleic Acid 6.00 Norethindrone Acetate 3.OO Dipropylene Glycol 4.OO Estradiol 0.50 Polyvinylpyrrollidone 1000 (Kollidon 30) 1OO.O Butylated Hydroxyanisole 1.OO Norethindrome Acetate 3.00 50 Estradiol O.10

100.0 EXAMPLE 51 COMPONENT PERCENT BY WEIGHT 55 Polysiloxane Adhesive 55.40 EXAMPLE 48 (BIO-PSAX7-4503) Polyacrylate Adhesive 2O.OO COMPONENT PERCENT BY WEIGHT (Monsanto GMS 737) Oleic Acid 6.00 Polysiloxane Adhesive 55.80 Dipropylene Glycol 4.00 (BIO-PSAX7-4503) 60 Polyvinylpyrrollidone 10.00 Polyacrylate Adhesive 20.00 (Kollidon 30) (Monsanto GMS 737) Butylated Hydroxyanisole OO Oleic Acid 6.00 Norethindrone Acetate 3.OO Dipropylene Glycol 4.00 Estradio 0.60 Polyvinylpyrrollidone O.OO (Kollidon 30) 65 100.0 Butylated Hydroxyanisole 1.00 5,656,286 50 -continued

EXAMPLE 52 COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT (Kollidon 30) Butylated Hydroxyanisole 1.00 Polysiloxane Adhesive 55.20 Norethindrome Acetate 3.00 (BIO-PSAX7-4503) Estradiol 0.20 Polyacrylate Adhesive 20.00 (Monsanto GMS 737) 100.0 Oleic Acid 6.00 Dipropylene Glycol 4.00 10 Polyvinylpyrrolidone 10.00 In the following examples the method of Example 54 was (Kollidon 30) used with the appropriate amounts of starting materials to Butylated Hydroxyanisole 100 yield compositions having the following ingredient concen Norethindrone Acetate 3.00 trations. Estradiol 0.80 15 100.0 EXAMPLE 55 COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 63.30 EXAMPLE 53 20 (BIO-PSAX7-4503) Polyacrylate Adhesive 20.00 COMPONENT PERCENT BY WEIGHT (Monsanto GMS 737) Polysiloxane Adhesive 55.00 Oleic Acid 6.00 (BIO-PSAX7-4503) Dipropylene Glycol 4.00 Polyacrylate Adhesive 20.00 Polyvinylpyrrolidone 2.50 (Monsanto GMS 737) 25 (Kollidon 30) Oleic Acid 6.00 Butylated Hydroxyanisole 1.00 Dipropylene Glycol 400 Norethindrone Acetate 3.00 Polyvinylpyrrolidone 0.00 Estradiol 0.20 (Kollidon 30) Butylated Hydroxyanisole 1.00 100.0 Norethindrone Acetate 3.00 30 Estradiol 1.OO

100.0 EXAMPLE 56 Estradiol flux through human epidermis in vitro from 35 COMPONENT PERCENT BY WEIGHT systems of Examples 46 through 53 (with 0.05% to 1.0% Polysiloxane Adhesive 60.80 estradiol) are presented in FIG. 17. This graph shows how a (BIO-PSAX7-4503) Polyacrylate Adhesive 2000 wide range in estradiol flux was achieved by the formulas of Monsanto GMS 737) this invention by varying the estradiol concentration. Nore Oleic Acid 6.00 thindrone acetate flux was not affected by estradiol 40 Dipropylene Glycol 4.00 concentration, and remained constant at about 0.8 ug//hr; see Polyvinylpyrrolidone 5.00 FIG. 18. (Kollidon 30) Butylated Hydroxyanisole 1.00 Norethindrone Acetate 3.00 Example 54 Estradiol 0.20 45 An estradiol/norethindrone acetate-polymer mixture was, 100.0 prepared by combining 0.20 parts of estradiol, 3.00 parts of norethindrone acetate, 4.00 parts of dipropylene glycol, 6.00 parts of oleic acid, 60.00 parts of toluene, 0.00 parts of polyvinylpyrrollidone (Kollidon 30), 1.00 parts of butylated hydroxyanisole, and 64.52 parts of polyacrylate adhesive 50 EXAMPLE 57 (GMS 737) in an appropriate container, and mixing well until the mixture was completely homogeneous. Then 93.00 COMPONENT PERCENT BY WEIGHT parts of polysiloxane adhesive (X7-4503) were added, and Polysiloxane Adhesive 55.80 the blend was thoroughly mixed. The resulting composition (BIO-PSAX7-4503) 55 Polyacrylate Adhesive 2000 has the ingredient concentrations on a "dry" basis, that is, (Monsanto GMS 737) after removal of volatile process solvents in ovens, given Oleic Acid 6.00 below. Dipropylene Glycol 4.00 Polyvinylpyrrolidone 10.00 (Kollidon 30) COMPONENT PERCENT BY WEIGHT Butylated Hydroxyanisole 100 Norethindrone Acetate 3.00 Polysiloxane Adhesive 65.80 Estradiol 0.20 (BIO-PSAX7-4503) Polyacrylate Adhesive 20.00 100.0 (Monsanto GMS 737) Oleic Acid 6.00 Dipropylene Glycol 4.00 65 FIG. 19 shows how systems with varying levels of Polyvinylpyrrolidone 0.00 polyvinylpyrrollidone (0 to 10%) had essentially the same drug (estradiol and norethindrone acetate) flux; Examples 5,656.286 51 52 54-57. However, polyvinylpyrrolidone was found to have In the following example, the nitroglycerin is added as a an effect on drug recrystallization for these systems. That is, solution in toluene mixed together with styrene-isoprene the incidence of crystal formation was reduced as the styrene (Kraton D 1107) polymer. polyvinylpyrrollidone concentration was increased; see Table XV. EXAMPLE 60 TABLE XV COMPONENT PERCENT BY WEIGHT Effects of polyvinylpyrrollidone on crystal formation. Polysiloxane Adhesive 46.00 (BIO-PSAX7-4503) % polyvinyl- # of crystals O Styrene-isoprene-styrene 3OOO Formula pyrrollidone in patch polymer Example 54 0.0 60 - 4 (Kraton D1107) Example 55 2.5 568 Dipropylene Glycol 2.00 Lecithin 2.00 Example 56 5.0 204 Nitroglycerin 2000 Example 57 100 O 15 *number of visible crystals in a 14.4 cm patch; average andsdoffive patches 1OOOO each. Example 61 Example 58 20 An isosorbide dinitrate-polymer mixture is prepared by A nitroglycerin-polymer mixture is prepared by combin combining 20.0 parts of isosorbide dinitrate, 4.00 parts of ing 20.0 parts of nitroglycerin, 2.00 parts of dipropylene dipropylene glycol, 4.00 parts of oleic acid, and 66.67 parts glycol, 2.00 parts of lecithin, and 83.33 parts of ethylene? of ethylene/vinyl acetate polymer (Elvax 40W) in an appro vinyl acetate polymer (Elvax 40W) in an appropriate priate container, and mixing well until the mixture is com container, and mixing well until the mixture is completely 25 pletely homogeneous. In this example, the isosorbide dini homogeneous. Nitroglycerin is available as a solution in trate is added as a solution in toluene mixed together with solvents such as ethanol, toluene, and propylene glycol from the ethylene/vinyl acetate polymer. Then 86.67 parts of ICI Americas Inc., Wilmington, Del. In this instance, the polysiloxane adhesive (BIO-PSA X7-4503) are added, and nitroglycerin is added as a solution in toluene mixed the blend is thoroughly mixed. The resulting composition together with the ethylene/vinyl acetate polymer. Then 85.00 30 has the ingredient concentrations on a “dry” basis, that is, parts of polysiloxane adhesive (X7-4503) are added, and the after removal of volatile process solvents in ovens, given blend is thoroughly mixed. The resulting composition has below. the ingredient concentrations on a “dry” basis, that is, after removal of volatile process solvents, given below. COMPONENT PERCENT BY WEIGHT 35 Polysiloxane Adhesive 52.00 COMPONENT PERCENT BY WEIGHT (BIO-PSAX7-4503) Ethylene? VinylAcetate 2OOO Polysiloxane Adhesive 51.00 Polymer (BIO-PSAX7-4503) (Elvax 40W) Ethylene? VinylAcetate 25.00 40 Dipropylene Glycol 4.00 Polymer Oleic Acid 4.00 (Elvax 40W) Isosorbide Dinitrate 2000 Dipropylene Glycol 2.00 Lecithin 2.00 100.00 Nitroglycerin 2OOO 100.00 45 In the following examples the method of Example 61 is used with the appropriate amounts of starting materials to yield compositions having the following ingredient concen In the following examples the method of Example 58 is trations. In this instance, the isosorbide dinitrate is added as used with the appropriate amounts of starting materials to a Solution in toluene mixed together with styrene-butadiene yield compositions having the following ingredient concen 50 styrene polymer (Kraton D1101). trations. In this instance, the nitroglycerin is added as a Solution in toluene mixed together with polyisobutylene (Vistanex LM-LS-LC). EXAMPLE 62

55 COMPONENT PERCENT BY WEIGHT EXAMPLE 59 Polysiloxane Adhesive 47.00 (BIO-PSAX7-4503) COMPONENT PERCENT BY WEIGHT Styrene-butadiene-styrene 25.00 Polysiloxane Adhesive 56.00 (Kraton D1101) (BIO-PSAX7-4503) Dipropylene Glycol 4.00 Polyisobutylene 20.00 60 Oleic Acid 4.00 (Vistanex LM-LS-LC) Isosorbide Dinitrate 2O.OO Dipropylene Glycol 2.00 Lecithin 2.00 OO.OO Nitroglycerine 20.00 100.00 65 In the following example, the isosorbide dinitrate is added as a solution in toluene mixed together with polyacrylate adhesive (Duro-Tak 80-1196). 5,656.286 53 54 8.00 parts of oleic acid, 3.00 parts of tocopherol acetate (Vitamin E acetate), and 66.67 parts of ethylene/vinyl EXAMPLE 63 acetate polymer (Elvax 40W) in an appropriate container, COMPONENT PERCENT BY WEIGHT and mixing well until the mixture is thoroughly mixed. Then Polysiloxane Adhesive 32.00 56.67 parts of polysiloxane adhesive (BIO-PSA X7-4301) (BIO-PSAX7-4503) are added, and the blend is thoroughly mixed. The resulting Polyacrylate Adhesive 30.00 composition has the ingredient concentrations on a “dry” (Duro-Tak 80-1196) Polyvinylpyrrolidone 10.00 basis, that is, after removal of volatile process solvents, (Kollidon 30) O given below. Dipropylene Gylcol 4.00 Oleic Acid 4.00 Isosorbide Dinitrate 20.00 COMPONENT PERCENT BY WEIGHT 100.00 15 Polysiloxane Adhesive 3400 (BIO-PSAX7-4301) Example 64 Ethylene? VinylAcetate 2000 A norethindrone acetate-polymer mixture is preparedby Polymer combining 3.00 parts of norethindrone acetate, 4.00 parts of (Elvax 40W) dipropylene glycol, 6.00 parts of oleic acid, 60.00 parts of 20 Butylene Glycol 5.00 toluene, 10.00 parts of polyvinylpyrrolidone (Kollidon 30), Oleic Acid 8.00 1.00 parts of butylated hydroxyanisole, and 64.52 parts of Tocopherol Acetate 3.00 polyacrylate adhesive (GMS 737) in an appropriate (Vitamin E Acetate) container, and mixing well until the mixture is completely Albuterol 30.00 homogeneous. Then 95.00 parts of polysiloxane adhesive 25 (BIO-PSAX7-4603) are added, and the blend is thoroughly 100.00 mixed. The resulting composition has the ingredient con centrations on a "dry" basis, that is, after removal of volatile process solvents, given below. 30

COMPONENT PERCENT BY WEIGH In the following examples the method of Example 66 is Polysiloxane Adhesive 57.00 used with the appropriate amounts of starting materials to (BIO-PSAX7-4603) yield compositions having the following ingredient concen Polyacrylate Adhesive 2000 35 trations. (GMS 737) Dipropylene Glycol 4.00 Oleic Acid 6.00 Polyvinylpyrrolidone 10.00 EXAMPLE 67 (Kollidon 30) COMPONENT PERCENT BY WEIGHT Norethindrone Acetate 3.00 40 Polysiloxane Adhesive 46.00 100.00 (BIO-PSAX7-4301) Polyisobutylene 2O.OO (Vistanex LM-MS-LC) In the following examples the method of Example 64 is Dipropylene Glycol 5.00 used with the appropriate amounts of starting materials to 45 Oleic Acid 6.00 yield compositions having the following ingredient concen Tocopherol Acetate 3.00 (Vitamin E Acetate) trations. Albuterol 2000

100.00 EXAMPLE 65 50 COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 54.00 (BIO-PSAX7.4603) EXAMPLE 68 Ethylene? VinylAcetate 25.00 Polymer 55 COMPONENT PERCENT BY WEIGHT (Elvax 40W) Polysiloxane Adhesive 54.00 Dipropylene Glycol 4.00 (BIO-PSAX7-4301) Oleic Acid 400 Styrene- 20.00 Polyvinylpyrrolidone 1000 ethylene?butylene-styrene (Kollidon 30) polymer (Kraton G.1657) Norethindrone Acetate 3.00 60 Lecithin 3.00 Oleic Acid 5.00 OOOO Tocopherol Acetate 3.00 (Vitamin E Acetate) Pilocarpine 15.00

Example 66 65 100.00 An albuterol-polymer mixture is prepared by combining 30.00 parts of albuterol base, 5.00 parts of butylene glycol, 5,656,286 55 56

EXAMPLE 69 EXAMPLE 73

COMPONENT PERCENT BY WEIGHT 5 COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 39.00 (BIO-PSAX7-4303) Polysiloxane Adhesive 6100 Ethylene? VinylAcetate 25.00 10 (BIO-PSAX7-4301) Polymer Ethylene? VinylAcetate 1OOO (Elvax 40W) Polymer Butylene Glycol 5.00 (Elvax 40W) Oleic Acid 800 Oleic Acid 6.00 Tocopheroi Acetate 3.00 15 (Vitamin E Acetate) Tocopherol Acetate 3.00 Philocarpine 2000 (Vitamin E Acetate) Haloperidol 2OOO OOOO 20 1OOOO

EXAMPLE 70

COMPONENT PERCENT BY WEIGHT 25 EXAMPLE 74 Polysiloxane Adhesive 53.00 COMPONENT PERCENT BY WEIGHT (BIO-PSAX7-4301) Polyisobutylene 2000 Polysiloxane Adhesive 4400 (Vistanex LM-MS-LC) (BIO-PSAX7-4301) Oleic Acid 5.00 30 Butyl Rubber 25.00 Tocopherol Linoleate 200 Butylene Glycol 5.00 (Vitamin E Linoleate) Linoleic Acid 8.00 Alprazolam 2000 Tocopherol Acetate 3.OO (Vitamin E Acetate) 100.00 Haloperidol 5.00

35 OOOO

EXAMPLE 7

COMPONENT PERCENT BY WEIGHT 40 EXAMPLE 75

Polysiloxane-Adhesive 3700 COMPONENT PERCENT BY WEIGHT (BIO-PSA X7-4303) Styrene Butadiene Rubber 2OOO Polysiloxane Adhesive 60.00 (Vistanex LM-MS-LC) (BIO-PSAX7-4301) Dipropylene Glycol 2OO Polybutene 15.00 Oleic Acid 800 45 Oleic Acid 5.00 Tocopherol Acetate 3OO Lecithin 500 (Vitamin E Acetate) Alprazolam 500 Alprazolam 30.00 100.00 100.00 50

EXAMPLE 76 EXAMPLE 72 COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT 55 Polysiloxane Adhesive 62.00 Polysiloxane Adhesive 56.00 (BIO-PSAX7-4301) (BIO-PSAX7-4301) Polyisobutylene 20.00 Styrene-isoprene-styrene 15.00 (Vistanex LM-MS-LC) Polymer Dipropylene Glycol 400 (Kraton D1107) 60 Oleic Acid 4.00 Propylene Gylcol 5.00 Polyvinylpyrrolidone 5.00 Linoleic Acid 800 (Kollidon 17PF) Lecithin 6.00 Lecithin 3.00 (Vitamin E Acetate) (Vitamin E Acetate) Haloperidol 10.00 Estradio 2.00

100.00 65 1OOOO 5,656.286 57 58 -continued

EXAMPLE 77 EXAMPLE 81 COMPONENT PERCENT BY WEIGHT 5 --- Polyacrylate Adhesive 55.00 COMPONENT PERCENT BY WEIGHT (GMS 737) Polyisobutylene 20.00 Dipropylene Glycol 5.00 Polysobutylene 20.00 Oleic Acid 8.00 Polyvinylpyrrollidone 10.00 10 (Vistanex LM-MS-LC) (Kollidon 30) Tocopherol Acetate 5.00 Haloperidol 2.00 (Vitamin E Acetate) 100.00 Nicotine 10.00

15 100.00

EXAMPLE 78 COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 51.00 20 EXAMPLE 82 (BIO-PSAX7-4301) Polysobutylene 20.00 COMPONENT PERCENT BY WEIGHT (Vistanex LM-MS-LC) Propylene Glycol 5.00 Polysiloxane Adhesive 52.00 Oleic Acid 6.00 5 (BIO-PSA X7-4301) Lecithin 3.00 2 Polyacrylate Adhesive- 20.00 Lidocaine 15.00 (Duro-Tak 80-1196) 100.00 Polyvinylpyrrollidone 10.00 (Kollidon 30) Dipropylene Glycol 5.00 3O Oleic Acid 8.00 (Vitamin E Acetate) EXAMPLE 79 Fentanyl 5.00

COMPONENT PERCENT BY WEIGHT 100.00 Polysiloxane Adhesive 53.00 35 (BIO-PSAX7-4301) Ethylene? VinylAcetate 15.00 Polymer (Elvax 40W) EXAMPLE 83 Dipropylene Glycol 5.00 Linoleic Acid 4.00 40 COMPONENT PERCENT BY WEIGHT Tocopherol Acetate 3.00 (Vitamin E Acetate) Polysiloxane Adhesive 63.00 Lidocaine 20.00 (BIO-PSAX7-4303) Ethylene? VinylAcetate 1500 100.00 Polymer (Elvax 40W) 45 Butylene Glycol 5.00 Oleic Acid 8.00 Tocopherol Acetate 3.00 (Vitamin E Acetate) EXAMPLE 80 - Fentanyl 6.00 COMPONENT PERCENT BY WEIGHT 50 100.00 Polysiloxane Adhesive 7200 (BIO-PSAX7-4301) Ethylene? VinylAcetate 20.00 Polymer (Elvax 40W) EXAMPLE 84 Tocopherol Acetate 3.00 55 (Vitamin E Acetate) COMPONENT PERCENT BY WEIGHT Nicotine 5.00 Polysiloxane Adhesive 65.00 100.00 (BIO-PSAX7-4301) Ethylene? VinylAcetate 20.00 60 Polymer (Elvax 40W) Polyethylene Glycol 400 5.00 Tocopherol Acetate 5.00 EXAMPLE 81 (Vitamin E Acetate) COMPONENT PERCENT BY WEIGHT Papaverine 5.00 Polysiloxane Adhesive 65.00 65 100.00 (BIO-PSAX7-4303) 5,656,286

-continued EXAMPLE 85 EXAMPLE 89 COMPONENT PERCENT BY WEIGHT 5 COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 81.00 Estradiol 0.20 (BIO-PSAX7.4601) Polyvinylpyrrolidone 10.00 100.00 (Kollidon 30) Dipropylene Glycol 3.00 Oleic Acid 5.00 10 Estradiol 2000 EXAMPLE90 100.00 COMPONENT PERCENT BY WEIGHT

15 Duro-Tak 69.00 (Monsanto 80-1196) Polyvinylpyrrolidone OOO EXAMPLE 86 (Kollidon 30) Butylene Glycol 5.00 COMPONENT PERCENT BY WEIGHT Oleic Acid 8.00 Polyisobutylene 81.00 2O Tocopherol Acetate 3OO (Vistanex LM-MS-LC) (Vitamin E Acetate) Polyvinylpyrrolidone 10.00 Fentanyl 5.00 (Kollidon 17PF) Dipropylene Glycol 2.00 100.00 Oleic Acid 6.00 Estradio 1.00 25 100.00 EXAMPLE 91

COMPONENT PERCENT BY WEIGHT 30 Polysiloxane Adhesive 58.0 EXAMPLE 87 (BIO-PSAX7-4503) Polyacrylate Adhesive 30.0 COMPONENT PERCENT BY WEIGHT (Monsanto GMS 737) Oleic Acid 6.0 Polysiloxane Adhesive 80.00 Dipropylene Glycol 4.0 (BIO-PSAX7-4503) 35 Polyvinylpyrrolidone 0.00 Polyvinylpyrrollidone O.O (Kollidon 17PF) (Kollidon 17PF) Dipropylene Glycol 3.00 Estradiol 2.0 Oleic Acid 5.00 Norethindrone Acetate 2.00 100.00 100.00 40 Although the invention has been described in terms of specific embodiments and applications, persons skilled in the art can, in light of this teaching, generate additional embodiments without exceeding the scope or departing from -----OEXAMPLE 88 45 the spirit of the claimed invention. Accordingly, it is to be understood that the drawing and description in this disclo COMPONENT PERCENT BY WEIGHT sure are proffered to facilitate comprehension of the Polyacrylate Adhesive 77.00 invention, and should not be construed to limit the scope (GMS 737) thereof. Polyvinylpyrrolidone 10.00 What is claimed is: (Kollidon 30) 50 Dipropylene Glycol 4.00 1. A transdermal drug delivery system comprising a Oleic Acid 6.00 pressure-sensitive adhesive composition, wherein said com Norethindrone Acetate 3.00 position comprises a blend of (a) a pressure-sensitive adhesive selected from the group 100.00 consisting of 55 (i) polyisoprene, polystyrene, polyethylene, polybuta diene , polyethylene/butylene, styrene?butadiene, styrene-butadiene-styrene, styrene-isoprene-styrene, EXAMPLE 89 styrene-ethylene/butylene-styrene block copolymers, butyl rubber, polytetrafluoroethylene, COMPONENT PERCENT BY WEIGHT 60 polyvinyl chloride, polyvinylidene chloride, Polyacrylate Adhesive 77.00 polychloroprene, polyacrylonitrile and (GMS 737) polychlorodiene, and mixtures thereof, in an amount Polyvinylpyrrolidone 10.00 (Kollidon 30) from about 14% to about 94% by weight of the total Dipropylene Glycol 400 pressure-sensitive adhesive composition; Oleic Acid 6.00 65 (ii) polyisobutylene and mixtures thereof in an amount Norethindrome Acetate 3.00 from about 10% to about 90% by weight of the total pressure-sensitive adhesive composition; and 5,656.286 61 62 (iii) polysiloxane and mixtures thereof in an amount 12. The transdermal drug delivery system according to from about 5% to about 95% by weight of the total claim 1, wherein the soluble polyvinylpyrrolidone has a pressure-sensitive adhesive composition; molecular weight from about 7,000 to about 54,000. (b) a soluble polyvinylpyrrolidone in an amount from 13. The transdermal drug delivery system according to about 1% to about 20% by weight of the total pressure claim 4, wherein said drug is present in said system from sensitive adhesive composition; about 0.1% to about 50% by weight of the total pressure (c) one drug or a mixture of two or more drugs; and sensitive adhesive layer. (d) optionally, an enhancer in an amount up to about by 14. The transdermal drug delivery system acoording to weight of the total pressure-sensitive adhesive compo claim 4, wherein said blend further contains at least one sition. 10 enhancer. 2. The transdermal drug delivery system according to 15. The transdermal drug delivery system according to claim 1, wherein the pressure-sensitive adhesive is a pol claim 14, wherein said enhancer is present in said system ysiloxane. from about 1% to about 20% by weight of the total pressure 3. A transdermal drug delivery system according to claim sensitive adhesive composition. 1, wherein said blend further contains at least one enhancer. 4. A transdermal drug delivery system comprising a 15 16. The transdermal drug delivery system of claim 4, pressure-sensitive adhesive composition, wherein said com further comprising a clay. position comprises of a blend of 17. The transdermal drug delivery system of claim 16, (a) a pressure-sensitive adhesive selected from the group wherein said clay is bentonite. consisting of 18. The transdermal drug delivery system of claim 4, (i) polyisoprene, polystyrene, polyethylene, wherein said drug is a steroid. polybutadiene, polyethylene/butylene, styrene/ 19. The transdermal drug delivery system of claim 18, butadiene, styrene-butadiene-styrene, styrene wherein said steroid is an estrogen selected from the group isoprene-styrene, styrene-ethylene/butylene-styrene consisting of colpormon, equilenin, estradiol benzoate, block copolymers, butyl rubber, estradiol 173-cypionate, moxestrol, mytatrienediol, polytetrafluoroethylene, polyvinyl chloride, polyvi 25 quinestradiol, quinestrol, estropipate, 78-estradiol, equilin, nylidene chloride, polychloroprene, polyacryloni mestranol, estrone, estriol, ethinyl estradiol and diethylstil trile and polychlorodiene, and mixtures thereof, in an bestrol. amount from about 14% to about 94% by weight of 20. The transdermal drug delivery system of claim 19, the total pressure-sensitive adhesive composition; wherein said estrogen is 17B-estradiol, and wherein said (ii) polyisobutylene and mixtures thereof in an amount 30 17B-estradiol is presentin said system in an amount of from from about 10% to about 90% by weight of the total about 0.1% to about 5% by weight. pressure-sensitive adhesive composition; and 21. The transdermal drug delivery system of claim 18, (iii) polysiloxane and mixtures thereof in an amount wherein said steroid is a progestational agent. from about 5% to about 95% by weight of the total 22. The transdermal drug delivery system of claim 21, pressure-sensitive adhesive composition; 35 wherein said progestational agent is selected from the group (b) a polyacrylate in an amount from about 5% to about consisting of progesterone, 19-norprogesterone, 85%, wherein said polyacrylate and said pressure norethindrone, norethindrone acetate, melengestrol, sensitive adhesive (a) differ in solubility parameter by chlormadinone, ethisterone, medroxyrogesterone acetate, an increment of at least 2 (J/cm)'; hdroxyprogesterone caproate, ethynodiol diacetate, (c) a soluble polyvinylpyrrolidone in an amount from 40 norethynodrel, 17o-hydroxyprogesterone, dydrogesterone, about 1% to about 20% by weight of the total pressure dimethisterone, ethinylestrenol, norgestrel, demegestone, sensitive adhesive composition; promegestone and megestrol acetate. (d) one drug or a mixture of two or more drugs; and 23. The transdermal drug delivery system of claim 22, (e) optionally, an enhancer in an amount up to about 20% wherein said progestational agent is norethindrone acetate, by weight of the total pressure-sensitive adhesive com 45 and wherein said norethindrone acetate is present in said position. system in an amount of from about 1% to about 5% by 5. The transdermal drug delivery system of claim 4 which weight. is in a defined geometric shape. 24. The transdermal drug delivery system of claim 18, 6. The transdermal drug delivery system of claim 5 which wherein said system comprises a mixture of a progestational is in the form of a sheet. 50 agent and an estrogen. 7. The transdermal drug delivery system of claim 5 which 25. The transdermal drug delivery system of claim 24, is in the form of an individual dosage unit. wherein said progestational agent is selected from the group 8.The transdermal drug delivery system of claim 4 further consisting of progesterone, 19-norprogesterone, comprising a backing material Superimposed on one surface norethindrone, norethindrone acetate, melengestrol, of said pressure sensitive adhesive composition, said back 55 chlormadinone, ethisterone, medroxyprogesterone acetate, ing material being substantially impermeable to said drug hydroxyprogesterone caproate, ethynodiol diacetate, contained therein. norethynodrel, 170-hydroxyprogesterone, dydrogesterone, 9. The transdermal drug delivery system of claim.8further dimethisterone, ethinylestrenol, norgestrel, demegestone, comprising a release liner superimposed on a surface of said promegestone and megestrol acetate. pressure sensitive adhesive composition opposite said back 26. The transdermal drug delivery system of claim 25. ing material. wherein said progestational agent is norethindrone acetate. 10. The transdermal drug delivery system of claim 4, 27. The transdermal drug delivery system of claim 24, wherein said system is a reservoir device having an adhesive wherein said estrogen is selected from the group consisting portion comprised of said blend. of colpormon, equilenin, estradiol benzoate, estradiol 17B 11. The transdermal drug delivery system according to 65 cypionate, moxestrol, mytatrienediol, quinestradiol, claim 4, wherein the pressure-sensitive adhesive is a pol quinestrol, estropipate, 173-estradiol, equilin, mestranol, ysiloxane. estrone, estriol, ethinyl estradiol and diethylstilbestrol. 5,656,286 63 64 28. The transdermal drug delivery system of claim 27, 47. The transdermal drug delivery system of claim 4, wherein said estrogen is 17B-estradiol. wherein said drug is an analgesic. 29. The transdermal drug delivery system of claim 4, 48. The transdermai drug delivery system of claim 47. wherein said drug is a B-adrenergic agonist. wherein the analgesic is selected from the group consisting 30. The transdermal drug delivery system of claim 29. offentanyl, buprenorphine, codeins, baclofen and Sumatrip wherein said B-adrenergic agonist is selected from the tan. group consisting of metaproterenol, terbutaline, albuterol, 49. The transdermal drug delivery system of claim 4, carbuterol, rimiterol, samefamol, fenoterol, soterenol, tra wherein said drug has an action on the central nervous toquinol and quinterenol. System. 31. The transdermal drug delivery system of claim 30, 50. The transdermal drug delivery system of claim 49, wherein said B-adrenergic agonist is albuterol, and wherein 10 wherein the drug is nicotine, methylphenidate and tacrine. said albuterol is present in the system in an amount of less 51. The transdermal drug delivery system of claim 4, than about 30% by weight. wherein said drug is a vasodilator. 32. The transdermal drug delivery system of claim 4, 52. The transdermal drug delivery system of claim 51, wherein said drug is a cardioactive agent. wherein said drug is papaverine. 33. The transdermal drug delivery system of claim 32, 15 53. The transdermal drug delivery system of claim 4, wherein the cardioactive agent is selected from the group comprising at least two drugs. consisting of nitroglycerin, isosorbide dinitrate, isosorbide 54. The transdermal drug delivery system of claim 18, mononitrates, quinidine sulfate, procainamide, wherein said steroid is selected from the group consisting of benzy droflumethiazide, ben droflume thiazide, fluoxymesterone, 17-methyl testosterone, 17 O.- chlorothiazide, nifedipline, nicardipine, Verapamil, 20 methyltestosterone 3-cyclopenty enol ether, oxymetholone, diltiazem, timolol, propranolol, captopril, clonidine, Stanozolol, testosterone, testosterone 17B-cypionate, test prazosin, enalapril, enalaprilat, fosinopril, indapamide, osterone enanthate, testosterone propionate. lisinopril, quinapril and ramipril. 55. The transdermal drug delivery system of claim 4, 34. The transdermal drug delivery system of claim 33, wherein the drug is an antiparkinsonian. wherein the cardioactive agent is nitroglycerin, and wherein 25 56. The transdermal drug delivery system of claim 55, said nitroglycerin is present in said system in an amount of wherein said antiparkinsonian is selected from the group less than about 25% by weight. consisting of pergolide and deprenyl. 35. The transdermal drug delivery system of claim 4, 57. The transdermai drug delivery system of claim 4, wherein Said drug is a cholinergic agonist. wherein the drug is a non-steroidal anti-inflammatory. 36. The transdermal drug delivery system of claim 35, 30 58. The transdermal drug delivery system of claim 57. wherein said cholinergic agonist is selected from the group wherein said non-steroidal anti-inflammatory is selected consisting of choline, acetylcholine, methacholine, from the group consisting of diclofenac, fenoprofen, carbachol, bethanechol, pilocarpine, muscarine and furbiprofen, ibuprofen, ketoprofen, ketorolac, nahumstone, arecoline. naproxen and piroxicam. 37. The transdermal drug delivery system of claim 36, 35 59. The transdermal drug delivery system of claim 4, wherein said cholinergic agohist is pilocarpine, and wherein wherein the drug is an anorectic. Said pilocarpine is present in said system in an amount of 60. The transdermal drug delivery system of claim 59, less than about 30% by weight. wherein said anorectic is selected from the group consisting 38. The transdermal drug delivery system of claim 4, of fenfluramine, mazindol and phentermine. wherein said drug is a tranquilizer. 40 61. The transdermal drug delivery system of claim 4, 39. The transdermal drug delivery system of claim 38, wherein the drug is a glucocorticoid selected from the group wherein said tranquilizer is selected from the group consist consisting of a clometas one, becomethas one, ing of alprazolam, chlordiazepoxide, clorazeptate, betamethas one, clobetasol, cortisone, desonide, halazepam, Oxazepam, prazepam, clonazepam, flurazepam, desoximetasone, flunisolide, fluocinolone acetonide, triazolam, lorazepam and diazepam. 45 flurandrenolide, mometasone furdate, prednisolone and 40. The transdermal drug delivery system of claim 39, prednisone. wherein said tranquilizer is alprazolam. 62. The transdermal drug delivery system of claim 4, 41. The transdermal drug delivery system of claim 4, wherein the drug is an antinauseant selected from the group wherein said drug is an antipsychotic. consisting of granisetron, ondanseteron and scopolamine. 42. The transdermal drug delivery system of claim 41, 50 63. The transdeal drug delivery. System of claim 4, wherein said antipsychotic is selected from the group con wherein the drug is an antibiotic selected from the group sisting of thiopropazate, chlorpromazine, triflupromazine, consisting of tetracyclines. mesoridazine, piperacetazine, thioridazine, acetophenazine, 64. The transdermal drug delivery system of claim 63, flu phena Zine, periphenazine, trifu operazine, wherein said tetracycline is doxycyline. chlorprathixene, thiothixene, haloperidol, bromperidol, lox 55 65. The transdermal drug delivery system of claim 4, apine and molindone. wherein the drug is selected from the group consisting of 43. The transdermal drug delivery system of claim 42, chlorhexidine and metronidazole. wherein said antipsychotic is haloperidol. 66. The transdermal drug delivery system of claim 4, 44. The transdermal drug delivery system of claim 4, wherein the drug is a prostaglandin selected from the group wherein said drug is an anesthetic. 60 consisting of prostaglandin E and prostaglandin E. 45. The transdermal drug delivery system of claim 44, 67. The transdermal drug delivery system of claim 4, wherein said anesthetic is selected from the group consisting wherein the drug is misoprostol. of lidocaine, tetracaine, dyclonine, dibucaine, cocaine, 68. The transdermal drug delivery system of claim 4, procaine, mepivacaine, bupivacaine, etidocaine, prilocaine wherein the drug is an antidiabetic selected from the group and benzocaine. 65 consisting of glypinamide. 46. The transdermal drug delivery system of claim 45, 69. A transdermal drug delivery system according to Wherein said anesthetic is lidocaine. claim 1 made by a process comprising blending 5,656.286 65 66 (a) a pressure-sensitive adhesive selected from the group block copolymers, butyl rubber, consisting of polytetrafluoroethylene, polyvinyl chloride, polyvi (i) polyisoprene, polystyrene, polyethylene, nylidene chloride, polychloroprene, polyacryloni polybutadiene, polyethylene/butylens, styrone/ trile and polychlorodiene, and mixtures thereof, in an butadiene, styrene-butadiene-styrene, styrene amount from about 14% to about 94% by weight of isoprene-styrene, styrene-ethylene?butylene-styrene the total pressure-sensitive adhesive composition; block copolymers butyl rubber, (ii) polyisobutylene and mixtures thereof in an amount polytetrafluoroethylene, polyvinyl chloride, polyvi from about 10% to about 90% by weight of the total nylidene chloride, polychloroprene, polyacryloni pressure-sensitive adhesive composition; and trile and polychlorodiene, and mixtures thereof, in an 10 (iii) polysiloxane and mixtures thereof in an amount amount from about 14% to about 94% by weight of the total pressure-sensitive adhesive composition; from about 5% to about 95% by weight of the total (ii) polyisobutylene and mixtures thereof in an amount pressure-sensitive adhesive composition; from about 10% to about 90% by weight of the total (b) a polyacrylate in an amount from about 5% to about pressure-sensitive adhesive composition; and 15 85%, wherein said polyacrylate and said pressure (iii) polysiloxane and mixtures thereof in an amount sensitive adhesive (a) differ in solubility parameter by from about 5% to about 95% by weight of the total an increment of at least 2 (J/cm)"; pressure-sensitive adhesive composition; (c) a soluble polyvinylpyrrolidone in an amount from (b) a soluble polyvinylpyrrolidone in an amount from about 1% to about 20% by weight of the total pressure about 1% to about 20% by weight of the total pressure 20 sensitive adhesive composition; sensitive adhesive composition; (d) one drug or a mixture of two or more drugs; and (c) one drug or a mixture of two or more drugs; and (e) optionally, an enhancer in an amount up to about 20% (d) optionally, an enhancer in an amount up to about 20% by weight of the total pressure-sensitive adhesive com by weight of the total pressure-sensitive adhesive com 25 position. position. 71. The transdermal drug delivery system according to 70. A transdermal drug delivery system according to claim 4, wherein the soluble polyvinylpyrrolidone has a claim 4 made by a process comprising blending molecular weight from about 5,000 to 100,000. (a) a pressure-sensitive adhesive selected from the group 72. The transdermal drug delivery system of claim 4, consisting of 30 wherein the drug is a mineralcorticoid. (i) polyisoprene, polystyrene, polyethylene, 73. The transdermal drug delivery system of claim 72, polybutadiene, polyethylene/butylene, styrene/ wherein said mineralcorticoid is fludrocortisone. butadiene, styrene-butadiene-styrene, styrene isoprene-styrene, styrene-ethylene/butylene-styrene :: *k. : : :