USOO6221383B1 (12) United States Patent (10) Patent No.: US 6,221,383 B1 Miranda et al. (45) Date of Patent: *Apr. 24, 2001
(54) SOLUBILITY PARAMETER BASED DRUG 0-201-828 11/1986 (EP). DELIVERY SYSTEMAND METHOD FOR 208395 1/1987 (EP). ALTERING DRUG SATURATION 0-272-045 6/1988 (EP). CONCENTRATION O-343-807 11/1989 (EP). O371 496 6/1990 (EP). (75) Inventors: Jesus Miranda; Steven Sablotsky, 0-416-8420529123 3/19933/1991 (EP). both of Miami, FL (US) 2 105990 4/1983 (GB). 54-89017 7/1979 (JP). (73) Assignee: Noven Pharmaceuticals, Inc., Miami, 58-225010 12/1983 (JP). FL (US) WO 91/O5529 5/1991 (WO). WO 93/08795 5/1993 (WO). (*) Notice: Subject to any disclaimer, the term of this WO 97/11689 4/1997 (WO). patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. OTHER PUBLICATIONS This patent is Subject to a terminal dis- Sloan, K.B. et al., “Use of Solubility Parameters of Drug and claimer. Vehicle to Predict Flux Through Skin", The Journal of Investigative Dermatology, Vol. 87 (No. 2) pp. 244-252 (21) Appl. No.: 09/318,121 (Aug. 1996). (22) Filed: May 25, 1999 (List continued on next page.) Related U.S. Application Data Primary Examiner. Shelley A. Dodson (60) Division of application No. 08/907,906, filed on Aug. 11, Assistant Examiner Michael A. Williamson 1997,C.'s"E.R.","SE"ES", which is a continuation-in-part of application "S.S.S. No. (74) Attorney, Agent, or Firm-Foley & Lardner (51) Int. Cl." ...... A61F 13/02 (57) ABSTRACT
(52) U.S. C. ------424/449; 424/448 Ablend of at least tWO polymers, Or at least OC polymer and (58) Field of Search ...... 424/448, 449 a Soluble polyvinylpyrrollidone, in combination with a drug provides a preSSure-Sensitive adhesive composition for a (56) References Cited transdermal drug delivery System in which the drug is U.S. PATENT DOCUMENTS delivered from the preSSure-Sensitive adhesive composition and through dermis when the preSSure-Sensitive adhesive 3.969,308 7/1976 Penneck ...... 260/37 SB composition is in contact with human skin. According to the 3,972,995 8/1976 Tsuk et al...... 424/28 invention, Soluble polyvinylpyrrollidone can be used to pre 4,291,015 9/1981 Keith et al...... 424/28 vent crystallization of the drug, without affecting the rate of (List continued on next page.) drug delivery from the pressure-Sensitive adhesive compo Sition. FOREIGN PATENT DOCUMENTS 2O27053 4/1991 (CA). 4 Claims, 19 Drawing Sheets 13
2
11
12 10 US 6,221,383 B1 Page 2
U.S. PATENT DOCUMENTS 5,230,896 7/1993 Yeh et al...... 424/443 5,230898 7/1993 Horstmann et all ... 424/449 4,292,301 9/1981 Keith et al...... 424/28 5,232,702 8/1993 Pfister et al...... 424/448 4,390,520 6/1983 Nagai et al. ... 424/28 5,232,703 8/1993 Blank ...... 424/449
4,438,139 3/1984 Keith et al. . ... 424/28 5,252,334 10/1993 Chiang et al...... 424/448 4,542,013 9/1985 Keith ...... 424/28 5,260,064 11/1993 Nakagawa et al. ... 424/448 4,585,452 4/1986 Sablotsky ... 604/896 5,262,165 11/1993 Govil et al...... 424/448 4,593,053 6/1986 Jevne et al. . 523/111 5,393,529 2/1995 Hoffman et al...... 424/448 4,668.232 5/1987 Cordes et al. . ... 64/897 5,676,968 10/1997 Lippet al.. 4,690,683 9/1987 Chien et al. 604/896 4,693,887 9/1987 Shah ...... 424/19 OTHER PUBLICATIONS 4,696,821 9/1987 Belsole ...... 424/448 4,699,146 10/1987 Sieverding . 128/640 Yu et al., “Transdermal Dual-Controlled Delivery of Test 4,750,482 6/1988 Sieverding . 128/156 osterone and Estradiol: (1) Impact of System Design,” Drug 4,769,013 9/1988 Lorenz et al. . 604/265 Devel, Indust. Pharm. 17(14): 1883–1904 (1991). 4,814,168 3/1989 Sablotsky et al...... 424/78 Ziller et al., “Control of Crystal Growth in Drug Suspen 4,845,081 7/1989 Sloan ------... 514/232.2 Sions,” Pharm. Ind. 52(8): 1017-1022 (1990). 4,883,669 11/1989 Chien et al...... 424/448 Kuhnert-Brandstätter et al., “Kristalisationsvorgänge in 4,906,169 3/1990 Chien et al...... 424/448 : ss organg 4,911,916 3/1990 Cleary ...... 424/449 Suspensionen von Steroidhormonen, Sci. Pharm. 4,931,281 6/1990 Kim et al...... 424/44s 35(4):287–297 (1967). 4,987,893 1/1991 Salamone et al. . 128/156 English translation of Japanese patent application No. 4,994.267 2/1991 Sablotsky ...... 424/78 2–48859, filed Feb. 27, 1990. 5,032,403 7/1991 Sinnreich ... . 424/448 English translation of European Patent Application No. 5,059,189 10/1991 Cilento et al...... 604/307 0–201–828 (1986). 5,071,656 12/1991 Lee et al...... 424/448 “The Merck Index, An Encyclopedia of Chemicals, Drugs, 5,122,5435,128,138 6/19927/1992 BlankKhanna ...... 514/772.5 424/449 And Biologicals.”- 1 - - - - 1 - ? (Budavariet al., eds.) pp. 391-392, (11 ti 5,141,750 8/1992 Lee et al. ... 424/44s. Ed. Merck & Co. 1989). 5,151,271 9/1992 Otsuka et al. . 424/443 Farley, D. “Estrogens.” FDA Consumer (page numbers 5,154,922 10/1992 Govil et al...... 424/448 unknown) (Nov. 1990). U.S. Patent Apr. 24, 2001 Sheet 1 of 19
FIG. 1
2 %
PRODUCT O Int Apr. 24, 2001 Sheet 2 of 19
OO rh O CO on co r CN ON CN via as
O Int Apr. 24, 2001 Sheet
d cs cs C) cs
-N -C > U.S. Patent Apr. 24, 2001 Sheet 7 of 19 US 6,221,383 B1 N - Ol SE CC X i i i IHI s i IH" 3 S s S. U.S. Patent Apr. 24, 2001 Sheet 8 of 19 Ll L. L. Š I Z s Apr. 24, 2001 Sheet 9 of 19 a >< N Nr O O Int Apr. 24, 2001 Sheet 10 0f 19 CN od r Co co CN oo r- O co CN CN on r- - -- -R al 2S S - 9 d U.S. Patent Apr. 24, 2001 Sheet 13 of 19 US 6,221,383 B1 ÅLITIGñTOSLENHELBWVHwdv(ºvu10||20)?/ U.S. Patent Apr. 24, 2001 Sheet 15 of 19 US 6,221,383 B1 V97„ulepensaETdWWXEDO BTdWWXE77O U.S. Patent Apr. 24, 2001 Sheet 19 of 19 US 6,221,383 B1 96 97ETCHWV/XH |6ETdWW.XE Z/ 03’30/-/ US 6,221,383 B1 1 2 SOLUBILITY PARAMETER BASED DRUG Crystal size and distribution thus become important DELIVERY SYSTEMAND METHOD FOR parameters which must be controlled in order to control ALTERING DRUG SATURATION delivery. These parameters are, however, usually difficult to CONCENTRATION control. Failure to control crystal size and distribution can result in products whose appearance Suggests that the manu CROSS-REFERENCE TO RELATED facturing process by which they are produced is not under APPLICATION control. More importantly, the presence of large crystals, This application is a divisional application of Ser. No. particularly in excessive amounts, can be detrimental to 08/907,906 filed Aug. 11, 1997 which is a continuation of adhesive-type transdermals. Crystals on the Surface of the Ser. No. 08/178,558 filed Jan. 7, 1994, now U.S. Pat. No. adhesive System can result in loSS of tack. Furthermore, 5,656,286 granted Aug. 12, 1997. 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 15 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 polyvinylpyrrolidone having differing Solubility parameters, 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. 25 of the drug in the multiple polymer adhesive System. The use of a transdermal composition, for example a It is also an object of this invention to provide a trans preSSure-Sensitive adhesive containing a medicament, dermal drug delivery System wherein the multiple polymer namely, a drug, as a means of controlling drug delivery adhesive System is simple to manufacture. through the skin at essentially a constant rate, is well known. It is a further object of this invention to provide a Such known delivery Systems involve incorporation of a transdermal drug delivery System wherein drug-loading of a medicament into a carrier Such as a polymeric matrix and/or multiple polymer adhesive System may be selectably varied a pressure-Sensitive adhesive formulation. The pressure without adverse effects on drug delivery rate and adhesive sensitive adhesive must adhere effectively to the skin and properties, Such as adhesion, tack, and Shear resistance. permit migration of the medicament from the carrier through It is additionally an object of this invention to provide a the skin and into the bloodstream of the patient. 35 transdermal drug delivery System wherein a novel multiple Drug concentration in a monolithic transdermal delivery polymer adhesive System is provided which has desirable System can vary widely depending on the drug and polymers physical properties. used. For example, certain drugs are effective in low doses and therefore the transdermal formulation may involve low SUMMARY OF THE INVENTION concentrations, illustratively 5% or less by weight of the 40 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 45 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 50 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 “polyvinylpyrrollidone,” or “PVP" refers to a There is a need in the art for an adhesive composition for 55 polymer, either a homopolymer or copolymer, containing transdermal drug delivery Systems which can Selectably N-vinylpyrrollidone as the monomeric unit. Typical PVP incorporate low concentrations of drug and deliver Same at polymers are homopolymeric PVPs and the copolymer vinyl an adequate and controlled rate or incorporate high concen acetate vinylpyrrolidone. The homopolymeric PVPs are trations of drugs while retaining good physical adhesive known to the pharmaceutical industry under a variety of properties. 60 designations including Po Vidone, Poly Vidone, In transdermal drug delivery Systems, the presence of Polyvidonum, Polyvidonum solubile, and Poly(1-vinyl-2- crystals (drugs and/or additives) is generally undesirable. If pyrrolidone). The copolymer vinyl acetate vinylpyrrolidone the drug is present in crystalline form, it is not available for is known to the pharmaceutical industry as CopolyVidon, release from the System, and therefore not available for CopolyVidone, and CopolyVidonum. delivery. Moreover, although drug crystals can first dissolve 65 The term “soluble' when used with reference to PVP and then release from the System, Such a proceSS is usually means that the polymer is Soluble in water and generally is rate-limiting and tends to reduce delivery. not Substantially croSS-linked, and has a molecular weight of US 6,221,383 B1 3 4 less than about 2,000,000. See, generally, Bihler, KOLLI The pressure-Sensitive adhesive compositions may further DON (R): 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 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, 1O 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 15 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. 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 whether the rate of release is to be enhanced or retarded. parameter, and a polyacrylate polymer having a Second 25 In particularly preferred embodiments, the drug is a Solubility parameter, the first and Second Solubility param Steroid, 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 f-adrenergic agonist, Such as albuterol, or a a characteristic net Solubility parameter. 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 35 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, 40 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 45 which modifies the delivery rate of the drug from the acrylate polymer is preferably present in an amount ranging preSSure-Sensitive adhesive diffusion matrix and through the from about 5% to about 85%. Preferably, the ratio of the dermis. polyacrylate polymer to the rubber-based pressure-Sensitive adhesive is from about 2:98 to about 96:4, and more BRIEF DESCRIPTION OF THE DRAWINGS preferably from about 2:98 to about 86:14 by weight. 50 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 55 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 while the polyacrylate polymer is preferably present in an transdermal drug delivery composition of the present inven amount ranging from about 5% to about 85%. Preferably, the tion (formulation of Example 1) and two commercially ratio of the polyacrylate polymer to the rubber-based 60 available nitroglycerin-containing transdermal delivery pressure-sensitive adhesive is from about 2:98 to about 96:4, devices: Transderm-Nitro(R) (a trademark of Ciba-Geigy and more preferably from about 2: 98 to about 86:14 by Corporation, Summit, N.J.), and Nitro-Dur(R) (a trademark of weight. Key Pharmaceuticals, Inc., Kenilworth, N.J.); In both binary and ternary blends, soluble PVP is prefer FIG. 3 is a graphical representation which Summarizes in ably present in the pressure-Sensitive adhesive composition 65 Vitro nitroglycerin flux results through cadaver Skin for the in an amount ranging from about 1% to about 20% by polymeric Systems of Examples 2-5. The composition of weight of the total pressure-Sensitive adhesive composition. Example 2 (polyacrylate-only adhesive) is compared to the US 6,221,383 B1 S 6 multiple polymer compositions of Examples 3, 4, and 5, in FIG. 17 shows estradiol flux through the human epidermis which the polyacrylate is blended with an ethylene vinyl from a PVP-containing compositions of this invention; acetate, a polyisobutylene, and a polysiloxane, respectively; FIG. 18 shows norethindrone flux through human epider FIG. 4 is a graphical representation of the Steady-state mis in a composition of this invention containing estradiol nitroglycerin flux through cadaver skin in vitro from a and soluble PVP; FIG. 19 shows average estradiol and norethindrone multiple polymer transdermal adhesive System of Example acetate flux from a composition of this invention containing 6 comprising various weight ratioS of polyacrylate and varying concentrations of soluble PVP; and polysiloxane, FIG. 20 shows the effect of Soluble PVP on estradiol flux FIG. 5 is a graphical representation of Steady-state estra through human epidermis. diol flux through cadaver skin in vitro from the drug delivery Systems of the prior art, Specifically single polymeric adhe DETAILED DESCRIPTION OF PREFERRED Sives of Silicone and acrylic, as compared to a multiple EMBODIMENTS polymer transdermal adhesive System (polyacrylate/ In one aspect of the present invention, a preSSure-Sensitive polysiloxane) of the present invention; adhesive composition is provided which comprises a blend 15 of at least two polymers and a soluble PVP, and a drug. The FIG. 6 is a graphical representation of average estradiol blend of at least two polymerS is herein referred to as a flux through cadaver skin in vitro from 0 to 22 hours and multiple polymer adhesive system. The term “blend” is used from 22 to 99 hours for a multiple polymer transdermal herein to mean that there is no, or Substantially no, chemical adhesive System comprising various weight ratioS of poly reaction or cross-linking (other than simple H-bonding) acrylate and polysiloxane, between the different polymers in the multiple polymer FIG. 7 is a graphical representation of Steady-state nore adhesive System. thindrone acetate flux through cadaver skin in vitro from the AS used herein, the term “preSSure-Sensitive adhesive” drug delivery Systems of the prior art, Specifically Single refers to a Viscoelastic material which adheres instanta polymeric adhesives of Silicone and acrylic, as compared to neously to most Substrates with the application of very slight a multiple polymer transdermal adhesive System preSSure and remains permanently tacky. A polymer is a (polyacrylate/polysiloxane) of the present invention; 25 preSSure-Sensitive adhesive within the meaning of the term FIG. 8 is a graphical representation of average estradiol as used herein if it has the properties of a pressure-Sensitive and norethindrone acetate flux through cadaver skin in vitro adhesive perse or functions as a pressure-Sensitive adhesive for a multiple polymer transdermal adhesive System com by admixture with tackifiers, plasticizers or other additives. prising both drugs and various weight ratios of polyacrylate The term preSSure-Sensitive adhesive also includes mix and polysiloxane, tures of different polymers and mixtures of polymers, Such FIG. 9 is a graphical representation showing the ratio of as polyisobutylenes (PIB), of different molecular weights, average estradiol to norethindrone acetate flux (estradiol flux wherein each resultant mixture is a pressure-Sensitive. In the divided by norethindrone acetate flux) through cadaver skin last case, the polymers of lower molecular weight in the in vitro for a multiple polymer transdermal adhesive System 35 mixture are not considered to be "tackifiers,” said term being comprising various weight ratioS of polyacrylate and pol reserved for additives which differ other than in molecular ySiloxane, weight from the polymers to which they are added. FIG. 10 is a graphical representation of steady-state flux AS used herein, the term “rubber-based pressure-Sensitive of pilocarpine through cadaver skin in vitro from the drug adhesive” refers to a viscoelastic material which has the delivery Systems of the prior art, Specifically single poly 40 properties of a pressure-Sensitive adhesive and which con meric adhesives of Silicone and acrylic, as compared to a tains at least one natural or Synthetic elastomeric polymer. multiple polymer transdermal adhesive System AS used herein, the term “drug, and its equivalent, (polyacrylate/polysiloxane) of the present invention; “bioactive agent,” is intended to have its broadest interpre FIG. 11 is a graphical representation of Steady-state tation as any therapeutically, prophylactically and/or phar albuterol and nitroglycerinflux through cadaver skin in vitro 45 macologically or physiologically beneficial active from multiple polymer transdermal adhesive Systems Substance, or mixture thereof, which is delivered to a living (polyacrylate/polysiloxane) of the present invention organism to produce a desired, usually beneficial, effect. (Examples 24–27), and Nitro-Dur(R), respectively; More Specifically, any drug which is capable of producing FIG. 12 is a graphical representation of Steady-state a pharmacological response, localized or Systemic, irrespec estradiol flux through cadaver skin in vitro from two differ 50 tive of whether therapeutic, diagnostic, or prophylactic in ent multiple polymer transdermal adhesive Systems nature, in plants or animals is within the contemplation of polyacrylate/polysiloxane and polyacrylate/polybutylene; the invention. Also within the contemplation of the inven FIGS. 13 and 14 show the relationship of flux rate (J) tion are Such bioactive agents as pesticides, insect repellents, plotted against apparent diffusion coefficient (D) and net Sun Screens, cosmetic agents, etc. It should be noted that the 55 drugs and/or bioactive agents may be used Singly or as a solubility parameter (SP), respectively, for Compositions mixture of two or more Such agents, and in amounts Suffi I-VI of Example 6. The net solubility parameter, SP, was cient to prevent, cure, diagnose or treat a disease or other calculated using a weighted average of the Solubility param condition, as the case may be. eters of the individual polymers comprising the matrix: The multiple polymer adhesive not only functions as a SPe=(Ps. SP+(PSP, 60 carrier matrix for the drug, but enhances the rate of release where (E is the weight percentage of polysiloxane and SP. of the drug, and hence the transdermal permeation rate. In is the Solubility parameter of polysiloxane. The Subscript Some embodiments of the invention, however, the multiple “pa” refers to the polyacrylate; polymer adhesive System will function to retard the trans FIG. 15 is a plot of diffusion coefficient versus net dermal permeation rate. Solubility parameter; 65 A soluble PVP is blended with one or more other poly FIG. 16 shows the average flux of estradiol for two mers in order to further modulate the transdermal perme compositions of this invention containing a soluble PVP; ation rate of the drug. US 6,221,383 B1 7 8 An important aspect of the present invention is the discovery that the transdermal permeation rate of a drug TABLE IA from the multiple polymer adhesive System can be selec tively modulated by adjusting the solubility of the drug in Solubility Parameter the device. AS used herein, the term “transdermal perme Polymers (cal/cm)4 (J/cm)4 ation rate” means the rate of passage of the drug through the skin; which, as known in the art, may or may not be affected Addition polymers of by the rate of release of the drug from the carrier. unsaturated esters The polymers comprising the multiple polymer adhesive Polymethyl methacrylate 9.3 9.O System are preferably inert to the drug, and are preferably 1O Polyethylmethacrylate 9.1 8.6 Polymethylacrylate 9.7 9.8 immiscible with each other, as can be Surmised by their Polyethylacrylate 9.2 8.8 different solubility parameters. Forming a blend of multiple Hydrocarbon polymers polymers results in an adhesive System having a character istic “net solubility parameter,” the selection of which Polyethylene 8.1 6.6 15 Polystyrene 9.1 8.6 advantageously permits a Selectable modulation of the deliv Polyisobutylene 7.7 5.7 ery rate of the drug by adjusting the Solubility of the drug in Polyisoprene 8.1 6.6 the multiple polymer adhesive System. Polybutadiene 8.4 6.6 Polyethylene/butylene 7.9 6.2 Solubility parameter, also referred to herein as “SP” has Halogen-containing polymers been defined as the Sum of all the intermolecular attractive forces, which are empirically related to the extent of mutual Polytetrafluoroethylene 6.2 2.7 Polyvinylchloride 9.5 9.4 Solubility of many chemical Species. A general discussion of Polyvinylidene chloride 12.2 24.9 Solubility parameters is found in an article by Vaughan, Polychloroprene 9.4 9.2 “Using Solubility Parameters in Cosmetics Formulation,” J. Polyacrylonitrile 12.7 26.O Condensation polymers Soc. Cosmet. Chem., Vol.36, pages 319-333 (1985). Many 25 methods have been developed for the determination of Nylon-66 13.6 27.8 Solubility parameters, ranging from theoretical calculations Epon resin 1004 (epoxy) 9.7 19.8 to totally empirical correlations. The most convenient Polysiloxanes method is Hildebrand's method, which computes the solu bility parameter from molecular weight, boiling point and Polydimethylsiloxane 7.3 14.9 density data, which are commonly available for many mate Copolymers rials and which yields values which are usually within the Polybutadiene-co-acrylonitrile: 9.25 18.9 range of other methods of calculation: 75/25 to 70/30 Polybutadiene-co-styrene: 8.5 17.4 75/25 to 72/28 35 excerpted from Kraton (R) Thermoplastic Rubber Shell Chemical Co. Prod where V=molecular weight/density and AE=energy of uct Brochure Number SC: 198-89 Vaporization. Alternatively written, SP=(AH/V-RT/V)' where AH= Table I-B below sets forth solubility parameters calcu heat of vaporization, R=gas constant, and T is the absolute lated by Fedors method and are expressed in units of temperature, K. For materials, Such as high molecular 40 (J/cm)'. weight polymers, which have vapor pressures too low to detect, and thus for which AH is not available, several TABLE I-B methods have been developed which use the summation of atomic and group contributions to AH: Solubility Parameter 45 Components (J/cm)4 ethylene/vinyl acetate 20.9 (40% VAC) polydimethylsiloxane 15.1 where Ah, is the contribution of the ith atom or group to the polyisobutylene 17.6 molar heat of vaporization. One convenient method has been polyethylene 17.6 proposed by R. F. Fedors, Polymer Engineering and 50 polyethyl methacrylate 19.8 polyethyl acrylate 20.9 Science, Vol. 14, p. 147 (1974). In this method AE, and Vare polymethyl acrylate 21.7 be obtained by Simply assuming that polymethyl methacrylate 22.3 polystyrene 22.5 AEv=X Ae, and V=X, vi, nitroglycerin 27.0 55 estradiol 24.5 where Ae, and V are the additive atomic and group contri norethindrone acetate 21.3 butions for the energy of vaporization and molar Volume, pilocarpine 22.9 respectively. albuterol 26.7 Yet another method of calculating the Solubility parameter of a material is described by Small, J. Applied Chem. Vol. 3, 60 In accordance with the principles of the invention, the p. 71 (1953). transdermal permeation rate is controlled by varying the Table I-A below sets forth solubility parameters of some polymer components of a ternary multiple polymer adhesive exemplary adhesive polymers which would be useful in the System So as to alter the difference in the Solubility param practice of the invention and shows the variation of SP with eter of the multiple polymer adhesive System relative to that molecular weight, free -OH and -COOH groups, the 65 of the drug (see Examples 2-5, or 28 and 29, hereinbelow). degree of cross-linking. Table IA is in (cal/cm)' and The solubility parameters of a rubber-based pressure (J/cm)' as calculated by Small's method. Sensitive adhesive and a polyacrylate polymer are different US 6,221,383 B1 10 from one another by an increment of at least 2 (J/cm)'. Solubility parameter difference results in a lower Saturation Most preferably they differ by at least 4 (J/cm)' concentration for nitroglycerin, and thereby a greater ther The transdermal permeation rate is also controlled by modynamic driving force. Conversely, the composition of varying the relative proportions of the polymers comprising the multiple polymer adhesive System can be selected So that the multiple polymer adhesive System (see Example 6 the Saturation concentration of the drug in the System is hereinbelow). modified, So the rate of delivery is retarded, Such as would The multiple polymer adhesive system is preferably for be desirable for administration of Scopolamine or nicotine. mulated So that it is a pressure-Sensitive adhesive at room Advantageously, the method and composition of the temperature and has other desirable characteristics for adhe present invention permit Selectable loading of the drug in the Sives used in the transdermal drug delivery art. Such char transdermal drug delivery System. The concentration by acteristics include good adherence to skin, ability to be weight of the drug in the transdermal drug delivery System peeled or otherwise removed without Substantial trauma to is preferably about 0.1 to about 50 percent, more preferably the Skin, retention of tack with aging, etc. In general, the about 0.1 to about 40 percent, and even more preferably multiple polymer adhesive System should have a glass about 0.3 to about 30 percent, Said percentages being based transition temperature (T), measured using a differential 15 on the total weight of the transdermal drug delivery System. scanning calorimeter, of between about -70° C. and 0° C. Irrespective of whether there is high-loading or low-loading Selection of the particular polymer composition is gov of the drug into the transdermal drug delivery System, the erned in large part by the drug to be incorporated in the preSSure-Sensitive adhesive composition of the present device, as well as the desired rate of delivery of the drug. invention can be formulated to maintain acceptable shear, Those skilled in the art can readily determine the rate of tack, and peel adhesive properties. delivery of drugs from the multiple polymer adhesive SyS Although not wishing to be bound by theory, particularly tem in order to Select Suitable combinations of polymers and in this case where the Structure of the composition has not drug for a particular application. Various techniques can be been analyzed, it is postulated that the polymers of varying used to determine the rate of delivery of the drug from the Solubility parameters, for example, the polysiloxane and the polymer. Illustratively, the rate of delivery can be deter 25 polyacrylate, result in a heterogenous mix, with the com mined by measuring the transfer of drug from one chamber ponents of the polymeric mixture performing as a mutually to another through cadaver skin over time, and calculating, interpenetrating polymeric network in the composition. In from the obtained data, the drug delivery or flux rate. other words, the multiple polymer adhesive System is a In a particularly preferred embodiment of the invention, mixture of essentially mutually insoluble or immiscible the multiple polymer adhesive System comprises a pressure polymers, in contradistinction to the typical prior art trans Sensitive adhesive blend of an acrylic polymer, a Silicone dermal drug delivery Systems derived from a single polymer polymer, and a soluble PVP. The term “acrylic polymer” is or a Solution of mutually Soluble polymers. used here as in the art interchangeably with “polyacrylate,” In the practice of preferred embodiments of the invention, “polyacrylic polymer,” and “acrylic adhesive.” The acrylic the polyacrylate polymer can be any of the homopolymers, based polymer and Silicone-based polymer are preferably in 35 copolymers, terpolymers, and the like of various acrylic a ratio by weight, respectively, from about 2:98 to about acids. In Such preferred embodiments, the polyacrylate 96:4, more preferably from about 2:98 to about 90:10, and polymer constitutes preferably from about 2% to about 95% even more preferably about 2:98 to about 86:14. The amount of the total weight of the total polymer blend, and preferably of acrylic-based (hereinafter referred to broadly as a about 3% to about 90%, and more preferably about 5% to polyarylate) polymer and Silicone-based polymer 40 about 85%, the amount of polyacrylate polymer being (hereinafter referred to broadly as a polysiloxane) is adjusted dependent on the amount and type of drug used. So as to modify the Saturation concentration of the drug in The acrylate polymers useful in practicing the invention the ternary multiple polymer adhesive System in order to are polymers of one or more monomers of acrylic acids and affect the rate of delivery of the drug from the system and other copolymerizable monomers. The acrylate polymers through the skin. 45 also include copolymers of alkyl acrylates and/or methacry In other particularly improved embodiments of the lates and/or copolymerizable Secondary monomers or mono invention, the polyacrylate polymer is present in an amount mers with functional groups. By varying the amount of each ranging from about 5-85% by weight of the composition type of monomer added, the cohesive properties of the and polyisobutylene is present in an amount ranging from resulting acrylate polymer can be changed as is known in the about 14-94% by weight of the composition. In yet another 50 art. In general, the acrylate polymer is composed of at least preferred embodiment, the polyisobutylene is present in an 50% by weight of an acrylate or alkyl acrylate monomer, amount ranging from about 10-90% by weight of said from 0 to 20% of a functional monomer copolymerizable composition and the polysiloxane is present in an amount with the acrylate, and from 0 to 40% of other monomers. ranging from about 5-95% by weight of said composition. Acrylate monomers which can be used include acrylic The adjustment to the Saturation concentration of the drug 55 acid, methacrylic acid, butyl acrylate, butyl methacrylate, in the multiple polymer adhesive System can either be an hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, increase or a decrease. It has been found that when a 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl polyacrylate having a solubility parameter SP of about 21 methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl (J/cm)' is used as the principal polymer of a nitroglycerin methacrylate, decyl acrylate, decyl methacrylate, dodecyl (SP about 27 (J/cm)') monolithic system, a significant 60 acrylate, dodecyl methacrylate, tridecyl acrylate, and tride increase in the transdermal permeation rate of nitroglycerin cyl methacrylate. can be achieved by the addition of a polymer having a lower Functional monomers, copolymerizable with the above Solubility parameter, for example a polysiloxane (SP about alkyl acrylates or methacrylates, which can be used include 15 (J/cm)'). By reducing the “net” solubility parameter of acrylic acid, methacrylic acid, maleic acid, maleic the multiple polymer transdermal adhesive System, the dif 65 anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, ference between the Solubility parameter of nitroglycerin acrylamide, dimethylacrylamide, acrylonitrile, dimethy and the multiple polymer adhesive system is modified. This laminoethyl acrylate, dimethylaminoethyl methacrylate, US 6,221,383 B1 11 12 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 Phole drine, Propylhexe drine, Pseudoephe drine, Rilmenidine, Synephrine, Tetrahydrozoline, Tiamenidine, Satas, “Acrylic Adhesives,” Handbook of Pressure-Sensitive TramaZoline, Tuaminoheptane, Tymazoline, Tyramine and Adhesive Technology 2nd ed., pp. 396-456 (D. Satas, ed.), Xylometazoline. Van Nostrand Reinhold, New York (1989). 2. B-Adrenergic agonists Such as Albuterol, Bambuterol, Suitable acrylic adhesives are commercially available and Bitolterol, Carbuterol, Clenbute rol, Clorprenaline, include the polyacrylate adhesives Sold under the trademarks Denopamine, Dioxethedrine, Dopexamine, Ephedrine, Duro-Tak 80-1194, Duro-Tak 80-1196, and Duro-Tak Epinephrine, Etafedrine, Ethylnorepinephrine, Fenoterol, 80-1197 by National Starch and Chemical Corporation, Formoterol, HeXoprenaline, Ibopamine, Isoetharine, Bridgewater, N.J. Other suitable acrylic adhesives are those Isoprote renal, Mabute rol, Metaprote renol, sold under the trademarks Gelva-Multipolymer Solution Methoxyphenamine, Oxyfedrine, Pirbuterol, Prenalterol, (GMS) 737 or 788 (Monsanto; St. Louis, Mo.). 15 Procaterol, Protokylol, Reproterol, Rimiterol, Ritodrine, The rubber-based pressure-sensitive adhesives useful in Soterenol, Terbuterol and Xamoterol. practicing the invention include hydrocarbon polymerS Such 3. C.-Adrenergic blockerS Such as AmoSulalol, Arotinolol, as natural and Synthetic polyisoprene, polybutylene and Dapiprazole, Doxazosin, Ergoloid MeSylates, Fenspiride, polyisobutylene, Styrene/butadiene polymerS Styrene Indoramin, Labetalol, Nicergoline, PraZosin, Terazosin, isoprene-styrene block copolymers, hydrocarbon polymers Tolazoline, Trimazosin and Yohimbine. Such as butyl rubber, halogen-containing polymerS Such as 4. B-Adrenergic blockerS Such as Acebutolol, Alprenolol, polyacrylic - nitrile, polyte trafluoroethylene, Amosulalol, Arotinolol, Atenolol, Befunolol, Betaxolol, polyvinylchloride, polyvinylide ne chloride, and Bevantolol, Bisoprolol, Bopindolol, Bucumolol, Belfetolol, polychlorodiene, and polysiloxanes and other copolymers Bufuralol, Bunitrolol, Bupranolol, Butidrine Hydrochloride, thereof. 25 Butofilolol, Carazolol, Carteolol, Carvedilol, Celiprolol, Suitable polysiloxanes include Silicone pressure-Sensitive Cetamolol, Cloranolol, Dilevalol, Epanolol, Esmolol, adhesives which are based on two major components: a Inde nolol, Labe talol, Levobunolol, Mepindolol, polymer, or gum, and a tackifying resin. The polysiloxane Metipranalol, Metoprolol, Moprolol, Nadoxolol, Nifenalol, adhesive is usually prepared by croSS-linking the gum, Nipradillol, Oxprenolol, Penbutolol, Pindolol, Practolol, typically a high molecular weight polydiorganosiloxane, Pronethalol, Propranolol, Sotalol, Sulfinalol, Talinolol, with the resin, to produce a three-dimensional Silicate Tertatolol, Timolol, Toliprolol and Xibenolol. Structure, via a condensation reaction in an appropriate 5. Alcohol deterrents Such as Calcium Cyanamide organic Solvent. The ratio of resin to polymer is the most Citrated, Disulfiram, Nadide and Nitrefazole. important factor which can be adjusted in order to modify 6. Aldose reductase inhibitorS Such as Epalrestat, the physical properties of polysiloxane adhesives. Sobieski, 35 Ponalrestat, Sorbinil and Tolrestat. et al., “Silicone Pressure Sensitive Adhesives,” Handbook of 7. Anabolics Such as Androisoxazole, Androstenediol, Pressure-Sensitive Adhesive Technology, 2nd ed., pp. Bolandiol, Bolasterone, Clostebol, Ethylestrenol. 508–517 (D. Satas, ed.), Van Nostrand Reinhold, New York Formyldienolone, 4-Hydroxy-19-nortestosterone, (1989). Methandriol, Methenolone, Methyltrienolone, Nandrolone, Further details and examples of Silicone pressure Sensitive 40 Nandrolone De cano ate, Nandrolone adhesives which are useful in the practice of this invention p-HeXyloxyphenylpropionate, Nandrolone Phenpropionate, are described in the following U.S. Patents: U.S. Pat. Nos. Norbolethone, Oxymesterone, Pizotyline, Quinbolone, 4.591,622; 4,584,355; 4,585,836; and 4,655,767. Stenbolone and Trenbolone. Suitable Silicone pressure-Sensitive adhesives are com 8. Analgesics (dental) Such as Chlorobutanol, Clove and mercially available and include the Silicone adhesives Sold 45 Eugenol. under the trademarks BIO-PSA X7-3027, BIO-PSA 9. Analgesics (narcotic) Such as Alfentanil, Allylprodine, X7-4503, BIO-PSAX7-4603, BIO-PSAX7-4301, BIO-PSA Alphaprodine, Anileridine, Benzylmorphine, Bezitramide, X7-4303, BIO-PSA X7-4919, BIO-PSA X7-2685, and BIO Bupre norphine, Butorphanol, ClonitaZene, Codeine, PSA X7-3122 by Dow Corning Corporation, Medical Codeine Methyl Bromide, Codeine Phosphate, Codeine Products, Midland, Mich. BIO-PSA-3027 is particularly 50 Sulfate, DeSomorphine, Dextromoramide, DeZocine, Suitable for use in formulations containing amine-functional Diampromide, Dihydrocodeine, Dihydrocodeinone Enol drugs, Such as albuterol. Acetate, Dihydromorphine, Dimenoxadol, Dimepheptanol, In the practice of preferred embodiments of the invention, Dimethylthiambutene, Dioxaphetyl Butyrate, Dipipanone, the polysiloxane constitutes preferably from about 9% to Eptazocine, Ethoheptazine, Ethylmethly thiambutene, about 97% of the total weight of the total polymer blend, and 55 Ethylmorphine, EtonitaZene, Fentanyl, Hydrocodone, preferably about 8% to about 97%, and more preferably Hydromorphone, Hydroxypethidine, Isomethadone, about 14% to about 94%. Ketobemidone, Levorphanol, Lofentanil, Meperidine, Exemplary of drugs that can be administered by the novel Meptazinol, Metazocine, Methadone Hydrochloride, transdermal drug delivery System of this invention include, Metopon, Morphine, Morphine Derivatives, Myrophine, but are not limited to: 60 Nalbuphine, Narceline, Nicomorphine, Norlevorphanol, 1. C.-Adrenergic agonists Such as Adrafinil, Adrenolone, Normethadone, Normorphine, Norpipanone, Opium, Amidephrine, Apraclonidine, Budralazine, Clonidine, Oxycodone, Oxymorphone, Papaveretum, Pentazocine, Cyclopentamine, Detomidine, Dimetofrine, Dipivefrin, Phenadoxone, Phenazocine, Pheoperidine, Piminodine, Ephedrine, Epinephrine, Fenoxazoline, Guanabenz, Piritramide, Proheptazine, Promedol, Properidine, Guan facine, Hydroxyamphetamine, Ib opamine, 65 Propiram, Propoxyphene, Sufentanil and Tilidine. Indiana Zoline, I Some the ptene, Mephen termine, 10. Analgesics (non-narcotic) Such as Acetaminophen, Meta raminol, Methoxamine Hydro chloride, AcetaminoSalol, Acetanilide, Acetylsalicylsalicylic Acid, US 6,221,383 B1 13 14 Alclofenac, Alminoprofen, Aloxiprin, Aluminum Bis Hydrochloride, Pseudococaine, Pyrrocaine, Quinine Urea (acetylsalicylate), Aminochlorthenoxazin, 2-Amino-4- Hydochloride, Risocaine, Salicyl Alcohol, Tetracaine picoline, Aninopropylon, Aminopyrine, Ammonium Hydrochloride, Thialbarbital, Thimylal, Thiobutabarbital, Salicylate, Antipyrine, Antipyrine Salicylate, Antrafenine, Thiopental Sodium, Tolycaine, Trimecaine and Zolamine. Apa Zone, Aspirin, Benorylate, Benoxaprofen, 13. Anorectics Such as Aminorex, Amphecloral, BenZpiperylon, BenZydamine, p-Bromoacetanilide, Amphetamine, BenZaphetamine, Chlorphen termine, 5-Bromosalicylic Acid Acetate, Bucetin, BufeXamac, Clobenzorex, Cloforex, Clortermine, Cyclexedrine, Destro Bumadizon, Butacetin, Calcium Acetylsalicylate, amphetamine Sulfate, Diethylpropion, Diphemethoxidine, Carbamazepine, Carbetidine, Carbiphene, CarSalam, N-Ethylamphetamine, Fenbu trazate, Fenfluramine, Chloralantipyrine, Chlorthenoxazin(e), Choline Salicylate, Fen prop ore X, Fur furyl methyl ampheta mine, Cinchophen, Ciramadol, Clometacin, Cropropamide, Le Vo phace top e rate, Ma Zind ol, Me fen ore X, Crotethamide, Dexoxadrol, Difenamizole, Diflunisal, Dihy Metamfe pro a mone, Methampheta mine, droxyaluminum Acetylsalicylate, Dipyrocetyl, Dipyrone, Norpseudoephedrine, Phendimetrazine, Phenmetrazine, EmorfaZone, Enfenamic Acid, Epirizole, EterSalate, Phenpentermine, Phenylpropanolamine Hydrochloride and EthenZamide, Ethoxazene, Etodolac, Felbinac, Fenoprofen, 15 Picilorex. Floctafenine, Flufenamic Acid, Fluoresone, Flupirtine, 14. Anthelmintics (Cestodes) Such as Arecoline, Aspidin, FluproduaZone, 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, crine. Ketorolac, p-Lactophenetide, Lefetamine, Loxoprofen, 15. Anthelmintics (Nematodes) Such as Alantolactone, Lysine Acetylsalicylate, Magnesium Acetylsalicylate, AmoScanate, AScaridole, Bephenium, Bitoscanate, Carbon Methotrimeprazine, Metofoline, Miroprofen, Morazone, Tetra chloride, Carva crol, Cyclob end azole, Morpholine Salicylate, Naproxen, Nefopam, Nifenazone, 5' Diethylcarbamazine, Diphenane, Dithiazanine Iodide, Nitro-2' propoxyacetanilide, Parsalmide, Perisoxal, Dymanthine, Gentian Violet, 4-Hexylresorcinol, Kainic Phenacetin, Phenazopyridine Hydrochloride, Phenocol, 25 Acid, Mebendazole, 2-Napthol, Oxantel, Papain, Piperazine, Phenopyrazone, PhenylAcetylsalicylate, Phenyl Salicylate, Piperazine Adipate, Piperazine Citrate, Piperazine Edetate Pheny ramidol, Pipebu Zone, Piperylone, Prodilidine, Calcium, Piperazine Tartrate, Pyrantel, Pyrvinium Pamoate, Propacetamol, PropyphenaZone, Proxazole, Quinine C.-Santonin, Stilbazium Iodide, Tetrachloroethylene, Salicylate, Ramifenazone, Rimazolium Metilsulfate, Tetramisole, thia bendazole, Thy mol, Thy myl Salacetamide, Salicin, Salicylamide, Salicylamide O-Acetic N-Isoamylcarbamate, Triclofenol Piperazine and Urea Acid, Salicylsulfuric Acid, Salsalte, Salverine, Simetride, Stibamine. Sodium Salicylate, Sulfamipyrine, Suprofen, Talniflumate, 16. Anthelmintics (Onchocerca) Such as Ivermectin and Tenoxicam, Terofenamate, Tetradrine, Tinoridine, Tolfe Suramin Sodium. namic Acid, Tolpronine, Tramadol, Viminol, Xenbucin and 17. Anthelmintics (Schistosoma) Such as Amoscanate, Zomepirac. 35 Amphotalide, Antimony Potassium Tartrate, Antimony 11. Androgens Such as Boldenone, Fluoxymesterone, Sodium Gluconate, Antimony Sodium Tartrate, Antimony Mestanolone, Mesterolone, Methandrostenolone, Sodium Thioglycollate, Antimony Thioglycollamide, 17-Methyl testosterone, 17 O.-Methyl testoster one Becanthone, Hycanthone, Lucanthone Hydrochloride, 3 - Cyclope nty 1 Enol Ether, Nore thandrolone, Niridazole, Oxamniquine, Praziquantel, Stibocaptate, Sti Nor methandrone, OXandrolone, Oxyme Sterone, 40 bophen and Urea Stibamine. oxymetholone, Prasterone, Stanlolone, Stanozolol, 18. Anthelmintic (Trematodes) such as Anthiolimine and Testosterone, Testosterone 17-Chloral Hemiacetal, Test Tetrachloroethylene. osterone 17B-Cypionate, Testosterone Enanthate, Testoster 19. Antiacne drugS Such as AlgeStone Acetophenide, one Nicotinate, Testosterone Pheynylacetate, Testosterone AZelaic Acid, Benzoyl Peroxide, CyOctol, Cyproterone, Propionate and Tiomesterone. 45 Motretinide, Resorcinol, Retinoic Acid and Tetroquinone. 12. Anesthetics (intravenous) Such as Acetamidoeugenol, 20. AntiallergicS Such as Amlexanox, Astemizole, Alfadolone Acetate, Alfaxalone, Amucaine, Amolanone, AZelastine, Cromolyn, Fenpiprane, Histamine, Ibudilast, Amylocaine Hydrochloride, BenoXinate, Betoxycaine, Nedocromil, Oxatomide, Pentigetide, Poison Ivy Extract, Biphe namine, Bupivacaine, Butacaine, Butaben, Poison Oak Extract, Poison Sumac Extract, Repirinast, Butanilicaine, Burethamine, Buthalital Sodium, 50 Tranilast, Traxanox and Urushiol. Butoxycaine, Carticaine, 2-Chloroprocaine Hydrochloride, 21. Antiamebics Such as ArSthinol, Bialamicol, Cocaethylene, Cocaine, Cyclomethycaine, Dibucaine CarbarSone, Cephaeline, Chlorbetamide, Chloroquine, Hydrochloride, Dimethisoquin, Dimethocaine, Diperadon Chlorphenoxamide, Chlortetracycline, Dehydroemetine, Hydrochloride, Dyclonine, Ecgonidine, Ecgonine, Ethyl Dibromopropamidine, Diloxanide, DephetarSone, Emetine, Aminobenzoate, Ethyl Chloride, Etidocaine, Etoxadrol, 55 Fumagillin, Glaucarubin, Glycobiarsol, 8-Hydroxy-7-iodo B-Eucaine, Euprocin, Fenalcomine, Fomocaine, 5-quinoline Sulfonic Acid, Iodochlorhydroxyquin, Hexobarbital, Hexylcaine Hydrochloride, Hydroxydione Iodoquinol, Paromomycin, Phanguinone, PhearSone Sodium, Hydroxyprocaine, Hydroxytetracaine, Isobutyl Sulfoxylate, Polybenzarsol, Propamidine, Quinfamide, p-Aminobenzoate, Kentamine, Leucinocaine MeSylate, Secnidazole, Sulfarside, Teclozan, Tetracycline, LeVoxadrol, Lidocaine, Mepivacaine, Meprylcaine 60 Thiocarbamizine, ThiocarbarSone and Tinidazole. Hydrochloride, Metabutoxycaine Hydrochloride, Metho 22. Antiandrogens Such as Bifluranol, Cyoctol, hexital Sodium, Methyl Chloride, Midazolam, Myrtecaine, Cyproterone, Delmadinone Acetate, Flutimide, Nilutamide Nae paine, Octacaine, Orthocaine, OXetha Zaine, and Oxendolone. Parethoxycaine, Phenacaine Hydrochloride, Phencyclidine, 23. Antianginals. Such as Acebutolol, Alprenolol, Phenol, Piperocaine, Piridocaine, Polidocanol, Pramoxine, 65 Amiodarone, Amlodipine, Arotinolol, Atenolol, Bepridil, Prilocaine, Procaine, Propanidid, Propanocaine, Bevantolol, Bucumolol, Bufetolol, Bufuralol, Bunitrolol, Proparacaine, Propipocaine, Propofol, Propoxycaine Bupranolol, Carozolol, Carteolol, Carvedilol, Celiprolol, US 6,221,383 B1 15 16 CinepaZet Maleate, Diltiazem, Epanolol, Felodipine, Clo me to cillin, Cloxacillin, Cyclacillin, Gallopamil, Imolamine, Indenolol, ISOSorbide Dinitrate, Dicloxacillin, Diphenicillin Sodium, Epicillin, IS radipine, Lima prost, 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, Sotalol, 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, Penicillin O, Penicillin V, Penicillin V Aprindine, Arotinolol, Atenolol, Bevantolol, Bretylium Ben Zathine, Penicillin V Hydrab amine, Tosylate, Bubumolol, Bufetolol, Bunaftine, Bunitrolol, Penime picycline, Phenethicillin Potassium, Bupranolol, Butidrine Hydrochloride, Butobendine, Piperacillin, Pivapicillin, Propicillin, Quinacillin, Capobenic Acid, Carazolol, Carteolol, Cifen line, Sulbenicillin, Talampicillin, Temocillin and Ticarcil Cloranolol, Disopyramide, Encainide, Esmolol, Flecainide, 15 lin; Gallopamil, Hydroquinidine, Indecainide, Indenolol, Iprat Lincosamides Such as Clindamycin and Lincomycin; ropium Bromide, Lidocaine, Lorajmine, Lorcainide, Meobentine, Metipranolol, Mexiletine, Moricizine, Macrollides Such as Azithromycin, Carbomycin, Nadoxolol, Nifenalol, Oxprenolol, Penbutolol, Pindolol, Clarithromycin, Erythromycin, Erythromycin Pirmenol, Practolol, Prajma line, Procainamide Acistrate, Erythromycin Estolate, Erythromycin Hydrochloride, Pronethalol, Propafenone, Propranolol, Glucoheptonate, Erythromycin Lactobionate, Erythro Pyrinoline, Quinidine Sulfate, Quinidine, Sotalol, Talinolol, mycin Propionate, Erythromycin Stearate, Josamycin, Timolol, Tocainide, Verapamil, Vicquidil and Xibenolol. Leucomycins, Mide camycins, Miokamycin, 25. Antiarteriosclerotics such as Pyridinol Carbamate. Oleandomycin, Primycin, Rokitamycin, Rosaramicin, 26. Antiarthritic/Antirheumatics Such as Allocupreide ROXithromycin, Spiramycin and Troleandomycin; Sodium, Auranofin, Aurothioglucose, Aurothioglycanide, 25 Polypeptides Such as Amphomycin, Bacitracin, Azathioprine, Calcium 3-Aurothio-2-propanol-1-Sulfonate, capreomycin, Colistin, Enduracidin, Enviomycin, Chloroquine, Clobu Zarit, Cuproxoline, Diace rein, Fusafungine, Gramicidin(s), Gramicidin S, Glucosamine, Gold Sodium Thiomalate, Gold Sodium Mika mycin, Polymyxin, Polymyxin Thiosulfate, Hydroxychloroquine, KebuZone, Lobenzarit, B-Methanesulfonic Acid, Pristinamycin, Ristocetin, Melittin, Methotrexate, Myoral and Penicillamine. Teicoplanin, Thio Strepton, Tuberactinomycin, 27. Antibacterial (antibiotic) drugs including: Tyrocidine, Tyrothricin, Vancomycin, Viomycin, Vio Aminoglycosides Such as Amikacin, Apramycin, mycin Pantothenate, Virginiamycin and Zinc Bacitra Arbekacin, Bambermycins, Butirosin, Dibekacin, cin; Dihdrostreptomycin, Fortimicin(s), Gentamicin, Tetracyclines Such as Apicycline, Chlortetracycline, Ispamicin, Kanamycin, Micronomicin, Neomycin, 35 Clomocycline, De meclocycline, Doxycycline, Neomycin Undecylenate, Netilmicin, Paromomycin, Guame cycline, Lyme cycline, Me clocycline, Ribo Stamycin, Sisomicin, Spectinomycin, Methacycline, Minocycline, Oxytetracycline, Streptomycin, StreptonicOZid and Tobramycin; Penimepicycline, Pipacycline, Rolitetracycline, Sancycline, Senociclin and Tetracycline; and Amphenicols Such as AZidamfenicol, Chloramphenicol, 40 Chloramphenicol Palmitate, Chloramphe nicol other antibiotics Such as CycloSerine, Mupirocin and Pantothenate, Florfenicol and Thiamphenicol; Tuberin. Ansamycins Such as Rifamide, Rifampin, Rifamycin and 28. Antibacterial drugs (Synthetic), including: Rifaximin; 2,4-Diaminopyrimidines Such as Brodimoprim, TetroX B-Lactams, including: 45 oprim and Trimethoprim; Carbapenems. Such as Imipenem; Nitrofurans such as Furaltadone, Furazolium Chloride, Cephalosporins Such as Cefactor, Cefadroxil, Nifuradene, Nifuratel, Nifurfoline, Nifurpirinol, Cefamandole, Cefatrizine, CefaZedone, Cefazolin, Nifurprazine, Nifurtoinol and Nitrofurantoin; Cefixime, Cefnmenoxime, Cefodizime, Cefonicid, Quinolones and Analogs Such as Amifloxacin, Cinoxacin, CefoperaZone, Ceforanide, Cefotaxime, Cefotiam, 50 Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin, Cefpimizole, Ce?pirimide, Cefpodoxime Proxetil, Flumequine, Lomefloxacin, Miloxacin, Nalidixic Acid, Cefroxadine, CefSulodin, Ceftazidime, Cefteram, Norfloxacin, Ofloxacin, Oxolinic Acid, Pefloxacin, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Pipemidic Acid, Piromidic Acid, Rosoxacin, Tema Cefuroxime, CefuZonam, Cephacetrile Sodium, floxacin and ToSufloxacin; Cephale Xin, Cephaloglycin, Cephaloridine, 55 Sulfonamides Such as Acetyl Sulfamethoxypyrazine, Cephalosporin, Cephalothin, Cephapirin Sodium, Acetyl SulfiSoxazole, AZOSulfamide, Benzylsulfamide, Cephradine and Piveefalexin; Chloramine-B, Chloramine-T, Dichloramine T. Cephamycins Such as CefbuperaZone, Cefnmetazole, Formosulfathiazole, N°Formylsulfisomidine, N°-f-D- Cefnminox, Cefetan and Cefoxitin; Glucosylsulfa nil amide, Mafen ide, 4'- Monobactams Such as Aztreonam, Carumonam and 60 (Methylsulfamoyl) Sulf a nila nilide, Tigemonam, p-Nitro sulfathiazole, No prylsulfamide, Oxacephems. Such as Flomoxef and Moxolactam, Phthalylsulfacetamide, Phthalylsulfathiazole, Penicillins such as Amidinocillin, Amdinocillin Sala Zo Sulfadimidine, Succinylsulfathiazole, Pivoxil, Amoxicillin, Ampicillan, Apalcillin, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine, ASpoxicillin, AZidocillan, AZlocillan, Bacampicillin, 65 Sulfachrysoidine, Sulfacy tine, Sulfadiazine, Benzylpenicillinic Acid, Benzylpenicillin Sodium, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Carbenicillin, Carfecillin Sodium, Carindacillin, Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, US 6,221,383 B1 17 18 Sulfaloxic Acid, Sulfamerazine, Sulfameter, phenylhydantoin, Narcobarbital, Nimetazepam, Sulfamethazine, Sulfamethizole, Sulfamethomidine, Nitrazepam, Paramethadione, Phenacemide, Phenetharbital, Sulfame thoxazole, Sulfame thoxypyrida Zine, Phene turide, 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, Sulfanily lurea, Suclofenide, Sulthiame, Tetrantoin, Trimethadione, Valproic N-Sulfanilyl-3,4-xylamide, Sulfanitran, Sulfaperine, Acid, Valpromide, Vigabatrin and Zonisamide. Sulfaphenazole. Sulfaproxyline, Sulfapyrazine, 31. Antidepressants, including: Sulfapyridine, SulfaSomizole, SulfaSymazine, 1O BicyclicS Such as Binedaline, CaroXaZone, Citalopram, Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulf iso Dimethazan, Indalpine, Fencamine, Indeloxazine midine and Sulfisoxazole; 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 15 HydrazideS/Hydrazines Such as Benmoxine, I proclozide, Acid, p-Sulfanilylbenzylamine, p.p'-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 Adina Zolam, Amitriptyline, Sulfosalicylate, Nitroxoline and Xibornol. Amitriptylin oxide, Amoxapine, Butriptyline, 29. AnticholinergicS Such as Adiphenine Hydrochloride, Clomipramine, Demexiptiline, Desipramine, Dibenzepin, Alverine, Ambutonomium Bromide, Aminopentamide, Dimetracrine, Dothiepin, Doxepin, Fluacizine, Imipramine, AmiXetrine, Amprotropine Phosphate, Anisotropine 25 Imipramine N-Oxide, Iprindole, Lofepramine, Melitracen, Methylbromide, Apoatropine, Atropine, Atropine N-Oxide, Metapramine, Nortriptyline, Noxiptilin, Opipramol, Benactyzine, Benapry Zine, BenZetimide, BenZilonium Pizotyline, Propizepine, Protriptyline, Quinupramine, Bromide, Benztropine Mesylate, Bevonium Methyl Sulfate, Tianeptine and Trimipramine; and Biperiden, Butropium Bromide, N-Butylscopolammonium otherS Such as Adrafinil, Benactyzine. Bromide, Bu Zepide, Camylo fine, Caramiphen Bupropion, Butacetin, Deanol, Deanol Aceglumate, Hydrochloride, Chlorbenzoxamine, Chlorphenoxamine, Deanol Acetamidobenzoate, Dioxadrol, Etoperidone, Cimetropium Bromide, Clidinium Bromide, Cyclodrine, Febarbamate, Femoxetine, Fenpentadiol, Fluoxetine, Cyclonium Iodide, Cycrimine Hydrochloride, Deptropine, Fluvoxamine, He matop orphyrin, Hyper cin in, Dexe timide, Dibutoline Sulfate, Dicyclomine Levo phacetope rane, Medifoxamine, Mina prine, Hydrochloride, Diethazine, Difemerine, Dihexyverine, 35 Moclobemide, Oxaflozane, Piberaline, Prolintane, Diphemanil Methylsulfate, N-(1,2-Diphenylethyl) Pyrisuccideanol, Rubidium Chloride, Sulpiride, Sultopride, nicotinamide, Dipiproverine, Diponium Bromide, Emepro Teniloxazine, ThoZalinone, Tofenacin, ToloXatone, nium Bromide, Endobenzyline Bromide, Ethopropazine, Tranylcypromine, L-Tryptophan, Viloxazine and Zimeldine. Ethybenztropine, Ethylbenzhydramine, Etomidoline, 32. Antidiabetics, including: Eucatropine, Fenpiverinium Bromide, Fentonium Bromide, 40 Flutropium Bromide, Glycopyrrolate, Heteronium Bromide, Biguanides such as Buformin, Metformin and Phen Hexocyclium Methyl Sulfate, Homatropine, Hyoscyamine, formin; I pratropium Bromide, Isopropamide, Levome pate, Hormones Such as Glucagon, Insulin, Insulin Injection, Mecloxamine, Mepenzolate Bromide, Metcaraphen, Meth Insulin Zinc Suspension, Isophane Insulin Suspension, antheline Bromide, Methixene, Methscopolamine Bromide, 45 Protamine Zinc Insulin Suspension and Zinc Insulin Octamylamine, Oxybutynin Chloride, oxyphencyclimine, Crystals, Oxyphenonium Bromide, Pentapiperide, Penthienate Sulfonylure a derivatives Such as Acetohexamide, Bromide, Phencarbamide, Phenglutarimide, Pipenzolate 1-Butyl-3-met a nily lure a, Carbutamide, Bromide, Piperidolate, Piperilate, Poldine Methysulfate, Chlorpropamide, Glibornuride, Gliclazide, Glipizide, Pridinol, Prifinium Bromide, Procyclidine, Propantheline 50 Gliquidone, Glisoxepid, Glyburide, Glybuthiazol(e), Bromide, PropenZolate, Propyromazine, Scopolamine, Sco Glybuzole, Glyhexamide, Glymidine, Glypinamide, polamine N-Oxide, Stilonium Iodide, Stramonium, Phenbutamide, Tolazamide, Tolbutamide and Tolcycla Sultroponium, Thihexinol, Thiphenamil, Tiemonium Iodide, mide; and Timepidium Bromide, Tiquizium Bromide, Tridihexethyl otherS Such as Acarbose, Calcium Mesoxalate and Migli Iodide, Trihexyphenidyl Hydrochloride, Tropacine, 55 tol. Tropenzile, Tropicamide, Trospium Chloride, Valethamate 33. Antidiarrheal drugs. Such as Acetyltannic Acid, Albu Bromide and Xeny tropium Bromide. min Tannate, Alkofanone, Aluminum Salicylates-Basic, 30. Anticonvulsants Such as Acetylpheneturide, Albutoin, Catechin, Dife noxin, Diphenoxylate, Lidamidine, Aloxidone, Aminoglutethimide, 4-Amino-3-hydroxybutyric Loperamide, Mebiquine, Trillium and Uzarin. Acid, Atrolactamide, Beclamide, Buramate, Calcium 60 34. Antidiuretics Such as Desmopressin, Fely pressin, Bromide, Carbamazepine, Cinromide, Clomethiazole, Lypressin, Ornipressin, Oxycinchophen, Pituitary-Posterior, Clonazepam, Decimenide, Diethadione, Dimethadione, Terlipressin and Vasopressin. Doxenitoin, Eterobarb, Ethadione, Ethosuximide, Ethotoin, 35. Antiestrogens Such as Delmadinone Acetate, Fluoresone, 5-Hydroxytryptophan, Lamotrigine, Magne Ethamoxytriphetol, Tamoxifen and Toremifene. sium Bromide, Magnesium Sulfate, Mephenytoin, 65 36. Antifungal drugs (antibiotics), including: Mephobarbital, Metharbital, Methetoin, Methsuximide, Polyenes Such as Amphotericin-B, Candicidin, 5-Methyl-5-(3-phenanthryl) hydantoin, 3-Methyl-5- Dermostatin, Filipin, Fungichromin, Hachimycin, US 6,221,383 B1 19 20 Hamycin, Lucensomycin, Mepartricin, Natamycin, 42. Antihyperlipoproteinemics, including: Nystatin, Pecilocin and Perimycin; and Aryloxyalkanoic acid derivatives Such as Beclorbrate, otherS Such as AZaserine, Griseofulvin, oligomycins, Neo Bazafibrate, Binifibrate, Ciprofibrate, Clinofibrate, mycin Undecylenate, Pyrrolnitrin, Siccanin, Tubercidin Clofibrate, Clofibric Acid, Etonfibrate, Fenofibrate, and Viridin. Gemfibrozil, Nicofibrate, Pirifibrate, Ronifibrate, Sim 37. Antifungal drugs (synthetic), including: fibrate and Theofibrate; Allylamines such as Naftifine and Terbinafine; Bile acid Sequesterants Such as Cholestyramine Resin, Imidazoles Such as Bifonazole, Butoconazole, Colestipol and Polidexide; Chlordantoin, Chlor=idazole, Cloconazole, HMG CoA reductase inhibitors such as Lovastatin, Prav Clotrimazole, Econazole, Enilconazole, Fenticonazole, astatin Sodium and Simvastatin; ISO conazole, Ke to conazole, Miconazole, Nicotinic acid derivatives Aluminum Nicotinate, Omoconazole, Oxiconazole, Nitrate, Sulconazole and Acipimox, Niceritrol, Nicoclonate, Nicomol and Tioconazole; OXiniacic Acid; Triazoles Such as Fluconazole, Itraconazole and Tercona 15 Thyroid hormones and analogS Such as EtiroXate, Thyro Zole; and propic Acid and ThyroXine, and otherS Such as Acrisorcin, Amorolfine, Biphenamine, Bromosalicylchloranilide, Buclosamide, Calcium otherS Such as Acifran, AZacosterol, Benfluorex, Propionate, Chlophenesin, Ciclopirox, Cloxyquin, B-Benzalbutyramide, Carnitine, Chondroitin Sulfate, Coparaffinate, Diamthazole, Dihydrochloride, Clomestone, Detaxtran, Dextran Sulfate Sodium, 58, EXalamide, Flucytosine, Halethazole, Hexetidine, 11, 14, 17-Eicosapentaenoic Acid, Eritade nine, Loflucarban, Nifuratel, Potassium Iodide, Propionic Furazbol, Meglutol, Melinamide, Mytatrienediol, Acid, Pyrithione, Salicylanilide, Sodium Propionate, Ornithine, Y-Oryzanol, Pantethine, Penataerythritol Sulbentine, Tenonitrozole, Tolciclate, Tolindate, Tetraacetate, C.-Phenylbutyramide, Pirozadil, Probucol, Tolnaftate, Tricetin, Ujothion, Undecylenic Acid and C-Sitosterol, Sultosilic Acid, Piperazine Salt, Tiadenol, Zinc Propionate. 25 Triparanol and Xenbucin. 38. Antiglaucoma drugs. Such as Acetazolamide, 43. Antihypertensive drugs, including: 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 Alp renolol, Arotinolol, Atenolol, Beta Xolol, 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: 35 Mepindolol, Metipranolol, Metoprolol, Moprolol, Alkylamine derivatives Such as Acrivastine, Bamipine, Nadolol, Nipradillol, Oxprenolol, Penbutolol, Pindolol, Brompheniramine, Chlorpheniramine, Dimethindene, Propranolol, Talinolol, Tetraolol, Timolol and Tolip Metron S., Pheniramine, Pyrrobutamine, Thenaldine, rolol; Tolpropamine and Triprolidine, Benzothiadiazine derivatives Such as Althiazide, A mino alkyl etherS Such as Bieta nautine, 40 Bendro flu methiazide, Ben Zthiazide, Bromodiphenhydramine, Carbinoxamine, Clemastine, Ben Zylhydrochlorothiazide, Buthiazide, Diphenly pyraline, Doxylamine, Embrammine, Chlorothiazide, Chlorthalidone, Cyclopenthiazide, Me dry la mine, Mephen phy dra mine, Cyclothiazide, Diazoxide, Epithiazide, Ethiazide, p-Methyldiphenhydramine, Orphen a drine, Fen qui Zone, Hydrochlor othiazide, Phenyltoloxamine, Piprinhydrinate and Setasine; 45 Hydroflumethiazide, Methyclothiazide, Meticrane, Ethylenediamine derivatives Such as Alloclamide, Metolazone, Paraflutizide, Polythiazide, Tetrachlorme p-Bromtripelennamine, Chloropyramine, Chlorothen, thiazide and Trichlormethiazide, Histapyrrodine, Methafurylene, Methaphenilene, N-Carboxyalkyl (peptide/lactam) derivatives such as Methapyrilene, Phenbenzamine, Pyrilamine, Talastine, Alacepril, Captopril, CilaZapril, Delapril, Enalapril, Thenyldiamine, Thonzylamine Hydrochloride, Tripe 50 Enalaprilat, Fosinopril, Lisinopril, Moveltipril, lennamine and Zolamine; Perindopril, Quinapril and Ramipril; Piperazines Such as Cetirizine, Chlorcyclizine, Dihydropyridine derivatives Such as Amlodipine, Cinnarizine, Clocinizine and Hydroxy Zine, Felodipine, Isradipine, Nicardipine, Nifedipine, Tricyclics, including: 55 Nilvadipine, Nisoldipine and Nitrendipine; Phenothiazines Such as Ahistan, Etyme mazine, Guanidine derivatives Such as Bethanidine, Debrisoquin, Fenethazine, N-Hydroxyethylprometha Zine Guanabenz, Guanacline, Guanadrel, GuanaZodine, Chloride, I Soprometha Zine, Mequita Zine, Guanethidine, Guanfacine, Guanochlor, GuanoXabenz Promethazine, Pyrathiazine and Thiazinamium and Guanoxan; Methyl Sulfate; and 60 Hydrazines and phthalazines Such as Budralazine, otherS Such as AZatadine, Clobenzepam, Cadra la Zine, Dihydra la Zine, Endra la Zine, Cyproheptadine, Deptropine, Isothipendyl, Lorata Hydragarbazine, Hydralazine, Pheniprazine, Pildrala dine and Prothipendyl; and Zine and Todralazine, other antihistamines Such as Antazoline, Astemizole, Imidazole derivatives Such as Clonidine, Lofexidine, AZelastine, Cetoxime, Clemizole, Clobenztropine, 65 Phentolamine, Tiamenidine and Tolonidine; Diphenazoline, Diphenhydramine, Mebhydroline, Quaternary ammonium compounds AZamethonium Phenindamine, Terfenadine and Tritoqualine. Bromide, Chlorisondamine Chloride, Hexamethonium, US 6,221,383 B1 21 22 Pentacynium Bis(methyl sulfate), Pentamethonium tisic Acid, Glycol Salicylate, Imidazole Salicylate, Bromide, Pentolinium Tartate, Phenactopinium Chlo Lysine Acetylsalicylate, MeSalamine, Morpholine ride and Trimethidiunum MethoSulfate; Salicylate, 1-Naphthyl Salicylate, Olsalazine, 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, Thiazinecarboxamides Such as DroXicam, ISOXicam, Rescinnamine, Reserpine and Syrosingopine, PiroXicam and Tenoxicam, and Sulfonamide derivatives Such as AmbuSide, Clopamide, other S Such as e-Acetamido cap roic 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, Difenpiramide, DitaZol, EmorfaZone, GuaiaZulene, Bufeniode, Chlorthalidone, Cicletaine, Ciclosidomine, Nabumetone, Nime Sulide, Orgotein, Oxaceprol, Cryptenamine Tannates, Fenoldopam, FloSequinan, Paranyline, Perisoxal, Pifoxime, ProquaZone, ProX Indoramin, Ketanserin, Metbutamate, Mecamylamine, 15 azole and Tenidap. Methyldopa, Methyl 4-Pyridyl Ke tone 48. Antimalarial drugs. Such as AcedapSone, Amodiaquin, Thiosemicarbarzone, Metola Zone, Minoxidil, 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 Cyclogu a nil, Gentiopic rin, Halo fantrine, NitroprusSide, Ticrynafen, Trimethaphan Camsylate, Hydroxychloroquine, Mefloquine Hydrochloride, Tyrosinase and Urapidil. 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, 25 Dihydrochloride, Quinine Ethylcarbonate, Quinine Formate, Methimazole, Methylthiouracil, Propylthiouracil, Sodium Quinine Gluconate, Quinine Hydriodide, Quinine Perchlorate, Thibenzazoline, Thiobarbital and 2-Thiouracil. 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, Ergo cornine, Ergo corninine, 46. Antihypothyroid drugs. Such as Levothyroxine 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: 35 50. Antinause ant drugs. Such as Acetylleucine Aminoarylcarboxylic acid derivatives Such as Enfenamic Monoe thanolamine, Ali Zapride, Ben Zguinamide, Acid, Etofenamate, Flufenamic Acid. IsoniXin, Bietanautine, Bromopride, Buclizine, Chlorpromazine, Meclofenamic Acid, Mefanamic Acid, Niflumic Acid, Clebopride, Cyclizine, Dimenhydrinate, Dipheniodol, Talniflumate, Terofenamate and Tolfenamic Acid; Domperidone, Granisetron, Meclizine, Methalltal, Arylacetic acid derivatives Such as Acemetacin, 40 Metoclopramide, Metopimazine, Nabilone, Ondansteron, Alclofenac, Amfenac, BufeXamac, Cinmetacin, Oxypendyl, Pipamazine, Piprinhydrinate, Prochlorperazine, Clopirac, Diclofenac Sodium, Etodolac, Felbinac, Scopolamine, Tetrahydrocannabinols, Thiethylperazine, Fenclofenac, Fenclorac, Fenclozic Acid, Fentiazac, ThioproperZaine and Trimethobenzamide. Glucametacin, Ibufenac, Indomethacin, ISOfeZolac, 51. Antineoplastic drugs, including: ISOXepac, LonaZolac, Metiazinic Acid, Oxametacine, 45 Alkylating agents, including: Proglumetacin, Sulindac, Tiaramide, Tolimetin and Alkyl Sulfonates Such as BuSulfan, ImproSulfan and Zomepirac, Piposulfan; Arylbutyric acid derivatives Such as Bumadizon, AZiridines Such as BenZOdepa, Carboquone, Meture Butibufen, Fenbufen and Xenbucin; depa and Uredepa; Arylcarboxylic acids Such as Clidanac, Ketorolac and 50 Ethylenimines and methylmelamines Such as Tinoridine; Altretamine, Triethylenemelamine, TriethylenephoS Arylpropionic acid derivatives Such as Alminoprofen, phoramide Triethylenethiophosphoramide and Trim Benoxaprofen, Bucloxic Acid, Carprofen, Fenoprofen, ethylolomelamine; Fluinoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Nitrogen mustard S. Such as Chlorambucil, 55 Chlornaphazine, Chclophosphamide, Estramustine, Indoprofen, Ketoprofen, Loxoprofen, Miroprofen, Ifosfamide, 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; 60 NitroSoureas Such as Carmustine, Chlorozotocin, Pyrazolones Such as ApaZone, BenZpiperylon, Feprazone, Fotemustine, Lomustine, Nimustine and Ranimus Mofebutazone, Morazone, Oxyphen but a Zone, tine, and Phenylbutazone, Pipebu Zone, Propyphena Zone, otherS Such as Dacarbazine, Mannomustine, RamifenaZone, SuxibuZone and ThiazolinobutaZone; Mitobronitol, Mitolactol and Pipobroman; Salicylic acid derivatives Such as AcetaminoSalol, 65 Antibiotics Such as Aclacinomycins, Actinomycin F, Aspirin, Benorylate, Bromosaligenin, Calcium Anthramycin, AZ, a Serine, Ble o my c in S, Acetylsalicylate, Diflunisal, EterSalate, Fendosal, Gen Cactinomycin, Carubicin, Car Zinophilin, US 6,221,383 B1 23 24 Chromomycins, Dactinomycin, Daunorubicin, OXOphenarsine, Hydrochloride, Pentamidine, Propamidine, 6-Diazol-5-oxo-L-nor leucine, Doxorubicin, Puromycin, Quinapyramine, Stilbamidine, Suramin Epirubicin, Mitomycins, Mycophenolic Acid, Sodium, Trypan Red and Tryparasmide. 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: 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 analog S Such as Fluld arabine, Chrysarobin, Etretinate and Pyrogallol. 6-Mercaptopurine, Thiamiprine and Thiogua 63. Antipsychotic drugs, including: maine; and Butyrophenones Such as Benperidol, Bromperidol, Pyrimidine analogS Such as Ancitabine, AZacitidine, Droperidol, Fluanisone, Haloperidol, Melperone, 6- AZauridine, Carmo fur, Cytarabine, 15 Doxifluridine, Enocitabine, Floxuridine, Fluroou Moperone, Pipamperone, Sniperone, Timiperone and racil and Tegafur, Enzyme S. Such as Trifluperidol; L-Asparaginase; and Phenothiazines Such as Acetophenazine, Butaperazine, otherS Such as Aceglatone, AmSacrine, BeStrabucil, Carphenazine, Chlorproethazine, Chlorpromazine, Bisantrene, Carboplatin, Cisplatin, Defofamide, Clo Spira Zine, Cy ame ma Zine, Dixy razine, Demecolcine, Diaziguone, Elfornithine, Ellip Fluphenazine, Imiclopazine, Mepazine, MeSoridazine, tinium Acetate, Etoglucid, EtopoSide, Gallium Methoxypromazine, Metofenazate, Oxaflumazine, Nitrate, Hydroxyurea, Interferon-C, Interferon-B, Perazine, Pericyazine, Perimethazine, Perphenazine, Interferon-Y, Interleukine-2, Lentinan, Pipe racetazine, Pipotiazine, Prochlorpe razine, Lonidamine, Mito guaZone, Mitoxantrone, Promazine, Sulforida Zine, Thiopropa Zate, Mopidamol, Nitracrine, Pentostatin, Phenamet, 25 Thioridazine, Trifluoperazine and Triflu promazine; Pira rub icin, Podophyllinic c Acid, Thioxanthenes Such as Chlorprothixene, Clopenthixol, 2-Ethy thydrazide, Procarbazine, PSK (R), Flupentixol and Thiothixene; RaZoxane, Sizofiran, Spirogermanium, Taxol, other tricyclicS Such as BenZquinamide, Carpipramine, Teniposide, TenuaZonic Acid, Triaziquone, 2.2, Clocapramine, Clomacran, Clothiapine, Clozapine, 2"-Trichlorotriethylamine, Urethan, Vinblastine, Opipramol, Prothipendyl, Tetrabenazine, and Vincristine and Vindesline; Zotepine, and 52. Antineoplastic (hormonal) drugs, including: otherS Such as Alizapride, Amisulpride, Buramate, Androgens Such as Calusterone, DromoStanolone Fluspirilene, Molindone, Penfluridol, Pimozide, Spir Propionate, EpitioStanol, MepitioStane and Testolac 35 ilene and Sulpiride. tone, 64. Antipyretics Such as Acetaminophen, AcetaminoSalol, Antiadrenals. Such as Aminoglutethimide, Mitotane and Acetanilide, Aconine, Aconite, Aconitine, Alclofenac, Alu TriloStane; minum Bis(acetylsalicylate), Aminochlorthenoxazin, Antiandrogens Such as Flutamide and Nilutamide, and Aminopyrine, Aspirin, Benorylate, BenZydamine, Antiestrogens Such as Tamoxifen and Toremifene. 40 Berberine, p-Bromoacetanilide, Buf eXamac, 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, Dipyrocetyl, Dipyrone, Epirizole, EterSalate, Imidazole Benserazide, Bietanautine, Biperiden, Bromocriptine, Salicylate, Indomethacin, ISOfeZolac, p-Lactophenetide, Budipine, Carbidopa, Deprenyl, DeXetimide, Diethazine, 45 Lysine Acetylsalicylate, Magnesium Acetylsalicylate, Droxidopa, Ethiopropazine, Ethylben Zhydramine, Meclofenamic Acid, Morazone, Morpholine Salicylate, Levodopa, Naxagolide, Pergolide, Piroheptine, Pridinol, Naproxen, NifenaZone, 5'-Nitro-2'-propoxyacetanilide, Prodipine, Terguride, Tigloidine and Trihexyphenidyl Phenacetin, Phenicarbazide, Phenocol, Phenopyrazone, Hydrochloride. Phenyl Acetylsalicylate, Phenyl Salicylate, Pipebuzone, 55. Antipheochromocytoma drugs. Such as Metyrosine, 50 Propacetamol, Propy phena Zone, Ramife naZone, Phenoxybenzamine and Phentolamine. Salacetamide, Salicylamide O-Acetic Acid, Sodium 56. Antipneumocystis drugs Such as Effornithine, Penta Salicylate, Sulfamipyrine, Tetrandrine and Tinoridine. midine and Sulfamethoxazole. 65. Antirickettsial drugs Such as p-Aminobenzoic Acid, 57. Antiprostatic hypertrophy drugs. Such as Gestonorone Chloramphenicol, Chloramphenicol Palmitate, Chloram Caproate, Mepartricin, Oxendolone and Proscar(R). 55 phenicol Pantothenate and Tetracycline. 58. Antiprotozoal drugs (Leshmania) Such as Antimony 66. Antiseborrheic drugs such as Chloroxine, 3-O- Sodium Gluconate, Ethylstibamine, HydroxyStilbamidine, Lauroylpyridoxol Diacetate, Piroctone, Pyrithione, N-Methylglucamine, Pentamidine, Stilbamidine and Urea Resorcinol, Selenium Sulfides and Tioxolone. Stibamine. 67. Antiseptics, including: 59. Antiprotozoal drugs (Trichomonas) Such as 60 Guanidines Such as Alexidine, Ambazone, Chlorhexidine AcetarSone, Aminitrozole, Anisomycin, AZanidazole, and Picloxydine; Forminitrazole, Furazolidone, Hachimycin, Lauroguadine, Halogens and halogen compounds Such as Bismuth Mepartricin, Metronidazole, Nifuratel, Nifuroxime, Iodide Oxide, Bismuth Iodosubgallate, Bismuth Nimorazole, Secnidazole, Silver Picrate, Tenonitrozole and Tribromophenate, Bornyl Chloride, Calcium Iodate, Tinidazole. 65 Chlorinated Lime, Cloflucarban, Flurosalan, Iodic 60. Antiprotozoal drugs (Trypanosma) Such as Acid, Iodine, Iodine Monochloride, Iodine Trichloride, Benznidazole, Eflornithine, Melarsoprol, Nifurtimox, Iodoform, Methenamine Tetraiodine, Oxychlorosene, US 6,221,383 B1 25 26 Povidone-Iodine, Sodium Hypochlorite, Sodium Dime morfan, Dime thoXanate, C., C.-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 azine Hydrochloride, Race methorphan, 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, Benexate Hydrochloride, Bismuth Subcitrate and Thimerosal; Sol (Dried), Carbenoxolone, Cetraxate, Cimetidine, Nitrofurans such as Furazolidone, 2-(Methoxymethyl)-5- Enprostil, Esaprazole, Famotidine, FtaXilide, Gefarnate, nitrofuran, Nidroxy Zone, Nifuroxime, Nifurzide and GuaiaZulene, IrSogladine, Misoprostol, Nizatidine, 15 Omeprazole, Ornoprostil, Y-Ory Zanol, Pifarnine, Nitrofurazone; Pirenzepine, Plaunotol, Ranitidine, Rioprostil, Rosaprostol, Phenols Such as Acetomeroctol, Bithionol, Cadmium Rotraxate, Roxatidine Acetate, Sofalcone, Spizofurone, Salicylate, Carvacrol, Chloroxylenol, Clorophene, Sucralfate, Teprenone, Trimoprostil, Thrithiozine, Troxipide CreSote, Cresol(s), p - CreSol, Fentic lor, 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; 73. Antivenin drugs such as Lyovac(R) Antivenin. Quinolines Such as Aminoquinuride, BenZOXiquine, 74. Antiviral drugs, including: Broxyquinoline, Chloro Xine, Chlorduinaldol, Purines and pyrimidinones Such as Acyclovir, Cytarabine, Cloxyquin, Ethylhydrocupreine, Euprocin, Halquinol, 25 Dideoxyadenosine, Dideoxycytidine, Dideoxyinosine, Hydrastine, 8-Hydroxquinoline, 8-Hydroxquinoline Edoxudine, Floxuridine, Ganciclovir, Idoxuridine, Sulfate and Iodochlorhydroxyquin; and 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-C, Dibromopropamidine, Ichthammol, Negatol(R), Interferon-B, Interferon-Y, Kethoxal, Lysozyme, Noxytiolin, Ornidazole, B-Propiolactone, C-Terpineol. Me thisa Zone, Moroxydine, Podophyllotoxin, 68. AntiSpasmodic drugs. Such as Alib endol, Ribavirin, Rimantadine, Stallimycin, Statolon, Tro Ambucetamide, Aminopromazine, Apoatropine, Bevonium 35 mantadine and Xenazoic Acid. Methyl Sulfate, Bietamiverine, Butaverine, Butropium 75. Anxiolytic drugs, including: Bromide, N-Butylscopolammonium Bromide, Caroverine, Arylpiperazines Such as BuSpirone, Gepirone and Ipsa Cimetropium Bromide, Cinnamedrine, Clebopride, Coniine Hydrobromide, Coniine Hydrochloride, Cyclonium Iodide, pirone; Benzodiazepine derivatives Such as Alprazolam, Difemerine, Diisopromine, Dioxaphetyl Butyrate, Dipo 40 Bromazepam, Camazepam, Chlordiazepoxide, nium Bromide, Drofenine, Emepronium Bromide, Clobazam, CloraZepate, Chotiazepam, Cloxazolam, Ethave rine, Fe cle mine, Fenalamide, Fenoverine, Diazepam, Ethyl Loflazepate, Etizolam, Fluidazepam, Fenpiprane, Fenpiverinium Bromide, Fentonium Bromide, Flutazolam, Flutoprazepam, Halazepam, Ketazolam, Flavoxate, Flopropione, Gluconic Acid, Guaiactamine, Lorazepam, Loxapine, Medazepam, Metaclazepam, Hydramitrazine, Hymecromone, Leiopyrrole, Mebeverine, 45 Moxaverine, Nafiverine, octamylamine, Octaverine, MeXaZolam, Nordazepam, Oxazepam, Oxazolam, Pentapiperide, Phenamacide Hydrochloride, Phloroglucinol, Pinazepam, Prazepam and Tofisopam; Pinaverium Bromide, Piperilate, Pipoxolan Hydrochloride, Carbamates Such as Cyclarbamate, Emylcamate, Pramiverin, Prifinium Bromide, Properidine, Propivane, Hydroxyphenamate, Meprobamate, Phenprobamate Propyromazine, Prozapine, Race femine, Rociverine, 50 and Tybamate; and Spasmolytol, Stilonium Iodide, Sultroponium, Tiemonium otherS Such as Alpidem, BenZOctamine, Captodiamine, Iodide, Tiquizium Bromide, Tiropramide, Trepibutone, ChlormeZanone, EtifoXine, Fluoresone, Glutamic Acid, Tricromyl, Trifolium, Trimebutine, N,N-1Trimethyl-3,3- Hydroxy Zine, Mecloralu rea, Mephenoxalone, diphenyl-propylamine, Tropenzile, TroSpium Chloride and Oxanamide, Phenaglycodol, Suriclone. Xeny tropium Bromide. 55 76. Benzodiazepine antagonistS Such as Flumazenil. 69. Antithrombotic drugs. Such as Anagrelide, Argatroban, 77. Bronchodilators, including: Cilosta Zol, Daltroban, Defibrotide, Enoxaparin, Ephedrine derivatives such as Albuterol, Bambuterol, Fraxiparine(R), Indobufen, Lamoparan, OZagrel, Picotamide, Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, Plafibride, Tedelparin, Ticlopidine and Triflusal. Dioxethedrine, Ephedrine, Epiniphrine, EproZinol, 70. AntituSSive drugs. Such as Allocamide, Amicibone, 60 Etafe drine, Ethylnorepinephrine, Fenote rol, Ben properine, BenZonatate, Bibenzonium Bromide, Hexoprenaline, Isoetharine, Isoproterenol, Mabuterol, Bromoform, Butamirate, Butlethamate, Caramiphen Metaprote renol, N-Methylephedrine, Pirbuterol, Ethane disulfonate, Carbetapentane, Chlophedianol, Procate rol, Protokylol, Reproterol, Rimiterol, Clobutinol, Cloperastine, Codeine, Codeine Methyl Soterenol, Terbutaline and Tulobuterol; Bromide, Codeine N-Oxide, Codeine Phosphate, Codeine 65 Quaternary ammonium compounds Such as Bevonium Sulfate, Cyclexanone, Dextromethorphan, Dibunate Methyl Sulfate, Clutropium Bromide, Ipratropium Bro Sodium, Dihydrocodeine, Dihydrocodeinone Enol Acetate, mide and OXitropium Bromide; US 6,221,383 B1 27 28 Xanthine derivatives Such as Acefylline, Acefylline Dexoxadrol, Dextroamphetamine Sulfate, Diethlpropion, Pipera Zine, Ambu phylline, Aminophylline, N-Ethylamphetamine, Ethamivan, Etifelmin, Etryptamine, Bamifylline, choline Theophyllinate, Doxofylline, Fencamfamine, Fenethylline, Fenosolone, Flurothyl, Dyphylline, Enprofylline, Etamiphyllin, Etofylline, Hexacyclonate Sodium, Homo camfin, Ma Zindol, Guaithylline, Proxyphylline, Theobromine, MegeXamide, Methamphetamine, Methylphenidate, 1-Theobromineacetic Acid and Theophylline; and Niketh amide, Pemoline, Penty lene tetrazole, others such as Fenspiride, Medibazine, Methoxyphe Phenidimetrazine, Phenmetrazine, Phentermine, Picrotoxin, nanime and Tretoquinol. Pipradrol, Prolintane and Pyrovalerone. 78. Calcium channel blockers, including: 89. Decongestants Such as Amidephrine, Cafaminol, Arylalkylamines Such as Bepridil, Ditiazem, Fendiline, Cyclopentamine, Ephedrine, Epinephrine, Fenoxazoline, Indanazoline, Metizoline, Naphazoline, Norde frin Gallopanil, Prenylamine, Terodiline and Verapamil; Hydrochloride, octodrine, Oxymetazoline, Phenylephrine Dihydropyridine derivatives such as Felodipine, Hydrochloride, Phenylpropanolamine Hydrochloride, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Phenylpropylmethylamine, Propylhexe drine, Nimodipine, Nisoldipine and Nitrendipine; 15 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, Ipriflavone, Pamidronic Acid, Parathyroid organomercurials Such as Chlormerodrin, Meralluride, Hormone and Teriparatide Acetate. Mercamphamide, Mercaptomerin Sodium, Mercumal 80. CardiotonicS Such as Acefylline, Acetyldigititoxins, lylic Acid, Mercumatilin Sodium, Mercurous Chloride 2-Amino-4-picoline, Amrinone, Benfurodil Hemisuccinate, and Mersalyl; Buclasdesine, Cerberoside, Camphotamide, Convallatoxin, 25 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, 7-Morpholinomethyltheophylline, Pamabrom, Pro Glycocyamine, Heptaminol, Hydrastinine, Ibopamine, theobromine and Theobromine; Lanotodises, Metamivam, Milrinone, Neriifolin, Oleandrin, Steroids Such as Canrenone, Oleandrin and Spironolac Ouabain, Oxyfedrine, Prenalterol, Proscillaridin, tone, ReSibu fogenin, Scillaren, Scillarenin, Strophanthin, Sulfonamide derivatives Such as Acetazolmide, Sulmazole, Theobromine and Xamoterol. AmbuSide, AZOSemide, Bumetanide, Butazolamide, 81. Chelating agents Such as DeferOZmine, Ditiocarb Chloraminophenamide, Clofenamide, Clopamide, Sodium, Edetate Calcium Disodium, Edetate Disodium, 35 Clorexolene, Diphenylmethane-4,4'-disulfonamide, Edeate Sodium, Edetate Trisodium, Penicillamine, Pentetate Disulfamide, EthoXZolamide, Furose mide, Calcium Trisodium, Pentectic Acid, Succimer and Trientine; Indapamide, Mefruside, Methazolamide, Piretanide, 82. Cholecystokinin antagonists Such as Proglumide. QuinethaZone, Torasemide, Tripamide and Xipamide; 83. Cholelitholytic agents such as Chenodiol, Methyl Uracils. Such as Aminometradine and Amisometradine, tert-Butyl Ether, Monooctanoin and Ursodiol. 40 otherS Such as Amano Zine, Amiloride, Arbutin, 84. Choleretics such as Alibendol, Anethole Trithion, Chlora Zanil, Ethacry nic Acid, Eto Zolin, AZintamide, Cholic Acid, Cicrotoic Acid, Clanobutin, Hydracarbazine, Isosorbide, Mannitol, Metochalcone, Cyclobutyrol, Cyclovalone, Cynarin(e), Dehydrocholic Muzolimine, Perhexiline, Ticrynafen and Urea. Acid, Deoxycholic Acid, Dimecrotic Acid, O.-Ethylbenzyl 93. Dopamine receptor agonists Such as Bromocriptine, Alcohol, Exiproben, Feguprol, Fencibutirol, Fenipentol, 45 Dopexamine, Fenoldopam, Ibopamine, Lisuride, Nax Florantyrone, Hyme cromone, 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- Carbaryl, Crotamiton, DDT, Dixanthogen, Isobornyl butanol, Piprozolin, Prozapine, 4-Salicyloylmorpholine, Thiocyanoacetate-Technical, Lime Sulfurated Solution, Sincalide, Taurocholic Acid, Timonacic, Tocamphyl, 50 LIndane, Malathion, Mercuric Oleate, Mesulphen and Trepibutone and Vanitiolide. Sulphur-Pharmaceutical. 85. Cholinergic agents Such as Aceclidine, Acetylcholine 95. Enzymes, including: Bromide, Acetylcholide Chloride, Aclatonium Napadisilate, Digestive enzymes Such as C.-Amylase (Swine Pancreas), Benzpyrinium Bromide, Bethanechol chloride, Carbachol, Lipase, Pancrelipase, Pepsin and Rennin; Carpronium chloride, Demecarium Bromide, Dexpanthenol, 55 Mucolytic enzymes Such as Lysozyme; Diisopropyl Paraoxon, Echothiophate Iodide, Edrophomium chloride, Eseridine, Furtrethonium, Isoflurophate, Metha Penicillin inactivating enzymes Such as Penicillinase; and choline chloride, Muscarine, NeoStigmine, Oxapropanium Proteolytic enzymes Such as Collagenase, Chymopapain, Iodide, Physostigmine and Pyridostigmine Bromide. Chymotrypsins, Papain and Trypsin. 86. Cholinesterase inhibitors such as Ambenonium 60 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. Chlorotrianisene, Dienestrol, Diethylstilbestrol, Dieth 88. Central nervous System Stimulants and agents Such as ylstilbestrol Diproprionate, Dimestrol, Fosfestrol, Amineptine, Amphetimine, Amphetaminil, Bemegride, 65 Hexestrol, Methallenestril and Methestrol; and BenZphetamine, Brucine, Caffeine, Chlorphentermine, Steroidal estrogens Such as Colpormon, Conjugated Clofenciclan, Clortermine, Coca, Demanyl Phosphate, Estrogenic Hormones, Equilenin, Equilin, Estradiol, US 6,221,383 B1 29 30 Estradiol Benzoate, Estradiol 17 B-Cypionate, Estriol, 116. Miotic drugs. Such as Carbachol, PhySoStigmine, Estrone, Ethinyl Estradiol, Mestranol, Moxestrol, Pilocarpine and Pilocarpus. Mytatrienediol, Quinestradiol and Quinestrol. 117. Monoamine oxidase inhibitors such as Deprenyl, 98. Gastric Secretion inhibitorS Such as Enterogastrone Iproclozide, Iproniazid, Isocarboxazid, Moclobemide, and Octreotide. Octomoxin, Pargyline, PhenelZine, Phenoxypropazine, 99. Glucocorticoids Such as 21-Acetoxyprefnenolone, Pivalylbenzhydrazine, Prodipine, Toloxatone and Tranyl Aalclometasone, AlgeStone, Amicinonide, Beclomethasone, cypromine. Betamethasone, BudeSonide, Chloroprednisone, Clobetasol, 118. Mucolytic agents Such as Acetylcy Steine, Blovetasone, Clocortolone, Cloprednol, Corticosterone, Cortisone, Cortiva Zol, Defla Zacort, De Sonide, Bromhe Xine, Carbocysteine, Domiodol, Letosteine, De Soxime taSone, De Xame thaSone, DifloraSone, Lysozyme, Mecysteine Hydrochloride, Mesna, Sobrerol, Diflucortolone, Diflupredinate, EnoXolone, Fluazacort, Stepronin, Tiopronin and Tyloxapol. Flucloronide, Flumehtasone, Flunisolide, Fluocinolone 119. Muscle relaxants (skeletal) Such as Afloqualone, Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone, Alcuronium, Atracurium BeSylate, Baclofen, BenZOctamine, Fluorometholone, Fluperolone Acetate, Fluprednidene Benzoquinonium Chloride, C-Calebassine, Carisoprodol, Acetate, Fluprednisolone, Flurandrenolide, Formocortal, 15 Chlor me Za none, Chlorp he n e Sin Carb amate, Halcinonide, HalometaSone, Halopredone Acetate, Chlorproethazine, ChloZOXaZone, Curare, Cyclarbamate, Hydrocortamate, Hydrocortisone, Hydrocortisone Acetate, Cyclobenzaprine, Dantrolene, Decamethonium Bromide, ydrocortisone Phosphate, Hydrocortisone 21-Sodium 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, Mephenesin, Prednisolone 21-Diethylaminoacetate, Prednisone Sodium Mephenoxalone, Metaxalone, Methocarbamol, Metocurine Phosphate, Prednisolone Sodium Succinate, Prednisolone Iodide, Nimetazepam, Orphenadrine, Pancuronium Sodium 21-m-Sulfo benzoate, Predniso lone Bromide, Phenprobamate, Phenyramidol, Pipecurium 21-Stearoylglycolate, Prednisolone Tebutate, Prednisolone 25 Bromide, Promoxolane, Quinine Sulfate, Styramate, Succi 21-Trimethylacetate, Prednisone, Prednival, Prednylidene, nylcholine Bromide, Succinylcholine Chloride, Succinyl Prednylide ne 21-Diethylaminoacetate, Tixocortal, choline Iodine, Suxethonium Bromide, Tetrazepam, Triamcinolone, Triamcinolone Acetonide, Triamcinolone Benetonide and Triamcinolone Hexacetonide. Thiocolchicoside, Tizanidine, Tolperisone, Tubocurarine 100. Gonad-Stimulating principles Such as BuSerelin, Chloride, Vecuronium Bromide and Zoxolamine. Clomiphene, Cyclofenil, Epimestrol, FSH, HCG and 120. Narcotic antagonists Such as Amiphenazole, LH-RH. Cyclazocine, Levallorphan, Nadide, Nalmfene, Nalorphine, 101. Gonadotropic hormones such as LH and PMSG. Nalorphine Dinicotinate, Naloxone and Naltrexone. 102. Growth hormone inhibitors such as Octreotide and 121. Neuroprotective agents Such as Dizocilpine. Somatostatin. 122. Nootropic agents Such as Aceglutamide, 103. Growth hormone releasing factors such as Semore 35 Acetylcarnitine, Aniracetam, Bife matlane, Exifone, lin. Fipexide, Idebenone, Indeloxazune Hydrochloride, 104. Growth stimulants such as Somatotropin. Nizofenone, Oxiracetam, Piracetam, Propentofylline, Pyriti 105. Hemolytic agents such as Phenylhydrazine and Phe nol and Tacrine. nylhydrazine Hydrochloride. 123. Ophthalmic agents Such as 15-ketoprostaglandins. 106. Heparin antagonists such as Hexadimethrine Bro 40 124. Ovarian hormone Such as relaxin. mide and Protamines. 125. Oxytocic drugs. Such as Carboprost, Cargutocin, 107. Hepatoprotectants Such as S-Adenosylmethionine, Deamino oxy to cin, Ergo no Vine, Ge me prost, Betaine, Catechin, Citolone, Malotilate, OraZamide, Methylergonovine, Oxytocin, Pituitary (Posterior), Prostag Phosphorylcholine, Protoporphyrin IX, Silymarin-Group, landin E, Prostaglandin F, and Sparteine. Thiotic Acid and Tiopronin. 45 126. Pepsin inhibitors such as Sodium Amylosulfate. 108. ImmunomodulatorS Such as Amiprilose, 127. Peristaltic stimulants such as Cisapride. Bucillamine, Ditiocarb Sodium, Inosine PranobeX, 128. Progestogens Such as Allylestrenol, Anagestone, Interferon-Y, Interleukin-2, Lentinan, Muroctasin, Platonin, Chlormadinone Acetate, Delma dinone Acetate, Procodazole, Tetramisole, Thymomodulin, Thymopentin De mege Stone, De Soge Strel, Dime this terone, and Ubenimex. 50 Dydrogesterone, Ethisterone, Ethynodiol, Flurogestone 109. Immunosuppressants Such as AZathioprine, Acetate, Ge Sto de ne, Ge Sto nor one Capro ate, Cyclosporins and Mizoribine. Halo progesterone, 17-Hydroxy-1 6-methylene - 110. Ion eXchange resins Such as Carbacrylic Resins, proge Sterone, 17 C.-Hydroxyprogesterone, 17 C.- Cholestyramine Resin, Colestipol, Polidexide, Resodec and Hydroxygesterone Caproate, Lynestrenol, Medrogestone, Sodium Polystyrene Sulfonate. 55 Medroxyprogesterone, Megestrol Acetate, Melengestrol, 111. Lactation Stimulating hormone Such as Prolactin. Norethindrone, Norethynodrel, Norgesterone, Norgestimate, 112. LH-RH agonists such as Buserelin, Goserelin, Norgestrel, Norgestrienone, Norvinisterone, Pentagestrone, Leuprolide, Nafarelin, and Triptorelin. Progesterone, Promegestone, Quingestrone and Trenge 113. Lipotropic agents Such as N-Acetylmethionine, Cho StOne. line Chloride, Choline Dehydrocholate, Choline Dihydrogen 60 129. Prolactin inhibitors such as Metergoline. Citrate, Inositol, Lecithin and Methionine. 130. Prostaglandins and prostaglandin analogS Such as 114. Lupus erythematoSuS Suppressants Such as Bismuth Arbaprostil, Carboprost, EnproStil, Bemeprost, Limaprost, Sodium Triglycollamate, Bismuth Subsalicylate, Chloro Misoprostol, Ornoprostil, Prostacyclin, Prostaglandin E, quine and Hydroxychloroquine. Prostaglandin E, Prostagland in F2, Rioprostil, 115. Mineralcorticoids such as Aldosterone, 65 Rosaprostol, Sulprostone and Trimoprostil. Deoxycorticosterone, Deoxycorticosterone Acetate and 131. Protease inhibitorS Such as Aprotinin, Camostat, Fludrocortisone. Gabexate and NafamoStat. US 6,221,383 B1 31 32 132. Respiratory Stimulants Such as Almitrine, 136. Thyrotropic hormones such as TRH and TSH. Bemegride, Carbon Dioxide, Cropropamide, Crotethamide, 137. UricoSurics such as Benzbromarone, Ethelbenecid, Dimefline, Dimorpholamine, Doxapram, Ethamivan, Orotic Acid, Oxycinchophen, Probenecid, Sulfinpyrazone, Fominoben, Lobeline, Mepixanox, Metamivam, 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 Flunarizine, Ibudilast, Ifenprodil, Nafronyl, Nicametate, Bisulfate, Quinine Urea Hydrochloride, Sodium Nicergoline, Nimodipine, Papaverine, Pentifylline, Ricinoleate, Sodium Tetradecyl Sulfate and Tribenoside. 1O Tinofedrine, Vincamine, Vinpocetine and Vicquidil. 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; Chloacizine, Chromonar, Clobenfurol, Clonitrate, Dilazep, Alcohols such as Chlorhexadol, Ethchlorvynol, Dipyridamole, Droprenilamine, Efloxate, Erythritol, Eryth Meparfynol, 4-Methyl-5-thiazoleethanol, tert-Pentyl 15 rity1 Tetranitrate, Etafe none, Fendiline, Flore dil, Alcohol and 2.2.2-Trichloroethanol; Ganglefene, Hexestrol Bis(B-diethylaminoethyl ether), Amides Such as Butoctamide, Diethylbromoacetamide, Hexobendine, Itramin Tosylate, Khellin, Lidoflazine, Man Ibrotamide, Isovaleryl Diethylamide, Niaprazine, nitol Hexanitrate, Medibazine, Nicorandil, Nitroglycerin, Tricetamide, Trimetozine, Zolpidem and Zopiclone; Pentaerythritol Tetranitrate, Pentrinitrol, Perhexiline, Barbituric acid derivatives such as Allobarbital, Pimefylline, Prenylamine, Propatyl Nitrate, Pyridofylline, Amobarbital, Aprobarbital, Barbital, Brallabarbital, Trapidil, Tricromyl, Trimetazidine, Trolnitrate Phosphate Butabarbital Sodium, Butalbital, Butallylonal, and Visnadine. Bute thal, Carbu barb, Cyclo barbital, 140. Vasodilators (peripheral) such as Aluminum Cyclopentobarbital, Enallylpropymal, 5-Ethyl-5-(1- Nicotinate, Bamethan, Bencyclane, Betahistine, Bradykinin, pipe ridyl) barbituric Acid, 5-Furfuryl-5- 25 Brovincamine, Bufoniode, Buflo medil, Butalamine, isopropylbarbituric Acid, Heptabarbital, Hexethal Ce tie dil, Ciclonicate, Cinepa Zide, Cinnari Zine, Sodium, Hexobarbital, Mephobarbital, Methitural, Cyclandelate, Diisopropylamine Dichloracetate, Eledoisin, Narcobarbital, Nealbarbital, Pentobarbital Sodium, Fenoxidil, Flunarisine, Heronicate, Ifenprodil, Inositol Phenallymal, Phenobarbital, Phenobarbital Sodium, Niacinate, ISOXSuprine, Kallidin, Kallikrein, Moxisylyte, Phenylmethylbarbituric Acid, Probarbital, Nafronyl, Nicametate, Nicergoline, Nicofuranose, Nicotinyl Propallylonal, Proxibarbal, Reposal, Secobarbital Alcohol, Nylidrin, Pentifylline, Pentoxifylline, Piribedil, Sodium, Talbutal, Tetrabarbital, Vinbarbital Sodium Protaglandin E, Suloctidil and Xanthinal Niacinate. and Vinylbital; 141. Vasoprotectants Such as Benzarone, Bioflavonoids, Benzodiazepine derivatives Such as Brotizolam, Chromocarb, Clobeoside, Diosmin, Dobesilate Calcium, Doxefazepam, Estazolam, Flunitrazepam, Flurazepam, 35 Escin, Rolescu tol, Leucocyanidin, Metescufylline, Haloxazolam, Lopra Zolam, Lorimetazepam, Quercetin, Rutin and Troxerutin. Nitrazepam, Quazepam, Temasepam and Triazolam, 142. Vitamins, Vitamin Sources, and Vitamin extracts Such Bromides such as Ammonium Bromide, Calcium as Vitamins A, B, C, D, E, and K and derivatives thereof, Bromide, Calcium Bromolactobionate, Lithium Calciferols, Glycyrrhiza and Mecobalamin. 40 143. 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, 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; 45 ery characteristics. Thus, in the case of drugs, the drug can Chloral derivatives Such as Carbocloral, Chloral Betaine, be in its free base or acid form, or in the form of Salts, esters, Chloral Form amide, Chloral Hydrate, or any other pharmacologically acceptable derivatives, or as Chloralantipyrine, Dichloralphenazone, Pentaerythritol components of molecular complexes. Chloral and Triclofos; The amount of drug to be incorporated in the composition Piperidinediones such as Glutehimide, Methyprylon, 50 varies depending on the particular drug, the desired thera Piperidione, Pyrithyldione, Taglutimide and Thalido peutic effect, and the time span for which the device is to mide; provide therapy. For most drugs, the passage of the drugs Quinazolone derivatives Such as Etaqualone, Mecloqua through the skin will be the rate-limiting Step in delivery. lone and Methaqualone, and Thus, the amount of drug and the rate of release is typically otherS Such as Acetal, Acetophenone, Aldol, Ammonium 55 adjusted So as to provide transdermal delivery characterized Valerate, Amphenidone, d-Bornyl C-Bromoisovalerate, by a Zero order time dependency for a prolonged period of d-Bornyl Iso vale rate, Bromoform, Calcium time. The minimum amount of drug in the System is Selected 2-Ethylbutanoate, Carfinate, C.-Chloro lose, based on the amount of drug which passes through the skin Clomethiazole, Cypripe dium, Do Xylamine, in the time span for which the device is to provide therapy. Etodroxizine, Etomidate, Fenadiazole, Homofenazine, 60 Normally, the amount of drug in the System can vary from Hydrobromic Acid, Mecloxamine, Menthyl Valerate, about 0.1% to about 50% by weight, and preferably, for the Opium, Paraldehyde, Perlapine, Propiomazine, lower drug doses permitted by this invention, from about Rilmazafone, Sodium Oxybate, Sulfonethylmethane 0.3% to about 30%. and Sulfonmethane. Of course, the composition of the transdermal drug deliv 135. Thrombolytic agents such as APSAC, Plasmin, Pro 65 ery System can also contain agents known to accelerate the Urokinase, Streptokinase, TiSSue Plasminogen Activator and delivery of the drug through the skin. These agents have Urokinase; been referred to as skin-penetration enhancers, accelerants, US 6,221,383 B1 33 34 adjuvants, and Sorption promoters, and are collectively referred to herein as "enhancers.” This class of agents TABLE II includes those with diverse mechanisms of action including those which have the function of improving the solubility PERCENT BY WEIGHT and diffusibility of the drug within the multiple polymer and Component Preferred Range Optimum Range those which improve percutaneous absorption, for example, First 97-9 94-14 by changing the ability of the Stratum corneum to retain Polymer Second O-95 5-85 moisture, Softening the Skin, improving the skins Polymer permeability, acting as penetration assistants or hair-follicle Polyvinyl- 1-20 5-15 openerS or changing the State of the skin including the 1O pyrrollidone boundary layer. Some of these agents have more than one Co-solvent(s) O-30 O-2O mechanism of action, but in essence they serve to enhance Enhancer(s) O-2O 0-15 the delivery of the drug. Drug(s) 0.1-50 O3-30 Some examples of enhancers are polyhydric alcohols Such as dipropylene glycol, propylene glycol, and polyethylene 15 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 known for use with transdermal drug delivery Systems. Squalene, and lanolin; fatty etherS Such as cetyl ether and Where the composition tends to absorb water, for example, oleyl ether, fatty acid esterS Such as isopropyl myristate when lecithin is used as a co-Solvent, hydrophilic Substances which enhance drug diffusibility; urea and urea derivatives are especially useful. One type of hydrophilic Substance such as allantoin which affect the ability of keratin to retain which has been Successfully employed is clay. The addition moisture; polar Solvents Such as dimethyldecylphosphoxide, of clay has been found to improve adhesiveness in trans methyloctylsulfoxide, dimethyl laury lamide, dermal formulations without reducing the rate of drug dodecylpyrrollidone, isosorbitol, dimethylacetonide, delivery. Suitable clays include aluminum Silicate clay, dimethylsulfoxide, decylmethylsulfoxide, and dimethylfor kaolinite, montmorillonite, atapulgite, illite, bentonite, hal mamide which affect keratin permeability; Salicylic acid 25 loysite and the like. which Softens the keratin; amino acids which are penetration In a device aspect of the invention, the preSSure-Sensitive assistants, benzyl nicotinate which is a hair follicle opener; adhesive composition can be used as an adhesive portion of and higher molecular weight aliphatic Surfactants Such as any transdermal drug delivery System (e.g., a reservoir lauryl Sulfate Salts which change the Surface State of the skin device) or it can comprise an adhesive monolithic device. Of and drugs administered. Other agents include oleic and course, the principles of the invention would still apply to linoleic acids, ascorbic acid, panthenol, butylated embodiments where the dermal composition is not a hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl preSSure-Sensitive adhesive and comprises the drug reser linoleate, propyl oleate, and isopropyl palmitate. WO. In certain embodiments of the invention a plasticizer or Reference to FIG. 1 shows a schematic illustration of an tackifying agent is incorporated into the formulation to 35 adhesive monolithic device embodiment of the invention 10. improve the adhesive characteristics of the pressure The transdermal drug delivery System comprises a mono Sensitive adhesive composition. A tackifying agent is par lithic body 11 of a defined geometric shape with a protective release liner 12 on one side of monolithic body 11 and a ticularly useful in those embodiments in which the drug does backing layer 13 on the other side. Removal of the release not plasticize the polymer. Suitable tackifying agents are liner 12 exposes the pressure-Sensitive multiple polymer those known in the art including: (1) aliphatic hydrocarbons; 40 adhesive composition which functions both as the drug (2) mixed aliphatic and aromatic hydrocarbons; (3) aromatic carrier matrix and as the means of applying the System to the hydrocarbons; (4) substituted aromatic hydrocarbons; (5) patient. hydrogenated esters; (6) polyterpenes; and (7) hydrogenated A device, or individual dosage unit, of the present inven Wood rosins. The tackifying agent employed is preferably tion can be produced in any manner known to those of Skill compatible with the blend of polymers. In preferred 45 in the art. After the dermal composition is formed, it may be embodiments, the tackifying agent is silicone fluid (e.g., 360 brought into contact with the backing layer in any manner Medical Fluid, available from Dow Corning Corporation, known to those of Skill in the art. Such techniques include Midland, Mich.) or mineral oil. Silicone fluid is useful for calender coating, hot melt coating, Solution coating, etc. Of blends comprising polysiloxane as a major component. In course, backing materials are well known in the art and can other embodiments, where a Synthetic rubber, for example, 50 comprise plastic films of polyethylene, Vinyl acetate resins, is a major component, mineral oil is a preferred tackifying ethylene/vinyl acetate copolymers, polyvinyl chloride, agent. polyurethane, and the like, metal foils, non-woven fabric, Some drugs, Such as the vasodilator nitroglycerin, func cloth and commercially available laminates. The backing tion as plasticizers in the composition because they are material generally has a thickness in the range of 2 to 1000 Soluble to a certain degree in the polymers comprising the 55 micrometers and the dermal composition is generally dis System. For drug molecules which are not readily Soluble in posed on backing material in a thickness ranging from about the polymer System, a co-Solvent for the drug and polymer 12 to 250 micrometers thick. can be added. Co-Solvents, Such as lecithin, retinal Suitable release liners are also well known in the art and derivatives, tocopherol, dipropylene glycol, triacetin, pro include the commercially available products of Dow Corn pylene glycol, Saturated and unsaturated fatty acids, mineral 60 ing Corporation designated Bio-Release(R) liner and Syl oil, Silicone fluid, alcohols, butylbenzyl phthalate, and the off R 7610 liner. For preferred embodiments in which a like are useful in the practice of the instant invention polysiloxane is part of the multiple polymeric adhesive depending on the Solubility of the drug in the multiple System, the release liner must be compatible with the sili polymer adhesive System. cone adhesive. An example of a Suitable commercially To Summarize, the preferred and optimum compositions 65 available liner is 3MS 1022 Scotch Pak. for the polyacrylate and polysiloxane embodiments are as The configuration of the transdermal delivery system of follows: the present invention can be in any shape or size as is US 6,221,383 B1 35 36 necessary or desirable. Illustratively, a Single dosage unit 6. Appropriate size and shape “systems' are die-cut from may have a Surface area in the range of 1 to 200 cm. the roll material and then pouched. Preferred sizes are from 5 to 60 cm. The order of Steps, the amount of the ingredients, and the In a method aspect of the invention, a plurality of poly amount and time of agitation or mixing may be importance mers having differing Solubility parameters are blended (but proceSS Variables which will depend on the Specific not chemically reacted or cross-linked) with soluble PVP to polymers, drug, coSolvents, and enhancers used in the for result in a preSSure-Sensitive adhesive composition, or trans mulation. These factors can be adjusted by those skilled in dermal drug delivery System adhesive System (with incor the art, while keeping in mind the object of providing a porated drug), which controls delivery of an incorporated uniform product. It is believed that a number of other drug into and through the epidermis. The blending of methods, including changing Some of the order of Steps, can be carried out and will give desirable results. In addition to polymers results in an adjustment of the Saturation concen having various shapes, the dosage units produces may come tration of the drug in the polymeric System and therefore in various sizes. A Surface area in the range of 1 to 200 permits Selective modulation of the transdermal drug deliv Square centimeters is contemplated, and the presently pre ery rate. The term “blending,” of course, incorporates choos ferred sizes are: 5, 10, 15, 20, 30, 30 and 60 are centimeters. ing the appropriate polymeric components, and the propor 15 Said PVP preferably has a molecular weight of about tions thereof, to achieve the desired effect. 2,000 to 1,100,000, more preferably 5,000 to 100,000, and In a preferred embodiment of the invention, a transdermal most preferably 7,000 to 54,000. drug delivery system is prepared by mixing a soluble PVP, Preferred embodiments comprise a soluble PVP with a polyacrylate, polysiloxane, drug, co-solvent(s), and tackify rubber-based preSSure-Sensitive adhesive and a polyacrylate ing agent, if needed, in an appropriate volatile Solvent(s), polymer. Particularly preferred blends include blends of a then casting the mixture and removing the Solvent(s) by polyacrylate, a polysiloxane and a soluble PVP. evaporation to form a film. Soluble PVP has been found to be highly effective in Suitable volatile Solvents include, but are not limited to, preventing crystallization of drugs, in adhesive-type trans alcohols Such as isopropanol and ethanol; aromatics Such as dermal drug delivery Systems according to the invention. In Xylenes and toluene, aliphatics Such as hexane, cyclohexane, 25 particular, soluble PVP has proved useful in maintaining a and heptane, and alkanoic acid esterS Such as ethyl acetate norethindrone acetate (NETA) system and an NETA/ and butyl acetate. estradiol System Substantially crystal-free. Other specific An exemplary general method for the preparation of an drugs for which soluble PVP is particularly usefully embodiment that contains a soluble PVP is as follows: employed according to the invention include albuterol, 1. Appropriate amounts of soluble PVP, solvent(s), estradiol, haloperidol and alprazolam. enhancer(s), and organic Solvent(s) (for example The amount and type of soluble PVP required in the toluene) are combined and thoroughly mixed together foregoing preferred embodiment will depend on the quantity in a Vessel. and type of drug present in the adhesive, as well as the type 2. The drug is then added to the mixture and agitation is of adhesive, but can be readily determined through routine carried out until the drug is uniformly mixed in. 35 experimentation. Typically, the PVP is present in an amount 3. Appropriate amounts of polysiloxane with or without from about 1% to about 20% by weight, preferably from polyacrylate are then added to the drug mixture, and about 5% to about 15% by weight. However, the amount of thoroughly mixed. PVP can be higher than 20% for example, up to 40%, 4. The formulation is then transferred to a coating opera depending on the particular drug used and on the desired tion where it is coated onto a protective release liner at 40 properties of the blend. a controlled specified thickness. The coated product is For example, when the drug is norethindrone acetate then passed through an oven in order to drive off all (NETA), an optimum concentration of about 10% by weight Volatile processing Solvents. PVP has been found to inhibit NETA crystal formation 5. The dried product on the release liner is then joined to without adversely affecting NETA flux from a multiple the backing material and wound into rolls for Storage. 45 polymer adhesive System (polyacrylate/polysiloxane). 6. Appropriate size and shape “systems' are die-cut from When the drug is estradiol, the inclusion of 5-10% of the roll material and then pouched. soluble PVP in the formulation not only increases the An exemplary general method for the preparation of an estradiol flux, but increases the total amount of estradiol embodiment that does not contain a Soluble PVP is as through the skin. When the drug is albuterol, an optimum follows: 50 concentration has been found to be about 5% by weight. 1. Appropriate amounts of polysiloxane and polyacrylate, Large amounts of soluble PVP can cause a decrease in the flux of drug. For example, when the PVP is present in dissolved in a Solvent(s), are combined and thoroughly amounts exceeding about 20% by weight, NETA flux begins mixed together in a vessel. to decrease. 2. The drug is then added to the polymer mixture and 55 agitation is carried out until the drug is uniformly The PVP employed according to the invention is dis mixed in. Solved together with one or more of the additional polymeric materials of the inventive blend. 3. Co-Solvents and enhancers, if necessary, can then be The type and quantity of soluble PVP also can have added to the drug-polymer mixture, and thoroughly Significant effects on the adhesive properties of the finished 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 PVP, whereas in low shear adhesives, the higher molecular a controlled specified thickness. The coated product is weight soluble PVP's are preferred. then passed through an 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 US 6,221,383 B1 37 38 dermal drug delivery Systems, and methods of making Same, Preferred are “Kollidon 17PF,” “Kollidon 25, and “Kol within the contemplation of the invention. These examples lidon 30.’ are in no way intended to be limiting of the Scope of the invention. Example 1 The following commercially available adhesives were A nitroglycerin-polymer mixture was prepared by com used in the blends comprising the multiple polymer adhesive bining 22.0 parts of nitroglycerin, 1.0 part of dipropylene System of the examples: glycol, 1.3 parts of lecithin, 0.8 parts of propylene glycol, “Duro-Tak 80-1194, 80-1196, 80-1054, 80-1074, 2.5 parts of 360 Medial Fluid (1000 cs), 1.0 part of 80-1058, 80-2434, 80-1070, 80-6172, and 80-1197 are bentonite, 63.6 parts of polyacrylate (Duro-Tak 80-1194), trademarks of National Starch and Chemical Corporation, and 85.6 parts of polysiloxane (BIO-PSA X7-4919), and Bridgewater, N.J. for acrylic adhesives (polyacrylates) in mixed well in an appropriate container. Nitroglycerin is organic solutions. “BIO-PSA X7-3027, X7-4919, X7-2685, available as a Solution in Solvents Such as ethanol, toluene, X7-3122, X7-4603, X7-4301, X7-4301, X7-4303 and and propylene glycol from ICI Americas Inc., Wilmington, X7-4503' are trademarks of Dow Corning Corporation, Del. In this instance, the nitroglycerin was added as a Medical Products, Midland, Mich. for silicone adhesives 15 Solution in toluene mixed together with the polyacrylate. (polysiloxanes) in organic solutions. BIO-PSA-3027 is par The resulting composition had the ingredient concentrations ticularly Suitable for use in formulations containing amine on a “dry” basis, that is, after removal of Volatile proceSS functional drugs, Such as albuterol and pilocarpine, in the Solvents, shown below. following examples. “Gelva-Multipolymer Solution (GMS) 737, 788, and 2480” are trademarks of Monsanto Company, St. Louis, Mo., for an acrylic adhesive in organic Solution. “VistaneX COMPONENT LM-LS-LC is a trademark of Exxon Chemical Company, WEIGHT PERCENT BY Houston, Tex., for a polyisobutylene polymer with a Flory Polysiloxane 42.8 25 (Dow Corning Silicone Adhesive BIO-PSA X7-4919) molecular weight of 42,600 to 46,100. Polyacrylate 28.6 “Elvax 40-W is a trademark of Du Pont Company, (National Starch Acrylic Adhesive, Wilmington, Del., for a polyethylene/vinyl acetate copoly Duro-Tak 80-1194) Polydimethylsiloxane fluid 2.5 mer (40% vinyl acetate content). (Dow Corning 360 Medical Fluid) Kraton D 1101, Kraton D 1107 and Kraton G 1657 are Lecithin 1.3 trademarks of the Shell Chemical Company, Houston, Tex., Propylene glycol O.8 for styrene-butadiene-styrene (S-B-S), Styrene-isoprene Dipropylene glycol 1.O styrene (S-I-S) and styrene-ethylene/butylene-styrene Bentonite 1.O (S-EB-S), respectively, block copolymer rubbers Nitroglycerin 22.0 Nitroglycerin is available as a Solution in a Solvent Such 35 1OO.O as ethanol, toluene, and propylene glycol from ICI Americas, Inc., Wilmington, Del. Nitroglycerin flux results through cadaver Skin in vitro The aforementioned polymeric adhesives are Supplied, or from the formulation of Example 1, Transderm-Nitro(R) (a prepared, as Solutions wherein the percent Solids by weight trademark of Ciba-Geigy Corporation, Summit, N.J.), and are as follows: 40 Nitro-Dur(R) (a trademark of Key Pharmaceuticals, Inc., Kenilworth, N.J.) are summarized in FIG. 2. As shown in FIG. 2, nitroglycerin flux from the dermal composition of Ingredient Percent Solids Example 1 (20.8 ug/cmhr) was approximately twice that 45 from Transderm-Nitros (9.5 lug/cm°hr) and about 1.5 times BIO-PSA X7-3O27 50 that from Nitro-Dur(E) (13.4 ug/cmhr). BIO-PSA X7-3122 65 BIO-PSA X7 4301 60 BIO-PSA X7-4303 60 Examples 2-5 BIO-PSA X7-4503 60 BIO-PSA X7-4603 60 In the following examples (2-5), the method of Example BIO-PSA X7-4919 50 50 1 was used with the appropriate amounts of Starting mate BIO-PSA X7-2685 50 rials to yield compositions having the following ingredient Duro-Tak 80-1194 45 concentrations set forth in tabular form in TABLE III. Duro-Tak 80-1196 45 Duro-Tak 80-1197 45 Example 2 is presented for comparative purposes and its Elvax 40-W 3O formulation is not within the Scope of the present invention. GMS 737 32 55 Example 3 and 5 are adhesive compositions comprising Kraton D 1101 3O Kraton D 1107 3O blends of polyacrylate and a Second polymer Selected to Kraton G 1657 illustrate the principles of the invention. All other Vistanex LM-MS-LC 3O components, Such as excipients or fillers, remain constant in composition and amount from Examples 2 to 5. 60 “360 Medical Fluid” is a trademark of Dow Corning Corporation for a polydimethylsiloxane fluid. In certain TABLE III embodiments of the invention, 360 Medical Fluid is added Ingredient as a tackifier to improve the adhesive characteristics of the (sp, J/CM4 Ex2 Ex.3 Ex.4 Ex.5 end product. 65 Polyacrylate (21) 73.2 33.1 33.1 33.1 “Kollidon” is a trademark of BASF AG, Ludwigshafen, Ethylene/vinyl acetate 40.1 Germany, for a polyvinylpyrrolidone (PVP) polymer. US 6,221,383 B1 39 40 attainment of Saturation concentration (unit activity) is fur TABLE III-continued ther verified by the fact that Composition VI had nitroglyc erin exudate; that is, the Surface of the adhesive was “wet' Ingredient with excess nitroglycerin. Of course, Composition VI, (sp, J/CM4 Ex2 Ex.3 Ex.4 Ex.5 which is all polysiloxane, is not within the contemplation of (21) the invention. Polyisobutylene (17) 40.1 Polysiloxane (15) 40.1 The composition of the blend of polymers is preferably Nitroglycerine (27) 20.8 20.8 20.8 20.8 chosen so that the flux rate of drug from the blend is at a Oleic acid 2.O 2.O 2.0 2.O maximum. Studies similar to those reported herein may be Propylene glycol O.8 O.8 O.8 O.8 employed to assist in Selecting the appropriate components Lecithin 1.2 1.2 1.2 1.2 Dipropylene glycol 1.O 1.O 1.O 1.O of the blend and the weight ratios thereof. In alternative Bentonite 1.O 1.O 1.O 1.O embodiments, it may be desirable to Select a composition in which the flux rate will be retarded. FIG. 3 graphically Summarizes the in Vitro nitroglycerin 15 Examples 7-9 flux results through cadaver epidermis from the dermal compositions of Examples 2 to 5. As seen in FIG.3, addition An estradiol-polymer mixture (Example 7) was prepared of either polyisobutylene (Example 4) or polysiloxane by combining 2.0 parts of 17 B-estradiol, 2.0 parts of pro (Example 5) both with SPs lower than polyacrylate pylene glycol, 3.0 parts of lecithin, 5.0 parts of oleic acid, resulted in doubling of the nitroglycerin flux as compared to 5.0 parts of dipropylene glycol, 93.3 parts of polyacrylate an all polyacrylate System (Example 2). However, addition (Duro-Tak 80-1196), and 63.1 parts of polysiloxane (BIO of ethylene/vinyl acetate (Example 3) with an SP value PSAX7-3122), and mixing well in an appropriate container. Similar to the polyacrylate-resulted in little effect on nitro The resulting composition had the ingredient concentrations glycerinflux as compared to the System of Example 2. Thus, on a “dry” basis, that is, after removal of Volatile proceSS the formulation of Example 3 is not within the scope of the 25 solvents, given below in TABLE VI. present invention. Examples 8 and 9 were made in accordance with the method of Example 7. The compositions of Examples 8 and Example 6 9 have the same drug and additional components, Such as the A Series of nitroglycerin-containing compositions (I-VI) co-Solvents, as Example 7, but are not within the Scope of were prepared in which the polyacrylate (Duro-Tak this invention inasmuch as the resulting adhesive matrices 80-1194) to polysiloxane (X7-3122) ratio was varied from are Single polymer Systems. Examples 8 and 9 are given for 100.0.0.0 (all polyacrylate) to 0.0:100.0 (all siloxane) by comparative purposes only. weight. Nitroglycerin concentration was held at 20% for all compositions. The ingredient concentrations of these com TABLE VI positions are shown below in TABLE IV. 35 Ingredient 7 8 9 TABLE IV Polyacrylate 42.O 83.O Polysiloxane 41.O 83.O Ingredient I I III IV V VI Estradiol 2.O 2.O 2.O Oleic acid 5.0 5.0 5.0 Polysiloxane 14.4 28.8 43.2 57.6 72.6 40 Propylene glycol 2.O 2.O 2.O Silicone 1.6 3.2 4.8 6.4 8.0 Lecithin 3.0 3.0 3.0 Fluid Dipropylene glycol 5.0 5.0 5.0 Polyacrylate 8O.O 64.O 48.0 32.8 16.0 Nitroglycerin 2O.O 2O.O 2O.O 2O.O 2O.O 2O.O 45 Estradiol flux in vitro from the systems of Examples 7, 8, In vitro skin flux was determined for these compositions and 9 is shown in FIG. 5. As seen in FIG. 5, delivery from and the results are Summarized in Table V and graphically the System of this invention utilizing the multiple polymer depicted in FIG. 4. adhesive (polyacrylate/polysiloxane) of Example 7 was Sub Stantially greater than delivery from the prior art Systems TABLE V 50 comprising single polymer adhesives (Examples 8 and 9). Polyacrylate Polysiloxane GTN Flux Tlag Examples 10-13 % % (ug/cm/hr (hr) In the following examples (10-13), the method of I 1OO.O O 1.6 O.O II 81.6 18.4 3.2 1.5 Example 7 was used with the appropriate amounts of III 62.5 37.5 4.2 2.0 55 Starting materials to yield compositions having the ingredi IV 43.2 56.8 4.5 2.3 ent concentrations set forth in TABLE VII. V 21.7 78.3 5.2 2.3 VI O 1OO 4.9 2.4 Nitro-Dur (E) 3.0 2.5 TABLE VII 60 Inqredient 1O 11 12 13 As shown, nitroglycerin (GTN) flux increased as the Polysiloxane 18.0 33.5 39.5 58.0 concentration of polysiloxane in the multiple polymer adhe Polyacrylate 65.O 39.5 33.5 15.O Estradiol 2.0 2.O 2.0 2.O Sive matrix increased up to a maximum, at around 80% Oleic acid 5.0 5.0 5.0 5.0 polysiloxane, after which no more increase in flux was seen. Propylene 2.0 2.O 2.0 2.O It appears that beyond a certain concentration of Siloxane 65 glycol polymer, the nitroglycerin activity ceases to increase (unit Lecithin 3.0 3.0 3.0 3.0 activity is reached), and the flux no longer increases. The US 6,221,383 B1 42 had the ingredient concentrations on a “dry” basis, that is, TABLE VII-continued after removal of Volatile process Solvents, given below in TABLE IX. Inqredient 1O 11 12 13 Silicone 5.0 15.O 15.O 15.O TABLE IX fluid Ingredient 17 18 19 2O Polysiloxane 72.O 8.0 6O.O 47.O FIG. 6 shows estradiol flux results for the compositions of Polyacrylate 5.0 15.O 3O.O Examples 10–13, average flux was calculated for each Estradiol 2.O 2.O 2.0 2.O composition from 0 to 22 hours and from 22 to 99 hours Norethindrone 2.O 2.O 2.0 2.O acetate from the start of the study. As seen in FIG. 6, estradiol flux Oleic Acid 2.O 2.O 2.0 2.O progressively increased with increased Silicone polymer Butylene 2.O 2.O 2.0 2.O content during the first 22 hours of delivery, but was affected glycol Lecithin 5.0 5.0 5.0 5.0 to a much lesser degree during the remainder of the Study 15 (22 to 99 hours). Thus, significant adjustment of the estradiol Silicone 15.O 14.O 12.0 1O.O delivery rate during the initial phase of delivery was fluid accomplished, with minor effects on the later delivery phase, by modulating the polysiloxane to polyacrylate polymer Flux results for the compositions of Examples 17-20 are ratio. FIG. 6 also illustrates that the delivery characteristics shown in FIG. 8. As shown in FIG. 8, the flux of both over time can be adjusted by the appropriate choice of estradiol (E2) and norethindrone acetate (NAc) varied as the polymers and respective weight ratioS. For example, the polysiloxane to polyacrylate polymer ratio was adjusted; formulation of Example 10 delivers drug at approximately estradiol flux gradually increased and then decreased with a the same rate over time whereas the formulation of Example maximum at about 15% acrylate, and the norethindrone 13 delivers more quickly in the early phase than the latter. 25 acetate flux continuously decreased with increasing acrylate content as would be expected from the data of FIG. 7. A Examples 14-16 further effect of varying the polysiloxane/polyacrylate poly A norethindrone acetate-polymer mixture was prepared mer ratio is exhibited by a plot of estradiol flux relative to by combining 0.6 parts of norethindrone acetate, 1.0 parts of norethindrone acetate flux (estradiol flux divided by nore butylene glycol, and 40.9 parts of polyacrylate (Duro-Tak thindrone acetate flux) as shown in FIG. 9. By adjusting the 80-1194), and mixing well in an appropriate container. The Silicone to acrylate polymer ratio, it was possible to modu resulting composition had the ingredient concentrations on a late the relative delivery of two drugs (estradiol and nore “dry” basis, that is, after removal of volatile process thindrone acetate) from the Systems of this invention. solvents, given below in TABLE VIII. The same method was employed to make Examples 15 and 16. 35 Examples 21-23 A pilocarpine-polymer mixture was prepared by combin TABLE VIII ing 5.0 parts of pilocarpine base, 1.2 parts of lecithin, 0.8 parts of propylene glycol, 2.0 parts of oleic acid, 2.5 parts of Ingredient 14 15 16 silicone fluid (polydimethylsiloxane, Dow Corning 360 Polyacrylate 92.0 46.0 40 Medical Fluid, 100 cs), and 77.0 parts of polysiloxane Polysiloxane 92.0 46.0 Norethindrone 3.0 3.0 3.0 (BIO-PSA X7-3027), and mixing well in an appropriate acetate container. Example 22 incorporated pilocarpine into a poly Butylene glycol 5.0 5.0 5.0 acrylate comprising National Starch Acrylic Adhesive, Duro-Tak 80-1196. Example 23 employed a blend of pol 45 ySiloxane and polyacrylate in accordance with the principles Norethindrone acetate flux in vitro from the systems of of the invention. The resulting compositions had the ingre Examples 14, 15, and 16 is shown in FIG. 7. As seen in FIG. dient concentrations on a “dry” basis, that is, after removal 7, norethindrone acetate delivery from the polyacrylate/ of volatile process solvents, given below in TABLE X. polysiloxane Systems of this invention (Example 16) was intermediate to delivery from the Single polymer Systems not 50 TABLE X of this invention (Example 14 and 15). Thus, blending the polyacrylate and polysiloxane results in modulation of the Ingredient 21 22 23 norethindrone acetate flux. Polyacrylate 82.O 41.O Polysiloxane 77.0 41.O Examples 17-20 55 Silicone 5.0 fluid AS estradiol/norethindrone acetate combination-polymer Pilocarpine 1.O.O 1O.O 1.O.O mixture was prepared by combining 0.6 parts of 17B Oleic acid 4.0 4.0 4.0 estradiol, 0.6 parts of norethindrone acetate, 0.6 parts of Propylene 1.6 1.6 1.6 butylene glycol, 0.6 parts of oleic acid, 1.5 parts of lecithin, glycol Lecithin 2.4 2.4 2.4 4.5 parts of silicone fluid (polydimethylsiloxane fluid, Dow 60 Corning 360 Medical Fluid, 100 cs), and 43.2 parts of fluid polysiloxane (BIO-PSA X7-4919), and mixing well in an appropriate container. The method of Example 7 was used Pilocarpine flux in vitro from the systems of Examples 21, with the appropriate amounts of Starting materials to yield 22, and 23 is shown in FIG. 10. As seen in FIG. 10, the the compositions of Example 18, 19 and 20. The polyacry 65 delivery rate from the system of this invention utilizing the late used in Examples 18-20 was National Starch Acrylic multiple polymer adhesive (polyacrylate/polysiloxane) of Adhesive, Duro-Tak 80-1197. The resulting compositions Example 23, was intermediate of the delivery rates from US 6,221,383 B1 43 44 Single polymer compositions (Examples 21 and 22) which resulting compositions had the ingredient concentrations on are not of this invention. In this embodiment of the a “dry” basis, that is, after removal of volatile process invention, the combination of polyacrylate and polysiloxane solvents, given below in TABLE XII. polymers adjusted the delivery of rate of pilocarpine within the ranges established by Single polymer compositions. TABLE XII Examples 24-27 Ingredient 28 29 An albuterol-polymer mixture was prepared by combin Polyacrylate 45.O 45.O Polyisobutylene 45.O ing 10.2 parts of albuterol base, 1.5 parts of lecithin, 1.0 part Polysiloxane 45.O of propylene glycol, 4.1 parts of oleic acid, 2.6 parts of Estradiol 2.O 2.O dipropylene glycol, 1.5 parts of butylene glycol, 1.5 parts of Oleic acid 5.0 5.0 Vitamin E acetate (tocoperyl acetate), 25.5 parts of poly Lecithin 3.0 3.0 acrylate (Duro-Tak 80-1196), 11.9 parts of polysiloxane A (BIO-PSA X7-3122), 20.1 parts of polysiloxane B (BIO PSA X7-3027), and 20.1 parts of isopropyl alcohol, and 15 Estradiol flux in vitro from the systems of Examples 28 mixing well in an appropriate container. The resulting com and 29 are shown in FIG. 12. As seen in FIG. 12, delivery position had the ingredient concentrations on a “dry” basis, from the multiple polymer adhesive system of Example 28 that is, after removal of Volatile process Solvents, given is comparable to delivery from Example 29. below in Table XI. The method of Example 24 was used with the appropriate Example 30 amounts of Starting materials to yield the compositions of In addition to flux measurements, the apparent diffusion Examples 25, 26, and 27. coefficient, D, was calculated from release data for nitro glycerin from matrices of Compositions I to VI (Example 6) TABLE XI 25 into an infinite sink. The method of D. R. Paul, Controlled Ingredient 24 25 26 27 Release Polymeric Formulations. ACS Symposium Series No. 33, Chapter 1 (1976) was used wherein the initial Polysiloxane A 14.O 13.8 14.O 14.O Polysiloxane B 19.6 19.2 28.0 19.6 concentration of nitroglycerin in the matrix, Co, was deter Polyacrylate 22.4 22.0 2O.O 22.4 mined (assuming a density of 1.0) and the relationship of the AIbuterol 2O.O 2O.O 2O.O 2O.O amount released, M., by a matrix of area, A, and the Oleic acid 8.0 8.0 8.0 8.0 diffusion coefficient is defined by: Propylene glycol 2.0 2.O 2.0 2.0 Dipropylene 5.0 5.0 5.0 5.0 glycol Butylene glycol 3.0 3.0 3.0 Vitamin E acetate 3.0 3.0 35 Plotting, M/A against t', results in a graph having a Vitamin E 1.O Slope, m, defined by: Vitamin E 3.0 linoleate Lecithin 3.0 3.0 3.0 3.0 m=2C(DfT)"? 40 The value of m can be ascertained by linear regression to Albuterol flux results through human cadaver skin in vitro get the slope of the best fit line. The diffusion coefficient is from the formulations of Examples 24, 25, 26, and 27, are calculated as: summarized in FIG. 11; nitroglycerin flux from Nitro-Dur(R) through the same skin Specimen is shown as a control. Flux values for the albuterol compositions of Example 24 to 27 45 ranged from about 17 ug/cm/hr to about 22 tug/cm°hr. The The results of these calculations for Compositions I to VI nitroglycerin flux value of about 28 ug/cmhr was slightly are shown below in Table XII. higher than the literature delivery rate for this product (20 tug/cm/hr, based on Nitro-Dur(R) product label of 0.1 mg/hr TABLE XIII from a 5 cm system). In order to adjust for the apparent higher permeability of the skin Specimen, albuterol flux 50 Composition Co(mg/cm) m (mg/cmha) D (cm/sec) D(x10) results can be multiplied by an adjustment factor of 0.714 I 241.O O8728 2.861 x 10 2.86 (20/28); this would result in flux values of about 12 ug/cm / II 233.3 O.94.83 3.605 x 10 36.05 III 231.3 1.0834 4.786 x 10 47.86 hr to about 16 g/cm/hr. IV 219.7 1.25O2 7.065 x 10 70.65 Therapeutic albuterol plasma concentrations are in the 55 V 217.0 1.592O 1.174 x 107 117.4 range of about 4 to 8 ng/mL, and are produced by delivery VI 215.O 2.4551 2.845 x 107 284.5 rates of about 115 to 230 ug/hr. The flux rates (12 to 16 Nitro-Dur 38O.O 1468O 3.256 x 10 32.56 tag/cm/hr) obtained from the compositions of this invention therefore would produce the necessary albuterol plasma FIGS. 13 and 14 show the relationship of flux rate (J) levels (4 to 8 ng/mL) for the treatment of asthma from 60 plotted against apparent diffusion coefficient (D) and net system sizes of about 10 to 20 cm. solubility parameter (SP), respectively, for Compositions I-VI. The net solubility parameter, SP, was calculated Examples 28-29 using a weighted average of the Solubility parameters of the Estradiol-polymer mixtures were prepared in accordance individual polymers comprising the matrix: with the method of Example 7. Example 28 is illustrative of 65 a multiple polymer adhesive System where polyacrylate is SP-PSP+(PSP blended with polyisobutylene (Vistanex LM-LS-LC). The US 6,221,383 B1 where (Pes the Weight percentage of polysiloxane and SP. is the solubility parameter of polysiloxane. The Subscript “pa' refers to the polyacrylate. FIG. 15 is a plot of diffusion coefficient verSuS net Solubility parameter. COMPONENT PERCENT BY WEIGHT Tables XIV-A and XIV-B list additional preferred 5 embodiments, which are prepared according to the proce- Polysiloxane(BIO-PSA X7-4503) Adhesive 40.O dure of Example 7 in the same manner as the preceding Polyacrylate Adhesive 40.O preferred embodiments. Table XIV-A lists the polymers and (Monsanto GMS 737) drugs utilized in each embodiment, while Table XIV-B lists Oleic Acid 8.0 additives so utilized. TABLE XIVA Ingredient (SP, J/cm/) 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 33.1 42.O 42.O 15.O 15.O Polyethylene (16.6) 40.1 Polyisoprene (16.6) 40.1 Polybutadiene (15) 41.O Polyethylene/butylene (15) 41.O Polytetrafluoroethylene (12.7) 6O.O Polybutadiene/styrene (17.4) 6O.O Polysiloxane (15) 46.0 46.0 41.O 41.O 42.O 42.O Polystyrene (18.6) 46.0 Polyvinyl chloride (19.4) 46.0 Polyvinylidene chloride (24.9) 41.O Polychloroprene (19.2) 41.O Polyacrylonitrile (26.0) 2O.O Butadiene/acrylonitrile (18.9) 2O.O Nitroglycerine (27) 20.8 20.8 17B-estradiol (24.5) 2.O 2.0 2.O 2.0 Norethindrone acetate (21.3) 2.O 2.0 3.0 3.0 Pilocaprine (22.9) 1.O.O 1O.O Albuterol (26.7) 2O.O 2O.O TABLE XIVB Ex. 31 Ex. 32 Ex. 33 Ex. 34 Ex. 35 Ex. 36 Ex. 37 Ex. 38 Ex. 39 Ex. 40 Ex. 41 Ex. 42 Oleic acid 2.O 2.O 5.0 5.0 2.0 2.O 4.0 4.0 8.0 8.O Propylene glycol O.8 O.8 2.0 2.O 1.6 1.6 2.O 2.O Dipropylene glycol 1.O 1.O 5.0 5.0 5.0 5.0 Butylene glycol 2.0 2.O 5.0 5.0 Bentonite 1.O 1.O 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 12.0 -continued 50 COMPONENT PERCENT BY WEIGHT Example 43 Dipropylene Glycol 6.O Polyvinylpyrrollidone 5.0 55 (Kollidon 30) An estradiol-polymer mixture was prepared by combining Estradiol 1.O 1.0 part of estradiol, 6.0 parts of dipropylene glycol, 8.0 parts of oleic acid, 35.0 parts of toluene, 5.0 parts of 1OO.O polyvinylpyrrolidone (Kollidon 30), and 129.03 parts of polyacrylate adhesive (GMS737) in an appropriate 60 container, and mixing well until the mixture was completely homogeneous. Then 66.67 parts of silicone adhesive (X7 4503) were added, and the blend was thoroughly mixed. The In the following examples the method of Example 43 was resulting composition has the ingredient concentrations on a 65 used with the appropriate amounts of Starting materials to “dry” basis, that is, after removal of volatile process yield compositions having the following ingredient concen Solvents, given below. trations. US 6,221,383 B1 Example 44 -continued COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT 5 Butylated Hydroxyanisole 1.OO Polysiloxane Adhesive 39.0 Norethindrome Acetate 3.OO (BIO-PSA X7-4503) Estradiol O.05 Polyacrylate Adhesive 40.O (Monsanto GMS 737) 1OO.O Oleic Acid 8.0 Dipropylene Glycol 6.O 1O Polyvinylpyrrolidone 5.0 (Kollidon 30) In the following examples the method of Example 46 was Estradiol 2.0 used with the appropriate amounts of Starting materials to 1OO.O yield compositions having the following ingredient concen 15 trations. Example 45 Example 47 2O COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 48.0 Polysiloxane Adhesive 55.90 (BIO-PSA X7-4503) (BIO-PSA X7-4503) Polyacrylate Adhesive 3O.O 25 Polyacrylate Adhesive 2O.O (Monsanto GMS 737) (Monsanto GMS 737) Oleic Acid 6.O Oleic Acid 6.OO Dipropylene Glycol 4.0 Dipropylene Glycol 4.OO Polyvinylpyrrolidone 1.O.O Polyvinylpyrrolidone 1O.OO (Kollidon 30) (Kollidon 30) Estradiol 2.0 Butylated Hydroxyanisole 1.OO - - 3O Norethindrome Acetate 3.OO 1OO.O Estradiol O.10 1OO.O Estradiol permeation through human epidermis in vitro 35 from systems of Examples 44 and 45 are shown in FIG. 16. This graph illustrates how the formulas of this invention Example 48 delivered significantly greater estradiol than EstradermTM, the commercially available estradiol product. 40 COMPONENT PERCENT BY WEIGHT Example 46 Polysiloxane Adhesive 55.8O (BIO-PSA X7-4503) An estradiol/norethindrone acetate-polymer mixture was Polyacrylate Adhesive 2O.OO prepared by combining 0.04 parts of estradiol, 2.48 parts of Many GMS 737) 6.OO norethindrone acetate, 3.31 parts of dipropylene glycol, 4.96 45 DipropyleneCIC ACL Glycol 4.OO parts of oleic acid, 49.62 parts of toluene, 8.27 parts of Polyvinylpyrrollidone 1O.OO polyvinylpyrrolidone (Kollidon 30), 0.83 parts of butylated Butylated(Kollidon 30)Hydroxyanisole 1.OO hydroxyanlsole, and 53.36 parts of polyacrylate adhesive Norethindrome Acetate 3.OO (GMS 737) in an appropriate container, and mixing well so Estradiol - E until the mixture was completely homogeneous. Then 77.12 1OO.O 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, after removal of Volatile process Solvents, given below. 55 Example 49 COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 55.95 60 Polysiloxane Adhesive 55.60 (BIO-PSA X7-4503) (BIO-PSA X7-4503) Polyacrylate Adhesive 2O.OO Polyacrylate Adhesive 2O.OO (Monsanto GMS 737) (Monsanto GMS 737) Oleic Acid 6.OO Oleic Acid 6.OO Dipropylene Glycol 4.OO Dipropylene Glycol 4.00 Polyvinylpyrrolidone 1O.OO 65 Polyvinylpyrrollidone 1O.OO (Kollidon 30) (Kollidon 30) US 6,221,383 B1 SO Example 53 -continued COMPONENT PERCENT BY WEIGHT Butylated Hydroxyanisole 1.OO COMPONENT PERCENT BY WEIGHT Norethindrome Acetate 3.OO Polysiloxane Adhesive 55.00 Estradiol O.40 (BIO-PSA X7-4503) Polyacrylate Adhesive 2O.OO 1OO.O (Monsanto GMS 737) Oleic Acid 6.OO 1O Dipropylene Glycol 4.OO Polyvinylpyrrollidone 1O.OO (Kollidon 30) Example 50 Butylated Hydroxyanisole 1.OO Norethindrome Acetate 3.OO Estradiol 1.OO 15 1OO.O COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 55.60 (BIO-PSA X7-4503) Polyacrylate Adhesive 2O.OO (Monsanto GMS 737) Estradiol flux through human epidermis in vitro from Oleic Acid 6.OO Dipropylene Glycol 4.OO systems of Examples 46 through 53 (with 0.05% to 1.0% Polyvinylpyrrolidone 1O.OO estradiol) are presented in FIG. 17. This graph shows how a (Kollidon 30) wide range in estradiol flux was achieved by the formulas of Butylated Hydroxyanisole 1.OO this invention by varying the estradiol concentration. Nore Norethindrome Acetate 3.OO 25 Estradiol O.SO thindrone acetate flux was not affected by estradiol concentration, and remained constant at about 0.8 ug/ /hr, 1OO.O See FIG. 18. Example 54 Example 51 An estradiol/norethindrone acetate-polymer mixture was prepared by combining 0.20 parts of estradiol, 3.00 parts of COMPONENT PERCENT BY WEIGHT 35 norethindrone acetate, 4.00 parts of dipropylene glycol, 6.00 Polysiloxane Adhesive 55.40 parts of oleic acid, 60.00 parts of toluene, 0.00 parts of (BIO-PSA X7-4503) polyvinylpyrrollidone (Kollidon 30), 1.00 parts of butylated Polyacrylate Adhesive 2O.OO hydroxyanisole, and 64.52 parts of polyacrylate adhesive (Monsanto GMS 737) (GMS 737) in an appropriate container, and mixing well Oleic Acid 6.OO 40 Dipropylene Glycol 4.OO until the mixture was completely homogeneous. Then 93.00 Polyvinylpyrrolidone 1O.OO parts of polysiloxane adhesive (X7-4503) were added, and (Kollidon 30) the blend was thoroughly mixed. The resulting composition Butylated Hydroxyanisole 1.OO Norethindrome Acetate 3.OO has the ingredient concentrations on a “dry” basis, that is, Estradiol O.60 after removal of volatile process Solvents in ovens, given 45 below. 1OO.O COMPONENT PERCENT BY WEIGHT 50 Example 52 Polysiloxane Adhesive 65.8O (BIO-PSA X7-4503) Polyacrylate Adhesive 2O.OO (Monsanto GMS 737) Oleic Acid 6.OO COMPONENT PERCENT BY WEIGHT Dipropylene Glycol 4.OO 55 Polysiloxane Adhesive 55.20 Polyvinylpyrrollidone O.OO (BIO-PSA X7-4503) (Kollidon 30) Polyacrylate Adhesive 2O.OO Butylated Hydroxyanisole 1.OO (Monsanto GMS 737) Norethindrome Acetate 3.OO Oleic Acid 6.OO Estradiol O.2O Dipropylene Glycol 4.OO Polyvinylpyrrolidone 1O.OO 60 1OO.O (Kollidon 30) Butylated Hydroxyanisole 1.OO Norethindrome Acetate 3.OO Estradiol O.80 In the following examples the method of Example 54 was 65 used with the appropriate amounts of Starting materials to yield compositions having the following ingredient concen trations. US 6,221,383 B1 Example 55 TABLE XV Effects of polyvinylpyrrolidone on COMPONENT PERCENT BY WEIGHT 5 - crystal formation Polysiloxane Adhesive 63.30 % polyvinyl- # of crystals (BIO-PSA X7-4503) Formula pyrrollidone in patch Polyacrylate Adhesive 2O.OO (Monsanto GMS 737) Example 54 O.O 60 - 4 Oleic Acid 6.OO Example 55 2.5 568 Dipropylene Glycol 4.OO 1O Example 56 5.0 2O 4 Polyvinylpyrrolidone 2.50 Example 57 1.O.O O (Kollidon 30) Butylated Hydroxyanisole 1.OO *number of visible crystals in a 14.4 cm patch; average and sd of five Norethindrome Acetate 3.OO patches each. Estradiol O.2O 15 Example 58 1OO.O A nitroglycerin-polymer mixture is prepared by combin ing 20.0 parts of nitroglycerin, 2.00 parts of dipropylene glycol, 2.00 parts of lecithin, and 83.33 parts of ethylene/ vinyl acetate polymer (Elvax 40W) in an appropriate Example 56 container, and mixing well until the mixture is completely homogeneous. Nitroglycerin is available as a Solution in Solvents Such as ethanol, toluene, and propylene glycol from ICI Americas Inc., Wilmington, Del. In this instance, the COMPONENT PERCENT BY WEIGHT nitroglycerin is added as a solution in toluene mixed Polysiloxane Adhesive 60.8O together with the ethylene/vinyl acetate polymer. Then 85.00 (BIO-PSA X7-4503) parts of polysiloxane adhesive (X7-4503) are added, and the Polyacrylate Adhesive 2O.OO blend is thoroughly mixed. The resulting composition has (Monsanto GMS 737) the ingredient concentrations on a “dry” basis, that is, after DipropyleneOleic Acid Glycol 4.OO6.OO removal1 ofOI volatilvolau?e process Solvents,1 t given belbelow. Polyvinylpyrrolidone S.OO (Kollidon 30) Butylated Hydroxyanisole 1.OO Norethindrome Acetate 3.OO COMPONENT PERCENT BY WEIGHT Estradiol O.2O 35 Polysiloxane Adhesive 51.OO 1OO.O (BIO-PSA X7-4503) Ethylene/Vinyl Acetate 25.00 Polymer (Elvax 40W) Dipropylene Glycol 2.OO 40 Lecithin 2.OO Example 57 Nitroglycerin 2O.OO 1OO.OO COMPONENT PERCENT BY WEIGHT 45 In the following examples the method of Example 58 is Polysiloxane Adhesive 55.8O used with the appropriate amounts of Starting materials to (BIO-PSA X7-4503) yield compositions having the following ingredient concen Polyacrylate Adhesive 2O.OO trations. In this instance, the nitroglycerin is added as a Oleic(Monsanto Acid GMS 737) 6.OO solutionluti in toltoluene mixedixed ttogetner th winith polyisobutylenelvisobutvl Dipropylene Glycol 4.OO 50 (Vistanex LM-LS-LC). Polyvinylpyrrolidone 1O.OO (Kollidon 30) Example 59 Butylated Hydroxyanisole 1.OO Norethindrome Acetate 3.OO Estradiol O.2O 55 COMPONENT PERCENT BY WEIGHT 1OO.O Polysiloxane Adhesive 56.OO (BIO-PSA X7-4503) Polyisobutylene 2O.OO (Vistanex LM-LS-LC) Dipropwlene Glvcol 2.OO FIG. 19 shows how systems with varying levels of 60 E. y 2.OO polyvinylpyrrolidone (0 to 10%) had essentially the same Nitroglycerin 2O.OO drug (estradiol and norethindrone acetate) flux, Examples 54-57. However, polyvinylpyrrolidone was found to have 1OO.OO an effect on drug recrystallization for these Systems. That is, the incidence of crystal formation was reduced as the 65 In the following example, the nitroglycerin is added as a polyvinylpyrrollidone concentration was increased; See Solution in toluene mixed together with Styrene-isoprene Table XV. styrene (Kraton D 1107) polymer. US 6,221,383 B1 S3 S4 Example 60 Example 63 COMPONENT PERCENT BY WEIGHT 5 COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 46.00 Polysiloxane Adhesive 32.OO (BIO-PSA X7-4503) (BIO-PSA X7-4503) Styrene-isoprene-styrene 3OOO Polyacrylate Adhesive 3O.OO polymer (Duro-Tak 80-1196) Kraton D1107 Polwwnlyvinylpyrrolid OICOC. 1O.OO Dipropylene Glycol 2.OO 1O (Kollidon 30) Lecithin 2.OO Dipropylene Gylcol 4.00 Nitroglycerin 2O.OO Oleic Acid 4.00 Isosorbide Dinitrate 2O.OO 1OOOO 1OO.OO 15 Example 61 E le 64 An isosorbide dinitrate-polymer mixture is prepared by XCp combining 20.0 parts of isosorbide dinitrate, 4.00 parts of Anorethindrone acetate-polymer mixture is prepared by dipropylene glycol, 4.00 parts of oleic acid, and 66.67 parts E. 3. patting to s parts of ethylene/vinyl acetate polymer (Elvax 40W) in an appro- 20 PSPS parts of oleic acid, 60.00 partso E.iat taiaIner, an d "Inmixi We ll Nuntil the mixmixture id: i R toluene,1.00 parts 10.00 of butylated parts of polyvinylpyrrollidonehydroxyanisole, and (Kollidon64.52 parts 30), of pletely homogeneous. In this example, the isosorbide dini- polyacrylate adhesive (GMS 737) in an appropriate trate is added as a solution in toluene mixed together with container, and mixing well until the mixture is completely the ethylene/vinyl acetate polymer. Then 86.67 parts of homogeneous. Then 95.00 parts of polysiloxane adhesive polysiloxane adhesive (BIO-PSA X7-4503) are added, and (BIO-PSA X7-4603) are added, and the blend is thoroughly the blend is thoroughly mixed. The resulting composition mixed. The resulting composition has the ingredient con has the ingredient concentrations on a “dry” basis, that is, CentrationS. On a “dry basis, that is, after removal of volatile after removal of volatile process Solvents in Ovens, given process Solvents, given below. below. 3O COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 57.OO (BIO-PSA X7-4603) ESA'?se 52.OO 35 Polyacrylate Adhesive 2O.OO Ethylene/VinylPolymer Acetate 2O.OO SMSpropylene SR GlvcolGlyco 4.00 E. 4OW Oleic Acid 6.OO S. y Rol col 4.00 Polyvinylpyrrolidone 1O.OO gype ly 4.00 (Kollidon 30) Isosorbide Dinitrate 2O.OO 40 Norethindrome Acetate 3.00 1OOOO 1OO.OO In the following examples the method of Example 64 is In the following examples the method of Example 61 is d with th g examp f ple 1 use d with the appropriateappropri amounts ofI starting materials to 45 yield" withcompositions the appropriate having amountsthe following of starting ingredient materials concen to yield compositions having the following ingredient concen- trations trations. In this instance, the isosorbide dinitrate is added as a Solution in toluene mixed together with Styrene-butadiene- Example 65 styrene polymer (Kraton D1101). Example 62 50 COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 54.OO (BIO-PSA X7-4603) COMPONENT PERCENT BY WEIGHT 55 Ethylene/Vinyl Acetate 25.00 Polysiloxane Adhesive 47.OO Polymer (BIO-PSA X7-4503) (Elvax 40W) Styrene-butadiene- 25.OO Dipropylene Glycol 4.00 styrene (Kraton D1101) Oleic Acid 4.00 Dipropylene Glycol 4.00 Polyvinylpyrrolidone 1O.OO Oleic Acid 4.00 60 (Kollidon 30) Isosorbide Dinitrate 2O.OO Norethindrome Acetate 3.00 1OOOO 1OO.OO In the following example, the isosorbide dinitrate is added 65 Example 66 as a Solution in toluene mixed together with polyacrylate An albuterol-polymer mixture is prepared by combining adhesive (Duro-Tak 80-1196). 30.00 parts of albuterol base, 5.00 parts of butylene glycol, US 6,221,383 B1 SS 8.00 parts of oleic acid, 3.00 parts of tocopherol acetate Example 69 (Vitamin E acetate), and 66.67 parts of ethylene/vinyl acetate polymer (Elvax 40W) in an appropriate container, and mixing well until the mixture is thoroughly mixed. Then 56.67 parts of polysiloxane adhesive (BIO-PSA X7-4301) COMPONENT PERCENT BY WEIGHT are added, and the blend is thoroughly mixed. The resulting Polysiloxane Adhesive 39.00 (BIO-PSA X7-4303) composition has the ingredient concentrations on a “dry” Ethylene/Vinyl 25.00 basis, that is, after removal of Volatile proceSS Solvents, Acetate Polymer given below. (Elvax 40W) 1O Butylene Glycol S.OO Oleic Acid 8.00 Tocopherol Acetate 3.00 (Vitamin E Acetate) COMPONENT PERCENT BY WEIGHT Philocarpine 2O.OO Polysiloxane Adhesive 34.00 (BIO-PSA X7-4301) 15 1OO.OO Ethylene/Vinyl Acetate 2O.OO Polymer (Elvax 40W) Butylene Glycol S.OO Example 70 Oleic Acid 8.OO Tocopherol Acetate 3.OO (Vitamin E Acetate) Albuterol 3OOO COMPONENT PERCENT BY WEIGHT 1OOOO Polysiloxane Adhesive 53.00 (BIO-PSA X7-4301) 25 Polyisobutylene 2O.OO (Vistanex LM-MS-LC) Oleic Acid S.OO In the following examples the method of Example 66 is Tocopherol Linoleate 2.OO used with the appropriate amounts of Starting materials to (Vitamin E Linoleate) yield compositions having the following ingredient concen Alprazolam 2O.OO trations. 1OO.OO Example 67 Example 71 35 COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 46.00 (BIO-PSA X7-4301) Polysiloxane Adhesive 37.OO Polyisobutylene 2O.OO 40 (BIO-PSA X7-4303) (Vistanex LM-MS-LC) Styrene Butadiene Rubber 2O.OO Dipropylene Glycol S.OO (Vistanex LM-MS-LC) Oleic Acid 6.OO Dipropylene Glycol 2.OO Tocopherol Acetate 3.OO Oleic Acid 8.OO (Vitamin E Acetate) Tocopherol Acetate 3.OO AIbuterol 2O.OO 45 (Vitamin E Acetate) Alprazolam 3O.OO 1OOOO 1OOOO 50 Example 68 Example 72 COMPONENT PERCENT BY WEIGHT 55 COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 54.OO Polysiloxane Adhesive 56.OO (BIO-PSA X7-4301) (BIO-PSA X7-4301) Styrene- 2O.OO Styrene-isoprene-styrene 15.OO ethylene/butylene-styrene Polymer polymer (Kraton G.1657) (Kraton D1107) Lecithin 3.OO 60 Propylene Gylcol S.OO Oleic Acid S.OO Linoleic Acid 8.00 Tocopherol Acetate 3.OO Lecithin (Vitamin E Acetate) (Vitamin E Acetate) Pilocarpine 15.OO Haloperidol 1OOOO 65 US 6,221,383 B1 Example 73 Example 77 COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 6100 Polyacrylate Adhesive 55.00 (BIO-PSA X7-4301) (GMS 737) Ethylene/Vinyl Acetate 1O.OO Polyisobutylene 2O.OO Polymer Dipropylene Glycol S.OO (Elvax 40W) Oleic Acid 8.OO Oleic Acid 6.OO 1O Polyvinylpyrrollidone 1O.OO Tocopherol Acetate 3.OO (Kollidon 30) (Vitamin E Acetate) Haloperidol 2.OO Haloperidol 2O.OO 1OOOO 1OOOO 15 Example 78 Example 74 COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 51.OO Polysiloxane Adhesive 44.OO (BIO-PSA X7-4301) (BIO-PSA X7-4301) Polysobutylene 2O.OO Butyl Rubber 25.OO 25 (Vistanex LM-MS-LC) Butylene Glycol S.OO Propylene Glycol S.OO Linoleic Acid 8.OO Oleic Acid 6.OO Tocopherol Acetate 3.OO Lecithin 3.OO (Vitamin E Acetate) Lidocaine 15.OO Haloperidol 15.OO 1OOOO 1OOOO Example 79 Example 75 35 COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 53.00 Polysiloxane Adhesive 6O.OO 40 (BIO-PSA X7-4301) (BIO-PSA X7-4301) Ethylene/Vinyl Acetate 15.OO Polybutene 15.OO Polymer Oleic Acid S.OO (Elvax 40W) Lecithin S.OO Dipropylene Glycol S.OO Alprazolam 15.OO Linoleic Acid 4.00 45 Tocopherol Acetate 3.00 1OOOO (Vitamin E Acetate) Lidocaine 2O.OO 1OO.OO Example 76 50 Example 80 COMPONENT PERCENT BY WEIGHT 55 Polysiloxane Adhesive 62.OO (BIO-PSA X7-4301) COMPONENT PERCENT BY WEIGHT Polyisobutylene 2O.OO (Vistanex LM-MS-LC) Polysiloxane Adhesive 72.OO Dipropylene Glycol 4.00 (BIO-PSA X7-4301) Oleic Acid 4.00 Ethylene/Vinyl Acetate 2O.OO Polyviriylpyrrolidone S.OO 60 Polymer (Kollidon 17PF) (Elvax 40W) Lecithin 3.OO Tocopherol Acetate 3.00 (Vitamin E Acetate) (Vitamin E Acetate) Estradiol 2.OO Nicotine S.OO 1OOOO 65 US 6,221,383 B1 Example 81 -continued COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT 5 Polyethylene Glycol 400 S.OO Polysiloxane Adhesive 65.OO Tocopherol Acetate S.OO (BIO-PSA X7-4303) (Vitainin E Acetate) Polysobutylene 2O.OO Papaverine S.OO (Vistanex LM-MS-LC) Tocopherol Acetate S.OO 1OO.OO (Vitamin E Acetate) 1O Nicotine 1O.OO 1OOOO Example 85 15 COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 81.00 Example 82 (BIO-PSA X7-4601) Polyvinylpyrrollidone 1O.OO 2O (Kollidon 30) Dipropylene Glycol 3.OO COMPONENT PERCENT BY WEIGHT Oleic Acid S.OO Estradiol 2O.OO Polysiloxane Adhesive 52.OO (BIO-PSA X7-4301) 1OOOO Polyacrylate Adhesive 2O.OO 25 (Duro-Tak 80-1196) Polyvinylpyrrolidone 1O.OO (Kollidon 30) Example 86 Dipropylene Glycol S.OO Oleic Acid 8.OO (Vitamin E Acetate) 3O Fentanyl S.OO COMPONENT PERCENT BY WEIGHT 1OOOO Polyisobutylene 81.00 (Vistanex LM-MS-LC) Polyvinylpyrrollidone 1O.OO 35 (Kollidon 17PF) Dipropylene Glycol 2.OO Oleic Acid 6.OO Example 83 Estradiol 1.OO 1OOOO 40 COMPONENT PERCENT BY WEIGHT Example 87 Polysiloxane Adhesive 63.OO p (BIO-PSA X7-4303) Ethylene/Vinyl Acetate 15.OO 45 Polymer (Elvax 40W) COMPONENT PERCENT BY WEIGHT Butylene Glycol S.OO Oleic Acid 8.OO Polysiloxane Adhesive 8O.OO Tocopherol Acetate 3.OO (BIO-PSA X7-4503) (Vitamin E Acetate) Polyvinylpyrrollidone 1O.OO Fentanyl 6.OO 50 (Kollidon 17PF) Dipropylene Glycol 3.OO 1OOOO Oleic Acid S.OO Norethindrome Acetate 2.OO 1OOOO 55 Example 84 Example 88 60 COMPONENT PERCENT BY WEIGHT COMPONENT PERCENT BY WEIGHT Polysiloxane Adhesive 65.OO Polyacrylate Adhesive 77.00 (BIO-PSA X7-4301) (GMS 737) Ethylene/Vinyl Acetate 2O.OO Polyvinylpyrrollidone 1O.OO Polymer 65 (Kollidon 30) ElvaxWax 4OW DipropyleneOWee GlycolWCO 4.00 US 6,221,383 B1 61 62 What is claimed is: -continued 1. A pressure-Sensitive adhesive composition Suitable for use in a transdermal drug delivery System, which composi COMPONENT PERCENT BY WEIGHT tion comprises a blend of: Oleic Acid 6.OO 5 (a) a rubber adhesive, wherein the rubber adhesive is Norethindrome Acetate 3.OO present in an amount from 5% to 97% by weight of the 1OOOO total composition; (b) a polyacrylate in an amount from 1% to 85% by weight of the total composition, wherein the ratio of the 1O Example 89 polyacrylate to the rubber adhesive is from 2:98 to 96:4; (c) a therapeutically effective amount a mixture of two or more drugs for transdermal drug delivery, wherein the COMPONENT PERCENT BY WEIGHT 15 drug is present in an amount weight 0.1% to 50% by Polyacrylate Adhesive 77.00 weight of the total composition, and wherein Said two (GMS 737) or more drugs include an androgenic Steroid and an Polyvinylpyrrolidone 1O.OO estrogen; and (Kollidon 30) Dipropylene Glycol 4.OO (d) a soluble polyvinylpyrrolidone, wherein the soluble Oleic Acid 6.OO polyvinylpyrrollidone is present in an amount of 1% to Norethindrome Acetate 3.OO 20% by weight of the total composition, Estradiol O.2O wherein the ratio of the drug to the soluble polyvinylpyr rolidone is from 1:10 to 10:1, and 1OOOO wherein the amount of soluble polyvinylpyrrolidone is suf 25 ficient to Solubilize all of the drug which is present in an amount that would exceed its Solubility in a composition that Example 90 contains a rubber adhesive and a polyacrylate, but lackS soluble polyvinylpyrrolidone. 2. A pressure-Sensitive adhesive composition Suitable for use in a transdermal drug delivery System, which composi COMPONENT PERCENT BY WEIGHT tion comprises a blend of: Duro-Tak 69.OO (Monsanto 80-1196) (a) a Synthetic elastomeric polymer; Polyvinylpyrrollidone 1O.OO (b) a soluble polyvinylpyrrolidone; (Kollidon 30) (c) a therapeutically effective amount of a drug or a Butylene Glycol S.OO 35 Oleic Acid 8.OO mixture of two or more drugs for transdermal drug Tocopherol Acetate 3.OO delivery, wherein Said two or more drugs include an (Vitamin E Acetate) androgenic Steroid and an estrogen; and Fentanyl S.OO (d) optionally one or more additives Selected from the 1OOOO group consisting of enhancers, fillers, plasticizers, 40 tackifying agents, and co-Solvents. 3. A pressure-Sensitive adhesive composition Suitable for Example 91 use in a transdermal drug delivery System, which composi tion comprises a blend of 45 (a) a rubber; (b) a soluble polyvinylpyrrolidone; COMPONENT PERCENT BY WEIGHT (c) a therapeutically effective amount of a drug or a Polysiloxane Adhesive 58.0 mixture of two or more drugs for transdermal drug (BIO-PSA X7-4503) delivery, wherein Said two or more drugs include an Polyacrylate Adhesive 3O.O 50 (Monsanto GMS 737) androgenic Steroid and an estrogen; and Oleic Acid 6.O (d) optionally one or more additives Selected from the Dipropylene Glycol 4.0 Polyvinylpyrrolidone O.O group consisting of enhancers, fillers, plasticizers, (Kollidon 17PF) tackifying agents, and co-Solvents. Estradiol 2.O 4. A pressure-Sensitive adhesive composition Suitable for 55 use in a transdermal drug delivery System, which composi 1OOOO tion comprises a blend of: (a) a rubber adhesive, wherein the rubber adhesive is present in an amount from 5% to 97% by weight of the Although the invention has been described in terms of total composition; Specific embodiments and applications, perSons skilled in 60 the art can, in light of this teaching, generate additional (b) a polyacrylate in an amount from 1% to 85% by embodiments without exceeding the Scope or departing from weight of the total composition, wherein the ratio of the the Spirit of the claimed invention. Accordingly, it is to be polyacrylate to the rubber adhesive is from 2:98 to understood that the drawing and description in this disclo 96:4; Sure are proffered to facilitate comprehension of the 65 (c) a therapeutically effective amount a drug for transder invention, and should not be construed to limit the Scope mal drug delivery, wherein the drug is present in an thereof. amount of 0.1% to 50% by weight of the total US 6,221,383 B1 63 64 composition, and wherein Said drug is Selected from the wherein the ratio of the drug to the soluble polyvinylpyr group consisting of terbinafine, Sumatriptan, rolidone is from 1:10 to 10:1, and physostigmine, loratadine, Simvastatin, praVStatin, wherein the amount of soluble polyvinylpyrrolidone is suf methimazole, alendranate, etidronate, ropinirole, ficient to Solubilize all of the drug which is present in an pramipexole, fenoldopam, and nimeSulide, and amount that would exceed its Solubility in a composition that (d) a soluble polyvinylpyrrolidone, wherein the soluble contains a rubber adhesive and a polyacrylate, but lackS polyvinylpyrrollidone is present in an amount of 1% to soluble polyvinylpyrrolidone. 20% by weight of the total composition, k k k k k