USOO6638528B1 (12) United States Patent (10) Patent No.: US 6,638,528 B1 Kanios (45) Date of Patent: Oct. 28, 2003

(54) COMPOSITIONS AND METHODS TO FOREIGN PATENT DOCUMENTS EFFECT THE RELEASE PROFILE IN THE TRANSIDERMALADMINISTRATION OF EP O 224 981 6/1987 ACTIVE AGENTS EP O 697 860 4/1994 EP 913 158 6/1999 (75) Inventor: David Kanios, Miami, FL (US) WO WO94/06436 3/1994 (73)73) AssiSignee: : NFpy, Ph armaceuticals,icals, IInc., MiamiMiami, WO WO94/26257WO95/22322 11/19948/1995 ( ) WO WO95/31.188 11/1995 (*) Notice: Subject to any disclaimer, the term of this WO WO96/21433 7/1996 patent is extended or adjusted under 35 WO WO98/17263 4/1998 U.S.C. 154(b) by 0 days. WO WO98/31349 7/1998 WO WO98/39042 9/1998 (21) Appl. No.: 10/086,457 WO WO99/55286 11/1999 WO WOOO/59483 10/2000 (22) Filed: Mar. 1, 2002 WO WOOO/74661 12/2000 Related U.S. Application Data WO PCT/USO1/O1999 8/2001 (63) Continuation of application No. 09/765,932, filed on Jan. 19, OTHER PUBLICATIONS 2001, now abandoned. (60) visional application No. 60/177,103, filed on Jan. 20, Dow Chemical Company, “Product Specification Sheet for 7 Ethocel FP Polymers.”y Oct. 1998, U.S.A. (51) Int. Cl." ...... A61K 9/70; A61K 13/00 (52) U.S. Cl...... 424/449; 424/448; 424/443; Dow Chemical Company, “Bibliography: ETHOCEL Eth 424/484 ylcellulose in Pharmaceuticals,” Jun. 1996, U.S.A. (58) Field of Search ...... 424/448, 449, 424/484, 487, 488, 443 (List continued on next page.) (56) References Cited U.S. PATENT DOCUMENTS Primary Examiner Thurman K. Page 4.584,355 A 4f1986 Blizzard et al. Assistant Examiner Robert M. Joynes 4,585,836 A 4/1986 Homan et al. (74) Attorney, Agent, or Firm-Jay G. Kolman, Esq. 4,591,622 A 5/1986 Blizzard et al. 4,638,043 A 1/1987 Szycher et al. (57) ABSTRACT 4,655,767 A 4f1987 Woodard et al. 4,746,509 A 5/1988 Haggiage et al. Compositions and methods for the transdermal delivery of 4,839,174 A 6/1989 Baker et al. active agents up to a period of Seven days or more at 4,840.796 A 6/1989 Sweet et al. Substantially a Zero-order release rate comprising a pharma 4,842,864 A 6/1989 Guillemet et al. RE32,991 E 7/1989 Szycher et al. ceutically acceptable adhesive matrix and a polymeric plas 4,883,669 A 11/1989 Chien et al. tic material that provides a release rate regulating effect on 4900,554 A 2/1990 Yanagibashi et al. the active agents. 4,994.267 A 2/1991 Sablotsky (List continued on next page.) 6 Claims, 6 Drawing Sheets

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U.S. PATENT DOCUMENTS OTHER PUBLICATIONS 5,118,779 6/1992 Szycher Dow Chemical Company, “Ethocel Polymers for General 5,176.915 1/1993 Hoffmann Applications,” Mar. 1998, U.S.A. 5,232,702 8/1993 Pfister et al. Dow Chemical Company, “Ethocel Premium Polymers for 5,446,070 8/1995 Mantelle Pharmaceutical Applications,” May 1996, U.S.A. 5,474.783 12/1995 Miranda et al. 5,523,095 6/1996 Wison et al. Dow Chemical Company, “Ethocel Premium Ethylcellulose 5,556,635 9/1996 Istin et al. in Pharmaceutical Applications,” Dec. 1991, U.S.A. 5,656,286 8/1997 Miranda et al. Wiley-Interscience/John Wiley & Sons, March, Jerry, 5,662.923 9/1997 Roreger Advanced Organic Chemistry. Reactions, Mechanisms, and 5,662.926 9/1997 Wicket al. Structure, 4th Ed., 1992. 5,676,969 10/1997 Wicket al. BASF Aktiengesellschaft, Buhler, Kollidon(R) Polyvinylpyr 5,679.373 10/1997 Wicket al. rolidone for the Pharmaceutical Industry, 2nd Ed., Aug. 5,716,609 2/1998 Jain et al. 1993. 5,810,786 9/1998 Jackson et al. 5,885,612 3/1999 Meconi et al. Van Nostrand Reinhold, New York, Satas, Donatas, “Acrylic 5,904,931 5/1999 Lipp et al. Adhesives,” pp. 396-456, 1989, Handbook of Pressure 5,906,814 5/1999 Epstein Sensitive Adhesive Technology, 2nd Edition. 6,010,715 1/2000 Wicket al. Van Nostrand Reinhold, New York, Sobieski, Loretta, et al., 6,024,974 * 2/2000 Li ...... 424/448 “Silicone Pressure Sensitive Adhesives, pp. 508-517; 6,143,319 11/2000 Meconi et al. 1989, Handbook of Pressure Sensitive Adhesive Technology, 6,190.689 B1 2/2001 Hoffmann et al. 2nd Ed. 6,231.885 B1 5/2001 Carrara 6,274,165 B1 8/2001 Meconi et al. * cited by examiner U.S. Patent Oct. 28, 2003 Sheet 1 of 6 US 6,638,528 B1

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US 6,638,528 B1 1 2 COMPOSITIONS AND METHODS TO In a matrix-type device, the active agent is dissolved or EFFECT THE RELEASE PROFILE IN THE dispersed in a carrier that typically yields a finite carrier TRANSIDERMALADMINISTRATION OF form, which can be self-adhesive or non-adhesive. Non ACTIVE AGENTS adhesive matrix-type devices, that is, those which Still rely upon a separate adhesive means to affix the device to the CROSS-REFERENCE TO RELATED user, employ a drug permeable adhesive layer (often referred APPLICATION to as an “in-line adhesive' Since the drug must pass through), applied over the drug matrix carrier layer. In an This application is a continuation application of U.S. Ser. attempt to better control the release rate of the drug, Such No. 09/765,932, filed Jan. 19, 2001 now abandoned, which devices often employ one or more additional drug permeable is based on and claims the benefit of Provisional Application layerS Such as rate controlling membranes, or containing No. 60/177,103, filed Jan. 20, 2000. Both of these applica excipients, Such as drug delivery enhancers. Hence, Such tions are incorporated in their entirety herein by reference. devices are also commonly referred to as multilayer or multilaminate. FIELD OF THE INVENTION In a "monolithic or monolayer matrix-type device, the 15 This invention relates generally to transdermal drug deliv active agent is typically Solubilized or homogenously ery Systems, and more particularly to pharmaceutically blended in an adhesive carrier composition, typically a acceptable adhesive matrix compositions, that use polymeric preSSure-Sensitive adhesive or bioadhesive, which functions plastic materials, in particular insoluble cellulose derivatives as both the drug carrier and the means of affixing the System Such as ethyl celluloses, to regulate the drug release profile. to the skin or mucosa. Such devices, commonly referred to The invention additionally relates to transdermal drug deliv as drug-in-adhesive devices, are described, for example, in ery Systems providing Substantially Zero order drug release U.S. Pat. Nos. 4,994,267, 5,446,070, 5,474,783 and 5,656, profiles for an extended period of time of up to Seven days 286, all of which are assigned to Noven Pharmaceuticals, or longer. Inc., Miami, Fla. 25 While matrix-type devices, especially drug-in-adhesive BACKGROUND OF THE INVENTION devices, have achieved more uniform and controlled drug deliver rates, and for longer periods of time, most transder The use of transdermal drug delivery Systems as a means mal Systems remain Subject to a higher initial drug release to topically administer an active agent is well known. Such than is required to achieve therapeutic efficacy. For many Systems incorporate the active agent into a carrier drugs and/or therapeutic Situations, it would be advanta composition, Such as a polymeric and/or pressure-Sensitive geous to eliminate or SuppreSS this higher initial release and adhesive composition, from which the active agent is deliv achieve a "steady State” (Zero order) release profile which ered through the Skin or mucosa of the user. uniformly delivers a therapeutically effective amount of In general, transdermal drug delivery Systems are either drug over the extended duration of device's desired use. reservoir-type or matrix-type devices. Both types of devices For example, the high initial release of certain drugs may employ a backing layer that forms the protective outer 35 cause adverse or undesired effects, or create toxicity Surface of the finished transdermal System and which is concerns, thereby foreclosing the use of transdermal admin exposed to the environment during use, and a release liner istration. In other instances, the higher initial release may or protective layer that forms the inner Surface and which reduce the amount of drug required for treatment to the point covers whatever adhesive means is employed for affixing the of risking underdosing, or may make it impractical to try and System to the Skin or mucosa of a user. The release liner or 40 increase the duration of the devices application while protective layer is removed prior to application, eXposing retaining therapeutic effectiveness. The ability to reduce the the adhesive means, which is typically a pressure-Sensitive frequency of replacing the transdermal drug delivery System adhesive. would concomitantly increase user compliance, reduce any In the “classic' reservoir-type device, the active agent is 45 lag or drop off in efficacious. blood levels, and reduce the usually dissolved or dispersed in a carrier that typically amount of drug required for treatment (also provided by yields a non-finite carrier form, like a fluid or gel, and which reducing the higher initial blood level associated with the is kept Separate from the adhesive means used to affix the higher release rate). device to the user. The device has a pocket or “reservoir” Therefore, despite the existence of many different types of which physically Serves to hold the active agent and carrier, 50 transdermal delivery Systems in the art, there remains a and which is formed in or by the backing layer itself. A continuing need for improving the release profile of drugs to peripheral adhesive layer is then used to affix the device to achieve Substantially Zero order, as well as extending the the user. The early reservoir-type devices incorporated drugs duration of use of each transdermal System. which were readily absorbed through the skin like nitro U.S. Pat. Ser. No. 07/897.269 discloses the use of glycerin glycerin and nicotine. 55 to counteract the burst effect of drugs in transdermal for Such devices have a number of disadvantages including a mulations. non-uniform drug release profile wherein a high dose of It has now been found that the addition of certain poly drug is released initially upon application to the user, often meric plastic polymers, in particular insoluble cellulose described as a “burst effect.” This burst or high initial release derivatives Such as ethyl celluloses, into a pressure-Sensitive of drug then drops off after a period of time to a rate that is 60 adhesive matrix composition, eliminates or Suppresses the less than is able to achieve a therapeutically effective initial high release rate of a drug Subject to a first order amount. Drug delivery according to this profile is described release rate profile Such that the System achieves Substan as first order release. tially Zero order release, and is able to maintain a Substan While such classic devices are still in use today, the term tially Zero order release profile for an extended period of reservoir is being used interchangeably with matrix-type 65 time up to Seven days or longer. devices which Still rely upon a separate adhesive means used Although not wishing to be bound by theory, particularly to affix the device to the user. in this case where the Structure of the composition has not US 6,638,528 B1 3 4 been analyzed, it is postulated that the insoluble polymeric It is still another object of the invention to achieve a plastic material affects the uptake/absorption of water or Substantially Zero-order release profile of the active agent for moisture from the application site into the matrix composi an extended period of time of up to Seven days or longer, and tion which would otherwise create Some of the kinetic effectively continue to deliver the active agent in a thera driving force for release of the drug. This appears especially peutically effective amount. Significant in the presence of hydrophobic drugs and/or in It is a further object of the invention to provide a method conjunction with the use of hydrophilic crystallization of eliminating or Suppressing the high initial release or burst inhibitors, Such as polyvinylpyrrollidones. of active agent from an adhesive matrix type transdermal Ethyl celluloses have been extensively used in industrial drug delivery System containing a drug Subject to a first applications since their commercial introduction in the mid order release profile. 1930s. They are recognized and widely used as well for It is yet another object of the invention to provide a many different purposes in pharmaceutical applications, transdermal drug delivery System that can deliver an active especially in conjunction with water-Sensitive ingredients. agent at Substantially Zero-order for an extended period of Ethyl celluloses are most frequently used as binders, fillers, time in excess of 72 hours and up to Seven days or more flavor fixatives, controlled release coatingS/barriers in 15 without Substantially increasing the Surface area of the microencapsulation and other Solid dosage forms, particu transdermal delivery System. larly multiparticulate Systems, granulation aids, tablet film BRIEF DESCRIPTION OF THE DRAWINGS formers and taste maskers. FIG. 1 is a Schematic illustration of a matrix-type trans The prior art generally discloses the use of insoluble dermal drug delivery System of the present invention. polymerS Such as ethyl cellulose as optional components in FIG. 2 is a graphical representation comparing the in vitro transdermal Systems as thickening agents and as cohesive flux rate of estradiol and norethindrone acetate through neSS Strengthening agents which effect the carrier's adhesive cadaver skin from a pressure-Sensitive adhesive matrix properties. For example, U.S. Pat. No. 5,232,702 discloses composition of the present invention with the flux rate for a the use of a variety of Substances that include ethyl cellulose composition of the prior art. and polyvinyl alcohol as cohesive Strengthening agents 25 FIG. 3 is a graphical representation of the in vitro first (reducing flow properties of silicone adhesives) in a trans order flux rate of estradiol through cadaver Skin from a dermal delivery System. transdermal drug delivery System of the prior art as com The present invention is able to regulate the release profile pared to the in Vitro Steady State flux rate of estradiol through of the drug in a transdermal System without modifying the cadaver Skin from an transdermal drug delivery System of adhesive properties of the pressure-Sensitive adhesive the present invention. matrix So that the transdermal System possesses the required FIG. 4 is a graphical representation of the in vitro flux degree of adhesion and tackiness to remain affixed to the Site rates of estradiol through cadaver skin from two pressure of application for extended periods of time, which can be Sensitive adhesive matrix compositions of the present inven Seven days or more, but at the same time can be easily 35 tion using various amounts of ethyl cellulose as compared to removed as required. the in vitro flux rate of estradiol from a pressure-Sensitive The prior art further generally discloses the use of adhesive matrix composition without ethyl cellulose. insoluble polymers in transdermal Systems as the non FIG. 5 is a graphical representation of the in vitro flux adhesive matrix carrier itself, and even as a "Suitable adhe rates of estradiol through cadaver skin from pressure sive” for the matrix carrier itself (but which presumably 40 Sensitive adhesive matrix compositions of the present inven includes the addition of a plasticizer or tackifier, or plasti tion comparing the effect of varying amounts of ethyl cizing liquid drug like nicotine, to create StickineSS Since cellulose with varying amounts of estradiol. Such polymers are not adhesives). For example, U.S. Pat. FIG. 6 is a graphical representation of the in vitro flux No. 6,010,715 discloses the use of thermoplastic polymers rates of estradiol and norethindrone acetate through cadaver that are melt-blended with active agents and enhancers that 45 skin from pressure-Sensitive adhesive matrix compositions are heat Stable at the melt temperature of the polymer. The comparing the effect of using a combination of ethyl cellu melt-blend can then be thermoformed into carrier layers lose and cellulose acetate butyrate versus either polymer without the use of common Solvents to produce a controlled alone. release layer in a transdermal drug delivery System. Cellu DETAILED DESCRIPTION OF THE lose derivatives Such as ethyl cellulose are generally dis 50 closed as "suitable adhesives” for use as the matrix. INVENTION U.S. Pat. No. 5,904,931 discloses the use of ethyl cellu The foregoing and other objects are achieved by this lose as a crystallization inhibitor in a transdermal drug invention which provides a transdermal drug delivery Sys delivery System. Cellulose ether and polyvinyl compounds tem wherein the use of a polymeric plastic material provides are generally described as additional matrix additives. 55 a release rate regulating effect on the active agents incor porated into the adhesive matrix composition. SUMMARY OF THE INVENTION Unless defined otherwise, all technical and Scientific It is therefore an objective of the present objective to terms used herein have the same meaning as commonly provide for methods and pharmaceutically acceptable understood by one of ordinary skill in the art to which the flexible, finite compositions and Systems for the transdermal 60 invention pertains. administration of active agents that achieve a Substantially The term “topical” or “topically” is used herein in its Zero-order release profile when applied to a user. conventional meaning as referring to direct contact with an It is another object of the invention to provide an adhesive anatomical Site or Surface area on a mammal including skin, matrix-type transdermal drug delivery System which teeth, nails and mucosa. achieves a Substantially Zero-order release profile of the 65 The term "mucosa' as used herein means any moist active agent by incorporating a polymeric plastic material anatomical membrane or Surface on a mammal Such as oral, into an adhesive drug matrix. buccal, vaginal, rectal, nasal or ophthalmic Surfaces. US 6,638,528 B1 S 6 The term “transdermal” as used herein means passage into lohde Viscometer). Ethyl cellulose polymers having Such and/or through skin or mucosa for localized or Systemic Solution Viscosities exhibit melting point temperatures in the delivery of an active agent. range of about 165° C. to about 200° C. Suitable ethyl The term "solubilized” is intended to mean that in the cellulose polymers are commercially available and include those sold under the trademark ETHOCEL(R) by the Dow carrier composition there is an intimate dispersion or disso Chemical Company, Midland, Mich. Preferred ETHOCEL(R) lution of the active agent at the crystalline, molecular or polymers are ETHOCEL(R) Standard 7, 10, 14 and 20, ionic level. AS Such, the active agent is considered herein to Premium or Industrial grades. be in “non-crystallized” form when in the compositions of A crystallization inhibitor or Solubility enhancer may also the present invention. be employed in the invention, for example polyvinylpyrroli As used herein, the term “flux' is defined as the absorp done polymers, polyethylene oxide, polyacrylic acid, poly tion of the drug through the skin or mucosa, and is described Vinyl alcohol, Silicone dioxide, Silica, celluloses and cellu by Fick's first law of diffusion: lose derivatives Such as hydroxymethyl cellulose, hydroxypropyl cellulose, gelatins, gums, Starches, dextrins and dextrans, Sterols, bile acids and other absorptive agents 15 that possess the capability to absorb and hold water or Where J is the flux in g/cm2/sec, D is the diffusion coeffi moisture. cient of the drug through the skin or mucosa in cm2/sec and Particularly preferred compounds are PVPs. The term Dcm/dx is the concentration gradient of the drug acroSS the “polyvinylpyrrolidone” or “PVP" refers to a polymer, ether skin or mucosa. a homopolymer or copolymer, containing vinylpyrrollidone The phrase “pharmaceutically acceptable flexible, finite” (also referred to as N-vinylpyrrollidone, N-vinyl-2- is intended to mean a Solid form capable of conforming to pyrrolidone and N-Vinyl-2-pyrrolidinone) as a monomeric a Surface to which it is applied, and which is capable of unit. PVP polymers include soluble and insoluble maintaining the contact in Such Solid form So as to facilitate homopolymeric PVPs, and copolymers such as topical application without adverse physiological response, Vinylpyrrollidone/vinyl acetate and Vinylpyrrollidone/ and without being appreciably decomposed by aqueous 25 dimethylamino-ethylmethacrylate. The cross-linked hom contact during use by a Subject. polymer (such as KOLLIDONGR CL from BASF) is The term “user' or “subject' is intended to include all insoluble and is generally known in the pharmaceutical warm-blooded mammals, preferably humans. industry under the designations polyvinylpolypyrrolidone, The phrase “substantially zero-order” as used herein crospovidone and PVP. The copolymer vinylpyrrolidone means transdermal delivery of an active agent at a release Vinyl acetate is generally known in the pharmaceutical rate which is approximately constant once Steady State is industry under the designations CopolyVidon (e), Copoly attained, typically within 12 to 24 hours after topical appli vidonum or VP-VAC. cation. While variability in blood levels of active agent are Particularly preferred PVPs are soluble. The term contemplated within the Scope of this meaning once Steady “Soluble” when used with reference to PVP means that the State release is attained, the depletion rate of active agent 35 polymer is Soluble in water and generally is not Substantially over the duration of use should typically not exceed about croSS-linked, and has a molecular weight of less than about 20% to about 25%. 2,000,000. See, generally, Buhler, KOLLIDONGR): POLYVI Any polymeric plastic material may be employed for the NYLPRYRROLIDONE FOR THE PHARMACEUTICAL present invention provided it is insoluble or Substantially INDUSTRY, BASF Aktiengesellschaft (1992). Soluble PVP insoluble in water, and includes cellulose derivatives Such as 40 polymers have been identified in the pharmaceutical indus cellulose acetates, (cellulose acetate butyrate, cellulose try under a variety of names, the most commonly used acetate propionate, cellulose acetate phthalate, etc.), methyl, include Povidone, Polyvidon (e), Polyvidonum, poly ethyl and propyl celluloses, polycarbonates, polystyrenes, (N-vinyl-2-pyrrolidinone, poly (N-vinylbutyrolactam), poly alkylacrylates Such as polymethyl methacrylate, polyethyl (1-vinyl-2-pyrrollidinone, poly 1-(2-oxo-lpyrrolidinyl) ethacrylate, polyethylene methacrylate and other lower alkyl 45 ethylene. acrylates, Vinyl polymers, polyurethanes, polyacrylonitriles, The amount and type of PVP required in the preferred and mixtures, combinations and multipolymers embodiments will depend on the quantity and type of drug (copolymers, terpolymers, etc.) thereof. present in the adhesive matrix composition, as well as the In preferred embodiments, the polymeric plastic material type of adhesives, but can be readily determined through is a cellulose derivative. Preferred are cellulose esters Such 50 routine experimentation. as cellulose acetates including cellulose acetate, cellulose Typically, the PVP is present in an amount from about 5% acetate butyrate, cellulose acetate phthalate, cellulose to about 50% by weight, preferably from about 10% to about acetate propionate, and cellulose ethers. 40% by weight based on the dry weight of the total adhesive Copending provisional application, Ser. No. 60/137,827, matrix composition. However, the amount of PVP can be describes the use of cellulose derivatives, particularly cel 55 higher than 20% for example, up to 40%, depending on the lulose esters, as drug Solubility enhancers in matrix carrier particular drug used and on the desired properties of the compositions. matrix blend. Particularly preferred cellulose ethers are ethyl cellulose Said PVP preferably has a molecular weight of about polymers. Ethyl cellulose polymers can be manufactured in 2,000 to 2,000,000, more preferably 5,000 to 100,000, and a variety of molecular weights, which translates into a range 60 most preferably 7,000 to 54,000. PVP having a molecular of Viscosities when in Solution. In practicing the Subject weight of about 1,000,000 to about 1,500,000 is also pre invention, it has been found that Solution Viscosities ranging ferred. from about 3 centipoise to about 49 centipoise are preferred, PVPs are sold to the pharmaceutical industry under the and more preferably from about 6 centipoise to about 40 trademarks KOLLIDON by BASF (Parsippanny, N.J.); centipoise, and optimally from about 6 centipoise to about 65 PLASDONE, POLYPLASDONE and COPOLYMER 958 22 centipoise (viscosities are for 5% solutions, in 80% by ISP Technologies, Wayne, N.J. Preferred PVPs are KOL toluene and 20% ethanol, measured at 25 C. in an Ubbe LIDON 12PF, 17PF, 25, 30, 90 and VA-64. US 6,638,528 B1 7 8 Particularly preferred embodiments of the invention properties, for example as neutral molecules, components of include soluble PVP in a polyacrylate and polysiloxane molecular complexes or free bases to improve Solubility or preSSure-Sensitive adhesive matrix blend. release characteristics, or as pharmaceutically acceptable The amount and type of polymeric plastic material ethers, esters, amides and the like which have desirable required in the practice of the invention will depend on the retention and release characteristics but which are easily one or more additional materials used in the adhesive matrix metabolized at body pH. composition, and on the amount and type of active agent(s). Compounds may be converted into pharmaceutically Generally, the amount of polymeric plastic material to be acceptable Salts, and the Salts may be converted into phar used is an amount Sufficient to deliver a therapeutically maceutically acceptable free compound using Standard pro effective amount of the active agent at a Substantially cedures known to those skilled in the art of Synthetic organic Zero-order kinetic rate of delivery for an extended period of chemistry and described, for example, by J. March, time of at least three days and up to Seven days or longer, and Advanced Organic Chemistry. Reactions, Mechanisms and to eliminate or Suppress the high initial release rate of a drug Structure, 4' Ed. (New York: Wiley-Interscience, 1992). Subject to a first order release profile. Typically, the amount Acid addition Salts are prepared from the free base (e.g., of polymeric plastic material to be used ranges from about 15 compounds having a neutral -NH2 or cyclic amine group) 0.5% to about 30%, preferably from about 2.5% to 20%, and using conventional means, involving reaction with a Suitable more preferably from about 5.0% to 15% by weight based acid. An acid addition Salt may be converted to the free base on the dry weight of the total adhesive matrix composition. by treatment with a suitable base. Basic salts of acid Amounts greater than 30% typically result in loss of adhe moieties which may be present (e.g., carboxylic acid groups) Sive properties necessary to maintain the System topically can be prepared in a similar manner using pharmaceutically for an extended period of time. acceptable inorganic or organic bases. Compounds may also The adhesive matrix compositions of the present inven be converted into pharmaceutically acceptable esters. Suit tion are designed to effectively deliver an active agent in a able esters include branched or unbranched, Saturated or therapeutically effective amount for an extended period of unsaturated C to C alky esters, for example, methyl, ethyl time up to Seven days or longer. AS used herein, “therapeu 25 and Vinyl esters. Preparation of esters involves functional tically effective” means an amount of an active agent that is ization of hydroxyl and/or carboxyl groups which may be Sufficient to achieve the desired local or Systemic effect or present. Pharmaceutically acceptable esters may be prepared result, Such as to prevent, cure, diagnose, mitigate or treat a using methods known to those skilled in the art and/or disease or condition, when applied topically over the dura described in the pertinent literature. Esters can be recon tion of intended use. Seven days is generally the preferred verted to the free acids, if desired, by using conventional maximum duration for application of a transdermal drug hydrogenolysis or hydrolysis procedures. Preparation of delivery System of the present invention because the Site of amides and pro-drugs can be performed in an analogous application is typically adversely affected when occluded for . a period of time greater than Seven days. However, if a Steroids and hormonal active agents (including both non-occlusive backing material (i.e., permeable to water 35 natural, Semi-Synthetic and Synthetic compounds and their vapor and/or oxygen) is used, then the transdermal System derivatives having Steroidal or hormonal activity) are pre may be applied for periods longer than Seven days without ferred and include, for example, (a) estrogens Such as adverse effects occurring, if at all, until a much later time. Colpormon, Conjugated Estrogens, Estradiol (17B- and Cl-) While delivery of drug by the present invention is preferred and its Esters (e.g., Acetate, Benzoate, Cypionate, Dipropi for at least a Seven-day continuous application, the trans 40 onate Diacetate, Enanthate, Estradiol-16,17-Hemisuccinate, dermal System may be used discontinuously (i.e., replaced at Undececenoate, Undecylate and Valerate), Estriol, Estrone, any time during rather than at the end of the intended Ethinyl Estradiol, Equilenin, Equilin, Mestranol, Methyl duration of use) Since the drug release profile is Substantially Estradiol, Moxestrol, My tatrienediol, Quinestradiol, Zero order. Quinestrol, Dienestrol, Clomifen, Chlorotrianisen, and The term “active agent” (and its equivalents "agent,” 45 Cyclofenil; (b) progestagenically effective hormones Such as “drug,” “medicament” and “pharmaceutical”) is intended to Allylestrenol, Anagestone, Chlormadinone Acetate, Delma have the broadest meaning and includes at least one of any dinone Acetate, Demegestone, DeSogeStrel, 3-Keto therapeutic, prophylactic, pharmacological or physiological De Soge Strel, Dime this terone, Dydrogesterone, active Substance, cosmetic and personal care preparations, Ethinylestrenol, Ethisterone, Ethynodiol (and Diacetate), and mixtures thereof, which is delivered to a mammal to 50 Flurogestone Acetate, GeStodene, GeStonorone Caproate, produce a desired, usually beneficial, effect. More Haloprogesterone, (17-Hydroxy- and 17-Acetate-) Specifically, any active agent that is capable of producing a 16-Methylene-Progesterone, 17C.-Hydroxyprogesterone pharmacological response, localized or Systemic, irrespec (Acetate and Caproate), Levonorgestrel, Lynestrenol, tive of whether therapeutic, diagnostic, cosmetic or prophy Medrogestone, Medroxyprogesterone (and Acetate), Mege lactic in nature, is within the contemplation of the invention. 55 Strol Acetate, Melengestrol, Norethindrone (Acetate and It should be noted that the active agents can be used Enanthate), Norethisterone, Norethynodrel, Norgesterone, Singularly or in combinations and mixtures. Norge Stimate, Norge Strel, Norge Strie none, There is no limitation on the type of active agent that can 19-Norprogesterone, Norvinisterone, Pentage Strone, be used in this invention. However, active agents that are Progesterone, Promegestone, Quingestrone and Trenge Solid or crystalline at room temperature are preferred over 60 Stone; and (c) androgenically effective hormones Such as liquid drugs, especially nicotine. Moreover, drug forms Aldosterone, Androsterone, Boldenone, Cloxotestosterone, other than the free base form are also preferred. Dehydroepiandrosterone, Fluoxymesterone, Mestanolone, The active agents contained in the adhesive matrix com Mesterolone, Methandrostenolone, Methyltestosterone, position can be in different forms Such as pharmaceutically 17C.-Methyl testeosterone, 17C.-Methyl testosterone acceptable Salts, bases, esters, amides or pro-drugs, or may 65 3 - Cyclope nty 1 Enol Ether, Nore thandrolone, be modified by appending one or more appropriate func Nor methandrone, OXandrolone, OXy meSterone, tionalities to enhance Selected physical or biological Oxymetholone, Prasterone, Stanlolone, Stanozolol, Test US 6,638,528 B1 10 osterone (Acetate, Enanthate, Isobutyrate, Propionate and Me taraminol, Methoxamine Hydrochloride, Undecanoate), Testosterone 17-Chloral Hemiacetal, Test Methylhexane amine, Metizolene, Mido drine, osterone 17B-Cypionate and Tiomesterone. Naphazoline, Norepinephrine, Norfenefrine, Octodrine, The adhesive matrix composition of the invention pref Octopamine, OXy meta Zoline, Phenylephrine erably contains 17(3-estradiol or ethinyl estradiol as the Hydrochloride, Phenylpropanolamine Hydrochloride, estrogen alone, or in combination with, Norethindrone Phenylpropylmethylamine, Pholedrine, Propylhexedrine, (Acetate and Enanthate) or Nore thisterone, as the Pseudoephe drine, Rilmenidine, Synephrine, progeStagen, and mixtures thereof. Tetrahydro Zoline, Tiamenidine, Trama Zoline, In embodiments containing combinations and mixtures of Tuaminoheptane, Tymazoline, Tyramine and Xylometa estrogens and progeStagens, the use of combinations and Zoline. mixtures of cellulose derivatives, particularly cellulose . B-Adrenergic agonists Such as Albuterol, Bambuterol, esters and ethers, provide improved drug release profiles for Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, an extended period of time as compared to an adhesive Denopamine, Dioxethedrine, Dopexamine, Ephedrine, matrix composition containing either one alone or none. Epinephrine, Etafedrine, Ethylnorepinephrine, Fenoterol, Preferred combinations or mixtures of cellulose esters and 15 Formoterol, HeXoprenaline, Ibopamine, Isoetharine, ethers are ethyl cellulose with cellulose acetate butyrate or Isoprote renal, Mabute rol, Metaprote renol, with cellulose acetate propionate. When used in combina Methoxyphenamine, Oxyfedrine, Pirbuterol, Prenalterol, tions and mixtures, the amount of each Such polymer typi Procaterol, Protokylol, Reproterol, Rimiterol, Ritodrine, cally ranges from about 2.5% to about 10% by weight based Soterenol, Terbuterol and Xamoterol. on the dry weight of the total adhesive matrix composition. . C.-Adrenergic blockerS Such as AmoSulalol, Arotinolol, Particularly preferred embodiments of such mixtures and Dapiprazole, Doxazosin, Ergoloid MeSylates, Fenspiride, combinations include soluble PVP, and typically in an Indoramin, Labetalol, Nicergoline, PraZosin, Terazosin, amount of about 5% to about 15% by weight based on the Tolazoline, Trimazosin and Yohimbine. dry weight of the total adhesive matrix composition. . B-Adrenergic blockerS Such as Acebutolol, Alprenolol, AS shown in FIG. 6, in pressure-Sensitive adhesive matrix 25 Amosulalol, Arotinolol, Atenolol, Befunolol, Betaxolol, compositions containing both 17B-estradiol (E) and nore Bevantolol, Bisoprolol, Bopindolol, Bucumolol, thindrone acetate (NETA) in a polyacrylate/polysiloxane Befetolol, Bufuralol, Bunitrolol, Bupranolol, Butidrine adhesive blend with 10% PVP, Formula 4 comprising 5.0% Hydrochloride, Butofilolol, Carazolol, Carteolol, ethyl cellulose and 5.0% cellulose acetate butyrate demon Carvedilol, Celiprolol, Cetamolol, Cloranolol, Dilevalol, Strated an improved release profile as compared to either Epanolol, Esmolol, Indenolol, Labetalol, Levobunolol, Formula 1 (only 10% PVP), Formula 2 (5.0% ethyl Mepindolol, Metipranalol, Metoprolol, Moprolol, cellulose) or Formula 3 (5.0% cellulose acetate butyrate). Nadoxolol, Nife nalol, Nip radillol, Oxprenolol, The foregoing formulas were prepared using the method of Penbutolol, Pindolol, Practolol, Pronethalol, Propranolol, Example 1 to yield the following ingredient concentrations Sotalol, Sulfinalol, Talinolol, Tertatolol, Timolol, Tolip set forth in tabular form in TABLE I. 35 rolol and Xibenolol. . Alcohol deterrents Such as Calcium Cyanamide Citrated, TABLE I Disulfiram, Nadide and Nitrefazole. . Aldose reductase inhibitorS Such as Epal restat, Formula 1 Formula 2 Formula 3 Formula 4 Ponalrestat, Sorbinil and Tolrestat. Polysiloxane 71.3 6O.O 6O.O 55.0 40 . Anabolics Such as Androisoxazole, Androstenediol, Adhesive Bolandiol, Bolasterone, Clostebol, Ethylestrenol. (BIO-PSA (R) 7-4603) Polyacrylate O.O 5.0 5.0 5.0 Formyldienolone, 4-Hydroxy-19-nortestosterone, Adhesive Methandriol, Me the no lone, Methyltrie no lone, (DURO-TAK (R) Nandrolone, Nandrolone Decanoate, Nandrolone 87-2287) 45 p - He Xyloxyphenylprop io nate, Nandrolone Polyacrylate 5.0 O.O O.O O.O Adhesive Phenpropionate, Norbolethone, Oxymesterone, (Gelva (R) 737) Pizotyline, Quinbolone, Stenbolone and Trenbolone. Ethyl Cellulose O.O 5.0 O.O 5.0 . Analgesics (dental) Such as Chlorobutanol, Clove and (Ethocel(R) 10) Eugenol. Cellulose Acetate O.O O.O 5.0 5.0 Butyrate 50 . Analgesics (narcotic) Such as Alfentanil, Allylprodine, (CAB-381-0.5) Alpha prodine, Anile ridine, Benzylmorphine, Polyvinylpyrrolidone 1O.O 1.O.O 1O.O 1.O.O Bezitramide, Buprenorphine, Butorphanol, ClonitaZene, (KOLLIDON (R 30) Codeine, Codeine Methyl Bromide, Codeine Phosphate, Oleic Acid 6.O O.O O.O O.O Dipropylene Glycol 4.0 9.O 9.O 9.O Codeine Sulfate, Desomorphine, Dextromoramide, Oleyl Alcohol O.O 6.O 6.O 6.O 55 Dezocine, Diampromide, Dihydrocodeine, Dihydroco Estradiol O.7 1.O 1.O 1.O deinone Enol Acetate, Dihydromorphine, Dimenoxadol, Norethindrone 3.0 4.0 4.0 4.0 Dimepheptanol, Dimethylthiambutene, Dioxaphetyl Acetate Butyrate, Dipipanone, Eptazocine, Ethoheptazine, Ethylmethlythiambutene, Ethylmorphine, Etonitazene, Other specific drugs for which the invention can be 60 Fentanyl, Hydrocodone, Hydrocodone Bitartrate, particularly usefully employed include: Hydromorphone, Hydroxypethidine, Isomethadone, 1. C.-Adrenergic agonists Such as Adrafinil, Adrenolone, Ketobemidone, Levorphanol, Lofentanil, Meperidine, Amidephrine, Apraclonidine, Budralazine, Clonidine, Meptazinol, Metazocine, Methadone Hydrochloride, Cyclopentamine, Detomidine, Dimetofrine, Diplivefrin, Metopon, Morphine, Morphine Derivatives, Myrophine, Ephedrine, Epinephrine, Fenoxazoline, Guanabenz, 65 Nalbuphine, Narceline, Nicomorphine, Norlevorphanol, Guanfacine, Hydroxyamphetamine, Ibopamine, Normethadone, Normorphine, Norpipanone, Opium, Indiana Zoline, Isome the ptene, Mephen termine, Oxycodone, Oxymorphone, Papaveretum, Pentazocine, US 6,638,528 B1 11 12 Phenadoxone, Phenazocine, Pheoperidine, Piminodine, Thimylal, Thiobutabarbital, Thiopental Sodium, Piritramide, Proheptazine, Promedol, Properidine, Tolycaine, Trimecaine and Zolamine. Propiram, Propoxyphene, Sufentanil and Tilidine. 12. Anore Xics Such as Aminore X, Amphe cloral, 10. Analgesics (non-narcotic) Such as Acetaminophen, Amphetamine, BenZaphetamine, Chlorphen termine, AcetaminoSalol, Acetanilide, Acetylsalicylsalicylic Acid, Clobenzorex, Cloforex, Clortermine, Cyclexedrine, Alclofenac, Alminoprofen, Aloxiprin, Aluminum Bis De Stro amphetamine Sulfate, Diethylpropion, (acetylsalicylate), Aminochlorthenoxazin, 2-Amino-4- Diphemethoxidine, N-Ethylamphetamine, Fenbutrazate, picoline, Aminopropylon, Aminopyrine, Ammonium Fenflura mine, Fen prop ore X, Salicylate, Antipyrine, Antipyrine Salicylate, Antrafenine, Furfurylmethylamphetamine, Levophacetoperate, Apa Zone, Aspirin, Benorylate, Benoxaprofen, Ma Zindol, Mefe no rex, Metamfe pro a mone, BenZpiperylon, BenZydamine, p-Bromoacetanilide, Methamphet a mine, No rp Seu do e phe drine, 5-Bromosalicylic Acid Acetate, Bucetin, BufeXamac, Phendime trazine, Phendime trazine Tart rate, Bumadizon, Butacetin, Calcium Acetylsalicylate, Phenmetrazine, Phenpentermine, Phenylpropanolamine Carbamazepine, Carbetidine, Carbiphene, CarSalam, Hydrochloride and Picilorex. Chloralantipyrine, Chlorthenoxazin(e), Choline 15 13. Anthelmintics (Cestodes) Such as Arecoline, Aspidin, Salicylate, Cinchophen, Ciramadol, Clometacin, Aspidinol, Dichlorophen(e), Embelin, Kosin, Napthalene, Cropropamide, Crotethamide, DeXOXadrol, Dilfenamizole, Niclosamide, Pellertierine, Pellertierine Tannate and Diflunisal, Dihydroxy aluminum Acetylsalicylate, Quinacrine. Dipyrocetyl, Dipyrone, EmorfaZone, Enfenamic Acid, 14. Anthelmintics (Nematodes) Such as Alantolactone, Epirizole, EterSalate, Ethen Zamide, Ethoxazene, Amoscanate, AScaridole, Bephenium, Bitoscanate, Car Etodolac, Felbinac, Fenoprofen, Floctafenine, Flufenamic bon Tetrachloride, Carvacrol, Cyclobendazole, Acid, Fluores one, Flu pirtine, Flu produa Zone, Diethylcarbamazine, Diphenane, Dithiazanine Iodide, Flurbiprofen, Fosfosal, Gentisic Acid, Glafenine, Dymanthine, Gentian Violet, 4-Hexylresorcinol, Kainic Ibufenac, Imidazole Salicylate, Indomethacin, Acid, Mebendazole, 2-Napthol, Oxantel, Papain, Indoprofen, ISOfeZolac, Isoladol, Isonixin, Ketoprofen, 25 Piperazine, Piperazine Adipate, Piperazine Citrate, Pip Ketorolac, p-Lactophenetide, Lefetamine, Loxoprofen, erazine Edetate Calcium, Piperazine Tartrate, Pyrantel, Lysine Acetylsalicylate, Magnesium Acetylsalicylate, Pyrvinium Pamoate, a-Santonin, Stilbazium Iodide, Methotrimeprazine, Metofoline, Miroprofen, Morazone, Tetrachloroethylene, Tetramisole, thiabendazole, Thymol, Morpholine Salicylate, Naproxen, Nefopam, Nifenazone, Thymyl N-Isoamylcarbamate, Triclofenol Piperazine and 5' Nitro-2' propoxyacetanilide, Parsalmide, Perisoxal, Urea Stibamine. Phenacetin, Phenazopyridine Hydrochloride, Phenocoll, 15. Anthelmintics (Onchocerca) Such as Ivermectin and Phenopyrazone, Phenyl Acetylsalicylate, Phenyl Suramin Sodium. Salicylate, Phenyramidol, Pipebu Zone, Piperylone, 16. Anthelmintics (Schistosoma) Such as Amoscanate, Prodilidine, Propacetamol, Propyphenazone, Proxazole, Amphotalide, Antimony Potassium Tartrate, Antimony Quinine Salicylate, Ramife naZone, Rima Zolium 35 Sodium Gluconate, Antimony Sodium Tartrate, Antimony Metilsulfate, Salacetamide, Salicin, Salicylamide, Salicy Sodium Thioglycollate, Antimony Thioglycollamide, lamide O-Acetic Acid, Salicylsulfuric Acid, Salsalte, Becanthone, Hycanthone, Lucanthone Hydrochloride, Salverine, Simetride, Sodium Salicylate, Sulfamipyrine, Niridazole, Oxamniquine, Praziquantel, Stibocaptate, Sti Suprofen, Talniflumate, Tenoxicam, Terofenamate, bophen and Urea Stibamine. Tetradrine, Tinoridine, Tolfenamic Acid, Tolpronine, 40 17. Anthelmintic (Trematodes) such as Anthiolimine and Tramadol, Viminol, Xenbucin and Zomepirac. Tetrachloroethylene. 11. Anesthetics Such as Acetamidoeugenol, Alfadolone 18. Antiacne drugs. Such as Adapelene, AlgeStone Acetate, Alfaxalone, Amucaine, Amolanone, Amylocaine Acetophenide, AZelaic Acid, Benzoyl Peroxide, Cyoctol, Hydrochloride, BenoXinate, Benzocaine, Betoxycaine, Cyproterone, Motretinide, Resorcinol, Retinoic Acid, Tet Biphenamine, Bupivacaine, Butacaine, Butaben, 45 roquinone and Tretinonine. Butanilicaine, Burethamine, Buthalital Sodium, 19. Antiallergics Such as Amlexanox, Astemizole, But oxycaine, Carticaine, 2- Chloroprocaine AZelastine, Cromolyn, Fenpiprane, Histamine, Ibudilast, Hydrochloride, Coca ethylene, Cocaine, Nedocromil, Oxatomide, Pentigetide, Poison Ivy Extract, Cyclomethy caine, Dibucaine Hydrochloride, Poison Oak Extract, Poison Sumac Extract, Repirinast, Dimethisoquin, Dimethocaine, Diperadon Hydrochloride, 50 Tranilast, Traxanox and Urushiol. Dyclonine, Ecgonidine, Ecgonine, Ethyl Aminobenzoate, 20. Antiamebics Such as ArSthinol, Bialamicol, CarbarSone, Ethyl Chloride, Etidocaine, Etoxadrol, B-Eucaine, Cephae line, Chlorb et amide, Chloro quine, Euprocin, Fenalcomine, Fomocaine, Hexobarbital, Hexy Chlorphenoxamide, Chlortetracycline, Dehydroemetine, lcaine Hydrochloride, Hydroxydione Sodium, Dibromopropamidine, Diloxanide, DephetarSone, Hydroxyprocaine, Hydroxytetracaine, Isobutyl 55 Emetine, Fumagillin, Glaucarubin, Glycobiar.Sol, p-Aminobenzoate, Kentamine, Leucinocaine MeSylate, 8-Hydroxy-7-iodo-5-quinoline sulfonic Acid, LeVoxadrol, Lidocaine, Mepivacaine, Meprylcaine Iodochlorhydroxyquin, Iodoquinol, Paromomycin, Hydrochloride, Metabutoxycaine Hydrochloride, Metho Phanquinone, Phearsone Sulfoxylate, Polybenzarsol, hexital Sodium, Methyl Chloride, Midazolam, Propamidine, Quinfamide, Secnidazole, Sulfarside, Myrtecaine, Nae paine, Octacaine, Orthocaine, 60 Teclozan, Tetracycline, Thiocarbamizine, ThiocarbarSone Oxethazaine, Parethoxycaine, Phenacaine Hydrochloride, and Tinidazole. Phencyclidine, Phenol, Piperocaine, Piridocaine, 21. Antiandrogens Such as Bifluranol, Cyoctol, Cyproterone, Polidocanol, Pramoxine, Prilocaine, Procaine, Delmadinone Acetate, Flutimide, Nilutamide and Oxen Propanidid, Propanocaine, Proparacaine, Propipocaine, dolone. Propofol, Propoxycaine Hydrochloride, Pseudococaine, 65 22. Antianginals. Such as Acebutolol, Alprenolol, Pyrrocaine, Quinine Urea Hydochloride, Risocaine, Sali Amiodarone, Amlodipine, Arotinolol, Atenolol, Bepridil, cyl Alcohol, Tetracaine Hydrochloride, Thialbarbital, Bevantolol, Bucumolol, Bufetolol, Bufuralol, Bunitrolol, US 6,638,528 B1 13 14 Bupranolol, Carozolol, Carteolol, Carvedilol, Celiprolol, ASpoxicillin, AZidocillan, AZlocillan, Bacampicillin, CinepaZet Maleate, Diltiazem, Epanolol, Felodipine, Benzylpenicillinic Acid, Benzylpenicillin Sodium, Gallopamil, Imolamine, Indenolol, ISOSorbide Dinitrate, Carbenicillin, Carfecillin Sodium, Carindacillin, Isradipine, Limaprost, Mepindolol, Metoprolol, Clo me to cillin, Cloxacillin, Cyclacillin, Molsidomine, Nadolol, Nicardipine, Nife dipline, Dicloxacillin, Diphenicillin Sodium, Epicillin, Nife nalol, Nilvadipine, Nipradillol, Nisoldipine, Fenbenicillin, Floxicillin, Hetacillin, Lenampicillin, Nitroglycerin, OXprenolol, Oxyfedrine, OZagrel, Metampicillin, Methicillin Sodium, Mezlocillin, Penbutolol, Pentaerythritol Tetranitrate, Pindolol, Pronethalol, Propranolol, Sotalol, Terodiline, Timolol, Nafcillin Sodium, Oxacillin, Penamecillin, Peneth Toliprolol and Verapamil. amate Hydriodide, Penicillin G Benethamine, Peni 23. Antiarrhythmics Such as Acebutol, Acecaine, Adenosine, cillin G BenZathine, Penicillin G Benzhydrylamine, Ajmaline, Alprenolol, Amiodarone, Amoproxan, Penicillin G Calcium, Penicillin G Hydrabamine, Aprindine, Arotinolol, Atenolol, Bevantolol, Bretylium Penicillin G Potassium, Penicillin G Procaine, Peni Tosylate, Bubumolol, Bufetolol, Bunaftine, Bunitrolol, cillen N, Penicillin O, Penicillin V, Penicillin V Bupranolol, Butidrine Hydrochloride, Butobendine, Ben Zathine, Penicillin V Hydrab amine, Capobenic Acid, Carazolol, Carteolol, Cifenline, 15 Penime picycline, Phenethicillin Potassium, Cloranolol, Disopyramide, Encainide, Esmolol, Piperacillin, Pivapicillin, Propicillin, Quinacillin, Flecainide, Gallopamil, Hydroquinidine, Indecainide, Sulbenicillin, Talampicillin, Temocillin and Ticarcil Indenolol, Ipratropium Bromide, Lidocaine, Lorajmine, lin; Lorcainide, Meobentine, Metipranolol, Mexiletine, Lincosamides Such as Clindamycin and Lincomycin; Moricizine, Nadoxolol, Nife nalol, Oxprenolol, Macrollides Such as Azithromycin, Carbomycin, Penbutolol, Pindolol, Pirmenol, Practolol, Prajmaline, Clarithromycin, Erythromycin, Erythromycin Procainamide Hydrochloride, Pronethalol, Propafenone, Acistrate, Erythromycin Estolate, Erythromycin Propranolol, Pyrinoline, Quinidine Sulfate, Quinidine, Glucoheptonate, Erythromycin Lactobionate, Erythro Sotalol, Talinolol, Timolol, Tocainide, Verapamil, Vicqui mycin Propionate, Erythromycin Stearate, Josamycin, dil and Xibenolol. 25 Leucomycins, Mide camycins, Miokamycin, 24. Antiarteriosclerotics such as Pyridinol Carbamate. 25. Antiarthritic/Antirheumatics Such as Allocupreide Oleandomycin, Primycin, Rokitamycin, Rosaramicin, Sodium, Auranofin, Aurothioglucose, Aurothioglycanide, ROXithromycin, Spiramycin and Troleandomycin; AZathioprine, Calcium 3-Aurothio-2-propanol-1- Polypeptides Such as Amphomycin, Bacitracin, Sulfonate, Celecoxib, Chloroquine, Clobu Zarit, Capreomycin, Colistin, Enduracidin, Enviomycin, CuproXoline, Diacerein, Glucosamine, Gold Sodium Fusafungine, Gramicidin(s), Gramicidin S, Thio malate, Gold Sodium Thio Sulfate, Mika mycin, Polymyxin, Polymyxin Hydroxychloroquine, Kebuzone, Lobenzarit, Melittin, B-Methanesulfonic Acid, Pristinamycin, Ristocetin, Methotrexate, Myoral and Penicillamine. Teicoplanin, Thiostrepton, Tuberactinomycin, 26. Antibacterial (antibiotic) drugs including: Tyrocidine, Tyrothricin, Vancomycin, Viomycin, Vio Aminoglycosides Such as Amikacin, Apramycin, 35 mycin Pantothenate, Virginiamycin and Zinc Bacitra Arbekacin, Bambermycins, Butirosin, Dibekacin, cin; Dihdrostreptomycin, Fortimicin(s), Gentamicin, Tetracyclines Such as Apicycline, Chlortetracycline, Ispamicin, Kanamycin, Micronomicin, Neomycin, Clomocycline, De meclocycline, Doxycycline, Neomycin Undecylenate, Netilmicin, Paromomycin, Guame cycline, Lyme cycline, Me clocycline, Ribo Stamycin, Sisomicin, Spectinomycin, 40 Methacycline, Minocycline, Oxytetracycline, Streptomycin, StreptonicOZid and Tobramycin; Penimepicycline, Pipacycline, Rolitetracycline, Amphenicols Such as AZidamfenicol, Chloramphenicol, Sancycline, Senociclin and Tetracycline; and Chloramphenicol Palmitate, Chloramphe nicol other antibiotics Such as CycloSerine, Mupirocin and Tuberin. Pantothenate, Florfenicol and Thiamphenicol; 45 Ansamycins Such as Rifamide, Rifampin, Rifamycin and 27. Antibacterial drugs (Synthetic), including: Rifaximin; 2,4-Diaminopyrimidines Such as Brodimoprim, TetroX B-Lactams, including: oprim and Trimethoprim; Carbapenems. Such as Imipenem; Nitrofurans such as Furaltadone, Furazolium Chloride, Cephalosporins Such as Cefactor, Cefadroxil, 50 Nifuradene, Nifuratel, Nifurfoline, Nifurpirinol, Cefamandole, Cefatrizine, CefaZedone, Cefazolin, Nifurprazine, Nifurtoinol and Nitrofurantoin; Cefixime, Cefnmenoxime, Cefodizime, Cefonicid, Quinolones and Analogs Such as Amifloxacin, Cinoxacin, CefoperaZone, Ceforanide, Cefotaxime, Cefotiam, Ciprofloxacin, Difloxacin, Enoxacin, Fleroxacin, Cefpimizole, Ce?pirimide, Cefpodoxime Proxetil, Flumequine, Lomefloxacin, Miloxacin, Nalidixic Acid, Cefroxadine, CefSulodin, Ceftazidime, Cefteram, 55 Norfloxacin, Ofloxacin, Oxolinic Acid, Pefloxacin, Ceftezole, Ceftibuten, Ceftizoxime, Ceftriaxone, Pipemidic Acid, Piromidic Acid, Rosoxacin, Tema Cefuroxime, CefuZonam, Cephacetrile Sodium, floxacin and ToSufloxacin; Cephale Xin, Cephaloglycin, Cephaloridine, Sulfonamides Such as Acetyl Sulfamethoxypyrazine, Cephalosporin, Cephalothin, Cephapirin Sodium, Acetyl SulfiSoxazole, AZOSulfamide, Benzylsulfamide, Cephradine and Piveefalexin; 60 Chloramine-B, Chloramine-T, Dichloramine T. Cephamycins Such as CefbuperaZone, Cefnmetazole, Formosulfathiazole, N°Formylsulfisomidine, N°-a-D- Cefnminox, Cefetan and Cefoxitin; Glucosylsulfa nil amide, Mafen ide, 4'- Monobactams Such as Aztreonam, Carumonam and (Methylsulfamoyl)sulfanila nilide, Tigemonam, p-Nitro sulfathiazole, No prylsulfamide, Oxacephems. Such as Flomoxef and Moxolactam, 65 Phthalylsulfacetamide, Phthalylsulfathiazole, Penicillins such as Amidinocillin, Amdinocillin Sala Zo Sulfadimidine, Succinylsulfathiazole, Pivoxil, Amoxicillin, Ampicillan, Apalcillin, Sulfabenzamide, Sulfacetamide, Sulfachlorpyridazine, US 6,638,528 B1 15 16 Sulfachrysoidine, Sulfacy tine, Sulfadiazine, Buramate, Calcium Bromide, Carb amazepine, Sulfadicramide, Sulfadimethoxine, Sulfadoxine, Cinromide, Clomethiazole, Clonazepam, Decimenide, Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Diethadione, Dimethadione, Doxenitoin, Eterobarb, Sulfaloxic Acid, Sulfamerazine, Sulfameter, Ethadione, Ethosu Ximide, Ethotoin, Fluoresone, Sulfamethazine, Sulfamethizole, Sulfamethomidine, Garbapentin, 5-Hydroxy tryptophan, Lamotrigine, Sulfame thoxazole, Sulfame thoxypyrida Zine, Lomactil, Magnesium Bromide, Magnesium Sulfate, Sulfametrole, Sulfamidochrysoidine. Sulfamoxole, Mephenytoin, Mephobarbital, Metharbital, Methetoin, Sulfanilamide, Sulfanilamidomethanesulfonic Acid Methsuximide, 5-Methyl-5-(3-phenanthryl)hydantoin, Triethanolamine Salt, 4-Sulfanilamidosalicylic Acid, 3-Methyl-5-phenylhydan to in, Narcobarbital, N'-Sulfanilylsulfanilamide, Sulfanily lurea, Nimetazepam, Nitrazepam, Parame thadione, N-Sulfanillyl-3, 4-xylamide, Sulfanitran, Sulfaperine, Phenace mide, Pheneth arbital, Phene turide, Sulfaphenazole. Sulfaproxyline, Sulfapyrazine, Phenobarbital, Phenobarbital Sodium, Phensuximide, Sulfapyridine, SulfaSomizole, SulfaSymazine, Phenylmethylbarbituric Acid, Phenytoin, Phethenylate Sulfathiazole, Sulfathiourea, Sulfatolamide, Sulfisomi Sodium, Potassium Bromide, Pregabatin, Primidone, dine and Sulfisoxazole; 15 Progabide, Sodium Bromide, Sodium Valproate, Sulfones Such as AcedapSone, Acediasulfone, AcetoSul Solanum, Strontium Bromide, Suclofenide, Sulthiame, fone Sodium, DapSone, DiathymoSulfone, Glucosul Tetrantoin, Tiagabine, Trimethadione, Valproic Acid, fone Sodium, Solasulfone, Succisulfone, Sulfanilic Valpromide, Vigabatrin and Zonisamide. Acid, p-Sulfanilylbenzylamine, p.p'-Sulfonyldianiline 29. Antidepressants, including: N.N' digalactoside, Sulfoxone Sodium and Thiazolsul BicyclicS Such as Binedaline, CaroXaZone, Citalopram, fone, and otherS Such as Clofoctol, Hexedine, Dimethazan, Indalpine, Fencamine, Indeloxazine Methenamine, Methenamine Anhydromethylene Hydrochcloride, Nefopam, Nomifensine, Oxitriptan, citrate, Methenamine Hippurate, Methe namine Oxypertine, Paroxetine, Sertraline, ThiaZeSim, Mandelate, Methenamine Sulfosalicylate, Nitroxoline Trazodone, Venlafaxine and Zometapine; and Xibornol. AnticholinergicS Such as Adiphenine 25 HydrazideS/Hydrazines Such as Benmoxine, I proclozide, Hydrochloride, Alverine, Ambutonomium Bromide, Aminopentamide, Amixe trine, Amprotropine Iproniazid, Isocarboxazid, Nialamide, Octamoxin and Phosphate, Anisotropine Methylbromide, Apoatropine, Phenelzine; Atropine, Atropine N-Oxide, Benacty Zine, Pyrrollidones Such as Cotinine, Rolicyprine and Rolipram; Benapry zine, Benzetimide, Benzilonium Bromide, Tetracyclics such as Maprotiline, Metralindole, Mianserin Benztropine Mesylate, Bevonium Methyl Sulfate, and Oxaprotiline. Bip e ride n, Butropium Bromide, Tricyclics Such as Adina Zolam, Amitriptyline, N-Butylscopolammonium Bromide, Buzepide, Amitriptylinoxide, Amoxapine, Butriptyline, Camylo fine, Caramiphen Hydrochloride, Clomipramine, Deme Xiptiline, De Sipramine, Chlorbenzoxamine, Chlorphenoxamine, Cimetropium 35 Dibenzepin, Dime tracrine, Dothiepin, Doxepin, Bromide, Clidinium Bromide, Cyclodrine, Cyclonium Flulacizine, Imipramine, Imipramine N-Oxide, Iodide, Cycrimine Hydrochloride, Deptropine, Iprindole, Lofepramine, Melitracen, Metapramine, Dexe timide, Dibutoline Sulfate, Dicyclomine Nortriptyline, Noxiptilin, Opipramol, Pizotyline, Hydrochloride, Diethazine, Difemerine, Dihexyverine, Propizepine, Protriptyline, Quinupramine, Tianeptine Diphemanil Methylsulfate, N-(1,2-Diphenylethyl) 40 and Trimipramine, and nicotinamide, Dipiproverine, Diponium Bromide, otherS Such as Adrafinil, Benacty Zine, Bupropion, Emepronium Bromide, Endobenzyline Bromide, Butacetin, Deanol, Deanol Aceglumate, Deanol Ethopropazine, Ethybenztropine, Ethylbenzhydramine, Acetamidobenzoate, Dioxadrol, Etope ridone, Etomidoline, Eucatropine, Fenpiverinium Bromide, Febarbamate, Femoxetine, Fenpentadiol, Fluoxetine, Fentonium Bromide, Flutropium Bromide, 45 Fluvoxamine, Fluvoxamine Male ate, Glycopyrrolate, Heteronium Bromide, Hexocyclium Hematoporphyrin, Hypercinin, Levophacetoperane, Methyl Sulfate, Homatropine, Hyoscyamine, Ipratro Medifoxamine, Minaprine, Moclobemide, Oxaflozane, pium Bromide, Isopropamide, Levome pate, Piberaline, Prolintane, Pyrisuccideanol, Rubidium Mecloxamine, Mepenzolate Bromide, Metcaraphen, Chloride, Sulpiride, Sultop ride, Teniloxazine, Methantheline Bromide, Methixene, Methscopolamine 50 Thozalinone, Tofenacin, ToloXatone, Tranylcypromine, Bromide, Oct a my lamine, Chloride, L-Tryptophan, Viloxazine and Zimeldine. Oxyphencyclimine, Oxyphenonium Bromide, 30. Antidiabetics, including: Pentapiperide, Penthienate Bromide, Phencarbamide, Biguanides such as Buformin, Metformin and Phen Phenglutarimide, Pipenzolate Bromide, Piperidolate, formin; Piperilate, Poldine Methysulfate, Pridinol, Prifinium 55 Bromide, Procyclidine, Propantheline Bromide, Hormones Such as Glucagon and Insulin; Propenzolate, Propyromazine, Scopolamine, Scopola Sulfonylure a derivatives Such as Acetohexamide, mine N-Oxide, Stilonium Iodide, Stramonium, 1-Butyl-3-met a nily lure a, Carbutamide, Sultroponium, Thihexinol, Thiphenamil, Tiemonium Chlorpropamide, Glibornuride, Gliclazide, Glipizide, Iodide, Timepidium Bromide, Tiquizium Bromide, 60 Gliquidone, Glisoxepid, Glyburide, Glybuthiazol(e), Tridihexethyl Iodide, Trihexyphenidyl Hydrochloride, Glybuzole, Glyhexamide, Glymidine, Glypinamide, Tropacine, Tropen Zile, Tropicamide, TroSpium Phenbutamide, Tolazamide, Tolbutamide and Tolcycla Chloride, Valethamate Bromide and Xeny tropium Bro mide; and mide. otherS Such as Acarbose, Calcium Mesoxalate and Migli 28. Anticonvulsants Such as Acetylpheneturide, Albutoin, 65 tol. Aloxidone, Aminoglute thimide, 4-Amino-3- 31. Antidiarrheal drugs. Such as Acetyltannic Acid, Albumin hydroxybutyric Acid, Atrolactamide, Beclamide, Tannate, Alkofanone, Aluminum Salicylates-Basic, US 6,638,528 B1 17 18 Catechin, Dife noxin, Diphenoxylate, Lidamidine, Chloride, Isoprometha Zine, Me quita Zine, Lomotil, Loperamide, Mebiquine, Trillium and UZarin. Promethazine, Pyrathiazine and Thiazinamium 32. Antidiuretics Such as Desmopressin, Fely pressin, Methyl Sulfate; and Lypressin, Ornipressin, Oxycinchophen, Pituitary otherS Such as AZatadine, Clobenzepam, Posterior, Terlipressin and Vasopressin. 5 Cyproheptadine, Deptropine, Isothipendyl, Lorata 33. Antiestrogens Such as Delmadinone Acetate, dine and Prothipendyl; and Ethamoxytriphetol, Tamoxifen and Toremifene. other antihistamines Such as Antazoline, Astemizole, 34. Antifungal drugs (antibiotics), including: AZelastine, Cetoxime, Clemizole, Clobenztropine, Polyenes Such as Amphotericin-B, Candicidin, Diphenazoline, Diphenhydramine, FluticaSone Dermostatin, Filipin, Fungichromin, Hachimycin, Propionate, Mebhydroline, Phenindamine, Terfena Hamycin, Lucensomycin, Mepartricin, Natamycin, dine and Tritoqualine. Nystatin, Pecilocin and Perimycin; and 40. Antihyperlipoproteinemics, including: otherS Such as AZaSerine, Griseofulvin, Oligomycins, Aryloxyalkanoic acid derivatives Such as Beclorbrate, Neomycin Undecylenate, Pyrrolnitrin, Siccanin, Tuber Bazafibrate, Binifibrate, Ciprofibrate, Clinofibrate, cidin and Viridin. 15 Clofibrate, Clofibric Acid, Etonfibrate, Fenofibrate, 35. Antifungal drugs (Synthetic), including: Gemfibrozil, Nicofibrate, Pirifibrate, Ronifibrate, Sim Allylamines such as Naftifine and Terbinafine; fibrate and Theofibrate; Imidazoles Such as Bifonazole, Butoconazole, Bile acid Sequesterants Such as Cholestyramine Resin, Chlordantoin, Chlormidazole, Cloconazole, Colestipol and Polidexide; Clotrimazole, Econazole, Enilconazole, Fenticonazole, HMG CoA reductase inhibitors such as Fluvastatin, ISO conazole, Ke to conazole, Miconazole, Lovastatin, Pravastatin Sodium and Simvastatin; Omoconazole, Oxiconazole, Nitrate, Sulconazole and Nicotinic acid derivatives Aluminum Nicotinate, Tioconazole; Acipimox, Niceritrol, Nicoclonate, Nicomol and Triazoles Such as Fluconazole, Itraconazole and Tercona OXiniacic Acid; Zole; and 25 Thyroid hormones and analogS Such as EtiroXate, Thyro otherS Such as Acrisorcin, Amorolfine, Biphenamine, propic Acid and ThyroXine, and Bromosalicylchloranilide, Buclosamide, Calcium otherS Such as Acifran, AZacosterol, Benfluorex, Propionate, Chlophenesin, Ciclopirox, Cloxyquin, a-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, a-Oryzanol, Pantethine, Penataerythritol Sulbentine, Tenonitrozole, Tolciclate, Tolindate, Tetraacetate, a-Phenylbutyramide, Pirozadil, Probucol, Tolnaftate, Tricetin, Ujothion, Undecylenic Acid and a-Sitosterol, Sultosilic Acid, Piperazine Salt, Tiadenol, Zinc Propionate. 35 Triparanol and Xenbucin. 36. Antiglaucoma drugs. Such as Acetazolamide, Befunolol, 41. Antihypertensive drugs, including: Betaxolol, Bupranolol, Carteolol, Dapipra Zoke, Arylethanolamine derivatives Such as AmoSulalol, Dichlorphe namide, Diplive frin, Epinephrine, Bufuralol, Dilevalol, Labetalol, Pronethalol, Sotalol Levobunolol, Methazolamide, Metipranolol, Pilocarpine, and Sulfinalol; Pindolol and Timolol. 40 Aryloxypropanolamine derivatives Such as Acebutolol, 37. Antigonadotropins Such as Danazol, Gestrinone and Alp renolol, Arotinolol, Atenolol, Beta Xolol, Paroxypropione. Bevantolol, Bisoprolol, Bopindolol, Bunitrolol, 38. Antigout drugs. Such as Allopurinol, Carprofen, Bupranolol, Butofilolol, Carazolol, Cartezolol, Colchicine, Probenecid and Sulfinpyrazone. Carvedilol, Celiprolol, Cetamolol, Epanolol, Indenolol, 39. Antihistamines, including: 45 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, 50 Benzothiadiazine derivatives Such as Althiazide, A mino alkyl etherS Such as Bieta nautine, 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, 55 Fen qui Zone, Hydrochlor othiazide, Phenyltoloxamine, Piprinhydrinate and Setasine; 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, 60 Alacepril, Captopril, CilaZapril, Delapril, Enalapril, Thenyldiamine, Thonzylamine Hydrochloride, Tripe 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: 65 Nilvadipine, Nisoldipine and Nitrendipine; Phenothiazines Such as Ahistan, Etyme mazine, Guanidine derivatives Such as Bethanidine, Debrisoquin, Fenethazine, N-Hydroxyethylprometha Zine Guanabenz, Guanacline, Guanadrel, GuanaZodine, US 6,638,528 B1 19 20 Guanethidine, Guanfacine, Guanochlor, GuanoXabenz Indoprofen, Ketoprofen, Loxoprofen, Miroprofen, and Guanoxan; Naproxen, Oxaprozin, Piketoprofen, Pirprofen, Hydrazines and phthalazines Such as Budralazine, Pranoprofen, Protizinic Acid, Suprofen and Tiaprofenic Cadra la Zine, Dihydrala Zine, Endra la Zine, Acid; Hydracarbazine, Hydralazine, Pheniprazine, Pildrala Pyrazoles such as Difenamizole and Epirizole; Zine and Todralazine; Pyrazolones Such as ApaZone, BenZpiperylon, Feprazone, Mofebutazone, Morazone, Oxyphen but a Zone, Imidazole derivatives Such as Clonidine, Lofexidine, Phenylbutazone, Pipebu Zone, Propyphena Zone, Phentolamine, Phentolamine Mesylate, Tiamenidine RamifenaZone, SuxibuZone and ThiazolinobutaZone; and Tolonidine; Salicylic acid derivatives Such as AcetaminoSalol, Quaternary ammonium compounds AZamethonium Aspirin, Benorylate, Bromosaligenin, Calcium Bromide, Chlorisondamine Chloride, Hexamethonium, Acetylsalicylate, Diflunisal, EterSalate, Fendosal, Gen Pentacynium Bis(methyl sulfate), Pentamethonium tisic Acid, Glycol Salicylate, Imidazole Salicylate, Bromide, Pentolinium Tartate, Phenactopinium Chlo Lysine Acetylsalicylate, MeSalamine, Morpholine ride and Trimethidiunum MethoSulfate; 15 Salicylate, 1-Naphthyl Salicylate, Olsalazine, Quinazoline derivatives Such as AlfuZosin, BunaZosin, Parsalmide, PhenylAcetylsalicylate, Phenyl Salicylate, Doxazosin, Prasosin, TeraZOsin and TrimaZOsin; Salacetamide, Salicylamine O-Acetic Acid, Salicylsul Reserpine derivatives Such as Bietaserpine, DeSerpidine, furic Acid, Salsalate and SulfaSalazine; Rescinnamine, Reserpine and Syrosingopine, Thiazinecarboxamides Such as DroXicam, ISOXicam, Sulfonamide derivatives Such as AmbuSide, Clopamide, PiroXicam and Tenoxicam, and Furosemide, Indapamide, QuinethaZone, Tripamide others such as ?-Acetamido cap roic Acid, and Xipamide; and S-Adenosylmethionine, 3-Amino-4-hydroxybutyric others Such as Ajmaline, a-Aminobutyric Acid, Acid, Amixetrine, BendaZac, BenZydamine, Bucolome, Bufeniode, Candesartan, Chlorthalidone, Cicletaine, Difenpiramide, DitaZol, EmorfaZone, GuaiaZulene, Ciclosidomine, Cryptenamine Tannates, EproSartan, 25 Nabumetone, Nime Sulide, Orgotein, Oxaceprol, Fenoldopam, Flose quinan, Indoramin, Irbesartan, Paranyline, Perisoxal, Pifoxime, ProquaZone, ProX Ketanserin, Losartan, Metbutamate, Mecamylamine, azole and Tenidap. Methyldopa, Methyl 4-Pyridyl Ketone Thiosemicarbarzone, 46. Antimalarial drugs. Such as AcedapSone, Amodiaquin, Metolazone, Minoxidil, Muzolimine, Pargyline, Pempidine, Arteether, Arte mether, Artemisinin, Arte Sunate, Pinacidil, Piperoxan, Primaperone, Protoveratrines, Bebeerine, Berberine, Chirata, Chlorguanide, Raubasine, Rescimetol, Rilmenidene, Saralasin, Sodium Chloroquine, Chlorproguanil, Cinchona, Cinchonidine, Nitroprusside, Ticrynafen, Trimethaphan Camsylate, Cinchonine, Cycloguanil, Gentiopicrin, Halofantrine, Tyrosinase, Urapidil and Valsartan. Hydroxychloroquine, Mefloquine Hydrochloride, 42. Antihyperthyroids Such as 2-Amino-4-methylthiazole, 3-MethylarSacetin, Pamaquine, Plasmocid, Primacquine, 2-Aminothiazole, Carbimazole, 3,5-Dibromo-L-tyrosine, 35 Pyrimethamine, Quinacrine, Quinine, Quinine Bisulfate, 3,5-Diiodotyrosine, Hinderin, Iodine, Iothiouracil, Quinine Carbonate, Quinine Dihydrobromide, Quinine Methimazole, Methylthiouracil, Propylthiouracil, Sodium Dihydrochloride, Quinine Ethylcarbonate, Quinine Perchlorate, Thiben Zazoline, Thiobarbital and Formate, Quinine Gluconate, Quinine Hydriodide, Qui 2-Thiouracil. nine Hydrochloride, Quinine Salicylate, Quinine Sulfate, 43. Antihypotensive drugs. Such as AmeZinium Methyl 40 Quinine Tannate, Quinine Urea Hydrochloride, Sulfate, Angiotensin Amide, Dimetofrine, Dopamine, Quinocide, Quinoline and Sodium Arsenate Diabasic. Etifelmin, Etilefrin, Gepefrine, Metaraminol, Midodrine, 47. Antimigraine drugs. Such as Alpiropride, Norepinephrine, Pholedrinead and Synephrine. Dihydroergotamine, Ele trip tan, Ergo cornine, 44. Antihypothyroid drugs. Such as Levothyroxine Sodium, Ergocorninine, Ergocryptine, Ergot, Ergotamine, Liothyronine, Thyroid, Thyroidin, Thyroxine, Tiratricol 45 FlumedroXone acetate, Fonazine, Lisuride, MethySergid and TSH. (e), Naratriptan, Oxetorone, Pizotyline, Rizatriptan and 45. Anti-Inflammatory (non-Steroidal) drugs, including: Sumatriptan. Aminoarylcarboxylic acid derivatives Such as Enfenamic 48. Antinause ant drugs. Such as Acetylleucine Acid, Etofenamate, Flufenamic Acid, IsoniXin, Monoethanolamine, Ali Zapride, BenZquinamide, 50 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, Metoclopramide, Metopimazine, Nabilone, Ondansteron, Alclofenac, Amfenac, BufeXamac, Cinmetacin, OXy pen dyl, Pip amazine, Pip rinhydrinate, Clopirac, Diclofenac Sodium, Etodolac, Felbinac, 55 Prochlorperazine, Scopolamine, Tetrahydrocannabinols, Fenclofenac, Fenclorac, Fenclozic Acid, Fentiazac, Thiethylperazine, ThioproperZaine and Trimethobenza Glucametacin, Ibufenac, Indomethacin, ISOfeZolac, mide. ISOXepac, LonaZolac, Metiazinic Acid, Oxametacine, 49. Antineoplastic drugs, including: Proglumetacin, Sulindac, Tiaramide, Tolimetin and Zomepirac, Alkylating agents, including: 60 Alkyl Sulfonates Such as BuSulfan, ImproSulfan and Arylbutyric acid derivatives Such as Bumadizon, Piposulfan; Butibufen, Fenbufen and Xenbucin; AZiridines Such as BenZOdepa, Carboquone, Meture Arylcarboxylic acids Such as Clidanac, Ketorolac and depa and Uredepa; Tinoridine; Ethylenimines and methylmelamines Such as Arylpropionic acid derivatives Such as Alminoprofen, 65 Altretamine, Sulfosamide, Triethylene melamine, Benoxaprofen, Bucloxic Acid, Carprofen, Fenoprofen, Triethylenephosphoramide, Triethylenethiophos Fluinoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, phoramide and Trimethylolomelamine; US 6,638,528 B1 21 22 Nitrogen mustards Such as Chlorambucil, Piroheptine, Pramipexole, Pridinol, Prodipine, Chlornaphazine, Chclophosphamide, Estramustine, Quinpirole, Remacemide, Ropinirole, Terguride, Tigloi Ifosfamide, Mechlorethamine, Mechlorethamine dine and Trihexyphenidyl Hydrochloride. Oxide Hydrochloride, Melphalan, Novembichin, 53. Antipheochromocytoma drugs. Such as Metyrosine, Phe Phenesterine, Prednimustine, Trofosfamide and noxybenzamine and Phentolamine. Uracil Mustard; 54. Antipneumocystis drugs Such as Effornithine, Pentami NitroSoureas Such as Carmustine, Chlorozotocin, dine and Sulfamethoxazole. Fotemustine, Lomustine, Nimustine and Ranimus 55. Antiprostatic hypertrophy drugs. Such as Gestonorone tine, and Caproate, Mepartricin, Oxendolone and Proscar7. otherS Such as Camp to the cin, Dacarbazine, 56. Antiprotozoal drugs (Leshmania) Such as Antimony Mannomustine, Mitobronitol, Mitolactol and Pipo Sodium Gluco nate, Ethylstiba mine, broman; HydroxyStilbamidine, N-Methylglucamine, Pentamidine, Antibiotics Such as Aclacinomycins, Actinomycin F, Stilbamidine and Urea Stibamine. Anthra mycin, AZ, a Serine, Ble o my c in S, 57. Antiprotozoal drugs (Trichomonas) Such as AcetarSone, Cactinomycin, Carubicin, Car Zinophilin, Aminitrozole, Anisomycin, AZanidazole, Forminitrazole, Chromomycins, Dactinomycin, Daunorubicin, 15 Furazolidone, Hachimycin, Lauroguadine, Mepartricin, 6-Diazol-5-oxo-L-nor leucine, Doxorubicin, Metronidazole, Nifuratel, Nifuroxime, Nimorazole, Epirubicin, Mitomycins, Mycophenolic Acid, Secnidazole, Silver Picrate, Tenonitrozole and Tinidazole. Nogalamycin, Olivomycins, Peplomycin, 58. Antiprotozoal drugs (Trypanosma) Such as Plicamycin, Porfiromycin, Puromycin, Benznidazole, Eflornithine, Melarsoprol, Nifurtimox, Rufocromomycin, Streptonigrin, Streptozocin, Oxophe narsine, Hydrochloride, Pentamidine, Tubercidin, Ubenimex, Zinostatin and Zorubicin; Propamidine, Puromycin, Quinapyramine, Stilbamidine, Antimetabolites, including: Suramin Sodium, Trypan Red and Tryparasmide. Folic acid analogS Such as Denopterin, Methotrexate, 59. Antipuritics Such as Camphor, Cyproheptadine, Pteropterin and Trimetrexate; Dichloris one, Glycine, Halo me taSone, Purine analog S Such as Fluld arabine, 25 3-Hydroxycamphor, Menthol, Mesulphen, Methdilazine, 6-Mercaptopurine, Thiamiprine and Thiogua Phenol, Polidocanol, Risocaine, Spirit of Camphor, maine; and Thenaldine, Tolpropamine and Trimeprazine. Pyrimidine analogS Such as Ancitabine, AZacitidine, 60. Antipsoriatic drugs. Such as Acitretin, Ammonium 6- AZauridine, Carmo fur, Cytarabine, Salicylate, Anthralin, 6-AZauridine, Bergapten(e), Doxifluridine, Enocitabine, Floxuridine, Fluroou Chrysarobin, Etretinate and Pyrogallol. racil and Tegafur, 61. Antipsychotic drugs, including: Enzymes Such as L-ASparaginase; and Butyrophenones Such as Benperidol, Bromperidol, otherS Such as Aceglatone, Amsacrine, Bestrabucil, Droperidol, Fluanisone, Haloperidol, Melperone, Bisantrene, Bryostatin 1, Carboplatin, Cisplatin, 35 Moperone, Pipamperone, Sniperone, Timiperone and De fof amide, De me colcine, Diaziquone, Trifluperidol; Dolastatins, Elfornithine, Elliptinium Acetate, Phenothiazines Such as Acetophenazine, Butaperazine, Etoglucid, EtopoSide, Gallium Nitrate, Carphenazine, Chlorproethazine, Chlorpromazine, Hydroxyurea, Interferon-á, Interferon-a, Clo Spira Zine, Cy ame ma Zine, Dixy razine, Interferon-a, Interleukine-2, Lentinan, Letrozole, 40 Fluphenazine, Imiclopazine, Mepazine, MeSoridazine, Lonidamine, Mito guaZone, Mitoxantrone, Methoxypromazine, Metofenazate, Oxaflumazine, Mopidamol, Nitracrine, Pentostatin, Phenamet, Perazine, Pericyazine, Perimethazine, Perphenazine, Pira rub icin, Podophyllinic c Acid, Pipe racetazine, Pipotiazine, Prochlorpe razine, 2-Ethy thy dra Zide, Polynitro club anes, Promazine, Sulforida Zine, Thiopropa Zate, Procarbazine, PSK7, Razoxane, Sizofiran, 45 Thioridazine, Trifluoperazine and Triflu promazine; Spirogermanium, Symplo Statin 1, Taxol, Thioxanthenes Such as Chlorprothixene, Clopenthixol, TenipoSide, TenuaZonic Acid, Triaziquone, Flupentixol and Thiothixene; 2.2.2"-Trichlorotriethylamine, Urethan, other tricyclicS Such as BenZquinamide, Carpipramine, Vinblastine, Vincristine, Vindesline and Vinorel Clocapramine, Clomacran, Clothiapine, Clozapine, bine. 50 Opipramol, Prothipendyl, Tetrabenazine, and 50. Antineoplastic (hormonal) drugs, including: Zotepine, and Androgens Such as Calusterone, DromoStanolone otherS Such as Alizapride, Amisulpride, Buramate, Propionate, EpitioStanol, MepitioStane and Testolac Fluspirilene, Molindone, Penfluridol, Pimozide, tone, Spirilene and Sulpiride. Antiadrenals. Such as Aminoglutethimide, Mitotane and 55 62. Antipyretics Such as Acetaminophen, AcetaminoSalol, TriloStane; Acetanilide, Aconine, Aconite, Aconitine, Alclofenac, Antiandrogens Such as Flutamide and Nilutamide, and Aluminum Bis(acetylsalicylate), Aminochlorthenoxazin, Antiestrogens Such as Tamoxifen and Toremifene. Aminopyrine, Aspirin, Benorylate, BenZydamine, 51. Antineoplastic adjuncts including folic acid replenishers Berberine, p-Bromoacetanilide, BufeXamac, Bumadizon, Such as Frolinic Acid. 60 Calcium Acetysalicylate, Chlorthenoxazin(e), Choline 52. Antiparkinsonian drugs Such as Amantadine, Salicy late, Clid anac, Dihydroxy aluminum Apomorphine, Benserazide, Bietanautine, Biperiden, Acetylsalicylate, Dipyrocetyl, Dipyrone, Epirizole, Bromocriptine, Budipine, Cabergoline, Carbidopa, EterSalate, Imidazole Salicylate, Indomethacin, Deprenyl (a/k/a L-deprenyl, L-deprenil, L-deprenaline IsofeZolac, p-Lactophenetide, Lysine Acetylsalicylate, and Sele giline), De Xe timide, Dieth a Zine, 65 Magnesium Acetylsalicylate, Meclofenamic Acid, Diphenhydramine, Droxidopa, Ethiopropa Zine, Morazone, Morpholine Salicylate, Naproxen, Ethylbenzhydramine, Levodopa, Naxagolide, Pergolide, Nifenazone, 5'-Nitro-2'-propoxyacetanilide, Phenacetin, US 6,638,528 B1 23 24 Phenicarbazide, Phenocoll, Phenopyrazone, Phenyl Hydrochloride, Phloroglucinol, Pinaverium Bromide, Acetylsalicylate, Phenyl Salicylate, Pipebu Zone, Piperilate, Pipoxolan Hydrochloride, Pramiverin, Pri Propacetamol, Propy phena Zone, Ramife naZone, finium Bromide, Properidine, Propivane, Propyromazine, Salacetamide, Salicylamide O-Acetic Acid, Sodium Prozapine, Racefemine, Rociverine, Spasmolytol, Stilo Salicylate, Sulfamipyrine, Tetrandrine and Tinoridine. nium Iodide, Sultroponium, Tiemonium Iodide, Tiqui 63. Antirickettsial drugs. Such as p-Aminobenzoic Acid, Zium Bromide, Tiropramide, Trepibutone, Tricromyl, Chloramphenicol, Chloramphenicol Palmitate, Chloram Trifolium, Trimebutine, N,N-Trimethyl-3,3-diphenyl phenicol Pantothenate and Tetracycline. propylamine, Tropenzile, TroSpium Chloride and Xeny 64. Antiseborrheic drugs such as Chloroxine, 3-O- tropium Bromide. Lauroylpyridoxol Diacetate, Piroctone, Pyrithione, 67. Antithrombotic drugs. Such as Anagrelide, Argatroban, Resorcinol, Selenium Sulfides and Tioxolone. Cilostazol, Chrysoptin, Daltroban, Defibrotide, 65. Antiseptics, including: Enoxaparin, Fraxiparine 7, Indobufen, Lamoparan, Guanidines Such as Alexidine, AmbaZone, Chlorhexidine OZagrel, Picotamide, Plafibride, Reviparin, Tedelparin, and Picloxydine; Ticlopidine, Triflusal and Warfarin. Halogens and halogen compounds Such as Bismuth 15 68. AntituSSive drugS Such as Allocamide, Amicibone, Iodide Oxide, Bismuth Iodosubgallate, Bismuth Benproperine, BenZonatate, Bibenzonium Bromide, Tribromophenate, Bornyl Chloride, Calcium Iodate, Bromoform, Butamirate, Butethamate, Caramiphen Chlorinated Lime, Cloflucarban, Flurosalan, Iodic Ethanedisulfonate, Carbetapentane, Chlophedianol, Acid, Iodine, Iodine Monochloride, Iodine Trichloride, Clobutinol, Cloperastine, Codeine, Codeine Methyl Iodoform, Methenamine Tetraiodine, Oxychlorosene, Bromide, Codeine N-Oxide, Codeine Phosphate, Codeine Povidone-Iodine, Sodium Hypochlorite, Sodium Sulfate, Cyclexanone, Dextromethorphan, Dibunate Iodate, Symclosene, Thymol Iodide, Triclocarban, Tri Sodium, Dihydrocodeine, Dihydrocodeinone Enol closan and Troclosene Potassium; Acetate, Dimemorfan, Dimethoxanate, a, Mercurial compounds Such as Hydragaphen, Meralein a-Diphenyl-2-piperidinepropanol, Dropropizine, Sodium, Merbromin, Mercuric Chloride, Mercuric 25 Drotebanol, Eprazinone, Ethyl Dibunate, Ethylmorphine, Chloride, Ammoniated, Mercuric Sodium Fominoben, Guiaiapate, Hydrocodone, Isoaminile, p-Phenolsulfonate, Mercuric Succinimide, Mercuric Le Vo propoxyphene, Mor clofone, Narce ine, Sulfide, Red, Mercurophen, Mercurous Acetate, Mer Normethadone, NoScapine, OXeladin, OXolamine, curous Chloride, Mercurous Iodide, Nitromersol, Pholcodine, Picoperine, Pipazethate, Piperidione, Prenox Potassium Tetraiodomercurate(II), Potassium diazine Hydrochloride, Racemethorphan, TaZiprinone Triiodomercurate(II) Solution, Thimerfonate Sodium Hydrochloride, Tipepidine and Zipeprol. and Thimerosal; 69. Antiulcerative drugs Such as Aceglutamide Aluminum Nitrofurans such as Furazolidone, 2-(Methoxymethyl)-5- Complex, ä-Acetamidocaproic Acid Zinc Salt, nitrofuran, Nidroxy Zone, Nifuroxime, Nifurzide and Acetoxolone, Arbaprostil, Benexate Hydrochloride, Bis 35 muth Subcitrate Sol (Dried), Carbenoxolone, Cetraxate, Nitrofurazone; Cimetidine, EnproStil, Esaprazole, Famotidine, Ftaxilide, Phenols Such as Acetomeroctol, Bithionol, Cadmium Gefarnate, GuaiaZulene, IrSogladine, Misoprostol, Salicylate, Carvacrol, Chloroxylenol, Clorophene, Nizatidine, Omeprazole, Ornoprostil, a-Oryzanol, CreSote, Cresol(s), p - CreSol, Fentic lor, Pifarnine, Pirenzepine, Plaunotol, Ranitidine, Rioprostil, Hexachlorophene, 1-Napthyl Salicylate, 2-Napthyl 40 Salicylate, 2,4,6-Tribromo-m-cresol, and 3', 4',5- Rosaprostol, Rotraxate, Roxatidine Acetate, Sofalcone, Trichlorosalicylanilide; Spizofurone, Sucralfate, Teprenone, Trimoprostil, Thrithiozine, Troxipide and Zolimidine. Quinolines Such as Aminoquinuride, BenZOXiquine, 70. Antiurolithic drugs. Such as Acetohydroxamic Acid, Broxyquinoline, Chloro Xine, Chlorduinaldol, Allopurinol, Potassium Citrate and Succinimide. Cloxyquin, Ethylhydrocupreine, Euprocin, Halquinol, 45 71. Antivenin drugs Such as Lyovac7 Antivenin. Hydrastine, 8-Hydroxquinoline, 8-Hydroxquinoline 72. Antiviral drugs, including: Sulfate and Iodochlorhydroxyquin; and Purines and pyrimidinones Such as Acyclovir, Cytarabine, otherS Such as Aluminum Acetate Solution, Aluminum Dideoxyadenosine, Dideoxycytidine, Dideoxyinosine, Subacetate Solution, Aluminum Sulfate, 3-Amino-4- Edoxudine, Floxuridine, Ganciclovir, Idoxuridine, hydroxybutyric Acid, Boric Acid, Chlorhexidine, 50 ChloroaZodin, m-Cresyl Acetate, Cupric Sulfate, Inosine Pranobex, MADU, Penciclovir, Trifluridine, Dibromopropamidine, Ichtham mol, Negatol 7, Vidrarbine and Zidovudine; and Noxytiolin, Ornidazole, a-Propiolactone, a-Terpineol. otherS Such as Acetylleucine Monoethanolamine, 66. Antispasmodic drugs Such as Alibendol, Ambucetamide, Amantadine, Amidinomycin, CoSalane, Cuminalde Aminopromazine, Apoatropine, Bevonium Methyl 55 hyde Thiosemicarb Zone, Foscarnet Sodium, Sulfate, Bietamiverine, Butaverine, Butropium Bromide, Imiquimod, Interferon-á, Interferon-á, Interferon-a, N-Butylscopolammonium Bromide, Caroverine, Kethoxal, Lysozyme, MethisaZone, Moroxydine, Cimetropium Bromide, Cinnamedrine, Clebopride, Coni Podophyllotoxin, Ribavirin, Rimantadine, Stallimycin, ine Hydrobromide, Coniine Hydrochloride, Cyclonium Statolon, Tromantadine and Xenazoic Acid. Iodide, Difemerine, Diisopromine, Dioxaphetyl Butyrate, 60 73. Anxiolytic drugs, including: Diponium Bromide, Drofenine, Emepronium Bromide, Arylpiperazines Such as BuSpirone, Gepirone, Isapirone Ethaverine, Feclemine, Fenalamide, Fenoverine, and TondoSpirone. Fenpiprane, Fenpiverinium Bromide, Fentonium Benzodiazepine derivatives Such as Alprazolam, Bromide, Flavoxate, Flopropione, Gluconic Acid, Bromazepam, Camazepam, Chlordiazepoxide, Guaiactamine, Hydramitrazine, Hyme cromone, 65 Clobazam, CloraZepate, Chotiazepam, Cloxazolam, Leiopyrrole, Mebeverine, Moxaverine, Nafiverine, Diazepam, Ethyl Loflazepate, Etizolam, Fluidazepam, Octamylamine, Octaverine, Pentapiperide, Phenamacide Flutazolam, Flutoprazepam, Halazepam, Ketazolam, US 6,638,528 B1 25 26 Lorazepam, Loxapine, Medazepam, Metaclazepam, 82. Choleretics such as Alibendol, Anethole Trithion, MeXaZolam, Nordazepam, Oxazepam, Oxazolam, AZintamide, Cholic Acid, Cicrotoic Acid, Clanobutin, Pinazepam, Prazepam and Tofisopam; Cyclobutyrol, Cyclovalone, Cynarin(e), Dehydrocholic Carbamates Such as Cyclarbamate, Emylcamate, Acid, Deoxycholic Acid, Dimecrotic Acid, a-Ethylbenzyl Hydroxyphenamate, Meprobamate, Phenprobamate Alcohol, Exiproben, Feguprol, Fencibutirol, Fenipentol, Florantyrone, Hyme cromone, Menbutone, 3-(o- and Tybamate; and Methoxyphenyl)-2-phenylacrylic Acid, Metochalcone, otherS Such as Alpidem, BenZOctamine, Captodiamine, Moquizone, Osalmid, Ox Bile Extract, 4.4'-Oxydi-2- ChlormeZanone, EtifoXine, Flesinoxan, Fluoresone, butanol, Piprozolin, Prozapine, 4-Salicyloylmorpholine, Glutamic Acid, Hydroxy Zine, Le Sopitron, Sincalide, Taurocholic Acid, Timonacic, Tocamphyl, Mecloralu rea, Mephenoxalone, Mirta Zepine, Trepibutone and Vanitiolide. Oxanamide, Phenaglycodol, Suriclone and Zatosetron. 83. Cholinergic agents Such as Aceclidine, Acetylcholine 74. Benzodiazepine antagonistS Such as Flumazenil. Bromide, Acetylcholide Chloride, Aclatonium 75. Bronchodilators, including: Napadisilate, BenZpyrinium Bromide, Bethanechol Ephedrine derivatives such as Albuterol, Bambuterol, chloride, Carbachol, Carpronium chloride, Demecarium Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, 15 Bromide, Dexpanthenol, Diisopropyl Paraoxon, Dioxethedrine, Ephedrine, Epiniphrine, EproZinol, Echothiophate Iodide, Edrophomium chloride, Eseridine, Etafe drine, Ethylnorepinephrine, Fenote rol, Furtrethonium, Isoflurophate, Methacholine chloride, Hexoprenaline, Isoetharine, Isoproterenol, Mabuterol, Muscarine, NeoStigmine, Oxapropanium Iodide, PhySOS Metaprote renol, N-Methylephedrine, Pirbuterol, tigmine and PyridoStigmine Bromide. Procate rol, Protokylol, Reproterol, Rimiterol, 84. Cholinesterase inhibitors such as Ambenonium Salmeterol, Soterenol, Terbutaline and Tulobuterol; Chloride, Distigmine Bromide and Galanthamine. 85. Cholinesterase reactivators Such as Obidoximine Chlo Quaternary ammonium compounds Such as Bevonium ride and Pralidoxime Chloride. Methyl Sulfate, Clutropium Bromide, Ipratropium Bro 86. Central nervous System Stimulants and agents Such as mide and OXitropium Bromide; 25 Amineptine, Amphetimine, Amphetaminil, Bemegride, Xanthine derivatives Such as Acefylline, Acefylline BenZphetamine, Brucine, Caffeine, Chlorphentermine, Pipera Zine, Ambu phylline, Aminophylline, Clofenciclan, Clortermine, Coca, Demanyl Phosphate, Bamifylline, choline Theophyllinate, Doxofylline, Dexoxadrol, Dextroamphetamine Sulfate, Diethlpropion, Dyphylline, Enprofylline, Etamiphyllin, Etofylline, N-Ethylamphetamine, Ethamivan, Etifelmin, Guaithylline, Proxyphylline, Theobromine, Etryptamine, Fencamfamine, Fenethylline, FenoSolone, 1-Theobromineacetic Acid and Theophylline; and Flurothyl, Galanthamine, Hexacyclonate Sodium, others such as Fenspiride, Medibazine, Montekulast, Homo cam fin, Ma Zind ol, Mege X amide, Methoxyphenanime, Tretoquinol and Zafirkulast. Methamphetamine, Methylphenidate, Nikethamide, 76. Calcium channel blockers, including: Pemoline, Pentylene tetrazole, Phenidimetrazine, Arylalkylamines Such as Bepridil, Ditiazem, Fendiline, 35 Phenmetrazine, Phentermine, Picrotoxin, Pipradrol, Pro Gallopanil, Prenylamine, Terodiline and Verapamil; lintane and Pyrovalerone. Dihydropyridine derivatives such as Felodipine, 87. Decongestants Such as Amidephrine, Cafaminol, Isradipine, Nicardipine, Nifedipine, Nilvadipine, Cyclopentamine, Ephedrine, Epinephrine, Fenoxazoline, Nimodipine, Nisoldipine and Nitrendipine; Indanazoline, Metizoline, Naphazoline, Norde frin 40 Hydrochloride, Octodrine, Oxymetazoline, Phenyleph Piperazine derivatives Such as Cinnarizine, Flunarisine rine Hydrochloride, Phenylprop an olamine and Lidoflazine, and Hydrochloride, Phenylpropyl methylamine, otherS Such as Bencyclane, Etafenone and Perhexiline. Propylhexedrine, Pseudoephedrine, Tetrahydrozoline, 77. Calcium regulatorS Such as Calcifediol, Calcitonin, Tymazoline and Xylometazoline. Calcitriol, Clodronic Acid, Dihydrotachysterol, 45 88. Dental agents, including: Elcatonin, Etidronic Acid, Ipriflavone, Pamidronic Acid, Parathyroid Hormone and Teriparatide Acetate. Bisphosphonates (anti-periodontal disease and bone 78. CardiotonicS Such as Acefylline, Acetyldigititoxins, resorption) Such as Alendronate, Clodronate, 2-Amino-4-picoline, Amrin one, Benfuro dil Etidronate, Pamidronate and Tiluldronate; He misuccinate, Bu clas de Sine, Cerbero Side, 50 Carries ProphylacticS Such as Arginine and Sodium Fluo Camphotamide, Convallatoxin, Cymarin, Denopamine, ride; DeSensitizing Agents Such as Potassium Nitrate Deslanoside, Ditalin, Digitalis, Digitoxin, Digoxin, and Citrate Oxalate. Dobutamine, Dopamine, Dopexamine, Enoximone, 89. DepigmentorS Such as Hydroquinine, Hydroquinone and Erythrophleine, Fenalcomine, Gitalin, Gito Xin, Monobenzone. Glycocyamine, Heptaminol, Hydrastinine, Ibopamine, 55 90. Diuretics, including: Lanotodises, Metamivam, Milrinone, Neriifolin, organomercurials Such as Chlormerodrin, Meralluride, Oleandrin, Ouabain, Oxyfe drine, Prenalterol, Mercamphamide, Mercaptomerin Sodium, Mercumal Proscillaridin, Resibufogenin, Scillaren, Scillarenin, lylic Acid, Mercumatilin Sodium, Mercurous Chloride Strophanthin, Sulmazole, Theobromine and Xamoterol. and Mersalyl; 79. Chelating agents such as Deferozmine, Ditiocarb 60 Pteridines Such as Furterene and Triamterene; Sodium, Edetate Calcium Disodium, Edetate Disodium, Purines Such S Acefylline, Edeate Sodium, Edetate Trisodium, Penicillamine, Pen 7-Morpholinomethyltheophylline, Pamabrom, Pro tetate Calcium Trisodium, Pentectic Acid, Succimer and theobromine and Theobromine; Trientine; Steroids Such as Canrenone, Oleandrin and Spironolac 80. Cholecystokinin antagonists Such as Proglumide. 65 tone, 81. Cholelitholytic agents such as Chenodiol, Methyl tert Sulfonamide derivatives Such as Acetazolmide, Butyl Ether, Monooctanoin and Ursodiol. AmbuSide, AZOSemide, Bumetanide, Butazolamide, US 6,638,528 B1 27 28 Chloraminophenamide, Clofenamide, Clopamide, 101. Growth hormone releasing factorS Such as Semorelin. Clorexolene, Diphenylmethane-4,4'-disulfonamide, 102. Growth stimulants such as Somatotropin. Disulfamide, EthoXZolamide, Furose mide, 103. Hemolytic agents such as Phenylhydrazine and Phe Indapamide, Mefruside, Methazolamide, Piretanide, nylhydrazine Hydrochloride. QuinethaZone, TorSemide, Tripamide and Xipamide; 104. Heparin antagonists such as Hexadimethrine Bromide Uracils. Such as Aminometradine and Amisometradine, and Protamines. otherS Such as Amano Zine, Amiloride, Arbutin, 105. Hepatoprotectants Such as S-Adenosylmethionine, Chlora Zanil, Ethacry nic Acid, Eto Zolin, Betaine, Catechin, Citolone, Malotilate, OraZamide, Hydracarbazine, Isosorbide, Mannitol, Metochalcone, Phosphorylcholine, Protoporphyrin IX, Silymarin-Group, Muzolimine, Perhexiline, Ticrynafen and Urea. 1O Thiotic Acid and Tiopronin. 91. Dopamine receptor agonists Such as Bromocriptine, 106. ImmunomodulatorS Such as Amiprilose, Bucillamine, Dopexamine, Fenoldopam, Ibopamine, Lisuride, NaX Ditiocarb Sodium, Inosine Pranobex, Interferon-y, agolide and Pergolide. Interleukin-2, Lentinan, MuroctaSin, Platonin, 92. Ectoparasiticides Such as Amitraz, Benzyl Benzoate, Procodazole, Tetramisole, Thymomodulin, Thymopentin Carbaryl, Crotamiton, DDT, Dixanthogen, Isobornyl 15 and Ubenimex. Thiocyanoacetate-Technical, Lime Sulfurated Solution, 107. Immunosuppressants Such as Azathioprine, CycloSpor LIndane, Malathion, Mercuric Oleate, Mesulphen and ins and Mizoribine. Sulphur-Pharmaceutical. 108. Ion exchange resins Such as Carbacrylic Resins, 93. Enzymes, including: Cholestyramine Resin, Colestipol, Polidexide, Resodec Digestive enzymes such as ?-Amylase (Swine Pancreas), and Sodium Polystyrene Sulfonate. Lipase, Pancrelipase, Pepsin and Rennin; 109. Lactation stimulating hormone such as Prolactin. Mucolytic enzymes Such as Lysozyme; 110. LH-RH agonists such as Buserelin, Goserelin, Goser Penicillin inactivating enzymes Such as Penicillinase; and elin Acetate, Leuprolide, Nafarelin, and Triptorelin. Proteolytic enzymes Such as Collagenase, Chymopapain, 111. Lipotropic agents Such as N-Acetylmethionine, Choline Chymotrypsins, Papain and Trypsin. 25 Chloride, Choline Dehydrocholate, Choline Dihydrogen 94. Enzyme inducers (hepatic) Such as Flumecinol. Citrate, Inositol, Lecithin and Methionine. 95. Estrogens (non-steroidal) Such as Ben Zestrol, 112. Lupus erythematoSuS Suppressants Such as Bismuth Brop aroe Strol, Chlorotrianise ne, Diene Strol, Sodium Triglycollamate, Bismuth Subsalicylate, Chloro Diethylstilbestrol, Diethylstilbestrol Diproprionate, quine and Hydroxychloroquine. Dimestrol, Fosfestrol, Hexestrol, Methallenestril and 113. Mineral corticoids such as Aldosterone, Methestrol. Deoxycorticosterone, Deoxycorticosterone Acetate and 96. Gastric Secretion inhibitorS Such as Enterogastrone and Fludrocortisone. Octreotide. 114. Miotic drugs. Such as Carbachol, Physostigmine, Pilo 97. Glucocorticoids Such as 21-Acetoxyprefnenolone, carpine and Pilocarpus. Aal clo metaSone, Alge Stone, Amic in on ide, 35 115. Monoamine oxidase inhibitors such as Deprenyl, Be clomethaSone, Betame thaSone, Bude Sonide, Iproclozide, Iproniazid, ISOcarboxazid, Moclobemide, Chlorop rednisone, Clobe tasol, Blove tas one, Octomoxin, Pargyline, PhenelZine, Phenoxypropazine, Clocortolone, Cloprednol, Corticosterone, Cortisone, Pivalylbenzhydrazine, Prodipine, Toloxatone and Tranyl CortivaZol, Deflazacort, DeSonide, DeSoximetasone, cypromine. Dexamethasone, Difloras one, Diflucortolone, 40 116. Mucolytic agents Such as Acetylcysteine, BromheXine, Difluprednate, Enoxolone, FluaZacort, Flucloronide, Carbocysteine, Domiodol, Letosteine, Lysozyme, MecyS Flumehtasone, Flunisolide, Fluocinolone Acetonide, teine Hydrochloride, Mesna, Sobrerol, Stepronin, Tiopro Fluocinonide, Fluocortin Butyl, Fluocortolone, nin and Tyloxapol. Fluorometholone, Fluperolone Acetate, Fluprednidene 117. Muscle relaxants (skeletal) Such as Afloqualone, Acetate, Fluprednisolone, Flurandrenolide, Formocortal, 45 Alculronium, Atracurium Be Sylate, Baclofen, Halcinonide, HalometaSone, Halopredone Acetate, Ben Zoctamine, Ben Zoquinonium Chloride, Hydrocortamate, Hydrocortisone, Hydrocortisone C-Calebassine, Carisoprodol, ChlormeZanone, Chlor Acetate, ydrocortisone Phosphate, Hydrocortisone phenesin Carbamate, Chlorproethazine, ChloZOXaZone, 21-Sodium Succinate, Hydrocortisone Tebutate, Curare, Cyclarbamate, Cyclobenzaprine, Dantrolene, Ma Zip re done, Me dry Sone, Me prednisone, 50 Decamethonium Bromide, Diazepam, Eperisone, Faza Methyol prednisolone, Mo metas one Fulroate, dinium Bromide, Flumetramide, Gallamine Triethiodide, Paramethasone, Prednicarbate, Prednisolone, Predniso Hexacarbacholine Bromide, Hexafluorenium Bromide, lone 21-Diethylaminoacetate, Prednisone Sodium Idrocilamide, Lauexium Methyl Sulfate, Leptodactyline, Phosphate, Prednisolone Sodium Succinate, Prednisolone Memantine, Mephenesin, Mephenoxalone, Metaxalone, Sodium 21-m-Sulfobenzoate, Prednisolone 55 Methocarbamol, Metocurine Iodide, Nimetazepam, 21-Stearoylglycolate, Prednisolone Tebutate, Predniso Orphenadrine, Pancuronium Bromide, Phenprobamate, lone 21-Trimethylacetate, Prednisone, Prednival, Phenyramidol, Pipecurium Bromide, Promoxolane, Qui Prednylidene, Prednylidene 21-Diethylaminoacetate, nine Sulfate, Styramate, Succinylcholine Bromide, Suc Tixocortal, Triamcinolone, Triamcinolone Acetonide, Tri cinylcholine Chloride, Succinylcholine Iodine, Suxetho amcinolone Benetonide and Triamcinolone Hexac 60 nium Bromide, TetraZepam, Thiocolchicoside, etonide. Tizanidine, Tolperisone, Tubocurarine Chloride, Vecuro 98. Gonad-Stimulating principles Such as Buserelin, nium Bromide and Zoxolamine. Clomiphene, Cyclofenil, Epimestrol, FSH, HCG and 118. Narcotic antagonists Such as Amiphenazole, LH-RH. Cyclazocine, LeVallorphan, Nadide, Nalm fene, 99. Gonadotropic hormones such as LH and PMSG. 65 Nalorphine, Nalorphine Dinicotinate, Naloxone and Nal 100. Growth hormone inhibitors Such as Octreotide and treXOne. Somatostatin. 119. Neuroprotective agents Such as Dizocilpine. US 6,638,528 B1 29 30 120. No otropic agentS Such as Ace glutamide, Chloralantipyrine, Dichloralphenazone, Pentaerythritol Acetylcarnitine, Aniracetam, Bifematlane, Exifone, Chloral and Triclofos; Fipexide, Idebenone, Indeloxazune Hydrochloride, Piperidinediones such as Glutehimide, Methyprylon, Nizofenone, Oxiracetam, Piracetam, Propentofylline, Piperidione, Pyrithyldione, Taglutimide and Thalido Pyritinol and Tacrine. mide; 121. Ophthalmic agents Such as 15-ketoprostaglandins. Quinazolone derivatives Such as Etaqualone, Mecloqua 122. Ovarian hormone Such as Relaxin. lone and Methaqualone, and 123. Oxytocic drugs. Such as Carboprost, Cargutocin, Deamino oxytocin, Ergono Vine, Ge me prost, otherS Such as Acetal, Acetophenone, Aldol, Ammonium Methylergonovine, Oxytocin, Pituitary (Posterior), Pros Valerate, Amphenidone, d-Bornyl à-Bromoisovalerate, taglandin E, ProStaglandin F and Sparteine. d-Bornyl Isovale rate, Bromoform, Calcium 124. Pepsin inhibitors such as Sodium Amylosulfate. 2-Ethylbutanoate, Carfinate, a-Chlorolose, 125. Peristaltic stimulants such as Cisapride. Clomethiazole, Cypripe dium, Do Xylamine, 126. Prolactin inhibitors such as Metergoline. Etodroxizine, Etomidate, Fenadiazole, Homofenazine, 127. Prostaglandins and prostaglandin analogS Such as Hydrobromic Acid, Mecloxamine, Menthyl Valerate, 15 Opium, Paraldehyde, Perlapine, Propiomazine, Arbaprostil, Carboprost, EnproStil, Beme prost, Rilmazafone, Sodium Oxybate, Sulfonethylmethane Limaprost, Misoprostol, Ornoprostil, Prostacyclin, Pros and Sulfonmethane. taglandin E, Prostaglandin E, Prostagland in F. 132. Thrombolytic agents such as APSAC, Plasmin, Pro RioproStil, Rosaprostol, Sulprostone and Trimoprostil. Urokinase, Streptokinase, TiSSue Plasminogen Activator 128. Protease inhibitorS Such as Aprotinin, CamoStat, and Urokinase; Gabexate and NafamoStat. 133. Thyrotropic hormones such as TRH and TSH. 129. Respiratory Stimulants Such as Almitrine, Bemegride, 134. UricoSurics Such as Benzbromarone, Ethelbenecid, Carbon Dioxide, Cropropamide, Crote thamide, Orotic Acid, Oxycin chophen, Probe ne cid, Dimefline, Dimorpholamine, Doxapram, Ethamivan, Sulfinpyrazone, Ticrynafen and Zoxazolamine. Fominoben, Lobeline, Mepixanox, Metamivam, 135. Vasodilators (cerebral) such as Bencyclane, Nikethamide, Picrotoxin, Pimeclone, Pyridofylline, 25 Cinnarizine, Citicoline, Cyclandelate, Ciclonicate, Diiso Sodium Succinate and Tacrine. propylamine Dichloractetate, Eburnamonine, Fenoxedil, 130. Sclerosing agents Such as Ethanolamine, Ethylamine, Flunarizine, Ibudilast, Ifenprodil, Nafronyl, Nicametate, 2-Hexyldecanoic Acid, Polidocanol, Quinine Bisulfate, Nicergoline, Nimodipine, Papaverine, Pentifylline, Quinine Urea Hydrochloride, Sodium Ricinoleate, Tinofedrine, Vincamine, Vinpocetine and Vicquidil. Sodium Tetradecyl Sulfate and Tribenoside. 136. Vasodilators (coronary) Such as Amotriphene, 131. Sedatives and hypnotics, including: Bendazol, Benfurodil Hemisuccinate, BenZiodarone, Acyclic ureides Such as Acecarbromal, Apronalide, Chloacizine, Chromonar, Clobenfurol, Clonitrate, Bomisovalum, Capuride, Carbromal and Ectylurea; DilaZep, Dipyridamole, Droprenilamine, Efloxate, Alcohols such as Chlorhexadol, Ethchlorvynol, Erythritol, Erythrityl Tetranitrate, Etafenone, Fendiline, Meparfynol, 4-Methyl-5-thiazoleethanol, tert-Pentyl 35 Floredil, Ganglefene, Hexestrol Bis(B-diethylaminoethyl Alcohol and 2.2.2-Trichloroethanol; ether), Hexobendine, Itramin Tosylate, Khellin, Amides Such as Butoctamide, Diethylbromoacetamide, Lidoflazine, Mannitol HeXanitrate, Medibazine, Ibrotamide, Isovaleryl Diethylamide, Niaprazine, Nicorandil, Nitroglycerin, Pentaerythritol Tetranitrate, Tricetamide, Trimetozine, Zolpidem and Zopiclone; Pentrinitrol, Perhexiline, Pimefylline, Prenylamine, Pro 40 patyl Nitrate, Pyridofylline, Trapidil, Tricromyl, Barbituric acid derivatives such as Allobarbital, Trimetazidine, Trolnitrate Phosphate and Visnadine. Amobarbital, Aprobarbital, Barbital, Brallabarbital, 137. Vasodilators (peripheral) such as Aluminum Nicotinate, Butabarbital Sodium, Butalbital, Butallylonal, Bame than, Bencyclane, Betahistine, Bradykinin, Bute thal, Carbu barb, Cyclo barbital, Cyclopentobarbital, Enallylpropymal, 5-Ethyl-5-(1- Brovincamine, Bufoniode, Buflomedil, Butalamine, 45 Cetiedil, Ciclonicate, Cinepazide, Cinnarizine, pipe ridyl) barbituric Acid, 5-Furfuryl-5- Cyclande late, Diisopropylamine Dichloracetate, isopropylbarbituric Acid, Heptabarbital, Hexethal Eledoisin, Fenoxidil, Flunarisine, Heronicate, Ifenprodil, Sodium, Hexobarbital, Mephobarbital, Methitural, Inositol Niacinate, ISOXSuprine, Kallidin, Kallikrein, Narcobarbital, Nealbarbital, Pentobarbital Sodium, Moxisylyte, Nafronyl, Nicame tate, Nicergoline, Phenallymal, Phenobarbital, Phenobarbital Sodium, 50 Nicofuranose, Nicotinyl Alcohol, Nylidrin, Pentifylline, Phenylmethylbarbituric Acid, Probarbital, Pentoxifylline, Piribedil, Protaglandin E, Suloctidil and Propallylonal, Proxibarbal, Reposal, Secobarbital Xanthinal Niacinate. Sodium, Talbutal, Tetrabarbital, Vinbarbital Sodium 138. Vasoprotectants such as Benzarone, Bioflavonoids, and Vinylbital; Chromocarb, Clobeoside, Diosmin, Dobesilate Calcium, Benzodiazepine derivatives Such as Brotizolam, 55 Escin, Rolescu tol, Leucocyanidin, Metescufylline, Doxefazepam, Estazolam, Flunitrazepam, Flurazepam, Quercetin, Rutin and Troxerutin. Haloxazolam, Lopra Zolam, Lorimetazepam, 139. Vitamins, Vitamin Sources, and Vitamin extracts Such as Nitrazepam, Quazepam, Temazepam and Triazolam, Vitamins A, B, C, D, E, and K and derivatives thereof, Bromides such as Ammonium Bromide, Calcium Calciferols, Glycyrrhiza and Mecobalamin. Bromide, Calcium Bromolactobionate, Lithium 60 140. Vulnerary agents Such as Acetylcysteine, Allantoin, Bromide, Magnesium Bromide, Potassium Bromide Asiaticoside, CadeXomer Iodine, Chitin, Dextranomer and Sodium Bromide; and Oxaceprol. Carbamates Such as Amyl Carbamate-Tertiary, 141. Anticoagulants Such as heparin. Ethinamate, Hexaprpymate, Meparfynol Carbamate, 142. Miscellaneous such as Erythropoietin (Hematinic), Novonal and Tricholorourethan; 65 Filgrastim, Finasteride (Benign Prostate Hypertrophy), Chloral derivatives Such as Carbocloral, Chloral Betaine, Interferon Beta 1-Alpha (Multiple Sclerosis) and Tret Chloral Form amide, Chloral Hydrate, inonin (Urinary Incontinence). US 6,638,528 B1 31 32 The amount of active agent to be incorporated in the The term “acrylic polymer” is intended to be used inter carrier composition will vary depending on the particular changeably with the terms acrylate polymer, polyacrylate active agent, the desired therapeutic effect, and the time Span and polyacrylic adhesive polymers as used herein and as for which the transdermal System is to provide therapy. known in the art. Normally, the amount of active agent in the transdermal 5 The acrylic polymers useful in practicing the invention system can vary from about 0.1% to about 50%, and are polymers of one or more monomers of acrylic acids and preferably from about 0.1% to about 30% by weight based other copolymerizable monomers. The acrylic polymerS also on the dry weight of the total adhesive matrix composition. include copolymers of alkyl acrylates and/or methacrylates For lower dose concentrations permitted by this invention, Such as with Steroids and hormones, the preferred amount is and/or copolymerizable Secondary monomers or monomers from about 0.1% to about 10%. with functional groups. By varying the amount of each type While not essential, it is preferred that the androgenic of monomer added, the cohesive properties of the resulting hormones be incorporated near, at or above Saturation with acrylic polymer can be changed as is known in the art. In respect to its concentration in the adhesive matrix compo general, the acrylic polymer is composed of at least 50% by Sition. weight of an acrylate or alkyl acrylate monomer, from 0 to The term “adhesive matrix composition” as used herein 15 20% of a functional monomer copolymerizable with the refers to any non-aqueous adhesive material into which an acrylate, and from 0 to 40% of other monomers. active agent is Solubilized or homogeneously blended either Acrylate monomers which can be used include acrylic without, or in combination or admixture with, other ingre acid, methacrylic acid, butyl acrylate, butyl methacrylate, dients useful for facilitating transdermal drug delivery, Such hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, as crystallization inhibitors, Solubility enhancers, perme- 20 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl ation enhancers, Solvents, co-Solvents and other types of acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, additives. An “adhesive” as used herein means any natural 2-ethylhexyl methacrylate, decyl acrylate, decyl or Synthetic material that is capable of Sticking to the Site of methacrylate, dodecyl acrylate, dodecyl methacrylate, tride topical application. The term “preSSure-Sensitive adhesive” cyl acrylate, and tridecyl methacrylate. as used herein refers to an adhesive which adheres instan- 25 Functional monomers, copolymerizable with the above taneously to most Surfaces with the application of very slight alkyl acrylates or methacrylates, which can be used include preSSure and remains permanently tacky. An adhesive is a acrylic acid, methacrylic acid, maleic acid, maleic preSSure-Sensitive adhesive within the meaning of that term anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, as used herein if it has the properties of an adhesive acrylamide, dimethylacrylamide, acrylonitrile, dimethy preSSure-Sensitive adhesive per Se or functions as the same 30 laminoethyl acrylate, dimethylaminoethyl methacrylate, by admixture with tackifiers, plasticizers, croSS-linking tert-butylaminoethyl acrylate, tert-butylaminoethyl agents or other additives. methacrylate, methoxyethyl acrylate and methoxyethyl Suitable adhesives include all of the non-toxic natural and methacrylate and other monomers having at least one unsat Synthetic polymers known for or Suitable for use in trans urated double bond which participates in copolymerization dermal devices as adhesives including acrylic polymers, 35 reaction in one molecule and a functional group on its side gums, Silicone-based polymers (broadly referred to as chain Such as a carboxyl group, a hydroxyl group, a Sulfoxyl “polysiloxanes”) and rubber-based adhesives such as group, an amino group, an amino group and an alkoxyl, as polyisobutylenes, polybutylenes, ethylene/vinyl acetate and well as a variety of other monmeric units including alkylene, Vinyl acetate based adhesives, Styrene/butadiene adhesives, hydroxy-Substituted alkylene, carboxylic acid-Substituted polyisoprenes, Styrenes and Styrene block copolymers and 40 alkylene, Vynylalkanoate, Vinylpyrrolidone, Vinylpyridine, block amide copolymers. Vinyl pira Zine, Vinyl pyrrole, Viny limidazole, Suitable polysiloxanes include Silicone pressure-Sensitive Vinylcaprolactam, Vinyloxazole, vyinlacate, Vinylpropionate adhesives which are based on two major components: a and Vinylmorpholine. polymer, or gum, and a tackifying resin. The polysiloxane Further details and examples of acrylic adhesives which adhesive is usually prepared by croSS-linking the gum, 45 are Suitable in the practice of the invention are described in typically a high molecular weight polydiorganosiloxane, Satas, “Acrylic Adhesives,” Handbook of Pressure-Sensitive with the resin, to produce a three-dimensional Silicate Adhesive Technology, 2" ed., pp. 396-456 (D. Satas, ed.), Structure, via a condensation reaction in an appropriate Van Nostrand Reinhold, New York (1989). organic Solvent. The ratio of resin to polymer is the most Suitable acrylic adhesives are commercially available and important factor which can be adjusted in order to modify 50 include the polyacrylate adhesives Sold under the trademarks the physical properties of polysiloxane adhesives. Sobieski, DURO-TAKCR) by National Starch Company, Bridgewater, et al., “Silicone Pressure Sensitive Adhesives,” Handbook of N.J.; GELVACR by Solutia, St. Louis, Mo.; HRJ by Pressure-Sensitive Adhesive Technology, 2nd ed., pp. Schenectady International, Inc., Chicago, Ill., and 508–517 (D. Satas, ed.), Van Nostrand Reinhold, New York EUDRAGITE) by Roehm Pharma GmbH, Darmstadt, Fed (1989). 55 eral Republic of Germany. Further details and examples of Silicone pressure The amount of the adhesive to be used depends on the Sensitive adhesives which are useful in the practice of this concentration of active agent used to achieve a therapeutic invention are described in the following U.S. Pat. Nos. effect. Typically, the adhesive is in an amount of about 5% 4.591,622; 4,584,355; 4,585,836; and 4,655,767. to about 90%, and preferably about 10% to about 90%, and Suitable Silicone pressure-Sensitive adhesives are com- 60 most preferably about 20% to about 75% by weight based on mercially available and include the Silicone adhesives Sold the dry weight of the total adhesive matrix composition. under the trademarks BIO-PSACR by Dow Corning The adhesive matrix compositions of the present inven Corporation, Medical Products, Midland, Michigan. tion can also contain one or more Solvents and/or In particularly preferred embodiments of the invention, co-Solvents. Such Solvents and/or co-Solvents are those the adhesive matrix composition comprises a pressure- 65 known in the art, and are non-toxic, pharmaceutically Sensitive adhesive, and more preferably a blend of one or acceptable Substances, preferably liquids, which do not more preSSure-Sensitive acrylic polymers and polysiloxanes. Substantially negatively affect the adhesive properties of the US 6,638,528 B1 33 34 transdermal System or the Solubility of the active agents at Surface State of the skin and drugs administered and esters of the concentrations used. The Solvent and/or co-Solvent can Sorbitol and Sorbitol anhydride such as polysorbate 20 be for the active agent or for the matrix materials, or both. commercially available under the trademark Tween(E) 20 Suitable solvents include volatile liquids such as alcohols from ICI Americas, Inc., as well as other polySorbates Such (e.g., methyl, ethyl, isopropyl alcohols and methylene as 21, 40,60, 61, 65, 80, 81, and 85. Other Suitable enhancers include oleic and linoleic acids, triacetin, ascorbic acid, chloride), ketones (e.g., acetone); aromatic hydrocarbons panthenol, butylated hydroxytoluene, tocopherol, toco Such as benzene derivatives (e.g., Xylenes and toluenes); pherol acetate, tocopheryllinoleate. If permeation enhancers lower molecular weight alkanes and cycloalkanes (e.g., are incorporated into the adhesive matrix composition, the hexanes, heptanes and cyclohexanes); and alkanoic acid amount typically ranges up to about 30%, and preferably esters (e.g., ethyl acetate, n-propyl acetate, isobutyl acetate, from about 0.1% to about 15%, by weight based on the dry n-butyl acetate isobutyl isobutyrate, hexyl acetate, weight of the total adhesive matrix composition. 2-ethylhexyl acetate or butyl acetate); and combinations and In addition to permeation enhancers, there may also be mixtures thereof. incorporated various pharmaceutically acceptable additives Suitable co-solvents include polyhydric alcohols, which and excipients available to those skilled in the art. These include glycols, triols and polyols Such as ethylene glycol, 15 additives include tackifying agents Such as aliphatic diethylene glycol, propylene glycol, dipropylene glycol, hydrocarbons, mixed aliphatic and aromatic hydrocarbons, trimethylene glycol, butylene glycol, polyethylene glycol, aromatic hydrocarbons, Substituted aromatic hydrocarbons, he Xylene glycol, poly o X ethylene, glycerin, hydrogenated esters, polyterpenes, Silicone fluid, mineral oil trimethylpropane, Sorbitol, polyvinylpyrrollidone, and the and hydrogenated wood roSins. Additional additives include like. binders such as lecithin which “bind” the other ingredients, Further Suitable co-Solvents include glycol etherS Such as or rheological agents (thickeners) containing Silicone Such ethylene glycol monoethyl ether, glycol esters, glycol ether as fumed Silica, reagent grade Sand, precipitated Silica, esterS Such as ethylene glycol monoethyl ether acetate and amorphous Silica, colloidal Silicon dioxide, fused Silica, ethylene glycol diacetate, Saturated and unsaturated fatty Silica gel, quartz and particulate Siliceous materials com acids, mineral oil, Silicone fluid, lecithin, retinol derivatives 25 mercially available as Syloid(R), Cabosil(R), Aerosil(R), and and the like, and ethers, esters and alcohols of fatty acids. Whitelite(R), for purposes of enhancing the uniform consis Although the exact amount of co-Solvents that may be tency or continuous phase of the final composition. Other additives and excipients include diluents, Stabilizers, fillers, used in the adhesive matrix composition depends on the clayS, buffering agents, biocides, humectants, anti-irritants, nature and amount of the other ingredients, Such amount antioxidants, preservatives, plasticizing agents, croSS typically ranges from about 0.1% to about 40%, and pref linking agents, flavoring agents, colorants, pigments and the erably from about 0.1% to about 30% by weight, and more like. Such Substances can be present in any amount Sufficient preferably from about 1% to about 20%, by weight based on to impart the desired properties to the carrier composition. the dry weight of the total adhesive matrix composition. Such additives or excipients are typically used in amounts In certain embodiments of the invention, a permeation up to 25%, and preferably from about 0.1% to about 10%, enhancer is incorporated into the adhesive matrix composi 35 by weight based on the dry weight of the total adhesive tion. The term "permeation enhancer as used herein refers matrix composition. to Substances used to increase permeability and/or accelerate The adhesive matrix compositions according to the the delivery of an active agent through the skin or mucosa, present invention can be prepared by first mixing appropri and include monhydric alcohols Such as ethyl, isopropyl, ate amounts of the polymeric plastic material in volatile butyl and benzyl alcohols; or dihydric alcohols such as 40 polar and/or non-polar organic liquids, Such as those previ ethylene glycol, diethylene glycol, or propylene glycol ously described as Suitable Volatile Solvents. Appropriate dipropylene glycol and trimethylene glycol, or polyhydric amounts of active agent(s) are then added to the mixture alcohols Such as glycerin, Sorbitol and polyethylene glycol, together with appropriate amounts of pressure-Sensitive which enhance drug Solubility; polyethylene glycol ethers of adhesive(s), Solvent(s) and/or co-solvent(s), with or without aliphatic alcohols (such as cetyl, lauryl, oleyl and Stearly) 45 enhancer(s), and thoroughly mixed. The mixture of the including polyoxyethylene (4) lauryl ether, polyoxyethylene adhesive matrix composition is next formed into a film at (2) oleyl ether and polyoxyethylene (10) oleyl ether com ambient temperature, preferably by coating or casting at a mercially available under the trademark BRIJ(R) 30, 93 and controlled specified thickness onto a flexible sheet material, 97 from ICI Americas, Inc., and BRIJCE 35, 52, 56, 58, 72, Such as a release liner, followed by evaporation of the 76, 78, 92, 96, 700 and 721; vegetable, animal and fish fats 50 volatile Solvents at elevated temperatures (e.g., by passing and oils Such as cotton Seed, corn, Safflower, olive and castor through an oven). The non-volatile or higher boiling point oils, Squalene, and lanolin; fatty acid esterS Such as propyl Solvents and/or co-Solvents, Such as the polyols, used in the oleate, decyl oleate, isopropyl palmitate, glycol palmitate, carrier composition remain therein. The carrier composition glycol laurate, dodecyl myristate, isopropyl myristate and has been coated or cast on the flexible sheet material, is then glycol Stearate which enhance drug diffusibility; fatty acid 55 laminated to another flexible sheet material preferably a alcohols Such as oleyl alcohol and its derivatives, fatty acid backing layer. Appropriate size and shape individual trans amides Such as oleamide and its derivatives, urea and urea dermal drug delivery Systems are cut and then packaged derivatives such as allantoin which affect the ability of (e.g., pouched). keratin to retain moisture; polar Solvents Such as The order of Steps, the amount of the ingredients, and the dimethyldecylphosphoxide, methyloctylsulfoxide, 60 amount and time of mixing may be important process dimethyllaurylamide, dodecylpyrrollidone, isosorbitol, variables which will depend on the Specific polymers, active dimethylacetonide, dimethylsulfoxide, decylmethylsulfox agents, Solvents and/or co-Solvents, enhancers and additives ide and dimethylformamide which affect keratin permeabil and excipients used in the composition. These factors can be ity; Salicylic acid which Softens the keratin; amino acids adjusted by those skilled in the art, while keeping in mind which are penetration assistants, benzyl nicotinate which is 65 the objects of achieving a Solubilized active agent and a hair follicle opener; and higher molecular weight aliphatic providing a uniform product that will also give desirable Surfactants Such as lauryl Sulfate Salts which change the results. US 6,638,528 B1 35 36 Reference to FIG. 1 shows a matrix-type transdermal drug in as much as the resulting adhesive matrix compositions do delivery System 10 comprising a pressure-Sensitive adhesive not contain a polymeric plastic material. matrix composition layer 11, a release liner 12, and a backing layer 13. Removal of the release liner 12 exposes TABLE II the pressure-Sensitive adhesive matrix composition for topi cal application to the user. Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Further details and examples of pressure-Sensitive Polysiloxane O.O 71.4 54.5 53.6 48.6 43.6 58.O 53.O adhesives, enhancers, Solvents, co-Solvents, release liners, Adhesive backing layers, and other additives, as well as transdermal (BIO-PSA (R) 7-4502) Systems generally, Suitable in practicing the invention are Polysiloxane described in U.S. Pat. Nos. 5,474,787 and 5,656,286, Ser. Adhesive Nos. 09/161,312 and 60/115,927, all of which are assigned (BIO-PSA (R) 7-4603) to Noven Pharmaceuticals, Inc. and incorporated herein by Polyacrylate reference. Adhesive 15 (DURO EXAMPLES TAK (R) 87-2287) The above description and following Specific examples Polyacrylate O.O 5.0 S.O 20.O 20.O 20.O 5.0 5.0 are hereby illustrative of pharmaceutically acceptable matrix Adhesive compositions and transdermal drug delivery Systems, and (Gelva (R) 788) methods of making Same, within the contemplation of the Ethyl Cellulose O.O O.O 15.O O.O O.O O.O. 10.O 15.O (Ethocel(R) 10) invention. The description and examples are in no way Ethyl Cellulose intended to be, or should be considered, limiting of the Scope (Ethocel(R) 20) of the invention. And while efforts have been made to ensure Polyvinyl OO 100 100 100 10.O 100 100 10.O accuracy with respect to numbers used (Such as amounts and pyrrollidone 25 (KOLLI temperatures), Some experimental error and deviation DON (R 30) should be accounted for and/or allowed. Polyvinyl Example 1 pyrrollidone (KOLLI An estradiol/norethindrone acetate pressure-Sensitive DON (R 90) adhesive matrix composition was prepared by combining Dipropylene 9.O 6.O 6.O 8.0 8.O 8.0 8.0 8.O 0.7 parts of estradiol and 3.0 parts of norethindrone acetate Glycol Oleyl Alcohol 6.O 6.O 6.O 6.O 6.O 6.O 6.O 6.O along with 3.0 parts of ethyl cellulose (Ethocele(R) 10, Dow Estradiol O.7 1.6 3.5 2.4 2.4 2.4 3.0 3.0 Chemical Corp., Midland, Mich.) in 30.0 parts ethyl acetate, Norethindrone 3.0 O.O O.O O.O O.O O.O O.O O.O 15.0 parts of toluene and 10.0 parts isopropyl alcohol. Then Acetate 12.2 parts of a polyacrylate adhesive (DURO-TAIE(R) 35 87-2510; National Starch Company, Bridgewater, N.J.) and What is claimed is: 109.2 parts of a polysiloxane adhesive (BIO-PSAE) 1. A transdermal delivery System for providing drug Q7-4603; Dow Corning Corp, Midland, Mich.) were added delivery acroSS Skin in a mammal comprising: and thoroughly mixed. Finally 9.0 parts of dipropylene (a) a pharmaceutically acceptable pressure-sensitive glycol and 6.0 parts oleyl alcohol were added and mixed 40 adhesive matrix consisting essentially of a blend of: thoroughly in an appropriate container until the mixture was (i) one or more adhesives Selected from the group completely homogenous. The resulting composition had the consisting of polyacrylates, poly Siloxanes, ingredient concentrations on a dry weight percent basis (i.e., polyisobutylene, polyisoprene, Styrenes, Styrene after evaporation of volatile solvents) as shown below. block copolymers and block amide copolymers in an amount from 20% to 75% by weight based on the dry 45 weight of the total adhesive matrix composition, (ii) an insoluble, non-adhesive ethyl cellulose polymer INGREDIENT DRUG WEIGHT 2% having a Solution viscosity in the range of 3 cps to 40 Polysiloxane Adhesive 66.3 cps, alone or in combination with an insoluble, (BIO-PSA (R) 7-4603) non-adhesive cellulose ester in a total amount from Polyacrylate Adhesive 5.0 50 2.5% to 20% by weight based on the dry weight of (DURO-TAK (R) 87-2287) the total adhesive matrix composition, Ethyl Cellulose 1.O.O (iii) at least one hydrophobic active agent, (Ethocel(R) 10) Dipropylene Glycol 9.O (iv) a hydrophilic crystallization inhibitor selected from Olelyl Alcohol 6.O the group consisting of Soluble Estradiol O.7 55 polyvinylpyrrolidone, Soluble cellulose and cellulose Norethindrome Acetate 3.0 derivatives, and polyethylene oxide in an amount from 5% to 15% by weight based on the dry weight 1OO.O of the total adhesive matrix composition, (v) a drug permeation enhancer in an amount up to 15% 60 by weight based on the dry weight of the total Examples 2-9 adhesive matrix composition, and In the following examples, the method of Example 1 was (vi) a polyhydric alcohol Solvent in an amount up to used with the appropriate amounts of Starting materials to 20% by weight based on the dry weight of the total yield compositions having the following ingredient concen adhesive matrix composition; trations set forth in tabular form in TABLE II. Examples 2, 65 wherein the adhesive matrix is capable of delivering the 3, and 5 are presented as control formulations for compara active agent at a Substantially Zero-order kinetic rate for tive purposes, but are not within the Scope of the invention period of time in excess of 72 hours. US 6,638,528 B1 37 38 2. The transdermal System according to claim 1, wherein 6. The transdermal System according to claim 5, wherein the ethyl cellulose polymer has a Solution Viscosity in the tie adhesives consist of 5%-40% by dry weight polyacrylate range of 3 cps to 22 cpS. adhesive and 30%-90% by dry weight polysiloxane adhesive, the polydric alcohol Solvent is dipropylene glycol 3. The transdermal System according to claim 1, wherein in an amount of 5%-10% by dry weight, the permeation the ethyl. cellulose polymer is combined with an insoluble, 5 enhancer is oleyl alcohol in an amount of 1%-10% by dry non-adhesive cellulose ester Selected from the group con weight, the hydrophilic crystallization inhibitor is soluble Sisting of cellulose acetate butyrate and cellulose acetate polyvinylpyrrolidone in an amount of 5%-15% by dry propionate. weight, and the hormonal agent consists of 17 B-estradiol in 4. The transdermal System according to claim 1, wherein an amount of 0.1%-5% by dry weight alone or in combi the hydrophilic crystallization inhibitor is soluble polyvi nation with norethindrone acetate in an amount of 1%-7% nylpyrrollidone. by dry weight, Said weights based on the dry weight of the 5. The transdermal System according to claim 1, wherein total composition. the one or more active agents are Selected from the group consisting of Steroidal and hormonal agents.