sign in sign up
<<
Home , Sulbentine, Tiamenidine

US006638528B1

12 United States Patent 10 Patent N0.: US 6 9 638 9 528 B1 Kanios (45) Date of Patent: Oct. 28, 2003

(54) COMPOSITIONS AND METHODS TO FOREIGN PATENT DOCUMENTS EFFECT THE RELEASE PROFILE IN THE TRANSDERMAL ADMINISTRATION OF EP 0 224 981 6/ 1987 ACTIVE AGENTS EP 0 697 860 4/1994 EP 913 158 6/1999 (75) Inventor: David Kanios, Miami, FL (US) WO WO94/06436 3/1994 73 AS _ ' N Ph _ l I M_ _ WO WO94/26257 11/1994 ( ) signee. FLOWEIS armaceutlca s, nc., 1am1, W0 “logs/22322 8/1995 ( ) WO WO95/31188 11/1995 ( * ) Notice: Subject to any disclaimer, the term of this W0 WO96/21433 7/1996 patent is extended or adjusted under 35 W0 “logs/17263 4/1998 U_S~C_ 154(k)) 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 WO00/59483 10/2000 (22) P116011 Mar- 1, 2002 WO WO00/74661 12/2000 Related US. Application Data W0 PCT/ USO” 01999 8/2001

(63) Continuation of application No. 09/765,932, ?led on Jan. 19, OTHER PUBLICATIONS 2001, now abandoned. (60) ggggslonal apphcanon NO' 60/172103’ ?led on Jan' 20’ DoW Chemical Company, “Product Speci?cation Sheet for 7 Ethocel FP Polymers,” Oct. 1998, USA. (51) Int. Cl...... A61K 9/70; A61K 13/00 (52) US. Cl...... 424/449; 424/448; 424/443; DoW Chemical Company, “Bibliography: ETHOCEL Eth 424/484 ylcellulose in Pharmaceuticals,” Jun. 1996, USA. (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 Assistant Examiner—Robert M. Joynes 4,584,355 A 4/ 1986 Blizzard et al. 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 4/1987 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. ceutically acceptable adhesive matrix and a polymeric plas RE32,991 E 7/1989 Szycher et al. 4,883,669 A 11/1989 Chien et al. tic material that provides a release rate regulating effect on 4,900,554 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

13

. . I ~ - - - ~ s - . - l I I - I I - q - l - 5 I - - - ~ - I I - - - . - - 1 I - I - ~ ~ | I ¢ . I .

12 US 6,638,528 B1 Page 2

US. 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, USA. 5,232,702 8/1993 P?ster et al. DoW Chemical Company, “Ethocel Premium Polymers for 5,446,070 8/1995 Mantelle Pharmaceutical Applications,” May 1996, USA. 5,474,783 12/1995 Miranda et al. DoW Chemical Company, “Ethocel Premium Ethylcellulose 5,523,095 6/1996 Wison et al. 5,556,635 9/1996 Istin et al. in Pharmaceutical Applications,” Dec. 1991, USA. 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 Wick et al. Structure, 4th Ed., 1992. 5,676,969 10/1997 Wick et al. BASF Aktiengesellschaft, Buhler, Kollidon® Polyvinylpyr 5,679,373 10/1997 Wick et 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. Van Nostrand Reinhold, NeW York, Satas, Donatas, “Acrylic 5,885,612 3/1999 Meconi et al. 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 Wick et 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 SensitiveAdhesive Technology, 6,190,689 2/2001 Hoffmann et al. 2nd Ed. 6,231,885 5/2001 Carrara 6,274,165 >>>>>>>>>>>>>>>>>>>> 8/2001 Meconi et al. * cited by examiner U.S. Patent Oct. 28,2003 Sheet 1 6f 6 US 6,638,528 B1

FIG.1 U.S. Patent Oct. 28,2003 Sheet 2 6f 6 US 6,638,528 B1

wwp

NMEDQE 359:m2;

0330/‘96.655202N512408n

mm; low; 10c.’ mud... OmdI mmd1 00.0 (lu/wo'bs/?n) xma aavuaAv

U.S. Patent Oct. 28,2003 Sheet 4 6f 6 US 6,638,528 B1

InIn

¢mmDQE wwpTWPON?mmNNw¢¢NO @5059:5.

lomd mNd| 00.0 U.S. Patent Oct. 28,2003 Sheet 5 6f 6 US 6,638,528 B1

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 ?nite carrier TRANSDERMAL ADMINISTRATION 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 af?x 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 US. Ser. attempt to better control the release rate of the drug, such No. 09/765,932, ?led Jan. 19, 2001 noW abandoned, Which devices often employ one or more additional drug permeable 10 is based on and claims the bene?t of Provisional Application layers such as rate controlling membranes, or containing No. 60/177,103, ?led 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 active agent is typically solubiliZed or homogenously This invention relates generally to transdermal drug deliv blended in an adhesive carrier composition, typically a ery systems, and more particularly to pharmaceutically pressure-sensitive adhesive or bioadhesive, Which functions acceptable adhesive matrix compositions, that use polymeric as both the drug carrier and the means of affixing the system plastic materials, in particular insoluble cellulose derivatives to the skin or mucosa. Such devices, commonly referred to such as ethyl celluloses, to regulate the drug release pro?le. 20 as drug-in-adhesive devices, are described, for example, in The invention additionally relates to transdermal drug deliv ery systems providing substantially Zero order drug release US. Pat. Nos. 4,994,267, 5,446,070, 5,474,783 and 5,656, 286, all of Which are assigned to Noven Pharmaceuticals, pro?les for an extended period of time of up to seven days Inc., Miami, Fla. or longer. While matrix-type devices, especially drug-in-adhesive 25 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 ef?cacy. For many systems incorporate the active agent into a carrier drugs and/or therapeutic situations, it Would be advanta 30 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 pro?le 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 35 For example, the high initial release of certain drugs may employ a backing layer that forms the protective outer cause adverse or undesired effects, or create toxicity surface of the ?nished 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 af?xing the 40 of risking underdosing, or may make it impractical to try and system to the skin or mucosa of a user. The release liner or increase the duration of the device’s 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 lag or drop off in efficacious. blood levels, and reduce the In the “classic” reservoir-type device, the active agent is 45 usually dissolved or dispersed in a carrier that typically amount of drug required for treatment (also provided by yields a non-?nite carrier form, like a ?uid or gel, and Which reducing the higher initial blood level associated With the is kept separate from the adhesive means used to af?x 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 pro?le of drugs to peripheral adhesive layer is then used to af?x 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 US. 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 pro?le 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 ?rst order amount. Drug delivery according to this pro?le is described release rate pro?le such that the system achieves substan as ?rst 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 pro?le 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 pro?le 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. signi?cant 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 polyvinylpyrrolidones. of active agent from an adhesive matrix type transdermal drug delivery system containing a drug subject to a ?rst Ethyl celluloses have been extensively used in industrial order release pro?le. applications since their commercial introduction in the mid 10 It is yet another object of the invention to provide a 1930s. They are recognized and Widely used as Well for 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, ?llers, time in excess of 72 hours and up to seven days or more Without substantially increasing the surface area of the ?avor ?xatives, controlled release coatings/barriers in 15 microencapsulation and other solid dosage forms, particu transdermal delivery system. larly multiparticulate systems, granulation aids, tablet ?lm 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 ?ux 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, US. Pat. No. 5,232,702 discloses composition of the present invention With the ?ux rate for a the use of a variety of substances that include ethyl cellulose composition of the prior art. 25 and polyvinyl alcohol as cohesive strengthening agents FIG. 3 is a graphical representation of the in vitro ?rst (reducing ?oW properties of silicone adhesives) in a trans order ?ux 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 pro?le pared to the in vitro steady state ?ux 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 ?ux degree of adhesion and tackiness to remain af?xed 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 ?ux 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 ?ux 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 sensitive adhesive matrix compositions of the present inven includes the addition of a plasticiZer or tacki?er, 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, US. Pat. FIG. 6 is a graphical representation of the in vitro ?ux 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 lose derivatives such as ethyl cellulose are generally dis DETAILED DESCRIPTION OF THE closed as “suitable adhesives” for use as the matrix. INVENTION US. 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 de?ned otherWise, all technical and scienti?c 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 ?exible, ?nite compositions and systems for the transdermal invention pertains. administration of active agents that achieve a substantially The term “topical” or “topically” is used herein in its Zero-order release pro?le 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 pro?le 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 5 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 carrier composition there is an intimate dispersion or disso those sold under the trademark ETHOCEL® by the DoW lution of the active agent at the crystalline, molecular or Chemical Company, Midland, Mich. Preferred ETHOCEL® polymers are ETHOCEL® 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 “?ux” is de?ned as the absorp 10 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 ?rst 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 ?ux in g/cm2/sec, D is the diffusion coef? 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 vinylpyrrolidone The phrase “pharmaceutically acceptable ?exible, ?nite” 20 (also referred to as N-vinylpyrrolidone, 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, vinylpyrrolidone/vinyl acetate and vinylpyrrolidone/ and Without being appreciably decomposed by aqueous 25 dimethylamino-ethylmethacrylate. The cross-linked hom contact during use by a subject. polymer (such as KOLLIDON® 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 30 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, KOLLIDON®: 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 identi?ed 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-pyrrolidinone, 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 suf?cient 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 ?rst order release pro?le. 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 C1 to C6 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 manner. 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 ot-) 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 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 pro?le is substantially Estradiol, Moxestrol, Mytatrienediol, 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 Desogestrel, Dimethisterone, Dydrogesterone, active substance, cosmetic and personal care preparations, Ethinylestrenol, Ethisterone, Ethynodiol (and Diacetate), and mixtures thereof, Which is delivered to a mammal to Flurogestone Acetate, Gestodene, Gestonorone Caproate, produce a desired, usually bene?cial, effect. More Haloprogesterone, (17-Hydroxy- and 17-Acetate-) speci?cally, any active agent that is capable of producing a 16-Methylene-Progesterone, 17ot-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. Norgestim ate, Norgestrel, Norgestrienone, There is no limitation on the type of active agent that can 19-Norprogesterone, Norvinisterone, Pentagestrone, be used in this invention. HoWever, active agents that are Progesterone, Promegestone, Quingestrone and Trenge solid or crystalline at room temperature are preferred over 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 17ot-Methyltesteosterone, 17ot-Methyltestosterone acceptable salts, bases, esters, amides or pro-drugs, or may 65 3-Cyclopentyl Enol Ether, Norethandrolone, be modi?ed by appending one or more appropriate func Normethandrone, Oxandrolone, Oxymesterone, tionalities to enhance selected physical or biological Oxymetholone, Prasterone, Stanlolone, StanoZolol, Test US 6,638,528 B1 10 osterone (Acetate, Enanthate, Isobutyrate, Propionate and , Hydrochloride, Undecanoate), Testosterone 17-Chloral Hemiacetal, Test Methylhexaneamine, MetiZolene, , osterone 17[3-Cypionate and Tiomesterone. , , Norfenefrine, Octodrine, The adhesive matrix composition of the invention pref , , erably contains 17[3-estradiol or ethinyl estradiol as the Hydrochloride, Hydrochloride, estrogen alone, or in combination With, Norethindrone Phenylpropylmethylamine, Pholedrine, Propylhexedrine, (Acetate and Enanthate) or Norethisterone, as the , , , progestagen, and mixtures thereof. TetrahydroZoline, Tiamenidine, TramaZoline, In embodiments containing combinations and mixtures of Tuaminoheptane, TymaZoline, Tyramine and Xylometa estrogens and progestagens, the use of combinations and 10 Zoline. mixtures of cellulose derivatives, particularly cellulose . [3- agonists such as Albuterol, , esters and ethers, provide improved drug release pro?les for , , , Clorprenaline, an extended period of time as compared to an adhesive , Dioxethedrine, , , matrix composition containing either one alone or none. Epinephrine, , Ethylnorepinephrine, , Preferred combinations or mixtures of cellulose esters and 15 , , Ibopamine, Isoetharine, ethers are ethyl cellulose With cellulose acetate butyrate or Isoproterenal, , Metaproterenol, With cellulose acetate propionate. When used in combina , , , , tions and mixtures, the amount of each such polymer typi , , , , , cally ranges from about 2.5% to about 10% by Weight based Soterenol, Terbuterol and . on the dry Weight of the total adhesive matrix composition. 20 . ot-Adrenergic blockers such as , , Particularly preferred embodiments of such mixtures and , , Mesylates, , combinations include soluble PVP, and typically in an , , , , , amount of about 5% to about 15% by Weight based on the , and . dry Weight of the total adhesive matrix composition. . [3-Adrenergic blockers such as , , As shoWn in FIG. 6, in pressure-sensitive adhesive matrix 25 Amosulalol, Arotinolol, , , , compositions containing both 17[3-estradiol (E2) and nore , , , , thindrone acetate (NETA) in a polyacrylate/polysiloxane Befetolol, , , , adhesive blend With 10% PVP, Formula 4 comprising 5.0% Hydrochloride, Buto?lolol, , , ethyl cellulose and 5 .0% cellulose acetate butyrate demon , , , , Dilevalol, strated an improved release pro?le as compared to either 30 , Esmolol, , Labetalol, I?VObIlIIOIOI, Formula 1 (only 10% PVP), Formula 2 (5.0% ethyl , Metipranalol, , , cellulose) or Formula 3 (5.0% cellulose acetate butyrate). , , , , The foregoing formulas Were prepared using the method of , , , , , Example 1 to yield the folloWing ingredient concentrations , Sul?nalol, , , , Tolip set forth in tabular form in TABLE I. 35 rolol and . .Alcohol deterrents such as Calcium Cyanamide Citrated, TABLE I Disul?ram, Nadide and NitrefaZole. . Aldose reductase inhibitors such as Epalrestat, Formula 1 Formula 2 Formula 3 Formula 4 Ponalrestat, Sorbinil and Tolrestat. Polysiloxane 71.3 60.0 60.0 55.0 40 . Anabolics such as AndroisoxaZole, Androstenediol, Adhesive Bolandiol, Bolasterone, Clostebol, Ethylestrenol. (BIO-PSA ® 7-4603) Polyacrylate 0.0 5.0 5.0 5.0 Formyldienolone, 4-Hydroxy-19-nortestosterone, Adhesive Methandriol, Methenolone, Methyltrienolone, (DURO-TAK ® Nandrolone, Nandrolone Decanoate, Nandrolone 87-2287) 45 p-Hexyloxyphenylpropionate, Nandrolone Polyacrylate 5.0 0.0 0.0 0.0 Adhesive Phenpropionate, Norbolethone, Oxymesterone, (Gelva ® 737) PiZotyline, Quinbolone, Stenbolone and Trenbolone. Ethyl Cellulose 0.0 5.0 0.0 5.0 . Analgesics (dental) such as Chlorobutanol, Clove and (Ethocel ® 10) Eugenol. Cellulose Acetate 0.0 0.0 5.0 5.0 Butyrate 50 . Analgesics (narcotic) such as Alfentanil, Allylprodine, (CAB-381-0.5) Alphaprodine, Anileridine, BenZylmorphine, Polyvinylpyrrolidone 10.0 10.0 10.0 10.0 BeZitramide, Buprenorphine, Butorphanol, ClonitaZene, (KOLLIDON ® 30) Codeine, Codeine Methyl Bromide, Codeine Phosphate, Oleic Acid 6.0 0.0 0.0 0.0 Dipropylene Glycol 4.0 9.0 9.0 9.0 Codeine Sulfate, Desomorphine, Dextromoramide, Oleyl Alcohol 0.0 6.0 6.0 6.0 55 DeZocine, Diampromide, Dihydrocodeine, Dihydroco Estradiol 0.7 1.0 1.0 1.0 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 speci?c drugs for Which the invention can be 60 Fentanyl, Hydrocodone, Hydrocodone Bitartrate, particularly usefully employed include: Hydromorphone, Hydroxypethidine, Isomethadone, 1. ot-Adrenergic agonists such as Adra?nil, Adrenolone, Ketobemidone, Levorphanol, Lofentanil, Meperidine, , , BudralaZine, , MeptaZinol, MetaZocine, Methadone Hydrochloride, Cyclopentamine, , , Dipivefrin, Metopon, Morphine, Morphine Derivatives, Myrophine, Ephedrine, Epinephrine, FenoxaZoline, , 65 Nalbuphine, Narceine, Nicomorphine, Norlevorphanol, , Hydroxyamphetamine, Ibopamine, Normethadone, Normorphine, Norpipanone, Opium, IndanaZoline, , Mephentermine, 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. Anorexics such as Aminorex, Amphecloral, 10. Analgesics (non-narcotic) such as Acetaminophen, Amphetamine, BenZaphetamine, Chlorphentermine, Acetaminosalol, Acetanilide, Acetylsalicylsalicylic Acid, ClobenZorex, Cloforex, Clortermine, Cyclexedrine, Alclofenac, Alminoprofen, Aloxiprin, Aluminum Bis Destroamphetamine Sulfate, Diethylpropion, (acetylsalicylate), AminochlorthenoxaZin, 2-Amino-4 Diphemethoxidine, N-Ethylamphetamine, FenbutraZate, picoline, Aminopropylon, Aminopyrine, Ammonium Fen?uramine, Fenproporex, Salicylate, Antipyrine, Antipyrine Salicylate, Antrafenine, Furfurylmethylamphetamine, Levophacetoperate, ApaZone, Aspirin, Benorylate, Benoxaprofen, 10 MaZindol, Mefenorex, Metamfeproamone, BenZpiperylon, BenZydamine, p-Bromoacetanilide, Methamphetamine, Norpseudoephedrine, 5-Bromosalicylic Acid Acetate, Bucetin, Bufexamac, PhendimetraZine, PhendimetraZine Tartrate, BumadiZon, Butacetin, Calcium Acetylsalicylate, PhenmetraZine, Phenpentermine, Phenylpropanolamine CarbamaZepine, Carbetidine, Carbiphene, Carsalam, Hydrochloride and . Chloralantipyrine, ChlorthenoxaZin(e), Choline 13. Anthelmintics (Cestodes) such as Arecoline, Aspidin, Salicylate, Cinchophen, Ciramadol, Clometacin, Aspidinol, Dichlorophen(e), Embelin, Kosin, Napthalene, Cropropamide, Crotethamide, Dexoxadrol, DifenamiZole, Niclosamide, Pellertierine, Pellertierine Tannate and Di?unisal, Dihydroxyaluminum Acetylsalicylate, Quinacrine. Dipyrocetyl, Dipyrone, EmorfaZone, Enfenamic Acid, 14. Anthelmintics (Nematodes) such as Alantolactone, EpiriZole, Etersalate, EthenZamide, EthoxaZene, 20 Amoscanate, Ascaridole, Bephenium, Bitoscanate, Car Etodolac, Felbinac, Fenoprofen, Floctafenine, Flufenamic bon Tetrachloride, Carvacrol, CyclobendaZole, Acid, Fluoresone, Flupirtine, FluproquaZone, DiethylcarbamaZine, Diphenane, DithiaZanine Iodide, Flurbiprofen, Fosfosal, Gentisic Acid, Glafenine, Dymanthine, Gentian Violet, 4-Hexylresorcinol, Kainic Ibufenac, Salicylate, Indomethacin, Acid, MebendaZole, 2-Napthol, Oxantel, Papain, Indoprofen, IsofeZolac, Isoladol, Isonixin, Ketoprofen, 25 , 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, PipebuZone, Piperylone, 16. Anthelmintics (Schistosoma) such as Amoscanate, Prodilidine, Propacetamol, PropyphenaZone, ProxaZole, Amphotalide, Antimony Potassium Tartrate, Antimony Quinine Salicylate, RamifenaZone, RimaZolium 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, Talni?umate, Tenoxicam, Terofenamate, bophen and Urea Stibamine. Tetradrine, Tinoridine, Tolfenamic Acid, Tolpronine, 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, Butoxycaine, Carticaine, 2-Chloroprocaine AZelastine, Cromolyn, Fenpiprane, Histamine, Ibudilast, Hydrochloride, Cocaethylene, Cocaine, Nedocromil, Oxatomide, Pentigetide, Poison Ivy Extract, Cyclomethycaine, Dibucaine Hydrochloride, Poison Oak Extract, Poison Sumac Extract, Repirinast, Dimethisoquin, Dimethocaine, Diperadon Hydrochloride, Tranilast, Traxanox and Urushiol. Dyclonine, Ecgonidine, Ecgonine, Ethyl AminobenZoate, 20. Antiamebics such as Arsthinol, Bialamicol, Carbarsone, Ethyl Chloride, Etidocaine, Etoxadrol, [3-Eucaine, Cephaeline, Chlorbetamide, Chloroquine, Euprocin, Fenalcomine, Fomocaine, Hexobarbital, Hexy Chlorphenoxamide, Chlortetracycline, Dehydroemetine, lcaine Hydrochloride, Hydroxydione Sodium, Dibromopropamidine, Diloxanide, Dephetarsone, Hydroxyprocaine, Hydroxytetracaine, Isobutyl 55 Emetine, Fumagillin, Glaucarubin, Glycobiarsol, p-AminobenZoate, Kentamine, Leucinocaine Mesylate, 8-Hydroxy-7-iodo-5-quinolinesulfonic 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, Naepaine, Octacaine, Orthocaine, TecloZan, Tetracycline, ThiocarbamiZine, Thiocarbarsone OxethaZaine, Parethoxycaine, Phenacaine Hydrochloride, and TinidaZole. Phencyclidine, Phenol, Piperocaine, Piridocaine, 21. Antiandrogens such as Bi?uranol, Cyoctol, Cyproterone, Polidocanol, Pramoxine, Prilocaine, Procaine, Delmadinone Acetate, Flutimide, Nilutamide and Oxen Propanidid, Propanocaine, Proparacaine, Propipocaine, dolone. Propofol, Propoxycaine Hydrochloride, Pseudococaine, 65 22. such as Acebutolol, Alprenolol, Pyrrocaine, Quinine Urea Hydochloride, Risocaine, Sali Amiodarone, Amlodipine, Arotinolol, Atenolol, Bepridil, cyl Alcohol, Tetracaine Hydrochloride, Thialbarbital, Bevantolol, Bucumolol, , 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, Clometocillin, CloXacillin, Cyclacillin, M_o1sidomine,_ , Nipardipine, Nifedipine, 5 Dicloxacillin, Diphenicillin Sodium, Epicillin, Nlfenaloh N11Vad1p1ne> N1prad1101> _ Nlsoldlplne> Fenbenicillin, FloXicillin, Hetacillin, Lenampicillin, Nltroglycenm OXPrenoloL OXYfedrlne> Ozagrel, Metampicillin, Methicillin Sodium, MeZlocillin, Penbutolol’ pentaerythritol Tetranitral?’ pmdolol’ Nafcillin Sodium, OXacillin, Penamecillin, Peneth ggcfinethlallol’ grvopranol?’ Sotalol’ Terodlhne’ Tlmolol’ amate Hydriodide, Penicillin G Benethamine, Peni p.ro 0 an . erapaml ' . . 10 cillin G BenZathine, Penicillin G BenZhydrylamine, 23.Ant1arrhythm1csAjmaline, Alprenolol, such asAcebutol,Aceca1ne,Adenos1ne, Amiodarone, AmoproXan, penlcluln. . . G calclllm’. penlcluln. . . G Hydlabamm??’. Aprindine, Arotinolol, Atenolol, Bevantolol, Remcllhn G PQQSSHHH’ Pen“??? G PYOCaIPe; Pem' Tosylate, Bubumolol, Bufetolol, Bunaftine, Bunitrolol, Cluen N’ Pemcllhn _O>_ pémcllhn V’ Pemcllh? V Bupranolol, Butidrine Hydrochloride, Butobendine, Ben_zath_lne> _Pen1c11hn Hydrabam_1ne> Capobenic Acid, CaraZolol, Carteolol, Cifenline, 15 P§n1m§P_1CYC1_1ne>_ Phenethwlllln Potassium, Cloranolol, Disopyramide, Encainide, Esmolol, Piperacillin, Pivapicillm, Propicillm, Qu1nac1ll1n, Flecainide, Gallopam?, Hydmquinidine, lndecainide, Sulbenicillin, Talampicillin,Temocillin and Ticarcil Indenolol, Ipratropium Bromide, Lidocaine, Lorajmine, lin; Lorcainide, Meobentine, , Mexiletine, Lincosamides such as Clindamycin and Lincomycin; MOFiCiZine, NadOXOlOl, Nifenalol, OXprenolol, 20 Macrolides such as AZithromycin, Carbomycin, Penbutolol, Pindolol, Pirmenol, Practolol, Prajmaline, clarithromycin, Erythromycin, Erythromycin Proca1nam1de Hydrochloride, Pronethalol, Propa'fenone, Acistrate, Erythromycin Estolate, Erythromycin Propranolol? Pynnqhne’ Qulmdln? Sulfate’ Qulmdln‘é Glucoheptonate, Erythromycin Lactobionate, Erythro §Fitab$gi1mdf1f Tlmolol’ Tocamlde’ Verapam?’ Vlqul' mycin Propionate, Erythromycin Stearate, Josamycin, 1 an 1 eno o...... 24. Antiarteriosclerotics such as Pyridinol Carbamate. 25 léfeiflgéntgili?s’prill/lnliienc 2115113124 gciirtgglilittll’ 25. Antiarthritic/Antirheumatics such as Allocupreide R .th y .’ S . y ’. dT yl ’d . _ ’ Sodium, Aurano?n, Aurothioglucose,Aurothioglycanide, OX1 rémycm’ plramycm an m éan Gnu/Sun’ _ AZathioprine, Calcium 3-Aurothio-2-propanol-1- Polypepnde5_ Such _as_ Amphomyéln, Baszltraclm sulfonate, CelecoXib, Chloroquine, ClobuZarit, 3O capreomyqm Cohstm; Eqduracldln, EPWPIPYCHI, CuproXoline, Diacerein, Glucosamine, Gold Sodium Fu_safungn_le> Gramlcldln(s_)> Gramlcldln _S> Thiomalate, Gold , Mlkamyelm _ POlymYXlm _P01YH1YX_1I1 HydroXychloroquine, KebuZone, LobenZarit, Melittin, B'Methane_Su1fOmC_AC1d> pnsnnamyclm _Rlstocet_m> MethotreXate, Myoral and Penicillamine. Telcqplanlm Thl9§treptom Tu_bera_Ct1nO_myC1_n> 26. Antibacterial (antibiotic) drugs including: 35 Tyro_cldlne> Tyrothnclnf YaFICOmXCm, V1OI_nyC1n> V10‘ Aminoglycosides Such as Amikacin, Apramycin, mycin Pantothenate, V1rg1n1amyc1n and Zinc Bac1tra Arbekacin, Bambermycins, Butirosin, Dibekacin, Cm; _ _ _ _ Dihdrostreptomycin, portimicirms), Gentamicin, Tetracyclines such as Apicycline, Chlortetracycl'me, Ispamicin, Kanamycin, Micronomicin, Neomycin, clomocychllm Demeclocy§llne> Doxycycllnm Neomycin Undecylenate, Netilmicin, Paromomycin, 4O Guamecycllnm Lymecyf?lnm Meclocycllnm Ribostamycin, Sisomicin, Spectinomycin, MePhaCyFhn§> M1I1_0CyC11I_1e> OXYFGtTaCYChPQ Streptomycin, StreptonicoZid and Tobramycin; penlmeplcychnef Plpacychne, Rohtetraeyehne, Amphenicols such as AZidamfenicol, Chloramphenicol, sancychne’ Senoclchn and Tetracychne; and chloramphenicol Palmitate, chloramphenicol other antibiotics such as Cycloserine, Mupirocin and Pantothenate, Florfenicol and Thiamphenicol; 45 Tubenn Ansamycins such as Rifamide, Rifampin, Rifamycin and 27. Antibacterial drugs (synthetic), including: RifaXimin; 2,4-Diaminopyrimidines such as Brodimoprim, TetroX [3-Lactams, including: oprim and Trimethoprim; Carbapenems such as Imipenem; Nitrofurans such as Furaltadone, FuraZolium Chloride, cephalosporins Such as cefactor, cefadrox?, 50 Nifuradene, Nifuratel, Nifurfoline, Nifurpirinol, Cefamandole, CefatriZine, CefaZedone, CefaZolin, Nifurprazine, Nifurtoinol and Nitrofllrantoin; Ce?xime, CefmenoXime, CefQdiZime, cefonicid, Quinolones and Analogs such as Ami?oxacin, CinoXacin, CefoperaZone, Ceforanide, CefotaXime, Cefotiam, CiPIO?OXaCiH, Di?OXaCin, EnOXaCin, FlerOXaCin, CefpimiZole, Cefpirimide, cefpodoxime Proxet?, Flumequine, Lome?oXacin, MiloXacin, NalidiXic Acid, CefroXadine, Cefsulodin, CeftaZidime, Cefteram, 55 NOf?OXaCiIl, O?OXaCiIl, OXOliIliC Acid, Pe?OXaCin, CefteZole, Ceftibuten, CeftiZoXime, CeftriaXone, PiPfIIIIidiC Acid, PirOIIlidiC Acid, ROSOXaCiH, Tema CefuroXime, CefuZonam, Cephacetrile Sodium, ?OXaCin and TOSIl?OXaCiH; CephaleXin, Cephaloglycin, Cephaloridine, Sulfonamides such as Acetyl SulfamethoXypyraZine, Cephalosporin, Cephalothin, Cephapirin Sodium, Acetyl Sul?soXaZole,AZosulfamide, BenZylsulfamide, Cephradine and Pivcefalexin; 6O Chloramine-B, Chloramine-T, Dichloramine T, Cephamycins such as CefbuperaZone, CefmetaZole, FormosulfathiaZole, NzFormylsul?somidine, NZ-a-D CefminoX, Cefetan and CefoXitin; Glucosylsulfanilamide, Mafenide, 4‘ Monobactams such as AZtreonam, Carumonam and (Methylsulfamoyl)sulfanilanilide, Tigemonam; p-NitrosulfathiaZole, Noprylsulfamide, OXacephems such as Flomoxef and MoXolactam; 65 Phthalylsulfacetamide, PhthalylsulfathiaZole, Penicillins such as Amidinocillin, Amdinocillin SalaZosulfadimidine, SuccinylsulfathiaZole, PivoXil, AmoXicillin, Ampicillan, Apalcillin, SulfabenZamide, Sulfacetamide, SulfachlorpyridaZine, US 6,638,528 B1 15 16 Sulfachrysoidine, Sulfacytine, SulfadiaZine, Buramate, Calcium Bromide, CarbamaZepine, Sulfadicramide, SulfadimethoXine, SulfadoXine, Cinromide, ClomethiaZole, ClonaZepam, Decimemide, Sulfaethidole, Sulfaguanidine, Sulfaguanol, Sulfalene, Diethadione, Dimethadione, DoXenitoin, Eterobarb, SulfaloXic Acid, SulfameraZine, Sulfameter, Ethadione, EthosuXimide, Ethotoin, Fluoresone, SulfamethaZine, SulfamethiZole, Sulfamethomidine, Garbapentin, S-Hydroxytryptophan, Lamotrigine, SulfamethoXaZole, SulfamethoXypyridaZine, Lomactil, Magnesium Bromide, Magnesium Sulfate, Sulfametrole, Sulfamidochrysoidine. SulfamoXole, Mephenytoin, Mephobarbital, Metharbital, Methetoin, Sulfanilamide, Sulfanilamidomethanesulfonic Acid MethsuXimide, 5-Methyl-S-(3-phenanthryl)hydantoin, Triethanolamine Salt, 4-Sulfanilamidosalicylic Acid, 3-Methyl-5-phenylhydantoin, Narcobarbital, N4-Sulfanilylsulfanilamide, Sulfanilylurea, NimetaZepam, NitraZepam, Paramethadione, N-Sulfanilyl-3, 4-Xylamide, Sulfanitran, Sulfaperine, Phenacemide, Phenetharbital, Pheneturide, SulfaphenaZole. SulfaproXyline, SulfapyraZine, Phenobarbital, Phenobarbital Sodium, PhensuXimide, Sulfapyridine, SulfasomiZole, SulfasymaZine, Phenylmethylbarbituric Acid, Phenytoin, Phethenylate SulfathiaZole, Sulfathiourea, Sulfatolamide, Sul?somi Sodium, Potassium Bromide, Pregabatin, Primidone, dine and Sul?soXaZole; 15 Progabide, Sodium Bromide, Sodium Valproate, Sulfones such as Acedapsone, Acediasulfone, Acetosul Solanum, Strontium Bromide, Suclofenide, Sulthiame, fone Sodium, , Diathymosulfone, Glucosul Tetrantoin, Tiagabine, Trimethadione, Valproic Acid, fone Sodium, Solasulfone, Succisulfone, Sulfanilic Valpromide, Vigabatrin and Zonisamide. Acid, p-SulfanilylbenZylamine, p,p‘-Sulfonyldianiline 29. , 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, Methenamine OXypertine, ParoXetine, Sertraline, ThiaZesim, Mandelate, Methenamine Sulfosalicylate, NitroXoline , VenlafaXine and Zometapine; and Xibornol. Anticholinergics such as Adiphenine 25 HydraZides/HydraZines such as BenmoXine, IprocloZide, Hydrochloride, Alverine, Ambutonomium Bromide, Aminopentamide, AmiXetrine, Amprotropine IproniaZid, IsocarboXaZid, Nialamide, OctamoXin and Phosphate, Anisotropine Methylbromide, Apoatropine, PhenelZine; Atropine, Atropine N-OXide, BenactyZine, Pyrrolidones such as Cotinine, Rolicyprine and Rolipram; BenapryZine, BenZetimide, BenZilonium Bromide, Tetracyclics such as , Metralindole, BenZtropine Mesylate, Bevonium Methyl Sulfate, and . Biperiden, Butropium Bromide, Tricyclics such as AdinaZolam, , N-Butylscopolammonium Bromide, BuZepide, , , , Camylo?ne, Caramiphen Hydrochloride, , , , ChlorbenZoXamine, ChlorphenoXamine, Cimetropium 35 DibenZepin, Dimetracrine, Dothiepin, , Bromide, Clidinium Bromide, Cyclodrine, Cyclonium FluaciZine, , Imipramine N-OXide, Iodide, Cycrimine Hydrochloride, Deptropine, Iprindole, , , , DeXetimide, Dibutoline Sulfate, Dicyclomine , NoXiptilin, , PiZotyline, Hydrochloride, DiethaZine, Difemerine, DiheXyverine, , , , Tianeptine Diphemanil Methylsulfate, N-(1,2-Diphenylethyl) and ; and nicotinamide, Dipiproverine, Diponium Bromide, others such as Adra?nil, BenactyZine, Bupropion, Emepronium Bromide, EndobenZyline Bromide, Butacetin, Deanol, Deanol Aceglumate, Deanol EthopropaZine, EthybenZtropine, EthylbenZhydramine, AcetamidobenZoate, DioXadrol, , Etomidoline, Eucatropine, Fenpiverinium Bromide, Febarbamate, FemoXetine, Fenpentadiol, FluoXetine, Fentonium Bromide, Flutropium Bromide, 45 FluvoXamine, FluvoXamine Maleate, Glycopyrrolate, Heteronium Bromide, HeXocyclium Hematoporphyrin, Hypercinin, Levophacetoperane, Methyl Sulfate, Homatropine, Hyoscyamine, Ipratro MedifoXamine, Minaprine, Moclobemide, OXa?oZane, pium Bromide, Isopropamide, Levomepate, Piberaline, Prolintane, Pyrisuccideanol, Rubidium MecloXamine, MepenZolate Bromide, Metcaraphen, Chloride, Sulpiride, Sultopride, TeniloXaZine, Methantheline Bromide, MethiXene, Methscopolamine ThoZalinone, Tofenacin, ToloXatone, Tranylcypromine, Bromide, Octamylamine, 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, Pri?nium 55 Bromide, Procyclidine, Propantheline Bromide, Hormones such as Glucagon and Insulin; PropenZolate, PropyromaZine, Scopolamine, Scopola Sulfonylurea derivatives such as AcetoheXamide, mine N-OXide, Stilonium Iodide, Stramonium, 1 -Butyl-3-metanilylurea, Carbutamide, Sultroponium, ThiheXinol, Thiphenamil, Tiemonium Chlorpropamide, Glibornuride, GliclaZide, GlipiZide, Iodide, Timepidium Bromide, TiquiZium Bromide, Gliquidone, GlisoXepid, Glyburide, GlybuthiaZol(e), TridiheXethyl Iodide, TriheXyphenidyl Hydrochloride, GlybuZole, GlyheXamide, Glymidine, Glypinamide, Tropacine, TropenZile, Tropicamide, Trospium Phenbutamide, TolaZamide, Tolbutamide and Tolcycla Chloride, Valethamate Bromide and Xenytropium Bro mide; and mide. others such as Acarbose, Calcium MesoXalate and Migli 28. Anticonvulsants such as Acetylpheneturide, Albutoin, tol. AloXidone, Aminoglutethimide, 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, DifenoXin, DiphenoXylate, Lidamidine, Chloride, IsopromethaZine, MequitaZine, Lomotil, Loperamide, Mebiquine, Trillium and UZarin. , PyrathiaZine and ThiaZinamium 32. Antidiuretics such as Desmopressin, Felypressin, Methyl Sulfate; and Lypressin, Ornipressin, OXycinchophen, Pituitary— others such as AZatadine, ClobenZepam, Posterior, Terlipressin and Vasopressin. , Deptropine, Isothipendyl, Lorata 33. Antiestrogens such as Delmadinone Acetate, dine and Prothipendyl; and EthamoXytriphetol, Tamoxifen and Toremifene. other antihistamines such as AntaZoline, AstemiZole, 34. drugs (antibiotics), including: AZelastine, CetoXime, ClemiZole, ClobenZtropine, Polyenes such as Amphotericin-B, Candicidin, DiphenaZoline, Diphenhydramine, Fluticasone Dermostatin, Filipin, Fungichromin, Hachimycin, Propionate, Mebhydroline, Phenindamine, Terfena , Lucensomycin, Mepartricin, , dine and Tritoqualine. , Pecilocin and Perimycin; and 40. Antihyperlipoproteinemics, including: others such as AZaserine, , Oligomycins, AryloXyalkanoic acid derivatives such as Beclorbrate, Neomycin Undecylenate, Pyrrolnitrin, Siccanin, Tuber BaZa?brate, Bini?brate, Cipro?brate, Clino?brate, cidin and Viridin. Clo?brate, Clo?bric Acid, Eton?brate, Feno?brate, 35. Antifungal drugs (synthetic), including: Gem?broZil, Nico?brate, Piri?brate, Roni?brate, Sim such as Nafti?ne and Terbina?ne; ?brate and Theo?brate; Bile acid sequesterants such as Cholestyramine Resin, such as , , Colestipol and PolideXide; Chlordantoin, , CloconaZole, , , EnilconaZole, , HMG CoA reductase inhibitors such as Fluvastatin, , , , Lovastatin, Pravastatin Sodium and Simvastatin; , , Nitrate, and Nicotinic acid derivatives Aluminum Nicotinate, ; AcipimoX, Niceritrol, Nicoclonate, Nicomol and such as , and Tercona OXiniacic Acid; Zole; and 25 Thyroid hormones and analogs such as EtiroXate, Thyro others such as Acrisorcin, Amorol?ne, Biphenamine, propic Acid and ThyroXine; and Bromosalicylchloranilide, Buclosamide, Calcium others such as Acifran, AZacosterol, Ben?uoreX, Propionate, Chlophenesin, , CloXyquin, a-BenZalbutyramide, Carnitine, Chondroitin Sulfate, Coparaf?nate, DiamthaZole, Dihydrochloride, Clomestone, DetaXtran, DeXtran Sulfate Sodium, 5,8, EXalamide, , HalethaZole, HeXetidine, 11,14,17-Eicosapentaenoic Acid, Eritadenine, Lo?ucarban, Nifuratel, , Propionic FuraZbol, Meglutol, Melinamide, Mytatrienediol, Acid, Pyrithione, Salicylanilide, Sodium Propionate, Ornithine, a-OryZanol, Pantethine, Penataerythritol Sulbentine, TenonitroZole, , Tolindate, Tetraacetate, a-Phenylbutyramide, PiroZadil, Probucol, , Tricetin, Ujothion, 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, DapipraZoke, Arylethanolamine derivatives such as Amosulalol, Dichlorphenamide, Dipivefrin, Epinephrine, Bufuralol, Dilevalol, Labetalol, Pronethalol, Sotalol , MethaZolamide, Metipranolol, Pilocarpine, and Sul?nalol; Pindolol and Timolol. AryloXypropanolamine derivatives such as Acebutolol, 37. Antigonadotropins such as DanaZol, Gestrinone and Alprenolol, Arotinolol, Atenolol, BetaXolol, ParoXypropione. Bevantolol, Bisoprolol, Bopindolol, Bunitrolol, 38. Antigout drugs such as Allopurinol, Carprofen, Bupranolol, Buto?lolol, CaraZolol, CarteZolol, Colchicine, Probenecid and Sul?npyraZone. Carvedilol, Celiprolol, Cetamolol, Epanolol, Indenolol, 39. Antihistamines, including: 45 Mepindolol, Metipranolol, Metoprolol, Moprolol, Alkylamine derivatives such as Acrivastine, Bamipine, Nadolol, Nipradilol, OXprenolol, Penbutolol, Pindolol, Brompheniramine, Chlorpheniramine, Dimethindene, Propranolol, Talinolol, Tetraolol, Timolol and Tolip Metron S, Pheniramine, Pyrrobutamine, Thenaldine, rolol; Tolpropamine and Triprolidine; BenZothiadiaZine derivatives such as AlthiaZide, Aminoalkyl ethers such as Bietanautine, Bendro?umethiaZide, BenZthiaZide, Bromodiphenhydramine, CarbinoXamine, Clemastine, BenZylhydrochlorothiaZide, ButhiaZide, Diphenlypyraline, DoXylamine, Embrammine, ChlorothiaZide, Chlorthalidone, CyclopenthiaZide, Medrylamine, Mephenphydramine, CyclothiaZide, DiaZoXide, EpithiaZide, EthiaZide, p-Methyldiphenhydramine, Orphenadrine, 55 FenquiZone, HydrochlorothiaZide, PhenyltoloXamine, Piprinhydrinate and Setasine; Hydro?umethiaZide, MethyclothiaZide, Meticrane, derivatives such as Alloclamide, MetolaZone, Para?utiZide, PolythiaZide, Tetrachlorme p-Bromtripelennamine, Chloropyramine, Chlorothen, and TrichlormethiaZide; Histapyrrodine, Methafurylene, Methaphenilene, N-Carboxyalkyl (peptide/lactam) derivatives such as Methapyrilene, PhenbenZamine, Pyrilamine, Talastine, Alacepril, Captopril, CilaZapril, Delapril, Enalapril, Thenyldiamine, ThonZylamine Hydrochloride, Tripe Enalaprilat, Fosinopril, Lisinopril, Moveltipril, lennamine and Zolamine; Perindopril, Quinapril and Ramipril; such as CetiriZine, ChlorcycliZine, Dihydropyridine derivatives such as Amlodipine, CinnariZine, ClociniZine and ; Felodipine, Isradipine, Nicardipine, Nifedipine, Tricyclics, including: 65 Nilvadipine, Nisoldipine and Nitrendipine; such as Ahistan, EtymemaZine, derivatives such as , Debrisoquin, FenethaZine, N-HydroXyethylpromethaZine GuanabenZ, Guanacline, , , US 6,638,528 B1 19 20 , Guanfacine, Guanochlor, Indoprofen, Ketoprofen, LoXoprofen, Miroprofen, and ; NaproXen, OXaproZin, Piketoprofen, Pirprofen, HydraZines and phthalaZines such as BudralaZine, Pranoprofen, ProtiZinic Acid, Suprofen and Tiaprofenic CadralaZine , DihydralaZine, EndralaZine, Acid; HydracarbaZine, HydralaZine, PhenipraZine, Pildrala PyraZoles such as DifenamiZole and EpiriZole; Zine and TodralaZine; PyraZolones such as ApaZone, BenZpiperylon, FepraZone, MofebutaZone, MoraZone, OXyphenbutaZone, ImidaZole derivatives such as Clonidine, , PhenybutaZone, PipebuZone, PropyphenaZone, , Phentolamine Mesylate, Tiamenidine RamifenaZone, SuXibuZone and ThiaZolinobutaZone; and ; derivatives such as Acetaminosalol, Quaternary ammonium compounds AZamethonium Aspirin, Benorylate, Bromosaligenin, Calcium Bromide, Chloride, , Acetylsalicylate, Di?unisal, Etersalate, Fendosal, Gen Pentacynium Bis(methyl sulfate), Pentamethonium tisic Acid, Glycol Salicylate, ImidaZole Salicylate, Bromide, Tartate, Phenactopinium Chlo Lysine Acetylsalicylate, Mesalamine, Morpholine ride and Trimethidiunum Methosulfate; 15 Salicylate, l-Naphthyl Salicylate, OlsalaZine, QuinaZoline derivatives such as , , Parsalmide, Phenyl Acetylsalicylate, Phenyl Salicylate, DoXaZosin, Prasosin, TeraZosin and TrimaZosin; Salacetamide, Salicylamine O-Acetic Acid, Salicylsul derivatives such as , , furic Acid, Salsalate and SulfasalaZine; , Reserpine and ; ThiaZinecarboXamides such as DroXicam, IsoXicam, Sulfonamide derivatives such as Ambuside, Clopamide, PiroXicam and TenoXicam; and Furosemide, Indapamide, QuinethaZone, Tripamide others such as a-Acetamidocaproic 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, Tannates, Eprosartan, 25 Nabumetone, Nimesulide, Orgotein, OXaceprol, , Flosequinan, Indoramin, Irbesartan, Paranyline, PerisoXal, PifoXime, ProquaZone, Prox , Losartan, Metbutamate, , and Tenidap. , Methyl 4-Pyridyl Ketone ThiosemicarbarZone, 46. Antimalarial drugs such as Acedapsone, Amodiaquin, MetolaZone, MinoXidil, MuZolimine, , , Arteether, Artemether, Artemisinin, Artesunate, Pinacidil, , Primaperone, Protoveratrines, Bebeerine, Berberine, Chirata, Chlorguanide, Raubasine, Rescimetol, Rilmenidene, Saralasin, Sodium Chloroquine, Chlorproguanil, Cinchona, Cinchonidine, Nitroprusside, Ticrynafen, Trimethaphan Camsylate, Cinchonine, Cycloguanil, Gentiopicrin, Halofantrine, Tyrosinase, and Valsartan. HydroXychloroquine, Me?oquine Hydrochloride, 42. Antihyperthyroids such as 2-Amino-4-methylthiaZole, 3-Methylarsacetin, Pamaquine, Plasmocid, Primaquine, 2-AminothiaZole, CarbimaZole, 3,5-Dibromo-L-, 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, ThibenZaZoline, Thiobarbital and Formate, Quinine Gluconate, Quinine Hydriodide, Qui 2-Thiouracil. nine Hydrochloride, Quinine Salicylate, Quinine Sulfate, 43. Antihypotensive drugs such as AmeZinium Methyl Quinine Tannate, Quinine Urea Hydrochloride, Sulfate, Angiotensin Amide, Dimetofrine, , Quinocide, Quinoline and Sodium Arsenate Diabasic. Etifelmin, Etilefrin, Gepefrine, Metaraminol, Midodrine, 47. Antimigraine drugs such as Alpiropride, Norepinephrine, Pholedrinead and Synephrine. , Eletriptan, Ergocornine, 44. Antihypothyroid drugs such as LevothyroXine Sodium, Ergocorninine, Ergocryptine, Ergot, , Liothyronine, Thyroid, Thyroidin, ThyroXine, Tiratricol 45 FlumedroXone acetate, FonaZine, , Methysergid and TSH. (e), Naratriptan, , PiZotyline, RiZatriptan and 45. Anti-In?ammatory (non-steroidal) drugs, including: Sumatriptan. 48. Antinauseant drugs such as Acetylleucine AminoarylcarboXylic acid derivatives such as Enfenamic Monoethanolamine, AliZapride, BenZquinamide, Acid, Etofenamate, Flufenamic Acid, IsoniXin, Bietanautine, Bromopride, BucliZine, , Meclofenamic Acid, Mefanamic Acid, Ni?umic Acid, Clebopride, CycliZine, Dimenhydrinate, Dipheniodol, Talni?umate, Terofenamate and Tolfenamic Acid; Domperidone, Granisetron, MecliZine, Methalltal, Arylacetic acid derivatives such as Acemetacin, Metoclopramide, MetopimaZine, Nabilone, Ondansteron, Alclofenac, Amfenac, BufeXamac, Cinmetacin, OXypendyl, PipamaZine, Piprinhydrinate, Clopirac, Diclofenac Sodium, Etodolac, Felbinac, 55 , 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, Tolmetin and Alkylating agents, including: Zomepirac; 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, Triethylenemelamine, BenoXaprofen, BucloXic Acid, Carprofen, Fenoprofen, Triethylenephosphoramide, Triethylenethiophos FlunoXaprofen, 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, , 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 Camptothecin, DacarbaZine, 56. AntiprotoZoal drugs (Leshmania) such as Antimony Mannomustine, Mitobronitol, Mitolactol and Pipo Sodium Gluconate, Ethylstibamine, broman; HydroXystilbamidine, N-Methylglucamine, , Antibiotics such as Aclacinomycins, Actinomycin F1, Stilbamidine and Urea Stibamine. Anthramycin, AZaserine, Bleomycins, 57. AntiprotoZoal drugs (Trichomonas) such as Acetarsone, Cactinomycin, Carubicin, CarZinophilin, 15 AminitroZole, Anisomycin, AZanidaZole, ForminitraZole, Chromomycins, Dactinomycin, Daunorubicin, FuraZolidone, Hachimycin, Lauroguadine, Mepartricin, 6-DiaZo-5-oXo-L-norleucine, 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, Por?romycin, Puromycin, BenZnidaZole, E?ornithine, Melarsoprol, NifurtimoX, Rufocromomycin, Streptonigrin, StreptoZocin, OXophenarsine, 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; 25 Dichlorisone, Glycine, Halometasone, Purine analogs such as Fludarabine , 3-HydroXycamphor, Menthol, Mesulphen, MethdilaZine, 6-Mercaptopurine, Thiamiprine and Thiogua Phenol, Polidocanol, Risocaine, Spirit of Camphor, naine; and Thenaldine, Tolpropamine and TrimepraZine. Pyrimidine analogs such as Ancitabine, AZacitidine, 60. Antipsoriatic drugs such as Acitretin, Ammonium 6-AZauridine, Carmofur, Cytarabine, Salicylate, Anthralin, 6-AZauridine, Bergapten(e), DoXi?uridine, 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, , , Bisantrene, Bryostatin 1, Carboplatin, Cisplatin, 35 Moperone, , Sniperone, Timiperone and Defofamide , Demecolcine, DiaZiquone, Tri?uperidol; Dolastatins, Elfornithine, Elliptinium Acetate, PhenothiaZines such as , , Etoglucid, Etoposide , Gallium Nitrate , CarphenaZine, ChlorproethaZine, ChlorpromaZine, HydroXyurea, Interferon-a, Interferon-a, ClospiraZine, , DiXyraZine, Interferon-a, Interleukine-2, Lentinan, LetroZole, , ImiclopaZine, MepaZine, , Lonidamine, MitoguaZone, MitoXantrone, MethoXypromaZine, MetofenaZate, OXa?umaZine, Mopidamol, Nitracrine, Pentostatin, Phenamet, , PericyaZine, PerimethaZine, , Pirarubicin, Podophyllinicc Acid, PiperacetaZine, , ProchlorperaZine, 2-EthythydraZide, Polynitrocubanes, , , , Procarb aZine, PSK7, RaZoXane, SiZo?ran, 45 , Tri?uoperaZine and Tri?upromaZine; Spirogermanium, Symplostatin 1 , TaXol, such as , , Teniposide, TenuaZonic Acid, TriaZiquone, and Thiothixene; 2.2‘.2 “ -Trichlorotriethylamine , Urethan, other tricyclics such as BenZquinamide, , Vinblastine, Vincristine, Vindesine and Vinorel , Clomacran, Clothiapine, , bine. Opipramol, Prothipendyl, TetrabenaZine, and 50. Antineoplastic (hormonal) drugs, including: ; and Androgens such as Calusterone, Dromostanolone others such as AliZapride, Amisulpride, Buramate, Propionate, Epitiostanol, Mepitiostane and Testolac Fluspirilene, Molindone, Pen?uridol, 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. Calcium Acetysalicylate, ChlorthenoXaZin(e), Choline 52. Antiparkinsonian drugs such as Am antadine, Salicylate, Clidanac, DihydroXyaluminum , BenseraZide, Bietanautine, Biperiden, Acetylsalicylate, Dipyrocetyl, Dipyrone, EpiriZole, , Budipine, , Carbidopa, Etersalate, ImidaZole Salicylate, Indomethacin, Deprenyl (a/k/a L-deprenyl, L-deprenil, L-deprenaline IsofeZolac, p-Lactophenetide, Lysine Acetylsalicylate, and selegiline), DeXetimide, DiethaZine, 65 Magnesium Acetylsalicylate, Meclofenamic Acid, Diphenhydramine, , Ethoprop aZine, MoraZone, Morpholine Salicylate, NaproXen, EthylbenZhydramine, Levodopa, NaXagolide, , NifenaZone, 5‘-Nitro-2‘-propoXyacetanilide, Phenacetin, US 6,638,528 B1 23 24 PhenicarbaZide, Phenocoll, PhenopyraZone, Phenyl Hydrochloride, Phloroglucinol, Pinaverium Bromide, Acetylsalicylate, Phenyl Salicylate, PipebuZone, Piperilate, PipoXolan Hydrochloride, Pramiverin, Pri Propacetamol, PropyphenaZone, RamifenaZone, ?nium 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-lTrimethyl-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 Sul?des and TioXolone. CilostaZol, Chrysoptin, Daltroban, De?brotide, 65. Antiseptics, including: EnoXaparin, FraXiparine7, Indobufen, Lamoparan, such as AleXidine, AmbaZone, ChlorheXidine OZagrel, Picotamide, Pla?bride, Reviparin, Tedelparin, and PicloXydine; Ticlopidine, Tri?usal 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, Clo?ucarban, 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 LevopropoXyphene, Morclofone, Narceine, Sul?de, 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, a-Acetamidocaproic Acid Zinc Salt, nitrofuran, NidroXyZone, 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, Fenticlor, HeXachlorophene, l-Napthyl Salicylate, 2-Napthyl Pifarnine, PirenZepine, Plaunotol, Ranitidine, Rioprostil, 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, ChloroXine, Chlorquinaldol, 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 hydroXybutyric Acid, Boric Acid, ChlorheXidine, EdoXudine, FloXuridine, Ganciclovir, IdoXuridine, ChloroaZodin, m-Cresyl Acetate, Cupric Sulfate, Inosine PranobeX, MADU, Penciclovir, Tri?uridine, Dibromopropamidine, Ichthammol, Negatol7, Vidrarbine and Zidovudiine; 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 ThiosemicarbZone, Foscarnet Sodium, Sulfate, Bietamiverine, Butaverine, Butropium Bromide, Imiquimod, Interferon-a, Interferon-a, Interferon-a, N-Butylscopolammonium Bromide, Caroverine, KethoXal, LysoZyme, MethisaZone, MoroXydine, Cimetropium Bromide, , Clebopride, Coni PodophyllotoXin, Ribavirin, Rimantadine, Stallimycin, ine Hydrobromide, Coniine Hydrochloride, Cyclonium Statolon, Tromantadine and XenaZoic Acid. Iodide, Difemerine, Diisopromine, DioXaphetyl Butyrate, 73. AnXiolytic drugs, including: Diponium Bromide, Drofenine, Emepronium Bromide, ArylpiperaZines such as , , 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, Hymecromone, 65 ClobaZam, CloraZepate, ChotiaZepam, CloXaZolam, Leiopyrrole, Mebeverine, MoXaverine, Na?verine, DiaZepam, Ethyl Lo?aZepate, EtiZolam, FluidaZepam, Octamylamine, Octaverine, Pentapiperide, Phenamacide FlutaZolam, FlutopraZepam, HalaZepam, KetaZolam,