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US 2002000.4065A1 (19) (12) Patent Application Publication (10) Pub. No.: US 2002/0004065 A1 Kanios (43) Pub. Date: Jan. 10, 2002

(54) COMPOSITIONS AND METHODS TO Related U.S. Application Data EFFECT THE RELEASE PROFILE IN THE TRANSIDERMALADMINISTRATION OF (63) Non-provisional of provisional application No. ACTIVE AGENTS 60/177,103, filed on Jan. 20, 2000. (76) Inventor: David Kanios, Miami, FL (US) Publication Classification (51) Int. Cl...... A61K 9/70 (52) U.S. Cl...... 424/449 Correspondence Address: Noven Pharmaceuticals, Inc. (57) ABSTRACT 11960 S.W. 144th Street Compositions and methods for the transdermal delivery of Miami, FL 33186 (US) active agents up to a period of Seven days or more at Substantially a Zero-order release rate comprising a pharma (21) Appl. No.: 09/765,932 ceutically acceptable adhesive matrix and a polymeric plas tic material that provides a release rate regulating effect on (22) Filed: Jan. 19, 2001 the active agents. Patent Application Pu blication Jan. 10, 2002 Sheet 1 of 6 US 2002/0004065 A1

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COMPOSITIONS AND METHODS TO EFFECT user, employ a permeable adhesive layer (often referred THE RELEASE PROFILE IN THE TRANSIDERMAL to as an “in-line adhesive' Since the drug must pass ADMINISTRATION OF ACTIVE AGENTS through), applied over the drug matrix carrier layer. In an attempt to better control the release rate of the drug, Such FIELD OF INVENTION devices often employ one or more additional drug permeable 0001. This invention relates generally to transdermal layerS Such as rate controlling membranes, or containing drug delivery Systems, and more particularly to pharmaceu excipients, Such as drug delivery enhancers. Hence, Such tically acceptable adhesive matrix compositions, that use devices are also commonly referred to as multilayer or polymeric materials, in particular insoluble cellulose multilaminate. derivatives Such as ethyl celluloses, to regulate the drug 0008. In a “monolithic or monolayer” matrix-type device, release profile. The invention additionally relates to trans the active agent is typically Solubilized or homogenously dermal drug delivery Systems providing Substantially Zero blended in an adhesive carrier composition, typically a order drug release profiles for an extended period of time of preSSure-Sensitive adhesive or bioadhesive, which functions up to Seven days or longer. as both the drug carrier and the means of affixing the System to the skin or mucosa. Such devices, commonly referred to BACKGROUND OF THE INVENTION as drug-in-adhesive devices, are described, for example, in U.S. Pat. Nos. 4,994,267, 5,446,070, 5,474,783 and 5,656, 0002 The use of transdermal drug delivery systems as a 286, all of which are assigned to Noven Pharmaceuticals, means to topically administer an active agent is well known. Inc., Miami, Fla. Such Systems incorporate the active agent into a carrier composition, Such as a polymeric and/or pressure-Sensitive 0009 While matrix-type devices, especially drug-in-ad adhesive composition, from which the active agent is deliv hesive devices, have achieved more uniform and controlled ered through the Skin or mucosa of the user. drug deliver rates, and for longer periods of time, most transdermal Systems remain Subject to a higher initial drug 0003. In general, transdermal drug delivery systems are release than is required to achieve therapeutic . For either reservoir-type or matrix-type devices. Both types of many and/or therapeutic Situations, it would be advan devices employ a backing layer that forms the protective tageous to eliminate or Suppress this higher initial release outer Surface of the finished transdermal System and which and achieve a "steady state” (Zero order) release profile is exposed to the environment during use, and a release liner which uniformly delivers a therapeutically effective amount or protective layer that forms the inner Surface and which of drug over the extended duration of device's desired use. covers whatever adhesive means is employed for affixing the System to the Skin or mucosa of a user. The release liner or 0010 For example, the high initial release of certain protective layer is removed prior to application, eXposing drugs may cause adverse or undesired effects, or create the adhesive means, which is typically a pressure-Sensitive concerns, thereby foreclosing the use of transdermal administration. In other instances, the higher initial release adhesive. may reduce the amount of drug required for treatment to the 0004. In the “classic' reservoir-type device, the active point of risking underdosing, or may make it impractical to agent is usually dissolved or dispersed in a carrier that try and increase the duration of the device's application typically yields a non-finite carrier form, like a fluid or gel, while retaining therapeutic effectiveness. The ability to and which is kept Separate from the adhesive means used to reduce the frequency of replacing the transdermal drug affix the device to the user. The device has a pocket or delivery System would concomitantly increase user compli “reservoir” which physically serves to hold the active agent ance, reduce any lag or drop off in efficacious levels, and carrier, and which is formed in or by the backing layer and reduce the amount of drug required for treatment (also itself. A peripheral adhesive layer is then used to affix the provided by reducing the higher initial blood level associ device to the user. The early reservoir-type devices incor ated with the higher release rate). porated drugs which were readily absorbed through the skin 0011. Therefore, despite the existence of many different like nitroglycerin and . types of transdermal delivery Systems in the art, there 0005 Such devices have a number of disadvantages remains a continuing need for improving the release profile including a non-uniform drug release profile wherein a high of drugs to achieve Substantially Zero order, as well as dose of drug is released initially upon application to the user, extending the duration of use of each transdermal System. often described as a “burst effect.” This burst or high initial 0012 U.S. patent Ser. No. 07/897.269 discloses the use release of drug then drops off after a period of time to a rate of glycerin to counteract the burst effect of drugs in trans that is less than is able to achieve a therapeutically effective dermal formulations. amount. Drug delivery according to this profile is described as first order release. 0013. It has now been found that the addition of certain polymeric plastic polymers, in particular insoluble cellulose 0006 While such classic devices are still in use today, the derivatives Such as ethyl celluloses, into a pressure-Sensitive term reservoir is being used interchangeably with matrix adhesive matrix composition, eliminates or Suppresses the type devices which Still rely upon a Separate adhesive means initial high release rate of a drug Subject to a first order used to affix the device to the user. release rate profile Such that the System achieves Substan 0007. In a matrix-type device, the active agent is dis tially Zero order release, and is able to maintain a Substan Solved or dispersed in a carrier that typically yields a finite tially Zero order release profile for an extended period of carrier form, which can be Self-adhesive or non-adhesive. time up to Seven days or longer. Non-adhesive matrix-type devices, that is, those which still 0014. Although not wishing to be bound by theory, rely upon a separate adhesive means to affix the device to the particularly in this case where the Structure of the compo US 2002/0004O65 A1 Jan. 10, 2002

Sition has not been analyzed, it is postulated that the 0021. It is another object of the invention to provide an insoluble polymeric plastic material affects the uptake/ab adhesive matrix-type transdermal drug delivery System Sorption of water or moisture from the application Site into which achieves a Substantially Zero-order release profile of the matrix composition which would otherwise create Some the active agent by incorporating a polymeric plastic mate of the kinetic driving force for release of the drug. This rial into an adhesive drug matrix. appears especially significant in the presence of hydrophobic 0022. It is still another object of the invention to achieve drugs and/or in conjunction with the use of hydrophilic a Substantially Zero-order release profile of the active agent crystallization inhibitors, Such as polyvinylpyrrolidones. for an extended period of time of up to Seven days or longer, 0.015 Ethyl celluloses have been extensively used in and effectively continue to deliver the active agent in a industrial applications since their commercial introduction therapeutically effective amount. in the mid-1930s. They are recognized and widely used as 0023. It is a further object of the invention to provide a well for many different purposes in pharmaceutical appli method of eliminating or Suppressing the high initial release cations, especially in conjunction with water-Sensitive ingre or burst of active agent from an adhesive matrix type dients. Ethyl celluloses are most frequently used as binders, transdermal drug delivery System containing a drug Subject fillers, fixatives, controlled release coatingS/barriers in microencapsulation and other dosage forms, particu to a first order release profile. larly multiparticulate Systems, granulation aids, film 0024. It is yet another object of the invention to provide formers and taste maskers. a transdermal drug delivery System that can deliver an active agent at Substantially Zero-order for an extended period of 0016. The prior art generally discloses the use of time in excess of 72 hours and up to Seven days or more insoluble polymerS Such as ethyl cellulose as optional com without Substantially increasing the Surface area of the ponents in transdermal Systems as thickening agents and as transdermal delivery System. cohesiveness Strengthening agents which effect the carrier's adhesive properties. For example, U.S. Pat. No. 5,232,702 discloses the use of a variety of Substances that include ethyl BRIEF DESCRIPTION OF DRAWINGS cellulose and polyvinyl as cohesive Strengthening 0025 FIG. 1 is a schematic illustration of a matrix-type agents (reducing flow properties of Silicone adhesives) in a transdermal drug delivery System of the present invention. transdermal delivery System. 0026 FIG. 2 is a graphical representation comparing the 0.017. The present invention is able to regulate the release in vitro flux rate of and norethindrone profile of the drug in a transdermal System without modi through cadaver skin from a pressure-sensitive adhesive fying the adhesive properties of the pressure-Sensitive adhe matrix composition of the present invention with the flux Sive matrix So that the transdermal System possesses the rate for a composition of the prior art. required degree of adhesion and tackiness to remain affixed to the site of application for extended periods of time, which 0027 FIG. 3 is a graphical representation of the in vitro can be Seven days or more, but at the same time can be easily first order flux rate of estradiol through cadaver Skin from a removed as required. transdermal drug delivery System of the prior art as com pared to the in Vitro Steady State flux rate of estradiol through 0.018. The prior art further generally discloses the use of cadaver Skin from an transdermal drug delivery System of insoluble polymers in transdermal Systems as the non the present invention. adhesive matrix carrier itself, and even as a "Suitable adhe sive” for the matrix carrier itself (but which presumably 0028 FIG. 4 is a graphical representation of the in vitro includes the addition of a plasticizer or tackifier, or plasti flux rates of estradiol through cadaver skin from two pres cizing liquid drug like nicotine, to create StickineSS Since Sure-Sensitive adhesive matrix compositions of the present Such polymers are not adhesives). For example, U.S. Pat. invention using various amounts of ethyl cellulose as com No. 6,010,715 discloses the use of thermoplastic polymers pared to the in vitro flux rate of estradiol from a pressure that are melt-blended with active agents and enhancers that Sensitive adhesive matrix composition without ethyl cellu are heat Stable at the melt temperature of the polymer. The lose. melt-blend can then be thermoformed into carrier layers 0029 FIG. 5 is a graphical representation of the in vitro without the use of common to produce a controlled flux rates of estradiol through cadaver skin from pressure release layer in a transdermal drug delivery System. Cellu Sensitive adhesive matrix compositions of the present inven lose derivatives Such as ethyl cellulose are generally dis tion comparing the effect of varying amounts of ethyl closed as "suitable adhesives” for use as the matrix. cellulose with varying amounts of estradiol. 0019 U.S. Pat. No. 5,904,931 discloses the use of ethyl 0030 FIG. 6 is a graphical representation of the in vitro cellulose as a crystallization inhibitor in a transdermal drug flux rates of estradiol and norethindrone acetate through delivery System. Cellulose and polyvinyl compounds cadaver Skin from pressure-Sensitive adhesive matrix com are generally described as additional matrix additives. positions comparing the effect of using a combination of ethyl cellulose and cellulose acetate butyrate versus either SUMMARY OF THE INVENTION polymer alone.

0020. It is therefore an objective of the present objective DETAILED DESCRIPTION OF THE to provide for methods and pharmaceutically acceptable INVENTION flexible, finite compositions and Systems for the transdermal administration of active agents that achieve a Substantially 0031. The foregoing and other objects are achieved by Zero-order release profile when applied to a user. this invention which provides a transdermal drug delivery US 2002/0004O65 A1 Jan. 10, 2002

System wherein the use of a polymeric plastic material acrylonitriles, and mixtures, combinations and multipoly provides a release rate regulating effect on the active agents mers (copolymers, terpolymers, etc.) thereof. incorporated into the adhesive matrix composition. 0043. In preferred embodiments, the polymeric plastic 0.032 Unless defined otherwise, all technical and scien material is a cellulose derivative. Preferred are cellulose tific terms used herein have the same meaning as commonly Such as cellulose including cellulose acetate, understood by one of ordinary skill in the art to which the cellulose acetate butyrate, cellulose acetate , cellu invention pertains. lose acetate propionate, and cellulose . 0033. The term “topical” or “topically” is used herein in 0044 Copending provisional application, Ser. No. its conventional meaning as referring to direct contact with 60/137.827, describes the use of cellulose derivatives, par an anatomical Site or Surface area on a mammal including ticularly cellulose esters, as drug enhancers in skin, teeth, nails and mucosa. matrix carrier compositions. 0034. The term “mucosa” as used herein means any moist 0045 Particularly preferred cellulose ethers are ethyl anatomical membrane or Surface on a mammal Such as oral, cellulose polymers. Ethyl cellulose polymers can be manu buccal, vaginal, rectal, nasal or ophthalmic Surfaces. factured in a variety of molecular weights, which translates 0035. The term “transdermal” as used herein means pas into a range of Viscosities when in . In practicing the Sage into and/or through skin or mucosa for localized or Subject invention, it has been found that Solution Viscosities Systemic delivery of an active agent. ranging from about 3 centipoise to about 49 centipoise are preferred, and more preferably from about 6 centipoise to 0036) The term “solubilized” is intended to mean that in about 40 centipoise, and optimally from about 6 centipoise the carrier composition there is an intimate dispersion or to about 22 centipoise (viscosities are for 5% , in dissolution of the active agent at the crystalline, molecular 80% and 20% , measured at 25 C. in an or ionic level. AS Such, the active agent is considered herein Ubbelohde viscometer). Ethyl cellulose polymers having to be in “non-crystallized' form when in the compositions of Such Solution viscosities exhibit temperatures the present invention. in the range of about 165° C. to about 200° C. Suitable ethyl cellulose polymers are commercially available and include 0037. As used herein, the term “flux” is defined as the those sold under the trademark ETHOCEL(R) by the Dow absorption of the drug through the Skin or mucosa, and is Chemical Company, Midland, Mich. Preferred ETHOCEL(R) described by Fick's first law of diffusion: polymers are ETHOCEL(R) Standard 7, 10, 14 and 20, Premium or Industrial grades. 0038. Where J is the flux in g/cm/sec, D is the diffusion 0046. A crystallization inhibitor or solubility enhancer coefficient of the drug through the skin or mucosa in cm/sec may also be employed in the invention, for example poly and Dcm/dx is the concentration gradient of the drug acroSS Vinylpyrrolidone polymers, polyethylene oxide, polyacrylic the skin or mucosa. acid, polyvinyl alcohol, Silicone dioxide, Silica, celluloses 0.039 The phrase “pharmaceutically acceptable flexible, and cellulose derivatives Such as hydroxymethyl cellulose, finite” is intended to mean a solid form capable of conform hydroxypropyl cellulose, gelatins, , Starches, dextrins ing to a Surface to which it is applied, and which is capable and dextrans, Sterols, acids and other absorptive agents of maintaining the contact in Such Solid form So as to that possess the capability to absorb and hold water or facilitate topical application without adverse physiological moisture. response, and without being appreciably decomposed by 0047 Particularly preferred compounds are PVPs. The aqueous contact during use by a Subject. term “polyvinylpyrrolidone” or “PVP" refers to a polymer, ether a homopolymer or copolymer, containing Vinylpyr 0040. The term “user” or “subject” is intended to include rolidone (also referred to as N-vinylpyrrolidone, N-vinyl-2- all warm-blooded mammals, preferably humans. pyrrolidone and N-Vinyl-2-pyrrolidinone) as a monomeric 0041. The phrase “substantially zero-order” as used unit. PVP polymers include soluble and insoluble herein means transdermal delivery of an active agent at a homopolymeric PVPs, and copolymers such as vinylpyrroli release rate which is approximately constant once Steady done/vinyl acetate and vinylpyrrollidone/dimethylamino State is attained, typically within 12 to 24 hours after topical ethylmethacrylate. The cross-linked hompolymer (Such as application. While variability in blood levels of active agent KOLLIDONGR CL from BASF) is insoluble and is generally are contemplated within the Scope of this meaning once known in the pharmaceutical industry under the designations Steady State release is attained, the depletion rate of active polyvinylpolypyrrolidone, crospovidone and PVP. The agent over the duration of use should typically not exceed copolymer Vinylpyrrolidone-Vinyl acetate is generally about 20% to about 25%. known in the pharmaceutical industry under the designations 0.042 Any polymeric plastic material may be employed Copolyvidon (e), Copolyvidonum or VP-VAc. for the present invention provided it is insoluble or substan 0048 Particularly preferred PVPs are soluble. The term tially insoluble in water, and includes cellulose derivatives “Soluble” when used with reference to PVP means that the Such as cellulose acetates, (cellulose acetate butyrate, cel polymer is Soluble in water and generally is not Substantially lulose acetate propionate, cellulose acetate phthalate, etc.), croSS-linked, and has a molecular weight of less than about methyl, ethyl and propyl celluloses, polycarbonates, poly 2,000,000. See, generally, Bihler, KOLLIDONGR): POLYVI Styrenes, alkylacrylates Such as polymethyl methacrylate, NYLPRYRROLIDONE FOR THE PHARMACEUTICAL polyethyl ethacrylate, polyethylene methacrylate and other INDUSTRY, BASF Aktiengesellschaft (1992). Soluble PVP lower alkyl acrylates, Vinyl polymers, polyurethanes, poly polymers have been identified in the pharmaceutical indus US 2002/0004O65 A1 Jan. 10, 2002 try under a variety of names, the most commonly used non-occlusive backing material (i.e., permeable to water include Povidone, Polyvidon (e), Polyvidonum, poly (N-vi vapor and/or oxygen) is used, then the transdermal System nyl-2- pyrrolidinone, poly (N-vinylbutyrolactam), poly may be applied for periods longer than Seven days without (1-vinyl-2-pyrrolidinone, poly 1-(2-oxo-1 pyrrolidinyl)eth adverse effects occurring, if at all, until a much later time. ylene. While delivery of drug by the present invention is preferred 0049. The amount and type of PVP required in the for at least a Seven-day continuous application, the trans preferred embodiments will depend on the quantity and type dermal System may be used discontinuously (i.e., replaced at of drug present in the adhesive matrix composition, as well any time during rather than at the end of the intended as the type of adhesives, but can be readily determined duration of use) Since the drug release profile is Substantially through routine experimentation. Zero order. 0050 Typically, the PVP is present in an amount from 0056 The term “active agent” (and its equivalents about 5% to about 50% by weight, preferably from about “agent,”“drug."medicament” and “pharmaceutical”) is 10% to about 40% by weight based on the dry weight of the intended to have the broadest meaning and includes at least total adhesive matrix composition. However, the amount of one of any therapeutic, prophylactic, pharmacological or PVP can be higher than 20% for example, up to 40%, physiological active Substance, cosmetic and personal care depending on the particular drug used and on the desired preparations, and mixtures thereof, which is delivered to a mammal to produce a desired, usually beneficial, effect. properties of the matrix blend. More specifically, any active agent that is capable of pro 0051 Said PVP preferably has a molecular weight of ducing a pharmacological response, localized or Systemic, about 2,000 to 2,000,000, more preferably 5,000 to 100,000, irrespective of whether therapeutic, diagnostic, cosmetic or and most preferably 7,000 to 54,000. PVP having a molecu prophylactic in nature, is within the contemplation of the lar weight of about 1,000,000 to about 1,500,000 is also invention. It should be noted that the active agents can be preferred. used singularly or in combinations and mixtures. 0.052 PVPs are sold to the pharmaceutical industry under 0057 There is no limitation on the type of active agent the trademarks KOLLIDON by BASF (Parsippanny, N.J.); that can be used in this invention. However, active agents PLASDONE, POLYPLASDONE and COPOLYMER 958 that are Solid or crystalline at room temperature are preferred by ISP Technologies, Wayne, N.J. Preferred PVPs are KOL over liquid drugs, especially nicotine. Moreover, drug forms LIDON 12PF, 17PF, 25, 30, 90 and VA-64. other than the free base form are also preferred. 0053 Particularly preferred embodiments of the inven 0.058. The active agents contained in the adhesive matrix tion include soluble PVP in a polyacrylate and polysiloxane composition can be in different forms Such as pharmaceu preSSure-Sensitive adhesive matrix blend. tically acceptable , bases, esters, or pro-drugs, or 0.054 The amount and type of polymeric plastic material may be modified by appending one or more appropriate required in the practice of the invention will depend on the functionalities to enhance Selected physical or biological one or more additional materials used in the adhesive matrix properties, for example as neutral molecules, components of composition, and on the amount and type of active agent(s). molecular complexes or free bases to improve Solubility or Generally, the amount of polymeric plastic material to be release characteristics, or as pharmaceutically acceptable used is an amount Sufficient to deliver a therapeutically ethers, esters, amides and the like which have desirable effective amount of the active agent at a Substantially retention and release characteristics but which are easily Zero-order kinetic rate of delivery for an extended period of metabolized at body pH. time of at least three days and up to Seven days or longer, and 0059 Compounds may be converted into pharmaceuti to eliminate or Suppress the high initial release rate of a drug cally acceptable Salts, and the Salts may be converted into Subject to a first order release profile. Typically, the amount pharmaceutically acceptable free compound using Standard of polymeric plastic material to be used ranges from about procedures known to those skilled in the art of Synthetic 0.5% to about 30%, preferably from about 2.5% to 20%, and organic chemistry and described, for example, by J. March, more preferably from about 5.0% to 15% by weight based Advanced Organic Chemistry. Reactions, Mechanisms and on the dry weight of the total adhesive matrix composition. Structure, 4" Ed. (New York: Wiley-Interscience, 1992). Amounts greater than 30% typically result in loss of adhe Acid addition Salts are prepared from the free base (e.g., Sive properties necessary to maintain the System topically compounds having a neutral -NH2 or cyclic group) for an extended period of time. using conventional means, involving reaction with a Suitable 0.055 The adhesive matrix compositions of the present acid. An acid addition may be converted to the free base invention are designed to effectively deliver an active agent by treatment with a suitable base. Basic salts of acid in a therapeutically effective amount for an extended period moieties which may be present (e.g., carboxylic acid groups) of time up to Seven days or longer. AS used herein, “thera can be prepared in a similar manner using pharmaceutically peutically effective” means an amount of an active agent that acceptable inorganic or organic bases. Compounds may also is Sufficient to achieve the desired local or Systemic effect or be converted into pharmaceutically acceptable esters. Suit result, Such as to prevent, cure, diagnose, mitigate or treat a able esters include branched or unbranched, Saturated or or condition, when applied topically over the dura unsaturated C to C alky esters, for example, methyl, ethyl tion of intended use. Seven days is generally the preferred and Vinyl esters. Preparation of esters involves functional maximum duration for application of a transdermal drug ization of hydroxyl and/or carboxyl groups which may be delivery System of the present invention because the Site of present. Pharmaceutically acceptable esters may be prepared application is typically adversely affected when occluded for using methods known to those skilled in the art and/or a period of time greater than Seven days. However, if a described in the pertinent literature. Esters can be recon US 2002/0004O65 A1 Jan. 10, 2002

verted to the free acids, if desired, by using conventional norethindrone acetate (NETA) in a polyacrylate/polysilox hydrogenolysis or hydrolysis procedures. Preparation of ane adhesive blend with 10% PVP, Formula 4 comprising amides and pro-drugs can be performed in an analogous 5.0% ethyl cellulose and 5.0% cellulose acetate butyrate C. demonstrated an improved release profile as compared to 0060 and hormonal active agents (including either Formula 1 (only 10% PVP), Formula 2 (5.0% ethyl both natural, Semi-Synthetic and Synthetic compounds and cellulose) or Formula 3 (5.0% cellulose acetate butyrate). their derivatives having Steroidal or hormonal activity) are The foregoing formulas were prepared using the method of preferred and include, for example, (a) Such as Example 1 to yield the following ingredient concentrations Colpormon, , Estradiol (17B- and Cl-) set forth in tabular form in TABLE I. and its Esters (e.g., Acetate, Benzoate, Cypionate, Dipropi onate Diacetate, Enanthate, Estradiol-16,17-Hemisuccinate, TABLE I Undececenoate, Undecylate and Valerate), , , Formula Ethinyl Estradiol, , , , Methyl 1. Formula 2 Formula 3 Formula 4 Estradiol, , Mytatrienediol, Quinestradiol, Polysiloxane 71.3 6O.O 6O.O 55.0 , , Clomifen, Chlorotrianisen, and Adhesive ; (b) progestagenically effective Such as (BIO-PSA (R) 7-4603) , , Acetate, Delma Polyacrylate O.O 5.0 5.0 5.0 dinone Acetate, , , 3-Keto Adhesive (DURO-TAK (R87-2287) DeSogeStrel, , , EthinyleStre Polyacrylate 5.0 O.O O.O O.O nol, , Ethynodiol (and Diacetate), Flurogestone Adhesive Acetate, , , Haloprogester (Gelva (R) 737) one, (17-Hydroxy- and 17-Acetate-) 16-Methylene-Proges Ethyl Cellulose O.O 5.0 O.O 5.0 (Ethocel(R) 10) terone, 17O-Hydroxyprogesterone (Acetate and Caproate), Cellulose Acetate O.O O.O 5.0 5.0 , , , MedroX Butyrate yprogesterone (and Acetate), Acetate, (CAB-381-0.5) Polyvinylpyrrolidone 1O.O 1O.O 1.O.O 1O.O , Norethindrone (Acetate and Enanthate), KOLLIDON (R 30) , Norethynodrel, , Norgesti Oleic Acid 6.O O.O O.O O.O mate, , , 19-Norprogesterone, Dipropylene Glycol 4.0 9.O 9.O 9.O , , , Promege Oleyl Alcohol O.O 6.O 6.O 6.O Stone, and ; and (c) androgeni Estradiol O.7 1.O 1.O 1.O cally effective hormones Such as , , Norethindrone 3.0 4.0 4.0 4.0 , , , Acetate , , , Methandros tenolone, , 17C.-Methyltesteosterone, 0064. Other specific drugs for which the invention can be 17C.-Methyltestosterone 3-Cyclopentyl Enol Ether, Nore particularly usefully employed include: thandrolone, , , Oxymester one, , , Stanlolone, , 0065 1. C.-Adrenergic such as , Adre (Acetate, Enanthate, Isobutyrate, Propionate nolone, , Apraclonidine, Budralazine, Cloni and Undecanoate), Testosterone 17- Hemiacetal, dine, , , Dimetofrine, Dipiv Testosterone 17f8-Cypionate and . efrin, , Epinephrine, Fenoxazoline, Guanabenz, , Hydroxyamphetamine, , Indanazo 0061 The adhesive matrix composition of the invention line, , , , Meth preferably contains 17 B-estradiol or ethinyl estradiol as the oxamine Hydrochloride, Methylhexaneamine, Metizolene, alone, or in combination with, Norethindrone Midodrine, Naphazoline, , , (Acetate and Enanthate) or Norethisterone, as the proge , , Oxymetazoline, Stagen, and mixtures thereof. Hydrochloride, Hydrochloride, Phe 0.062. In embodiments containing combinations and mix nylpropylmethylamine, , , Pseu tures of estrogens and progeStagens, the use of combinations doephedrine, Rilmenidine, , Tetrahydrozoline, and mixtures of cellulose derivatives, particularly cellulose Tiamenidine, TramaZoline, , Tymazoline, esters and ethers, provide improved drug release profiles for and Xylometazoline. an extended period of time as compared to an adhesive matrix composition containing either one alone or none. 0066 2. B-Adrenergic agonists such as Albuterol, Bam Preferred combinations or mixtures of cellulose esters and buterol, Bitolterol, Carbuterol, , Clorprenaline, ethers are ethyl cellulose with cellulose acetate butyrate or , Dioxethedrine, , Ephedrine, Epi with cellulose acetate propionate. When used in combina nephrine, , Ethylnorepinephrine, Fenoterol, For tions and mixtures, the amount of each Such polymer typi moterol, HeXoprenaline, Ibopamine, Isoetharine, Isoproter cally ranges from about 2.5% to about 10% by weight based enal, Mabuterol, Metaproterenol, , on the dry weight of the total adhesive matrix composition. , Pirbuterol, Prenalterol, Procaterol, Protokylol, Particularly preferred embodiments of such mixtures and Reproterol, Rimiterol, Ritodrine, Soterenol, Terbuterol and combinations include soluble PVP, and typically in an Xamoterol. amount of about 5% to about 15% by weight based on the 0067 3. C.-Adrenergic blockers such as Amosulalol, Aro dry weight of the total adhesive matrix composition. tinolol, , , MeSylates, Fen 0.063 As shown in FIG. 6, in pressure-sensitive adhesive Spiride, Indoramin, Labetalol, , , Tera matrix compositions containing both 173-estradiol (E) and Zosin, , and . US 2002/0004O65 A1 Jan. 10, 2002

0068 4. B-Adrenergic blockers such as Acebutolol, cetyl, Dipyrone, EmorfaZone, Enfenamic Acid, Epirizole, Alprenolol, AmoSulalol, Arotinolol, Atenolol, Befunolol, EterSalate, , Ethoxazene, , Felbinac, Betaxolol, Bevantolol, Bisoprolol, Bopindolol, Bucumolol, Fenoprofen, Floctafenine, , Fluoresone, Befetolol, Bufuralol, Bunitrolol, Bupranolol, , FluproduaZone, , Fosfosal, Gentisic Hydrochloride, Butofilolol, Carazolol, Carteolol, Acid, , Ibufenac, Salicylate, Indometha , Celiprolol, Cetamolol, Cloranolol, Dilevalol, cin, Indoprofen, IsofeZolac, Isoladol, Isonixin, , Epanolol, Esmolol, Indenolol, Labetalol, Levobunolol, , p-Lactophenetide, , Loxoprofen, Mepindolol, Metipranalol, Metoprolol, Moprolol, Nadox Lysine Acetylsalicylate, Acetylsalicylate, Meth olol, Nifenalol, Nipradillol, Oxprenolol, Penbutolol, Pin otrimeprazine, , Miroprofen, , Mor dolol, Practolol, Pronethalol, , , Sulfi pholine Salicylate, , , Nifenazone, 5' malol, Talinolol, Tertatolol, Timolol, Toliprolol and Nitro-2' propoxyacetanilide, Parsalmide, Perisoxal, Phen Xibenolol. acetin, Phenazopyridine Hydrochloride, Phenocoll, Phe nopyrazone, Phenyl Acetylsalicylate, , 0069 5. Alcohol deterrents such as Cyanamide Phenyramidol, Pipebuzone, , , Propac Citrated, Disulfiram, Nadide and Nitrefazole. etamol, , , Salicylate, 0070) 6. inhibitors such as Epalrestat, RamifenaZone, Metilsulfate, Salacetamide, Ponalrestat, Sorbinil and Tolrestat. , , Salicylamide O-, Salicyl Sulfuric Acid, Salsalte, Salverine, Simetride, Sodium Sali 0071 7. Anabolics such as , Androstene cylate, Sulfamipyrine, Suprofen, Talniflumate, Tenoxicam, diol, , , , . Terofenamate, Tetradrine, Tinoridine, , Tol Formyldienolone, 4-Hydroxy-19-nortestosterone, Meth pronine, , , Xenbucin and Zomepirac. andriol, Methenolone, Methyltrienolone, , Nan drolone Decanoate, Nandrolone p-HeXyloxyphenylpropi 0075) 11. such as Acetamidoeugenol, Alfa onate, Nandrolone Phenpropionate, Norbolethone, dolone Acetate, , Amucaine, Amolanone, Amy , Pizotyline, , and locaine Hydrochloride, BenoXinate, , Betox . ycaine, Biphenamine, Bupivacaine, Butacaine, Butaben, Butanilicaine, Burethamine, Sodium, Butox 0072 8. (dental) such as , ycaine, Carticaine, 2-Chloroprocaine Hydrochloride, Clove and Eugenol. , , Cyclomethycaine, Dibucaine Hydrochlo ride, Dimethisoquin, , Diperadon 0073) 9. Analgesics () such as , Allyl Hydrochloride, Dyclonine, Ecgonidine, Ecgonine, Ethyl , Alphaprodine, , , Bez Aminobenzoate, Ethyl Chloride, Etidocaine, , itramide, , , , B-Eucaine, Euprocin, Fenalcomine, Fomocaine, Hexobar , Codeine Methyl , Codeine Phosphate, bital, Hexylcaine Hydrochloride, Sodium, Codeine Sulfate, , , Dezo Hydroxyprocaine, Hydroxytetracaine, Isobutyl p-Ami cine, , , Dihydrocodeinone nobenzoate, Kentamine, Leucinocaine MeSylate, LeVOXa Enol Acetate, , , Dimephep drol, , Mepivacaine, Hydrochloride, tanol, , , Dipi Metabutoxycaine Hydrochloride, Sodium, panone, , , Ethylmethlythiam Methyl Chloride, , Myrtecaine, Naepaine, , , , , Octacaine, Orthocaine, Oxethazaine, Parethoxycaine, Phen , Hydrocodone Bitartrate, , acaine Hydrochloride, , , , , , , Levor , Polidocanol, Pramoxine, Prilocaine, Procaine, phanol, , Meperidine, , , , Propanocaine, Proparacaine, Propipocaine, Pro Hydrochloride, , , Morphine pofol, Propoxycaine Hydrochloride, Pseudococaine, Pyr Derivatives, , , Narceline, Nicomor rocaine, Quinine Hydochloride, Risocaine, Salicyl phine, , , , Nor Alcohol, Tetracaine Hydrochloride, , Thimylal, pipanone, , , , Papavere , Thiopental Sodium, Tolycaine, Tri tum, , , , Pheoperidine, , , , mecaine and . Promedol, , , Propoxyphene, 0076) 12. Anorexics such as , Amphecloral, and TilidLine. , BenZaphetamine, , , , , Cyclexedrine, Destro 0074 10. Analgesics (non-narcotic) such as Acetami amphetamine Sulfate, Diethylpropion, Diphemethoxidine, nophen, AcetaminoSalol, Acetanilide, Acetylsalicylsalicylic N-Ethylamphetamine, , , Fenpro Acid, Alclofenac, Alminoprofen, , Aluminum porex, Furfurylmethylamphetamine, Levophacetoperate, Bis(acetylsalicylate), Aminochlorthenoxazin, 2-Amino-4- , , Metamfeproamone, Methamphet picoline, Aminopropylon, Aminopyrine, Ammonium Sali amine, Norpseudoephedrine, , Phendime cylate, Antipyrine, Antipyrine Salicylate, , Apa trazine , , Phenpentermine, Phenyl Zone, , Benorylate, Benoxaprofen, BenZpiperylon, propanolamine Hydrochloride and . , p-Bromoacetanilide, 5-Bromosalicylic Acid Acetate, Bucetin, BufeXamac, Bumadizon, Butacetin, Cal 0077 13. (Cestodes) such as , cium Acetylsalicylate, , Carbetidine, Carbi Aspidin, Aspidinol, (e), Embelin, Kosin, phene, CarSalam, Chloralantipyrine, Chlorthenoxazin(e), Napthalene, , Pellertierine, Pellertierine Tan Salicylate, Cinchophen, , Clometacin, nate and Quinacrine. Cropropamide, Crotethamide, , , 0078 14. Anthelmintics (Nematodes) such as Alantolac , Dihydroxyaluminum Acetylsalicylate, Dipyro tone, AmoScanate, , Bephenium, Bitoscanate, US 2002/0004O65 A1 Jan. 10, 2002

Carbon Tetrachloride, Carvacrol, Cyclobendazole, Diethyl ranolol, Disopyramide, , Esmolol, , carbamazine, Diphenane, , Dymanthine, , Hydroquinidine, Indecainide, Indenolol, Iprat Gentian Violet, 4-, , Mebenda ropium Bromide, Lidocaine, Lorajmine, Lorcainide, Zole, 2-Napthol, , Papain, , Piperazine Meobentine, Metipranolol, , Moricizine, Nadox Adipate, Piperazine Citrate, Piperazine Edetate Calcium, olol, Nifenalol, Oxprenolol, Penbutolol, Pindolol, Pirmenol, Piperazine Tartrate, , Pamoate, á-Santo Practolol, Prajmaline, Procainamide Hydrochloride, Prone nin, Stilbazium Iodide, Tetrachloroethylene, Tetramisole, thalol, Propafenone, Propranolol, Pyrinoline, Sul thiabendazole, , Thymyl N-Isoamylcarbamate, Tri fate, Quinidine, Sotalol, Talinolol, Timolol, , Vera clofenol Piperazine and Urea Stibamine. pamil, Vicquidil and Xibenolol. 0079) 15. Anthelmintics (Onchocerca) such as 0088 24. Antiarteriosclerotics such as Pyridinol Carbam and Sodium. ate. 0080) 16. Anthelmintics () such as Amoscan 0089 25. Antiarthritic/Antirheumatics such as Allocupre ate, Amphotalide, Potassium Tartrate, Antimony ide Sodium, , , Aurothiogly Sodium Gluconate, Antimony Sodium Tartrate, Antimony canide, , Calcium 3-Aurothio-2-propanol-1- Sodium Thioglycollate, Antimony Thioglycollamide, Sulfonate, , , Clobu Zarit, CuproXoline, Becanthone, Hycanthone, Lucanthone Hydrochloride, Niri Diacerein, Glucosamine, Sodium Thiomalate, Gold dazole, , , Stibocaptate, Sodium , , Kebuzone, and Urea Stibamine. Lobenzarit, Melittin, , Myoral and Penicil 0081 17. (Trematodes) such as Anthi lamine. olimine and Tetrachloroethylene. 0090) 26. Antibacterial () drugs including: 0082) 18. Antiacne drugs such as Adapelene, 0091 Aminoglycosides such as Amikacin, Apramy Acetophenide, , Benzoyl , Cyoctol, cin, Arbekacin, Bambermycins, Butirosin, Dibeka , , Resorcinol, Retinoic Acid, Tetro cin, Dihdrostreptomycin, Fortimicin S), Gentamicin, quinone and Tretinonine. Ispamicin, Kanamycin, Micronomicin, , 0.083. 19. Antiallergics such as Amlexanox, , Neomycin Undecylenate, Netilmicin, Paromomycin, , Cromolyn, , , Ibudilast, Ribostamycin, Sisomicin, Spectinomycin, Strepto Nedocromil, , Pentigetide, Ivy Extract, mycin, StreptonicOZid and Tobramycin; Poison Oak Extract, Poison Sumac Extract, Repirinast, 0092 Amphenicols such as AZidamfenicol, Tranilast, Traxanox and Urushiol. Chloramphenicol, Chloramphenicol Palmitate, 0084 20. Antiamebics such as Arsthinol, Bialamicol, Chloramphenicol Pantothenate, Florfenicol and CarbarSone, Cephaeline, Chlorbetamide, Chloroquine, Thiamphenicol; Chlorphenoxamide, Chlortetracycline, Dehydroemetine, 0093 Ansamycins such as Rifamide, Rifampin, Dibromopropamidine, Diloxanide, DephetarSone, Emetine, Rifamycin and ; Fumagillin, Glaucarubin, Glycobiarsol, 8-Hydroxy-7-iodo 5-quinolineSulfonic Acid, Iodochlorhydroxyquin, 0094 B-Lactams, including: Iodoquinol, Paromomycin, Phanquinone, PhearSone Sul 0.095 such as , foxylate, Polybenzarsol, , Quinfamide, Sec 0.096 such as Cefactor, nidazole, Sulfarside, Teclozan, , Thiocarbam Cefadroxil, Cefamandole, Cefatrizine, Cefaze izine, ThiocarbarSone and . done, Cefazolin, Cefixime, CefinenoXime, Cefo 0085 21. such as , Cyoctol, dizime, Cefonicid, CefoperaZone, Ceforanide, Cyproterone, Acetate, Flutimide, Cefotaxime, Cefotiam, Cefpimizole, Cefpirimide, and . Cefpodoxime Proxetil, Cefroxadine, Cefsulodin, Ceftazidime, Cefteram, Ceftezole, Ceftibuten, 0.086 22. such as Acebutolol, Alprenolol, Ceftizoxime, Ceftriaxone, Cefuroxime, Cefu , , Arotinolol, Atenolol, , Zonam, Cephacetrile Sodium, Cephalexin, Cepha Bevantolol, Bucumolol, Bufetolol, Bufuralol, Bunitrolol, loglycin, , , Cephal Bupranolol, Carozolol, Carteolol, Carvedilol, Celiprolol, Maleate, , Epanolol, , Gallo othin, Cephapirin Sodium, Cephradine and pamil, , Indenolol, , Israd Piveefalexin; ipine, Limaprost, Mepindolol, Metoprolol, , 0097 Cephamycins such as Cefbuperazone, Nadolol, , , Nifenalol, , Cefinetazole, Cefninox, Cefetan and Cefoxitin; Nipradillol, , Nitroglycerin, Oxprenolol, Oxy fedrine, OZagrel, Penbutolol, Pentaerythritol Tetranitrate, 0.098 Monobactams such as Aztreonam, Caru Pindolol, Pronethalol, Propranolol, Sotalol, , monam and Tigemonam, Timolol, Toliprolol and . 0099 Oxacephems such as Flomoxef and Mox 0087. 23. Antiarrhythmics such as Acebutol, Acecaine, olactam, Adenosine, Ajmaline, Alprenolol, Amiodarone, Amoproxan, 0100 such as Amidinocillin, Amdi Aprindine, Arotinolol, Atenolol, Bevantolol, nocillin Pivoxil, Amoxicillin, Ampicillan, Apalcil Tosylate, Bubumolol, Bufetolol, , Bunitrolol, lin, ASpoxicillin, AZidocillan, AZlocillan, Bupranolol, Butidrine Hydrochloride, Butobendine, Bacampicillin, Benzylpenicillinic Acid, Benzyl Capobenic Acid, Carazolol, Carteolol, Cifenline, Clo Sodium, Carbenicillin, Carfecillin US 2002/0004O65 A1 Jan. 10, 2002

Sodium, Carindacillin, Clometocillin, Cloxacillin, ide, p-Nitrosulfathiazole, Noprylsulfamide, Cyclacillin, , Diphenicillin Sodium, Phthalylsulfacetamide, Phthalylsulfathiazole, Sala Epicillin, Fenbenicillin, Floxicillin, , Zosulfadimidine, Succinylsulfathiazole, Sulfabenza Lenampicillin, Metampicillin, Methicillin mide, , Sulfachlorpyridazine, Sulfach Sodium, Mezlocillin, Sodium, Oxacillin, rySoidine, Sulfacytine, , Sulfadicramide, Penamecillin, Penethamate Hydriodide, Penicillin Sulfadimethoxine, , Sulfaethidole, Sulf G Benethamine, Penicillin G BenZathine, Penicil aguanidine, Sulfaguanol, , Sulfaloxic Acid, lin G Benzhydrylamine, Penicillin G Calcium, Sulfamerazine, Sulfameter, Sulfamethazine, Sul famethizole, Sulfamethomidine, Sulfamethoxazole, Penicillin G Hydrabamine, Penicillin G Potas Sulfamethoxypyridazine, Sulfametrole, Sulfamido sium, Penicillin G Procaine, Penicillen N, Peni chrysoidine. Sulfamoxole, Sulfanilamide, Suifanil cillin O, Penicillin V, Penicillin V BenZathine, amidomethaneSulfonic Acid Triethanolamine Salt, Penicillin V Hydrabamine, Penimepicycline, 4-Sulfanilamidosalicylic Acid, N'-Sulfanilylsulfa Phenethicillin Potassium, Piperacillin, Pivapicil nilamide, Sulfanily lurea, N-Sulfanillyl-3,4-xylamide, lin, Propicillin, Quinacillin, Sulbenicillin, Sulfanitran, Sulfaperine, Sulfaphenazole. Sul Talampicillin, Temocillin and Ticarcillin; faproxyline, Sulfapyrazine, Sulfapyridine, Sulfa 0101 Lincosamides such as and Somizole, Sulfasymazine, Sulfathiazole, Sulfathio Lincomycin; urea, Sulfatolamide, Sulfisomidine and Sulfisoxazole; 0102 Macrollides such as Azithromycin, Carbomy cin, Clarithromycin, , Erythromycin 0111 Sulfones such as Acedapsone, Acediasulfone, Acistrate, Erythromycin Estolate, Erythromycin AcetoSulfone Sodium, , DiathymoSulfone, Gluco Glucoheptonate, Erythromycin Lactobionate, Eryth Sulfone Sodium, Solasulfone, Succisulfone, Sulfanilic Acid, romycin Propionate, Erythromycin Stearate, Josa p-Sulfanilylbenzylamine, pp'-Sulfonyldianiline-N,N' diga mycin, Leucomycins, Midecamycins, Miokamycin, lactoside, Sulfoxone Sodium and Thiazolsulfone; and others Such as , Hexedine, Methenamine, Methenamine Oleandomycin, Primycin, Rokitamycin, Rosarami Anhydromethylene-citrate, Methenamine Hippurate, Meth cin, Roxithromycin, Spiramycin and Troleandomy enamine Mandelate, Methenamine Sulfosalicylate, Nitroxo CIn line and . Such as Adiphenine 0.103 Polypeptides such as Amphomycin, Bacitra Hydrochloride, , Ambutonomium Bromide, Amino cin, Capreomycin, Colistin, Enduracidin, Enviomy pentamide, Amixetrine, Amprotropine Phosphate, Anisotro cin, Fusafungine, Gramicidin(s), Gramicidin S, pine Methylbromide, Apoatropine, , Atropine Mikamycin, Polymyxin, Polymyxin B-Methane N-Oxide, , Benapry Zine, Benzetimide, Benzilo Sulfonic Acid, Pristinamycin, Ristocetin, Teicopla nium Bromide, Benztropine Mesylate, Methyl nin, Thiostrepton, Tuberactinomycin, Tyrocidine, Sulfate, , Butropium Bromide, N-Butylscopolam Tyrothricin, Vancomycin, Viomycin, Viomycin Pan monium Bromide, Buzepide, Camylofine, tothenate, Virginiamycin and Bacitracin; Hydrochloride, , , , , Cyclodrine, 0104 such as Apicycline, Chlortetra Cyclonium Iodide, Cycrimine Hydrochloride, , cycline, Clomocycline, , Doxycy Dibutoline Sulfate, Dicyclomine Hydrochlo cline, Guamecycline, Lymecycline, Meclocycline, ride, Diethazine, , , Diphemanil Methacycline, , Oxytetracycline, Pen Methylsulfate, N-(1,2-Diphenylethyl), Dip imepicycline, Pipacycline, Rolitetracycline, Sancyc iproverine, Diponium Bromide, , line, Senociclin and Tetracycline; and Endobenzyline Bromide, Ethopropazine, Ethybenztropine, 0105 other such as , Mupi Ethylbenzhydramine, Etomidoline, Eucatropine, Fenpiver inium Bromide, , Flutropium Bromide, rocin and Tuberin. Glycopyrrolate, Heteronium Bromide, Methyl 0106 27. Antibacterial drugs (synthetic), including: Sulfate, , , pratropium Bromide, , Levomepate, Mecloxamine, 0107 2,4-Diaminopyrimidines such as Brodi Bromide, Metcaraphen, Bromide, Methix moprim, TetroXoprim and Trimethoprim; ene, MethScopolamine Bromide, Octamylamine, Chloride, 0.108 such as Furaltadone, Furazolium , , Pentapip Chloride, Nifuradene, Nifuratel, Nifurfoline, eride, Bromide, Phencarbamide, Phenglutarim Nifurpirinol, Nifurprazine, Nifurtoinol and Nitro ide, , , Piperilate, Methysulfate, , , , furantoin, , Propenzolate, Propyromazine, Sco 0109 Quinolones and Analogs such as Amifloxacin, polamine, N-Oxide, Stilonium Iodide, Stramo Cinoxacin, , Difloxacin, Enoxacin, nium, Sultroponium, Thihexinol, Thiphenamil, Tiemonium Fleroxacin, Flumequine, Lomefloxacin, Miloxacin, Iodide, , Tiquizium Bromide, Tridi Nalidixic Acid, Norfloxacin, , Oxolinic hexethyl Iodide, Hydrochloride, Tropacine, Acid, Pefloxacin, Pipemidic Acid, Piromidic Acid, Tropenzile, , , Valethamate RoSoxacin, Temafloxacin and ToSufloxacin; Bromide and Xeny tropium Bromide. 0110 Sulfonamides such as Acetyl Sulfamethoxy 0112 28. such as Acetylpheneturide, pyrazine, Acetyl Sulfisoxazole, AZOSulfamide, Ben , Aloxidone, , 4-Amino-3-hy Zylsulfamide, Chloramine-B, Chloramine-T, droxybutyric Acid, Atrolactamide, , Buramate, Dichloramine T, Formosulfathiazole, Calcium Bromide, Carbamazepine, Cinromide, Clomethia N-Formylsulfisomidine,N'-a-D-Glucosylsulfanil Zole, , Decimenide, Diethadione, Dimethadi , Mafenide, 4'-(Methylsulfamoyl)sulfanilanil one, Doxenitoin, , , , Etho US 2002/0004O65 A1 Jan. 10, 2002 toin, Fluoresone, Garbapentin, 5-Hydroxytryptophan, 0.125 31. Antidiarrheal drugs such as Acetyltannic Acid, , Lomactil, Magnesium Bromide, Magnesium Albumin Tannate, Alkofanone, Aluminum Salicylates-Ba Sulfate, , Mephobarbital, , Meth Sic, , DilfenoXin, , Lidamidine, etoin, Methsuximide, 5-Methyl-S-(3-phenanthryl)hydan Lomotil, , Mebiquine, Trillium and UZarin. toin, 3-Methyl-5-phenylhydantoin, , 0.126 32. Antidiuretics such as Desmopressin, Fely , , , , pressin, Lypressin, Ornipressin, , Pituitary Phenetharbital, , , Phenobarbital Sodium, , Phenylmethylbarbituric Acid, Posterior, Terlipressin and Vasopressin. , Phethenylate Sodium, , Pre 0127 33. such as , gabatin, , , , Sodium , and . , Solanum, Bromide, Suclofenide, Sulthiame, Tetrantoin, , , Valproic 0128 34. drugs (antibiotics), including: Acid, , and . 0.129 Polyenes such as Amphotericin-B, Candici din, Dermostatin, Filipin, Fungichromin, Hachimy 0113 29. , including: cin, Hamycin, Lucensomycin, , Natamy 0114 Bicyclics such as Binedaline, , cin, Nystatin, Pecilocin and Perinycin; and , , , , Hydrochcloride, Nefopam, 0.130 others such as AZaserine, , Oli , Oxitriptan, , , gomycins, Neomycin Undecylenate, Pyrrolnitrin, , Thiazesim, , and Siccanin, Tubercidin and Viridin. ; 0131 35. Antifungal drugs (synthetic), including: 0115) Hydrazides/Hydrazines such as Benmoxine, 0132 Allylamines such as Naftifine and Terbin , , , , afine; and ; 0.133 such as Bifonazole, Butoconazole, 0116 Pyrrollidones such as , Rolicyprine Chlordantoin, Chlormidazole, Cloconazole, Clotri and Rolipram; mazole, Econazole, Enilconazole, Fenticonazole, 0117 such as , Metralin ISOconazole, , , Omocona dole, and . Zole, Oxiconazole, Nitrate, Sulconazole and Tio conazole; 0118 such as , , , , , Clomi 0134) Triazoles such as , pramine, , , , and ; and Dimetracrine, Dothiepin, , , Imi 0.135 others such as Acrisorcin, Amorolfine, Biphe pramine, N-Oxide, , namine, Bromosalicylchloranilide, Buclosamide, , , , Nortrip Calcium Propionate, Chlophenesin, CiclopiroX, tyline, Noxiptilin, , Pizotyline, Cloxyquin, Coparaffinate, Diamthazole, Dihydro , , , Tianept chloride, Exalamide, Flucytosine, Halethazole, Hex ine and ; and etidine, Loflucarban, Nifuratel, , 0119 others such as Adrafinil, Benactyzine, Bupro Propionic Acid, Pyrithione, , Sodium pion, Butacetin, Deanol, Deanol Aceglumate, Propionate, Sulbentine, Deanol Acetamidobenzoate, Dioxadrol, Etoperi 0.136 Tenonitrozole, Tolciclate, Tolindate, Tolnaf done, , , , Flu tate, oxetine, , Fluvoxamine Maleate, Hematoporphyrin, Hypercinin, , 0.137 Tricetin, Ujothion, Undecylenic Acid and , , , Oxafloz Zinc Propionate. ane, , , Pyrisuccideanol, , , Sultopride, Tenilox 0.138. 36. Antiglaucoma drugs such as , azine, , , , Tranyl Befunolol, Betaxolol, Bupranolol, Carteolol, Dapiprazoke, cypromine, L-, and Zimel Dichlorphenamide, Dipivefrin, Epinephrine, Levobunolol, dine. Methazolamide, Metipranolol, , Pindolol and Timolol. 0120 30. Antidiabetics, including: 0.139 37. such as , 0121 such as Buformin, Metformin and and . Phenformin; 0140 38. Antigout drugs such as Allopurinol, Carprofen, 0.122 Hormones such as Glucagon and ; , Probenecid and Sulfinpyrazone. 0123 Sulfonylurea derivatives such as Acetohexa 0141 39. , including: mide, 1-Butyl-3-metanily lurea, , Chlo rpropamide, , , , 0.142 Alkylamine derivatives such as , , Glisoxepid, Glyburide, Glybuthiazol(e), , , Chlorpheniramine, Glybuzole, Glyhexamide, Glymidine, Glypinamide, Dimethindene, Metron S, , Pyrrob Phenbutamide, , and Tolcy utamine, Thenaldine, and Triproli clamide; and dine, 0.124 others such as Acarbose, Calcium Mesoxalate 0.143 Aminoalkyl ethers such as Bietanautine, Bro and Miglitol. modiphenhydramine, , , US 2002/0004O65 A1 Jan. 10, 2002

Diphenlypyraline, , Embrammine, 0159 Aryloxypropanolamine derivatives such as , Mephenphydramine, p-Methyl Acebutolol, Alprenolol, Arotinolol, Atenolol, BetaX , , , olol, Bevantolol, Bisoprolol, Bopindolol, Bunitrolol, Piprinhydrinate and Setasine; Bupranolol, Butofilolol, Carazolol, Cartezolol, 0144. derivatives such as Allocla Carvedilol, Celiprolol, Cetamolol, Epanolol, Inde mide, p-Bromtripelennamine, , nolol, Mepindolol, Metipranolol, Metoprolol, , , Methafurylene, Meth Moprolol, Nadolol, Nipradillol, Oxprenolol, Penb aphenilene, , , Pyril utolol, Pindolol, Propranolol, Talinolol, Tetraolol, amine, , , Timolol and Toliprolol; Hydrochloride, and Zolamine; 0160 derivatives such as Althiaz ide, , Benzthiazide, Benzylhy 0145 such as , Chlorcycliz drochlorothiazide, Buthiazide, , Chlo ine, , and Hydroxy Zine; rthalidone, , , 0146 Tricyclics, including: , Epithiazide, Ethiazide, Fenguizone, , , Methy 0147 such as Ahistan, Etyme clothiazide, , , Paraflutizide, mazine, , N-Hydroxyethylpromethaz , Tetrachlormethiazide and Trichlorme ine Chloride, , , , , Pyrathiazine and Thiazinamium 0161 N-Carboxyalkyl (/lactam) derivatives Methyl Sulfate; and Such as Alacepril, Captopril, CilaZapril, Delapril, 0.148 others such as , , Enalapril, Enalaprilat, Fosinopril, Lisinopril, Movel , Deptropine, , Lora tipril, Perindopril, Quinapril and Ramipril; tadine and ; and 0162 Dihydropyridine derivatives such as Amlo 0149 other antihistamines such as , dipine, Felodipine, , Nicardipine, Nife Astemizole, AZelastine, Cetoxime, , dipine, Nilvadipine, Nisoldipine and ; , Diphenazoline, Diphenhydramine, 0163 Guanidine derivatives such as Bethanidine, Propionate, Mebhydroline, Phenin Debrisoquin, Guanabenz, Guanacline, Guanadrel, damine, and . GuanaZodine, Guanethidine, Guanfacine, Gua 0150. 40. Antihyperlipoproteinemics, including: nochlor, Guanoxabenz and Guanoxan; 0.164 Hydrazines and phthalazines such as Budrala 0151. Aryloxyalkanoic acid derivatives such as Zine, Cadralazine, Dihydralazine, Endralazine, Hyd Beclorbrate, Bazafibrate, Binifibrate, , racarbazine, Hydralazine, , Pildralazine , , Clofibric Acid, Etonfibrate, , , Nicofibrate, Pirifibrate, and Todralazine; , and Theofibrate; 0.165 Imidazole derivatives such as , , , Phentolamine Mesylate, 0152 sequesterants such as Tiamenidine and Tolonidine; Cholestyramine Resin, Colestipol and Polidexide; 0166 Quaternary ammonium compounds Azame 0153. HMG CoA reductase inhibitors such as Flu thonium Bromide, Chloride, Hex vastatin, , Pravastatin Sodium and Simv amethonium, Pentacynium Bis(methylsulfate), Pen astatin; tamethonium Bromide, Tartate, 0154) Nicotinic acid derivatives Aluminum Nicoti Phenactopinium Chloride and Trimethidiunum nate, AcipimoX, Niceritrol, Nicoclonate, Niconol and MethoSulfate; OXiniacic Acid; 0.167 Quinazoline derivatives such as , O155 hormones and analogs such as BunaZoSin, Doxazosin, Prasosin, and Tri EtiroXate, Thyropropic Acid and ThyroXine, and maZOsin; 0168 derivatives such as Bietaserpine, 0156 others such as Acifran, AZacosterol, Benfluo DeSerpidine, Rescinnamine, Reserpine and Syrosin reX, al-Benzalbutyramide, Carnitine, Chondroitin gopine, Sulfate, Clomestone, DetaXtran, Dextran Sulfate Sodium, 5,8,11,14,17-Eicosapentaenoic Acid, Erita 0169 derivatives such as Ambuside, denine, Furazbol, Meglutol, Melinamide, , , , , Mytatrienediol, Ornithine, a-ory Zanol, , Tripamide and , and Penataerythritol Tetraacetate, á-Phenylbutyramide, 0170 others such as Ajmaline, a-Aminobutyric Pirozadil, Probucol, à-Sitosterol, Sultosilic Acid, Acid, Bufeniode, Candesartan, Chlorthalidone, Piperazine Salt, Tiadenol, Triparanol and Xenbucin. Cicletaine, Ciclosidomine, Cryptenamine Tannates, O157 41. Antihypertensive drugs, including: EproSartan, Fenoldopam, , Indoramin, Irbesartan, , LOSartan, Metbutamate, 0158 Arylethanolamine derivatives such as Amosu , Methyldopa, Methyl 4-Pyridyl lalol, Bufuralol, Dilevalol, Labetalol, Pronethalol, Ketone Thiosemicarbarzone, Metolazone, Minoxi Sotalol and Sulfinalol; dil, , Pargyline, , , US 2002/0004O65 A1 Jan. 10, 2002 11

Piperoxan, Primaperone, Protoveratrines, 0183 Thiazinecarboxamides such as Droxicam, Raubasine, Rescimetol, Rilmenidene, Saralasin, ISOXicam, PiroXicam and Tenoxicam, and Sodium Nitroprusside, Ticrynafen, Trimethaphan Camsylate, Tyrosinase, and Valsartan. 0.184 others such as ?-Acetamidocaproic Acid, S-Adenosylmethionine, 3-Amino-4-hydroxybutyric 0171 42. Antihyperthyroids such as 2-Amino-4-meth Acid, Amixetrine, Bendazac, BenZydamine, Buco ylthiazole, 2-Aminothiazole, , 3,5-Dibromo-L- lome, Dilfenpiramide, DitaZol, EmorfaZone, Guaia , 3,5-Diiodotyrosine, Hinderin, , Iothiouracil, Zulene, Nabumetone, NimeSulide, Orgotein, Methimazole, , , Sodium Oxaceprol, Paranyline, Perisoxal, Pifoxime, Proqua , Thibenzazoline, and 2-Thiouracil. Zone, Proxazole and Tenidap. 0172) 43. Antihypotensive drugs such as Amezinium 0185. 46. Antimalarial drugs such as Acedapsone, Amo Methyl Sulfate, Angiotensin Amide, Dimetofrine, Dopam diacquin, Arteether, , , , ine, Etifelmin, Etilefrin, , Metaraminol, Mido Bebeerine, , Chirata, Chlorguanide, Chloroquine, drine, Norepinephrine, Pholedrinead and Synephrine. , Cinchona, Cinchonidine, Cinchonine, 0173 44. Antihypothyroid drugs such as , Gentiopicrin, , Hydroxychloro Sodium, , Thyroid, Thyroidin, Thyroxine, quine, Hydrochloride, 3-Methylarsacetin, Pam and TSH. aquine, Plasmocid, , , Quina crine, Quinine, Quinine Bisulfate, Quinine Carbonate, 0174 45. Anti-Inflammatory (non-steroidal) drugs, Quinine Dihydrobromide, Quinine Dihydrochloride, Qui including: nine Ethylcarbonate, Quinine Formate, Quinine Gluconate, 0.175 Aminoarylcarboxylic acid derivatives such as Quinine Hydriodide, Quinine Hydrochloride, Quinine Sali Enfenamic Acid, Etofenamate, Flufenamic Acid, cylate, Quinine Sulfate, Quinine Tannate, Quinine Urea ISOnixin, , Mefanamic Acid, Hydrochloride, Quinocide, and Sodium Arsenate , Talniflumate, Terofenamate and Diabasic. Tolfenamic Acid; 0186 47. Antimigraine drugs such as Alpiropride, Dihy 0176 Arylacetic acid derivatives such as Acemeta droergotamine, Eletriptan, Ergocornine, Ergocorninine, cin, Alclofenac, Amfenac, BufeXamac, Cinmetacin, Ergocryptine, , Ergotamine, acetate, Clopirac, Sodium, Etodolac, Felbinac, Fonazine, , MethySergid(e), Naratriptan, , Fenclofenac, Fenclorac, , Fentiazac, Pizotyline, Rizatriptan and Sumatriptan. Glucametacin, Ibufenac, Indomethacin, ISOfeZolac, 0187 48. Antinauseant drugs such as Acetylleucine ISOXepac, Lonazolac, Metiazinic Acid, Oxametacine, Monoethanolamine, , BenZquinamide, Bietanau Proglumetacin, Sulindac, Tiaramide, Tolimetin and tine, , , , , Zomepirac, , , Dipheniodol, , 0177 Arylbutyric acid derivatives such as Bumadi Granisetron, , Methalltal, , Zon, Butibufen, Fenbufen and Xenbucin; Metopimazine, Nabilone, Ondansteron, Oxypendyl, Pipam azine, Piprinhydrinate, , Scopolamine, Tet 0.178 Arylcarboxylic acids such as Clidanac, rahydrocannabinols, , ThioproperZaine and Ketorolac and Tinoridine; Trimethobenzamide. 0179 Arylpropionic acid derivatives such as Almi noprofen, Benoxaprofen, Bucloxic Acid, Carprofen, 0188 49. Antineoplastic drugs, including: Fenoprofen, Flunoxaprofen, Flurbiprofen, Ibupro 0189 Alkylating agents, including: fen, Ibuproxam, Indoprofen, Ketoprofen, Loxopro fen, Miroprofen, Naproxen, Oxaprozin, Piketopro 0.190 Alkyl sulfonates such as Busulfan, Impro fen, Pirprofen, Pranoprofen, Protizinic Acid, Sulfan and Piposulfan; Suprofen and Tiaprofenic Acid; 0191) Aziridines such as Benzodepa, Carbo 0180 Pyrazoles such as Difenamizole and Epiri quone, Meturedepa and Uredepa; Zole; 0.192 Ethylenimines and methylmelamines such 0181 Pyrazolones such as Apazone, BenZpiperylon, as Altretamine, Sulfosamide, Triethylen Feprazone, Mofebutazone, Morazone, Oxyphenb emelamine, Triethylenephosphoramide, Triethyl utazone, Phenybutazone, Pipebuzone, Propy enethiophosphoramide and Trimethylolom , RamifenaZone, SuxibuZone and Thiaz elamine; olinobutaZone; 0193 mustards such as Chlorambucil, 0182 derivatives such as Acetaminos Chlornaphazine, Chclophosphamide, Estramus alol, Aspirin, Benorylate, Bromosaligenin, Calcium tine, Ifosfamide, Mechlorethamine, Mechlore Acetylsalicylate, Diflunisal, EterSalate, Fendosal, thamine Oxide Hydrochloride, Melphalan, Gentisic Acid, Glycol Salicylate, Imidazole Salicy late, Lysine Acetylsalicylate, MeSalamine, Morpho Novembichin, Phenesterine, , Tro line Salicylate, 1-Naphthyl Salicylate, Olsalazine, fosfamide and Uracil Mustard; Parsalmide, PhenylAcetylsalicylate, Phenyl Salicy 0194 Nitrosoureas such as Carmustine, Chloro late, Salacetamide, Salicylamine O-Acetic Acid, Zotocin, Fotemustine, Lomustine, Nimustine and Salicylsulfuric Acid, and , Ranimustine; and US 2002/0004O65 A1 Jan. 10, 2002 12

0.195 others such as Camptothecin, Dacarbazine, Prodipine, Quinpirole, , , Terguride, Mannomustine, Mitobronitol, Mitolactol and Tigloidine and Trihexyphenidyl Hydrochloride. Pipobroman; 0210 53. Antipheochromocytoma drugs such as Mety 0196) Antibiotics such as Aclacinomycins, Acti rosine, and Phentolamine. nomycin F1, , AZaserine, Bleomy cins, Cactinomycin, Carubicin, CarZinophilin, 0211 54. Antipneumocystis drugs such as Efformithine, Chromomycins, Dactinomycin, Daunorubicin, and Sulfamethoxazole. 6-Diazo-5-oxo-L-norleucine, Doxorubicin, Epiru 0212 55. Antiprostatic hypertrophy drugs such as Gesto bicin, Mitomycins, Mycophenolic Acid, Nogala norone Caproate, Mepartricin, Oxendolone and Proscar7. mycin, Olivomycins, Peplomycin, , 0213 56. drugs (Leshmania) such as Anti Porfiromycin, , Rufocromomycin, mony Sodium Gluconate, Ethylstibamine, HydroxyStilbami Streptonigrin, Streptozocin, Tubercidin, Uben dine, N-Methylglucamine, Pentamidine, Stilbamidine and imex, Zinostatin and Zorubicin; Urea Stibamine. 0.197 Antimetabolites, including: 0214) 57. Antiprotozoal drugs (Trichomonas) such as 0198 Folic acid analogs such as Denopterin, AcetarSone, Aminitrozole, Anisomycin, AZanidazole, Form Methotrexate, Pteropterin and ; initrazole, Furazolidone, Hachimycin, Lauroguadine, Mepartricin, , Nifuratel, Nifuroxime, 0199 analogs such as Fludarabine, 6-Mer , Secnidazole, Picrate, Tenonitrozole and captopurine, Thiamiprine and Thioguanaine; and Tinidazole. 0200 analogs such as Ancitabine, 0215 58. Antiprotozoal drugs (Trypanosma) such as AZacitidine, 6-AZauridine, Carmofur, Cytarabine, Benznidazole, Eflornithine, Melarsoprol, Nifurtimox, Doxifluridine, Enocitabine, Floxuridine, Fluroou Oxophenarsine, Hydrochloride, Pentamidine, Propamidine, racil and Tegafur, Puromycin, Quinapyramine, Stilbamidine, Suramin 0201 Such as L-Asparaginase; and Sodium, Trypan Red and Tryparasmide. 0202 otherS Such as Aceglatone, Amsacrine, 0216 59. Antipuritics such as Camphor, Cyproheptadine, Bestrabucil, Bisantrene, Bryostatin 1, Carbopl , , , 3-Hydroxycamphor, atin, Cisplatin, Defofamide, , Diazi , Mesulphen, , Phenol, Polidocanol, quone, Dolastatins, Elformithine, Elliptinium Risocaine, Spirit of Camphor, Thenaldine, Tolpropamine Acetate, Etoglucid, Etoposide, Gallium Nitrate, and Trimeprazine. Hydroxyurea, Interferon-á, Interferon-a, Inter 0217 60. Antipsoriatic drugs such as Acitretin, Ammo feron-a, Interleukine-2, Lentinan, , nium Salicylate, Anthralin, 6-AZauridine, Bergapten(e), Lonidamine, MitoguaZone, Mitoxantrone, Mopi Chrysarobin, Etretinate and Pyrogallol. damol, Nitracrine, Pentostatin, Phenamet, Piraru bicin, Podophyllinicc Acid, 2-Ethythydrazide, 0218 61. drugs, including: Polynitrocubanes, Procarbazine, PSK7, Razox 0219 such as Benperidol, Bromp ane, Sizofiran, Spirogermanium, SymploStatin 1, eridol, , , , Melp Taxol, Teniposide, TenuaZonic Acid, Triaziquone, erone, Moperone, Pipamperone, Sniperone, Timiper 2.2.2"-Trichlorotriethylamine, Urethan, Vinblas one and Trifluperidol; tine, Vincristine, Vindesline and Vinorelbine. 0220 Phenothiazines such as , 0203 50. Antineoplastic (hormonal) drugs, including: , Carphenazine, , 0204 such as , Dromo Chlorpromazine, Clospirazine, , Dix Stanolone Propionate, , and yrazine, , Imiclopazine, Mepazine, , Methoxypromazine, Metofenazate, ; Oxaflumazine, , Pericyazine, Perimethaz 0205 Antiadrenals such as Aminoglutethimide, ine, , , , and ; Prochlorperazine, , , Thio propazate, , and Triflu 0206 Antiandrogens such as and Niluta promazine; mide, and 0207 Antiestrogens Such as Tamoxifen and 0221) such as , Clo Toremifene. penthixol, and Thiothixene; 0222 other tricyclics Such as Benzquinamide, 0208 51. Antineoplastic adjuncts including folic acid , , Clomacran, replenisherS Such as Frolinic Acid. Clothiapine, , Opipramol, Prothipendyl, 0209) 52. Antiparkinsonian drugs such as , Tetrabenazine, and , and Apomorphine, Benserazide, Bietanautine, Biperiden, Bro mocriptine, , Cabergoline, Carbidopa, Deprenyl 0223 others such as Alizapride, , Bura (a/k/a L-deprenyl, L-deprenil, L-deprenaline and ), mate, , , , DeXetimide, Diethazine, Diphenhydramine, , , Spirilene and Sulpiride. Ethopropazine, Ethylbenzhydramine, Levodopa, Nax 0224) 62. Antipyretics Such as Acetaminophen, Acetami agolide, Pergolide, , Pramipexole, Pridinol, noSalol, Acetanilide, Aconine, Aconite, Aconitine, US 2002/0004O65 A1 Jan. 10, 2002

Alclofenac, Aluminum Bis(acetylsalicylate), Aminochlorth 3-Amino-4-hydroxybutyric Acid, , Chlo enoxazin, Aminopyrine, Aspirin, Benorylate, BenZydamine, rhexidine, ChloroaZodin, m-Cresyl Acetate, Cupric Berberine, p-Bromoacetanilide, BufeXamac, Bumadizon, Sulfate, Dibromopropamidine, Ichthammol, Nega Calcium Acetysalicylate, Chlorthenoxazin(e), Choline Sali tol7, Noxytiolin, Ornidazole, a-Propiolactone, a-Ter cylate, Clidanac, Dihydroxyaluminum Acetylsalicylate, pineol. Dipyrocetyl, Dipyrone, Epirizole, EterSalate, , Indomethacin, ISOfeZolac, p-Lactophenetide, 0235 66. Antispasmodic drugs such as Alibendol, Ambu Lysine Acetylsalicylate, Magnesium Acetylsalicylate, cetamide, Aminopromazine, Apoatropine, Bevonium Meclofenamic Acid, Morazone, Morpholine Salicylate, Methyl Sulfate, Bietamiverine, Butaverine, Butropium Bro Naproxen, Nifenazone, 5'-Nitro-2'-propoxyacetanilide, mide, N-Butylscopolammonium Bromide, , , Phenicarbazide, Phenocol, Phenopyrazone, Cimetropium Bromide, , Clebopride, Coniine Phenyl Acetylsalicylate, Phenyl Salicylate, PipebuZone, Hydrobromide, Coniine Hydrochloride, Cyclonium Iodide, , PropyphenaZone, RamifenaZone, Salaceta Difemerine, , Dioxaphetyl Butyrate, Dipo mide, Salicylamide O-Acetic Acid, , Sul nium Bromide, , Emepronium Bromide, Ethaver famipyrine, and Tinoridine. ine, Feclemine, Fenalamide, , Fenpiprane, Fen piverinium Bromide, Fentonium Bromide, , 0225 63. Antirickettsial drugs such as p-Aminobenzoic Flopropione, Gluconic Acid, Guaiactamine, Hydramitra Acid, Chloramphenicol, Chloramphenicol Palmitate, Zine, , Leiopyrrole, , , Chloramphenicol Pantothenate and Tetracycline. Nafiverine, octamylamine, Octaverine, Pentapiperide, Phe 0226 64. Antiseborrheic drugs such as , 3-O namacide Hydrochloride, , Pinaverium Bro -Lauroylpyridoxol Diacetate, Piroctone, Pyrithione, Resor mide, Piperilate, Pipoxolan Hydrochloride, Pramiverin, Pri cinol, Selenium Sulfides and . finium Bromide, Properidine, Propivane, Propyromazine, Prozapine, Racefemine, , Spasmolytol, Stilonium 0227 65. , including: Iodide, Sultroponium, , Tiquizium Bro 0228 Guanidines such as Alexidine, Ambazone, mide, , , Tricromyl, Trifolium, Tri and Picloxydine; mebutine, N,N-1Trimethyl-3,3-diphenyl-propylamine, Tro penzile, Trospium Chloride and Xeny tropium Bromide. 0229 Halogens and halogen compounds Such as Iodide Oxide, Bismuth Iodosubgallate, Bis 0236 67. Antithrombotic drugs such as Anagrelide, muth Tribromophenate, Bornyl Chloride, Calcium Argatroban, Cilostazol, Chrysoptin, Daltroban, Defib:rotide, Iodate, Chlorinated Lime, Cloflucarban, Flurosalan, Enoxaparin, Fraxiparine7, Indobufen, Lamoparan, OZagrel, Iodic Acid, Iodine, Iodine Monochloride, Iodine Picotamide, Plafibride, Reviparin, Tedelparin, Ticlopidine, Trichloride, , Methenamine Tetraiodine, Triflusal and . Oxychlorosene, Povidone-Iodine, Sodium 0237 68. Antitussive drugs such as Allocamide, Amici Hypochlorite, Sodium Iodate, Symclosene, Thymol bone, , , , Iodide, , and Troclosene Bromoform, , Butethamate, Caramiphen Potassium; Ethanedisulfonate, Carbetapentane, Chlophedianol, Clobu 0230 Mercurial compounds such as Hydragaphen, tinol, , Codeine, Codeine Methyl Bromide, Meralein Sodium, , Mercuric Chloride, Codeine N-Oxide, Codeine Phosphate, Codeine Sulfate, Mercuric Chloride, Ammoniated, Mercuric Sodium Cyclexanone, , Sodium, Dihy p-Phenolsulfonate, Mercuric , Mercuric drocodeine, Dihydrocodeinone Enol Acetate, , Sulfide, Red, Mercurophen, Mercurous Acetate, , á,á-Diphenyl-2-piperidinepropanol, Dro Mercurous Chloride, Mercurous Iodide, Nitromer propizine, , , Ethyl Dibunate, Ethyl sol, Potassium Tetraiodomercurate(II), Potassium morphine, , Guiaiapate, Hydrocodone, Isoami Triiodomercurate(II) Solution, Thimerfonate nile, , , Narceline, Sodium and Thimerosal; Normethadone, , , , Pholcod 0231 Nitrofurans such as Furazolidone, 2-(Meth ine, Picoperine, PipaZethate, , oxymethyl)-5-, NidroxyZone, Nifuroxime, Hydrochloride, Racemethorphan, Taziprinone Hydrochlo Nifurzide and ; ride, and . 0232 such as Acetomeroctol, , 0238 69. Antiulcerative drugs such as Salicylate, Carvacrol, , Clo Aluminum Complex, i-Acetamidocaproic Acid Zinc Salt, rophene, CreSote, (s), p-CreSol, , , Arbaprostil, Benexate Hydrochloride, Bis , 1-Napthyl Salicylate, 2-Napthyl muth Subcitrate Sol (Dried), , Cetraxate, Salicylate, 2,4,6-Tribromo-m-cresol, and 3',4',5- , Enprostil, Esaprazole, , Ftaxilide, Trichlorosalicylanilide; Gefarnate, GuaiaZulene, IrSogladine, Misoprostol, Nizati dine, , Ornoprostil, a-Oryzanol, Pifarnine, 0233 such as Aminoquinuride, Benzox , Plaunotol, , Rioprostil, Rosaprostol, iquine, Broxyquinoline, ChloroXine, , Rotraxate, , Sofalcone, Spizofurone, Cloxyquin, Ethylhydrocupreine, Euprocin, Sucralfate, Teprenone, Trimoprostil, Thrithiozine, Troxipide Halquinol, , 8-Hydroxquinoline, 8-Hy and Zolimidine. droxquinoline Sulfate and Iodochlorhydroxyquin; and 0239 70. Antiurolithic drugs such as Acetohydroxamic Acid, Allopurinol, Potassium Citrate and Succinimide. 0234 others such as Aluminum Acetate Solution, Aluminum Subacetate Solution, Aluminum Sulfate, 0240 71. Antivenin drugs such as Lyovac7 Antivenin. US 2002/0004O65 A1 Jan. 10, 2002

0241 72. Antiviral drugs, including: 0255 76. Calcium channel blockers, including: 0242 and pyrimidinones such as Acyclovir, 0256 Arylalkylamines such as Bepridil, Ditiazem, Cytarabine, Dideoxyadenosine, Dideoxycytidine, , Gallopanil, , Terodiline and Dideoxyinosine, Edoxudine, FloXuridine, Ganciclo Verapamil, vir, Idoxuridine, Inosine Pranobex, MADU, Penci 0257 Dihydropyridine derivatives such as Fello clovir, Trifluridine, Vidrarbine and ; and dipine, Isradipine, Nicardipine, Nifedipine, Nilvad 0243 others such as Acetylleucine Monoethanola ipine, , Nisoldipine and Nitrendipine; mine, Amantadine, Amidinomycin, CoSalane, Cumi naldehyde Thiosemicarbzone, Foscarnet Sodium, 0258 Piperazine derivatives such as Cinnarizine, Imiquimod, Interferon-á, Interferon-a, Interferon-a, Flunarisine and ; and Kethoxal, Lysozyme, MethisaZone, MoroXydine, 0259 others such as , and Podophyllotoxin, Ribavirin, , Stallimy . cin, Statolon, Tromantadine and Xenazoic Acid. 0260 77. Calcium regulators such as , Calci 0244 73. drugs, including: tonin, , Clodronic Acid, , Elca 0245 Arylpiperazines Such as , , tonin, Etidronic Acid, priflavone, Pamidronic Acid, Par Isapirone and TondoSpirone. athyroid and Acetate. 0246 derivatives such as Alpra 0261) 78. Cardiotonics such as Acefylline, Acetyldigiti Zolam, , , Chlordiazep , 2-Amino-4-picoline, Amrinone, Benfurodil oxide, , , Chotiazepam, Clox Hemisuccinate, Buclasdesine, Cerberoside, Camphotamide, aZolam, , , , Convallatoxin, Cymarin, Denopamine, Deslanoside, Ditalin, Fluidazepam, , , , , Digoxin, , , , , , , Dopexamine, EnoXimone, Erythrophleine, Fenalcomine, , , , Nor Gitalin, Gitoxin, Glycocyamine, , Hydrastinine, dazepam, , , , Ibopamine, Lanotodises, Metamivam, Milrinone, Neriifolin, and , Oleandrin, Ouabain, Oxyfedrine, Prenalterol, Proscillaridin, ReSibufogenin, Scillaren, Scillarenin, Strophanthin, Sulma 0247 such as , Emylca Zole, and Xamoterol. mate, , , Phen probamate and ; and 0262 79. Chelating agents Such as Deferozmine, Ditio carb Sodium, Edetate Calcium Disodium, Edetate Diso 0248 others such as , , Cap dium, Edeate Sodium, Edetate Trisodium, , todiamine, , , , Pentetate Calcium Trisodium, Pentectic Acid, Succimer and Fluoresone, , Hydroxy Zine, LeSo Trientine; pitron, Mecloralurea, , Mirtazepine, , , and 0263. 80. antagonists such as Proglu . mide. 0249 74. Benzodiazepine antagonists such as Flumaze 0264 81. Cholelitholytic agents such as Chenodiol, nil. Methyl tert-Butyl Ether, Monooctanoin and Ursodiol. 0250) 75. Bronchodilators, including: 0265 82. Choleretics such as Alibendol, Trithion, AZintamide, , Cicrotoic Acid, Clanobu 0251 Ephedrine derivatives such as Albuterol, tin, , Cyclovalone, Cynarin(e), Dehydrocholic Bambuterol, Bitolterol, Carbuterol, Clenbuterol, Acid, , Dimecrotic Acid, a-Ethylbenzyl Clorprenaline, Dioxethedrine, Ephedrine, Epiniph Alcohol, Exiproben, Feguprol, Fencibutirol, Fenipentol, rine, EproZinol, Etafedrine, Ethylnorepinephrine, Florantyrone, Hymecromone, Menbutone, 3-(o-Methox Fenoterol, HeXoprenaline, Isoetharine, Isoproter yphenyl)-2-phenylacrylic Acid, Metochalcone, Moquizone, enol, Mabuterol, Metaproterenol, N-Methylephe Osalmid, Ox Bile Extract, 4.4'-Oxydi-2-butanol, , drine, Pirbuterol, Procaterol, Protokylol, Reproterol, Prozapine, 4-Salicyloylmorpholine, Sincalide, Taurocholic Rimiterol, Salmeterol, Soterenol, Terbutaline and Acid, Timonacic, Tocamphyl, Trepibutone and Vanitiolide. Tulobuterol; 0266 83. Cholinergic agents such as , Acetyl 0252 Quaternary ammonium compounds Such as choline Bromide, Acetylcholide Chloride, Aclatonium Bevonium Methyl Sulfate, Clutropium Bromide, Napadisilate, BenZpyrinium Bromide, chlo and ; ride, , Carpronium chloride, Demecarium Bro 0253) derivatives such as Acefylline, Ace mide, Dexpanthenol, Diisopropyl , Echothiophate fylline Piperazine, Ambuphylline, , Iodide, Edrophomium chloride, Eseridine, Furtrethonium, Bamifylline, choline Theophyllinate, Doxofylline, Isoflurophate, chloride, , Neostig Dyphylline, Enprofylline, Etamiphyllin, Etofylline, mine, Oxapropanium Iodide, and PyridoStig Guaithylline, Proxyphylline, Theobromine, 1-Theo mine Bromide. bromineacetic Acid and ; and 0267 84. Cholinesterase inhibitors such as Ambenonium 0254 others such as Fenspiride, Medibazine, Mon Chloride, Distigmine Bromide and Galanthamine. tekulast, Methoxyphenanime, Tretoquinol and 0268 85. Cholinesterase reactivators such as Obidox Zafirkulast. imine Chloride and Chloride. US 2002/0004O65 A1 Jan. 10, 2002

0269 86. Central nervous system and agents 0284 92. such as , Benzyl Ben Such as , Amphetimine, Amphetaminil, Beme Zoate, , Crotamiton, DDT, Dixanthogen, Isobornyl gride, , , , Chlorphenter Thiocyanoacetate-Technical, Lime Sulfurated Solution, LIn mine, , Clortermine, Coca, Demanyl Phos dane, , Mercuric Oleate, Mesulphen and Sulphur phate, Dexoxadrol, Sulfate, Pharmaceutical. Diethlpropion, N-Ethylamphetamine, Ethamivan, Etifelmin, Etryptamine, Fencamfamine, , FenoSolone, 0285) 93. Enzymes, including: , Galanthamine, Sodium, 0286 Digestive enzymes such as ?-Amylase (Swine Homocamfin, Mazindol, MegeXamide, , Pancreas), Lipase, Pancrelipase, Pepsin and Rennin; , , , Pentylenetetra Zole, Phenidimetrazine, Phenmetrazine, , Picro 0287. Mucolytic enzymes such as Lysozyme; , , Prolintane and . 0288 Penicillin inactivating enzymes such as Peni 0270 87. Decongestants such as Amidephrine, Cafami cillinase; and nol, Cyclopentamine, Ephedrine, Epinephrine, Fenoxazo 0289 Proteolytic enzymes such as Collagenase, line, Indanazoline, Metizoline, Naphazoline, Nordefrin Chymopapain, Chymotrypsins, Papain and Trypsin. Hydrochloride, Octodrine, Oxymetazoline, Phenylephrine Hydrochloride, Phenylpropanolamine Hydrochloride, Phe 0290 94. inducers (hepatic) such as Flumecinol. nylpropylmethylamine, Propylhexedrine, , 0291 95. Estrogens (non-steroidal) such as , Tetrahydrozoline, Tymazoline and Xylometazoline. Broparoestrol, , Dienestrol, Diethylstil 0271 88. Dental agents, including: bestrol, Diproprionate, , Fos festrol, , and . 0272 Bisphosphonates (anti- and bone resorption) Such as Alendronate, Clodr 0292 96. Gastric secretion inhibitors such as Enterogas onate, Etidronate, Pamidronate and Tiluldronate; trone and . 0293 97. such as 21-Acetox 0273 Carries Prophylactics such as and yprefnenolone, Aalclometasone, AlgeStone, Amicinonide, Sodium Fluoride; DeSensitizing Agents Such as Beclomethasone, , , Chloropred Potassium Nitrate and Citrate Oxalate. nisone, , Blovetasone, , , 0274 89. Depigmentors such as Hydroquinine, Hydro , , , , DeS quinone and Monobenzone. onide, , , , , , , , Flu 0275 90. , including: cloronide, Flumehtasone, , 0276 Organomercurials such as , Acetonide, , Butyl, , , Mercamphamide, Mercaptomerin , Acetate, Acetate, , Flurandrenolide, , Sodium, Mercumallylic Acid, Mercumatilin Sodium, , Halometasone, Acetate, Hydro Mercurous Chloride and ; cortamate, , , yaro 0277 Pteridines such as Furterene and ; cortisone Phosphate, Hydrocortisone 21-Sodium Succinate, Hydrocortisone Tebutate, , , Mepre 0278 Purines such as Acefylline, 7-Morpholinom dnisone, Methyolprednisolone, Furoate, ethyltheophylline, Pamabrom, Protheobromine and , , , Prednisolone Theobromine; 21-Diethylaminoacetate, Sodium Phosphate, 0279 Steroids such as , Oleandrin and Prednisolone Sodium Succinate, Prednisolone Sodium ; 21-m-Sulfobenzoate, Prednisolone 21-Stearoylglycolate, , Prednisolone 21-Trimethylacetate, 0280 Sulfonamide derivatives such as Aceta Prednisone, Prednival, , Prednylidene 21-Di Zolmide, AmbuSide, , , Buta ethylaminoacetate, Tixocortal, , Triamcino Zolamide, Chloraminophenamide, , lone Acetonide, Triamcinolone Benetonide and Triamcino Clopa.mide, Clorexolene, -4.4'- lone Hexacetonide. disulfonamide, Disulfamide, , Furo 0294. 98. Gonad-Stimulating principles such as Buser Semide, Indapamide, , Methazolamide, elin, Clomiphene, Cyclofenil, , FSH, HCG and , QuinethaZone, Torsemide, Tripamide and Xipamide; LH-RH. 0295) 99. Gonadotropic hormones such as LH and 0281 Uracils such as Aminometradine and Ami PMSG. Sometradine, 0296 100. Growth hormone inhibitors such as Octreotide 0282 others such as Amanozine, , Arbu and Somatostatin. tin, Chlorazanil, Ethacrynic Acid, , Hydra carbazine, ISOSorbide, , Metochalcone, 0297 101. Growth hormone releasing factors such as Muzolimine, Perhexiline, Ticrynafen and Urea. Semorelin. 0283 91. Dopamine agonists such as Bro 0298 102. Growth stimulants such as Somatotropin. mocriptine, Dopexamine, Fenoldopam, Ibopamine, 0299) 103. Hemolytic agents such as Phenylhydrazine Lisuride, Naxagolide and Pergolide. and Phenylhydrazine Hydrochloride. US 2002/0004O65 A1 Jan. 10, 2002

0300 104. antagonists such as Hexadimethrine 0314. 118. Narcotic antagonists such as , Bromide and . , , Nadide, Nalmfene, , 0301 105. Hepatoprotectants such as S-Adenosylme Nalorphine Dinicotinate, and . thionine, Betaine, Catechin, Citolone, Malotilate, Oraza 0315 119. Neuroprotective agents such as . mide, , Protoporphyrin IX, Silymarin 0316 120. Nootropic agents such as Aceglutamide, Ace Group, Thiotic Acid and Tiopronin. tylcarnitine, , Bifematlane, Exifone, , 0302) 106. Immunomodulators such as Amiprilose, Buci Idebenone, Indeloxazune Hydrochloride, Nizofenone, llamine, Ditiocarb Sodium, Inosine Pranobex, Interferon-y, , , Propentofylline, and Interleukin-2, Lentinan, Muroctasin, Platonin, Procodazole, Tacrine. Tetramisole, Thymomodulin, Thymopentin and . 0317 121. Ophthalmic agents such as 15-ketoprostaglan 0303 107. Immunosuppressants such as Azathioprine, dins. Cyclosporins and Mizoribine. 0318) 122. Ovarian hormone such as . 0304 108. exchange resins such as Carbacrylic Res 0319 123. Oxytocic drugs such as Carboprost, Carguto ins, Cholestyramine Resin, Colestipol, Polidexide, Resodec cin, Deaminooxytocin, Ergonovine, Gemeprost, Methyler and Sodium Polystyrene Sulfonate. gonovine, Oxytocin, Pituitary (Posterior), Prostaglandin E, 0305 109. stimulating hormone such as Pro Prostaglandin F and Sparteine. lactin. 0320 124. Pepsin inhibitors such as Sodium Amylosul 0306 110. LH-RH agonists such as , , fate. GoSerelin Acetate, Leuprolide, , and . 0321) 125. Peristaltic stimulants such as . 0307 111. Lipotropic agents such as N-Acetylmethion 0322) 126. inhibitors such as Metergoline. ine, Choline Chloride, Choline Dehydrocholate, Choline 0323) 127. Prostaglandins and prostaglandin analogs Dihydrogen Citrate, Inositol, and . Such as Arbaprostil, Carboprost, Enprostil, Bemeprost, 0308) 112. erythematosus suppressants such as Limaprost, Misoprostol, Ornoprostil, ProStacyclin, ProStag Bismuth Sodium Triglycollamate, Bismuth Subsalicylate, landin E, Prostaglandin E, ProStagland in F, Rioprostil, Chloroquine and Hydroxychloroquine. Rosaprostol, Sulprostone and Trimoprostil. 0309 113. Mineralcorticoids such as Aldosterone, 0324 128. Protease inhibitors such as Aprotinin, Camo Deoxycorticosterone, Deoxycorticosterone Acetate and Stat, GabeXate and NafamoStat. . 0325 129. Respiratory stimulants such as , 0310 114. Miotic drugs such as Carbachol, Physostig , , Cropropamide, Crotethamide, mine, Pilocarpine and Pilocarpus. , Dimorpholamine, , Ethamivan, Fomi noben, , , Metamivam, Nikethamide, 0311 115. Monoamine oxidase inhibitors such as Depre , , Pyridofylline, Sodium Succinate and nyl, Iproclozide, Iproniazid, ISOcarboxazid, Moclobemide, Tacrine. Octomoxin, Pargyline, PhenelZine, , Pivalylbenzhydrazine, Prodipine, Toloxatone and Tranyl 0326 130. Sclerosing agents such as Ethanolamine, cypromine. Ethylamine, 2-Hexyldecanoic Acid, Polidocanol, Quinine Bisulfate, Quinine Urea Hydrochloride, Sodium Ricino 0312) 116. Mucolytic agents such as , Bro leate, Sodium Tetradecyl Sulfate and Tribenoside. mheXine, Carbocysteine, , , Lysozyme, Hydrochloride, , , , 0327 131. and , including: Tiopronin and . 0328. Acyclic ureides such as , Apronalide, BomisoValum, Capuride, 0313 117. Muscle relaxants (skeletal) such as Afloqua and Ectylurea; lone, Alcuronium, Atracurium BeSylate, , BenZOc tamine, Benzoquinonium Chloride, C-Calebassine, Cariso 0329 such as Chlorhexadol, Ethchlor prodol, ChlormeZanone, Chlorphenesin , Vynol, Meparfynol, 4-Methyl-5-thiazoleethanol, Chlorproethazine, ChloZOXaZone, , Cyclarbamate, tert-Pentyl Alcohol and 2.2.2-Trichloroethanol; , Dantrolene, Bromide, 0330 Amides such as Butoctamide, Diethylbro Diazepam, Eperisone, , Flumetramide, moacetamide, Ibrotamide, ISOValeryl Diethylamide, , Hexacarbacholine Bromide, , Tricetamide, , and Hexafluorenium Bromide, Idrocilamide, Lauexium Methyl ; Sulfate, Leptodactyline, , , Mephe noxalone, , , Iodide, 0331 Barbituric acid derivatives such as Allobar Nimetazepam, Orphenadrine, , Phen bital, , , , Brallabar probamate, Phenyramidol, Pipecurium Bromide, Promox bital, Sodium, , , olane, Quinine Sulfate, , Succinylcholine Bro Butethal, , , Cyclopentobar mide, Succinylcholine Chloride, Succinylcholine Iodine, bital, Enallylpropymal, 5-Ethyl-5-(1-piperidyl) bar Suxethonium Bromide, , , Tiza bituric Acid, 5-Furfuryl-5-isopropylbarbituric Acid, nidine, , , Vecuronium Heptabarbital, Sodium, , Bromide and Zoxolamine. Mephobarbital, , Narcobarbital, Nealbar US 2002/0004O65 A1 Jan. 10, 2002 17

bital, Sodium, Phenallymal, Phenobar lamine, Propatyl Nitrate, Pyridofylline, , Tricromyl, bital, Phenobarbital Sodium, Phenylmethylbarbituric , Phosphate and . Acid, , , ProXibarbal, , Sodium, , Tetrabar 0344) 137. Vasodilators (peripheral) such as Aluminum bital, Sodium and ; Nicotinate, , Bencyclane, , , Brovincamine, Bufoniode, , , 0332 Benzodiazepine derivatives such as Broti , , , Cinnarizine, Cyclande Zolam, , , , late, Diisopropylamine Dichloracetate, , Fenoxidil, , , , Flunarisine, Heronicate, , InoSitol Niacinate, ISOX Lorimetazepam, Nitrazepam, , Suprine, , Kallikrein, , Nafronyl, Nica and , metate, Nicergoline, Nicofuranose, , Nylidrin, , , , Protaglan 0333 such as Ammonium Bromide, Cal cium Bromide, Calcium Bromolactobionate, din E, and Xanthinal Niacinate. Bromide, Magnesium Bromide, Potassium 0345 138. Vasoprotectants such as Benzarone, Biofla Bromide and Sodium Bromide; vonoids, Chromocarb, Clobeoside, Diosmin, Dobesilate 0334 Carbamates such as Amyl Carbamate-Ter Calcium, Escin, Rolescutol, Leucocyanidin, Metescufylline, tiary, , Hexaprpymate, Meparfynol Car , Rutin and Troxerutin. bamate, Novonal and Tricholorourethan; 0346) 139. , sources, and vitamin 0335 Chloral derivatives such as Carbocloral, Chlo extracts Such as Vitamins A, B, C, D, E, and K and ral Betaine, Chloral Formamide, , derivatives thereof, Calciferols, Glycyrrhiza and Mecobal Chloralantipyrine, , Pentaeryth amin. ritol Chloral and ; 0347 140. Vulnerary agents such as Acetylcysteine, 0336 Piperidinediones such as Glutehimide, Meth Allantoin, Asiaticoside, CadeXomer Iodine, Chitin, Dextra yprylon, Piperidione, , Taglutimide and nomer and Oxaceprol. ; 0348 141. Anticoagulants such as heparin. 0337 Quinazolone derivatives such as , 0349) 142. Miscellaneous such as Erythropoietin (Hema and ; and tinic), Filgrastim, (Benign Prostate Hypertro 0338 others such as Acetal, , Aldol, phy), Interferon Beta 1-Alpha (Multiple Sclerosis) and Tre Ammonium Valerate, Amphenidone, d-Bornyl tinonin (Urinary Incontinence). à-Bromoisovalerate, d-Bornyl Isovalerate, Bromo 0350. The amount of active agent to be incorporated in form, Calcium 2-Ethylbutanoate, Carfinate, á-Chlo the carrier composition will vary depending on the particular rolose, , Cypripedium, Doxylamine, active agent, the desired therapeutic effect, and the time Span , , , Homofena for which the transdermal System is to provide therapy. zine, Hydrobromic Acid, Mecloxamine, Menthyl Normally, the amount of active agent in the transdermal Valerate, Opium, , , Propiom system can vary from about 0.1% to about 50%, and azine, , , Sulfonethyl preferably from about 0.1% to about 30% by weight based methane and . on the dry weight of the total adhesive matrix composition. 0339) 132. Thrombolytic agents such as APSAC, Plas For lower dose concentrations permitted by this invention, min, Pro-Urokinase, Streptokinase, Tissue Plasminogen Such as with Steroids and hormones, the preferred amount is Activator and Urokinase; from about 0.1% to about 10%. 0340 133. Thyrotropic hormones such as TRH and TSH. 0351 While not essential, it is preferred that the andro genic hormones be incorporated near, at or above Saturation 0341 134. Uricosurics such as Benzbromarone, Ethe with respect to its concentration in the adhesive matrix benecid, Orotic Acid, Oxycinchophen, Probenecid, Sulfin composition. pyrazone, Ticrynafen and . 0352. The term “adhesive matrix composition” as used 0342) 135. Vasodilators (cerebral) such as Bencyclane, herein refers to any non-aqueous adhesive material into Cinnarizine, , , Ciclonicate, Diiso which an active agent is Solubilized or homogeneously propylamine Dichloractetate, Eburnamonine, Fenoxedil, blended either without, or in combination or admixture with, , Ibudilast, Ifenprodil, Nafronyl, Nicametate, other ingredients useful for facilitating transdermal drug Nicergoline, Nimodipine, , Pentifylline, delivery, Such as crystallization inhibitors, Solubility Tinofedrine, , Vinpocetine and Vicquidil. enhancers, permeation enhancers, Solvents, co-Solvents and 0343 136. Vasodilators (coronary) such as Amotriphene, other types of additives. An “adhesive” as used herein means Bendazol, Benfurodil Hemisuccinate, , Chloa any natural or Synthetic material that is capable of Sticking cizine, Chromonar, Clobenfurol, Clonitrate, , Dipy to the Site of topical application. The term “preSSure-Sensi ridamole, Droprenilamine, , Erythritol, Erythrityl tive adhesive' as used herein refers to an adhesive which Tetranitrate, Etafenone, Fendiline, Floredil, Ganglefene, adheres instantaneously to most Surfaces with the applica Hexestrol Bis(B-diethylaminoethyl ether), , tion of very slight preSSure and remains permanently tacky. Itramin Tosylate, Khellin, Lidoflazine, Mannitol Hexani An adhesive is a pressure-Sensitive adhesive within the trate, Medibazine, , Nitroglycerin, Pentaerythritol meaning of that term as used herein if it has the properties Tetranitrate, Pentrinitrol, Perhexiline, Pimefylline, Preny of an adhesive pressure-Sensitive adhesive per Se or func US 2002/0004O65 A1 Jan. 10, 2002

tions as the same by admixture with tackifiers, plasticizers, acrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl croSS-linking agents or other additives. acrylate, and tridecyl methacrylate. 0353 Suitable adhesives include all of the non-toxic 0361 Functional monomers, copolymerizable with the natural and Synthetic polymers known for or Suitable for use above alkyl acrylates or methacrylates, which can be used in transdermal devices as adhesives including acrylic poly include acrylic acid, methacrylic acid, maleic acid, maleic mers, gums, Silicone-based polymers (broadly referred to as anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, "polysiloxanes”) and rubber-based adhesives Such as poly acrylamide, dimethylacrylamide, acrylonitrile, dimethy isobutylenes, polybutylenes, ethylene/vinyl acetate and laminoethyl acrylate, dimethylaminoethyl methacrylate, Vinyl acetate based adhesives, Styrene/ adhesives, tert-butylaminoethyl acrylate, tert-butylaminoethyl meth polyisoprenes, Styrenes and Styrene block copolymers and acrylate, methoxyethyl acrylate and methoxyethyl meth block amide copolymers. acrylate and other monomers having at least one unsaturated double bond which participates in copolymerization reaction 0354) Suitable polysiloxanes include silicone pressure in one molecule and a on its Side chain Such Sensitive adhesives which are based on two major compo as a carboxyl group, a hydroxyl group, a Sulfoxyl group, an nents: a polymer, or gum, and a tackifying resin. The amino group, an amino group and an alkoxyl, as well as a polysiloxane adhesive is usually prepared by croSS-linking variety of other monmeric units including alkylene, the gum, typically a high molecular weight polydiorganosi hydroxy-Substituted alkylene, carboxylic acid-Substituted loxane, with the resin, to produce a three-dimensional sili alkylene, Vynylalkanoate, Vinylpyrrolidone, Vinylpyridine, cate Structure, via a condensation reaction in an appropriate Vinylpirazine, Vinylpyrrole, Vinylimidazole, Vinylcaprolac organic . The ratio of resin to polymer is the most tam, Vinyloxazole, vyinlacate, Vinylpropionate and vinyl important factor which can be adjusted in order to modify morpholine. the physical properties of polysiloxane adhesives. Sobieski, et al., “Silicone Pressure Sensitive Adhesives,'Handbook of 0362. Further details and examples of acrylic adhesives Pressure-Sensitive Adhesive Technology, 2nd ed., pp. 508 which are Suitable in the practice of the invention are 517 (D. Satas, ed.), Van Nostrand Reinhold, New York described in Satas, “Acrylic Adhesives,'Handbook of Pres (1989). Sure-Sensitive Adhesive Technology, 2" ed., pp.396-456 (D. 0355 Further details and examples of silicone pressure Satas, ed.), Van Nostrand Reinhold, New York (1989). Sensitive adhesives which are useful in the practice of this 0363 Suitable acrylic adhesives are commercially avail invention are described in the following U.S. Patents: U.S. able and include the polyacrylate adhesives Sold under the Pat. Nos. 4,591,622; 4,584,355; 4,585,836; and 4,655,767. trademarks DURO-TAKCR) by National Starch Company, Bridgewater, N.J.; GELVA(E) by , St. Louis, Mo.; HRJ 0356 Suitable silicone pressure-sensitive adhesives are by Schenectady International, Inc., Chicago, Ill., and commercially available and include the Silicone adhesives EUDRAGITE) by Roehm Pharma GmbH, Darmstadt, Fed sold under the trademarks BIO-PSACR by Dow Corning eral Republic of . Corporation, Medical Products, Midland, Mich. 0364. The amount of the adhesive to be used depends on 0357. In particularly preferred embodiments of the inven the concentration of active agent used to achieve a thera tion, the adhesive matrix composition comprises a pressure peutic effect. Typically, the adhesive is in an amount of about Sensitive adhesive, and more preferably a blend of one or 5% to about 90%, and preferably about 10% to about 90%, more preSSure-Sensitive acrylic polymers and polysiloxanes. and most preferably about 20% to about 75% by weight 0358. The term “acrylic polymer” is intended to be used based on the dry weight of the total adhesive matrix com interchangeably with the terms acrylate polymer, polyacry position. late and polyacrylic adhesive polymers as used herein and as 0365. The adhesive matrix compositions of the present known in the art. invention can also contain one or more Solvents and/or 0359 The acrylic polymers useful in practicing the co-Solvents. Such Solvents and/or co-Solvents are those invention are polymers of one or more monomers of acrylic known in the art, and are non-toxic, pharmaceutically acids and other copolymerizable monomers. The acrylic acceptable Substances, preferably liquids, which do not polymerS also include copolymers of alkyl acrylates and/or Substantially negatively affect the adhesive properties of the methacrylates and/or copolymerizable Secondary monomers transdermal System or the Solubility of the active agents at or monomers with functional groups. By varying the amount the concentrations used. The Solvent and/or co-Solvent can of each type of monomer added, the cohesive properties of be for the active agent or for the matrix materials, or both. the resulting acrylic polymer can be changed as is known in 0366 Suitable solvents include volatile liquids such as the art. In general, the acrylic polymer is composed of at alcohols (e.g., methyl, ethyl, isopropyl alcohols and meth least 50% by weight of an acrylate or alkyl acrylate mono ylene chloride), ketones (e.g., ); aromatic hydrocar mer, from 0 to 20% of a functional monomer copolymeriz bons Such as derivatives (e.g., and tolu able with the acrylate, and from 0 to 40% of other mono enes); lower molecular weight alkanes and cycloalkanes CS. (e.g., , heptanes and ); and alkanoic 0360 Acrylate monomers which can be used include acid esters (e.g., ethyl acetate, n-propyl acetate, isobutyl acrylic acid, methacrylic acid, butyl acrylate, butyl meth acetate, n-butyl acetate isobutyl isobutyrate, hexyl acetate, acrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl 2-ethylhexyl acetate or butyl acetate); and combinations and acrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, mixtures thereof. isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acry 0367 Suitable co-solvents include polyhydric alcohols, late, 2-ethylhexyl methacrylate, decyl acrylate, decyl meth which include glycols, triols and polyols Such as ethylene US 2002/0004O65 A1 Jan. 10, 2002 glycol, diethylene glycol, propylene glycol, dipropylene and preferably from about 0.1% to about 15%, by weight glycol, trimethylene glycol, butylene glycol, polyethylene based on the dry weight of the total adhesive matrix com glycol, hexylene glycol, polyoxethylene, glycerin, trimeth position. ylpropane, , polyvinylpyrrollidone, and the like. 0371. In addition to permeation enhancers, there may 0368. Further suitable co-solvents include glycol ethers also be incorporated various pharmaceutically acceptable Such as ethylene glycol monoethyl ether, glycol esters, additives and excipients available to those skilled in the art. glycol ether esterS Such as ethylene glycol monoethyl ether These additives include tackifying agents Such as aliphatic hydrocarbons, mixed aliphatic and aromatic hydrocarbons, acetate and ethylene glycol diacetate, Saturated and unsat aromatic hydrocarbons, Substituted aromatic hydrocarbons, urated fatty acids, mineral , Silicone fluid, lecithin, hydrogenated esters, polyterpenes, Silicone fluid, mineral oil derivatives and the like, and ethers, esters and alcohols of and hydrogenated wood roSins. Additional additives include fatty acids. binders such as lecithin which “bind” the other ingredients, 0369 Although the exact amount of co-solvents that may or rheological agents (thickeners) containing Silicone Such be used in the adhesive matrix composition depends on the as fumed Silica, reagent grade Sand, precipitated Silica, nature and amount of the other ingredients, Such amount amorphous Silica, colloidal Silicon dioxide, fused Silica, typically ranges from about 0.1% to about 40%, and pref Silica gel, quartz and particulate Siliceous materials com erably from about 0.1% to about 30% by weight, and more mercially available as Syloid(R), Cabosil(R), Aerosil(R), and preferably from about 1% to about 20%, by weight based on Whitelite(R), for purposes of enhancing the uniform consis the dry weight of the total adhesive matrix composition. tency or continuous phase of the final composition. Other additives and excipients include diluents, Stabilizers, fillers, 0370. In certain embodiments of the invention, a perme clayS, buffering agents, biocides, humectants, anti-irritants, ation enhancer is incorporated into the adhesive matrix antioxidants, , plasticizing agents, croSS-link composition. The term "permeation enhancer as used ing agents, flavoring agents, colorants, pigments and the herein refers to Substances used to increase permeability like. Such Substances can be present in any amount Sufficient and/or accelerate the delivery of an active agent through the to impart the desired properties to the carrier composition. skin or mucosa, and include monhydric alcohols Such as Such additives or excipients are typically used in amounts ethyl, isopropyl, butyl and benzyl alcohols, or dihydric up to 25%, and preferably from about 0.1% to about 10%, alcohols Such as ethylene glycol, diethylene glycol, or by weight based on the dry weight of the total adhesive propylene glycol dipropylene glycol and trimethylene gly matrix composition. col; or polyhydric alcohols Such as glycerin, Sorbitol and , which enhance drug Solubility; poly 0372 The adhesive matrix compositions according to the ethylene glycol ethers of aliphatic alcohols (Such as cetyl, present invention can be prepared by first mixing appropri lauryl, oleyl and Stearly) including polyoxyethylene (4) ate amounts of the polymeric plastic material in volatile lauryl ether, polyoxyethylene (2) oleyl ether and polyoxy polar and/or non-polar organic liquids, Such as those previ ethylene (10) oleyl ether commercially available under the ously described as Suitable Volatile Solvents. Appropriate trademark BRIJGR) 30, 93 and 97 from ICI Americas, Inc., amounts of active agent(s) are then added to the mixture and BRIJ(R) 35, 52, 56,58, 72, 76, 78, 92, 96,700 and 721; together with appropriate amounts of pressure-Sensitive vegetable, animal and and Such as cotton Seed, adhesive(s), Solvent(s) and/or co-solvent(s), with or without corn, Safflower, olive and castor oils, , and lanolin; enhancer(s), and thoroughly mixed. The mixture of the esterS Such as propyl oleate, decyl oleate, isopro adhesive matrix composition is next formed into a film at pyl palmitate, glycol palmitate, glycol laurate, dodecyl ambient temperature, preferably by coating or casting at a myristate, isopropyl myristate and glycol Stearate which controlled specified thickness onto a flexible sheet material, enhance drug diffusibility; fatty acid alcohols Such as oleyl Such as a release liner, followed by evaporation of the alcohol and its derivatives, fatty acid amides Such as olea volatile Solvents at elevated temperatures (e.g., by passing mide and its derivatives, urea and urea derivatives Such as through an oven). The non-volatile or higher boiling point allantoin which affect the ability of keratin to retain mois Solvents and/or co-Solvents, Such as the polyols, used in the ture, polar Solvents Such as dimethyldecylphosphoxide, carrier composition remain therein. The carrier composition methyloctylsulfoxide, dimethyllaurylamide, dodecylpyrroli has been coated or cast on the flexible sheet material, is then done, isosorbitol, dimethylacetonide, dimethylsulfoxide, laminated to another flexible sheet material preferably a decylmethylsulfoxide and dimethylformamide which affect backing layer. Appropriate size and shape individual trans keratin permeability; Salicylic acid which Softens the kera dermal drug delivery Systems are cut and then packaged tin, amino acids which are penetration assistants, benzyl (e.g., pouched). nicotinate which is a hair follicle opener; and higher molecu 0373 The order of steps, the amount of the ingredients, lar weight aliphatic Surfactants Such as lauryl Sulfate Salts and the amount and time of mixing may be important which change the Surface State of the skin and drugs admin process variables which will depend on the Specific poly istered and esters of Sorbitol and Sorbitol anhydride such as mers, active agents, Solvents and/or co-Solvents, enhancers polysorbate 20 commercially available under the trademark and additives and excipients used in the composition. These Tween(E) 20 from ICI Americas, Inc., as well as other factors can be adjusted by those skilled in the art, while polysorbates such as 21, 40,60, 61, 65, 80, 81, and 85. Other keeping in mind the objects of achieving a Solubilized active Suitable enhancers include oleic and linoleic acids, triacetin, agent and providing a uniform product that will also give ascorbic acid, , butylated hydroxytoluene, toco desirable results. pherol, acetate, tocopheryl linoleate. If perme ation enhancers are incorporated into the adhesive matrix 0374 Reference to FIG. 1 shows a matrix-type transder composition, the amount typically ranges up to about 30%, mal drug delivery System 10 comprising a pressure-Sensitive US 2002/0004O65 A1 Jan. 10, 2002 20 adhesive matrix composition layer 11, a release liner 12, and N.J.) and 109.2 parts of a polysiloxane adhesive (BIO a backing layer 13. Removal of the release liner 12 exposes PSACE) Q7-4603; Dow Corning Corp, Midland, Mich.) were the pressure-Sensitive adhesive matrix composition for topi added and thoroughly mixed. Finally 9.0 parts of dipropy cal application to the user. lene glycol and 6.0 parts oleyl alcohol were added and 0375. Further details and examples of pressure-sensitive mixed thoroughly in an appropriate container until the adhesives, enhancers, Solvents, co-Solvents, release liners, mixture was completely homogenous. The resulting com backing layers, and other additives, as well as transdermal position had the ingredient concentrations on a dry weight Systems generally, Suitable in practicing the invention are percent basis (i.e., after evaporation of volatile Solvents) as described in U.S. Pat. Nos. 5,474,787 and 5,656,286, Ser. shown below. No. 09/161,312 and 60/115,927, all of which are assigned to Noven Pharmaceuticals, Inc. and incorporated herein by reference. INGREDIENT DRUG WEIGHT2% EXAMPLES Polysiloxane Adhesive 66.3 (BIO-PSA (R) 7-4603) 0376 The above description and following specific Polyacrylate Adhesive 5.0 examples are hereby illustrative of pharmaceutically accept (DURO-TAK (R) 87-2287) Ethyl Cellulose 1.O.O able matrix compositions and transdermal drug delivery (Ethocel(R) 10) Systems, and methods of making Same, within the contem Dipropylene Glycol 9.O plation of the invention. The description and examples are in Olelyl Alcohol 6.O no way intended to be, or should be considered, limiting of Estradiol O.7 the scope of the invention. And while efforts have been made Norethindrome Acetate 3.0 to ensure accuracy with respect to numbers used (Such as amounts and temperatures), Some experimental error and deviation should be accounted for and/or allowed. Example 1 Examples 2-9 0377. An estradiol/norethindrone acetate pressure-sensi 0378. In the following examples, the method of Example tive adhesive matrix composition was prepared by combin 1 was used with the appropriate amounts of Starting mate ing 0.7 parts of estradiol and 3.0 parts of norethindrone rials to yield compositions having the following ingredient acetate along with 3.0 parts of ethyl cellulose (Ethocel(R) 10, concentrations set forth in tabular form in TABLE II. Dow Chemical Corp., Midland, Mich.) in 30.0 parts ethyl Examples 2, 3, and 5 are presented as control formulations acetate, 15.0 parts of toluene and 10.0 parts isopropyl for comparative purposes, but are not within the Scope of the alcohol. Then 12.2 parts of a polyacrylate adhesive (DURO invention in as much as the resulting adhesive matrix TAKCR) 87-2510; National Starch Company, Bridgewater, compositions do not contain a polymeric plastic material.

TABLE II

Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9

Polysiloxane O.O 71.4 54.5 53.6 48.6 43.6 58.O 53.0 Adhesive (BIO-PSA (R) 7-4502) Polysiloxane Adhesive (BIO-PSA (R) 7-4603) Polyacrylate Adhesive (DURO-TAK (R87-2287) Polyacrylate O.O 5.0 5.0 2O.O 2O.O 2O.O 5.0 5.0 Adhesive (Gelva (R) 788) Ethyl Cellulose O.O O.O 15.O O.O O.O O.O 1.O.O 15.O (Ethocel(R) 10) Ethyl Cellulose (Ethocel(R) 20) Poly vinyl pyrrollidone (KOLLIDON (R 30) Polyvinylpyrrolidone (KOLLIDON (R 90) Dipropylene Glycol 9.O 6.O 6.O 8.0 8.0 8.0 8.0 8.0 Oleyl Alcohol 6.O 6.O 6.O 6.O 6.O 6.O 6.O 6.O Estradiol O.7 1.6 3.5 2.4 2.4 2.4 3.0 3.0 Norethindrone 3.0 O.O O.O O.O O.O O.O O.O O.O Acetate US 2002/0004O65 A1 Jan. 10, 2002 21

What is claimed is: consisting of Steroidal and hormonal agents, analgesics and 1. A transdermal delivery system for delivery of a thera anti-migraine agents, anesthetics, anti-inflammatory and peutically effective amount of an active agent comprising: corticoid agents, central nervous System Stimulants and agents, cardioactive agents, anti-Parkinson's and anti (a) a pharmaceutically acceptable pressure-Sensitive Alzheimer's agents, anti-psychotic agents, anti- adhesive matrix carrier composition, agents, anti-, anxiolytic agents, Sedatives, hyp (b) one or more polymeric plastic materials which are notics, anti-microbial agents, and anti- agents. Substantially insoluble in water in an amount up to 10. The transdermal system according to claim 9, wherein 30%, said amount being sufficient to provide a sub the Steroidal and hormonal agents are Selected from the Stantially Zero-order drug release profile in exceSS of 72 group consisting of ethinyl estradiol, progesterone, norethin hours, drone, norethindrone acetate, norethisterone, methyltest (c) one or more active agents, osterone, testosterone, and mixtures thereof. 11. The transdermal System according to claim 10, (d) a crystallization inhibitor capable of absorbing and wherein the estradiol is 17 B-estradiol. holding water, and 12. The transdermal System according to claim 1, com (e) optionally, one or more Solvents, co-solvents and prising about 10%-40% polyacrylate adhesive, about 30%- permeation enhancers. 60% polysiloxane adhesive, about 2%-10% dipropylene 2. The transdermal System according to claim 1, wherein glycol, about 1%-10% oleyl alcohol, about 5%-20% ethyl the one or more insoluble polymeric materials are Selected cellulose, about 5%-15% polyvinylpyrrolidone and about from the group consisting of celluloses, cellulose deriva 1%-5%. 17 B-estradiol by weight based on the dry weight of tives, polycarbonates, polystyrenes, alkylacrylates, polyvi the total composition. nyl chloride, polyurethanes and polyacrylonitrile. 13. The transdermal System according to claim 1, com 3. The transdermal System according to claim 2, wherein prising about 3%-25% polyacrylate adhesive, about 30%- the cellulose derivatives are cellulose esters and cellulose 70% polysiloxane adhesive, about 5%-15% dipropylene ethers. glycol, about 1%-10% oleyl alcohol, about 5%-15% poly 4. The transdermal System according to claim 3, wherein vinylpyrrolidone, about 1%-15% ethyl cellulose, about the cellulose ethers are ethyl cellulose polymers. 0%-15% cellulose acetate butyrate, about 0%-15% cellulose 5. The transdermal System according to claim 3, wherein acetate propionate, about 0.1%-5%. 173-estradiol, and about the cellulose esters are Selected from the group consisting of 1%-7% morethindrone acetate by weight based on the dry cellulose acetate, cellulose acetate butyrate, cellulose acetate weight of the total composition. phthalate and cellulose acetate propionate. 14. A method of prolonged transdermal administration of 6. The transdermal System according to claim 1, wherein a therapeutically effective amount of one or more active the Solvents and co-Solvents are polyhydric alcohols. agents to a Subject comprising the Steps of: 7. The transdermal System according to claim 1, wherein the preSSure-Sensitive adhesive matrix carrier is a blend of a (a) providing the transdermal System of claim 1, and polyacrylate adhesive and a polysiloxane adhesive. 8. The transdermal System according to claim 1, wherein (b) topically applying the transdermal System to admin the crystallization inhibitor is polyvinylpyrrolidone. ister the one or more active agents. 9. The transdermal System according to claim 1, wherein the one or more active agents are Selected from the group