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US 201100973 84Al (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0097384 A1

Kanios et al. 43 Pub. Date: A r. 28 9 201 1

(54) TRANSDERMAL DELIVERY DEVICE Publication Classi?cation INCLUDING AN OCCLUSIVE BACKING (51) Int. Cl.

(75) Inventors: JuanDavid A. Kanios, Mantelle, Miami, Miami, FL (US);FL (US); A611, 9/12 168 (200601) Viet Nguyen, Miami, FL (US) ( ' ) A61P 25/00 (2006.01)

(73)(21) Assignee:Appl. No.: Noven12/981,126 Pharmaceuticals, Inc. (52) US. Cl...... 424/448; 514/398

(22) Filed: Dec. 29, 2010 (57) ABSTRACT _ _ A transdermal drug delivery system for the topical applica Related U‘s‘ Apphcatlon Data tion of one or more active agents contained in one or more (62) Division of application No. 11/245,190, ?led on Oct. Polymeric and/Or adhesive Carrier layers, proximate to a non‘ 7, 2005, now pat No_ 7,620,487' drug containing polymeric backing layer Which can control the delivery rate and pro?le of the transdermal drug delivery (60) Provisional application No, 60/616,861, ?led on Oct system by adjusting the moisture vapor transmission rate of 8, 2004. the polymeric backing layer. Patent Application Publication Apr. 28, 2011 Sheet 1 0f 2 US 2011/0097384 A1

K270i. Patent Application Publication Apr. 28, 2011 Sheet 2 0f 2 US 2011/0097384 A1

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TRANSDERMAL DRUG DELIVERY DEVICE the reservoir-type device, the active agent is generally kept INCLUDING AN OCCLUSIVE BACKING separate from the adhesive. The device has a pocket or “res ervoir” Which physically serves to hold the active agent and carrier, and Which is formed in or by a backing layer. A [0001] This application claims the bene?t of provisional peripheral adhesive layer is then used to af?x the device to the application 60/616,861 ?led Oct. 8, 2004, Which is hereby user. incorporated by reference in its entirety. [0009] The reservoir-type devices have a number of disad vantages including a non-uniform drug release pro?le Where FIELD OF THE INVENTION a high dose of drug is initially released upon application to the user, often described as a “burst effect.” This burst or high [0002] This invention relates generally to transdermal drug initial release of drug then drops off after a period of time to delivery systems, and more particularly to pharmaceutically a rate that necessary to achieve a therapeutically effective acceptable adhesive matrix compositions. The invention amount. Drug delivery according to this pro?le is generally additionally relates to transdermal drug delivery systems pro described as ?rst order release. viding acceptable drug release pro?les for an extended period [0010] While classic reservoir-type devices are still in use of time of up to seven days or longer. today, the term reservoir is being used interchangeably herein [0003] In particular, the present invention is directed to a transdermal drug delivery system for the topical application With matrix-type devices Which still rely upon a separate adhesive means used to af?x the device to the user. of one or more active agents contained in one or more poly meric and/ or adhesive carrier layers, proximate to a non-drug [0011] In a matrix-type device, the active agent is dissolved containing polymeric backing layer. The backing layer can be or dispersed in a carrier that typically is in a ?nite carrier form. processed or manufactured separately from the polymeric The carrier form can be self-adhesive or non-adhesive. Non and/or adhesive drug carrier layer(s) to prevent or minimize adhesive matrix-type devices, that is, those Which still rely on loss of drug or other system components, and combined prior a separate adhesive means to af?x the device to the user, to topical application. In the alternative, the backing device employ a drug permeable adhesive layer (often referred to as can be processed together With the polymeric and/ or adhesive an “in-line adhesive” since the drug must pass through this drug carrier layer(s). The drug delivery rate and pro?le can be layer) applied over the drug matrix carrier layer. To better controlled by adjusting certain characteristics of the poly control the release rate of the drug, the non-adhesive matrix meric backing layer. type devices often employ one or more additional drug per meable layers such as, for example, rate controlling mem BACKGROUND OF THE INVENTION branes. The non-adhesive matrix-type devices often contain excipients, such as drug delivery enhancers, to help control [0004] The use of transdermal drug delivery systems to the release rate. These devices are often referred to as multi topically administer an active agent is Well knoWn. These layer or multilaminate. systems incorporate the active agent into a carrier composi [0012] In a “monolithic” or “monolayer” matrix-type tion, such as a polymeric and/or pressure-sensitive adhesive device, the active agent is typically solubiliZed or homog composition, from Which the active agent is delivered through enously blended in an adhesive carrier composition, typically the skin or mucosa of the user. a pressure-sensitive adhesive orbioadhesive, Which functions [0005] Many factors in?uence the design and performance as both the drug carrier and the means of af?xing the system of such drug delivery devices, such as the individual to the skin or mucosa. Such devices, commonly referred to as themselves, the physical/ chemical characteristics of the sys drug-in-adhesive devices, are described, for example, in Us. tem’s components and the performance/behavior relative to Pat. Nos. 4,994,267; 5,446,070; 5,474,783 and 5,656,286, all other system components once combined, external/environ of Which are assigned to Noven Pharmaceuticals, Inc., mental conditions during manufacturing and storage thereaf Miami, Fla. and herein incorporated by reference. ter, the properties of the topical site of application, the desired [0013] While matrix-type devices, especially drug-in-ad rate of drug delivery and onset, the drug delivery pro?le, and hesive devices, achieve more uniform and controlled drug the intended duration of delivery. Cost, appearance, siZe and deliver rates over longer periods of time, most transdermal ease of manufacturing are also important considerations. systems remain subject to a higher initial drug release than is [0006] Active-ingredient-containing transdermal drug required to achieve therapeutic ef?cacy. For many drugs and/ delivery systems (“patches”) are essentially divided into tWo or therapeutic situations, it Would be advantageous to elimi major technical systems: reservoir systems and matrix sys nate or suppress this higher initial release and achieve a tems. The present invention relates to matrix systems Where “steady state” (Zero order) release pro?le Which uniformly the active ingredient(s) are embedded in a semi-solid matrix delivers a therapeutically effective amount of drug over the made up of a single polymer or a blend of polymers. extended duration of device’s desired use, preferably up to 7 [0007] Both types of devices employ a backing layer that days or more. forms the protective outer surface of the ?nished transdermal [0014] The high initial blood level concentration of certain system and Which is exposed to the environment during use. drugs may cause adverse or undesired effects, or create tox A release liner or protective layer that forms the inner surface icity concerns, thereby limiting the use of transdermal admin covers the polymeric adhesive Which is employed for af?xing istration. In other instances, the higher initial blood level the system to the skin or mucosa of a user. The release liner or concentration may reduce the amount of drug required for protective layer is removed prior to application, exposing the treatment to the point of risking under dosing, or the higher adhesive, typically a pressure-sensitive adhesive. initial blood level concentration may make it impractical to [0008] In the “classic” reservoir-type device, the active increase the duration of the device’s application While retain agent is typically dissolved or dispersed in a carrier to yield a ing therapeutic effectiveness. Reducing the frequency of non-?nite carrier form, such as, for example, a ?uid or gel. In replacing the transdermal drug delivery system Would US 2011/0097384 A1 Apr. 28, 2011

increase user compliance, reduce any lag or drop off in e?i one or more polymeric and/or adhesive carrier layers, proxi cacious blood levels, and reduce the amount of drug required mate to a non-drug containing polymeric backing layer Which for treatment (also provided by reducing the higher initial is manufactured to optimiZe drug loading While providing blood level associated With the higher release rate). desirable adhesion to skin or mucosa as Well as providing [0015] Drug concentration in transdermal delivery systems modulation of the drug delivery and pro?le. The polymeric can vary Widely depending on the drug and polymers used. backing layer is designed to provide control of permeation LoW drug concentrations in the adhesive can result in di?i rate, onset and pro?le of the active agent from the system. culties in achieving an acceptable delivery rate of the medi [0022] The transdermal delivery device may comprise at cament, preferably one approximating Zero order kinetics. least one layer formed of a single polymer or a blend of High drug concentrations, on the other hand, frequently affect polymers to serve as a pressure-sensitive adhesive composi the adhesion properties of the adhesives, and tend to promote tion for applying the system to the dermis. unWanted crystalliZation. [0023] The invention is also directed to compositions and [0016] Simple diffusion models for permeation of drugs methods of controlling drug delivery rates, onset and pro?les through the skin suggest that permeation rates are concentra of at least one active agent in a transdermal delivery system, tion dependent, that is, dependent on both the amount and the comprising selecting a speci?c a non-drug containing poly degree of drug Within the pressure-sensitive adhesive compo meric backing layer having speci?c physical and/or chemical sition. Some adhesives, such as, for example, polyacrylate characteristics. The drug carrier composition may be com adhesives have a high a?inity for many drugs and thus tend to prised of (a) one or more acrylic-based polymers having one solubiliZe higher concentrations of drug than do, for example, or more functionality or (b) one or more silicone-based poly rubber adhesives. HoWever, the use of polyacylates alone as mers having one or more silanol contents (capping) and/or the adhesive is not Without its drawbacks as polyacrylate resin to polymer ratios, alone or in combination, and are adhesives; for example, may tend to cause skin irritation, present in proportions to provide a desired for the especially When the transdermal device is used for extended drug. By selectively tailoring the moisture vapor transmission periods of time. rate of the backing layer, drug delivery, onset and pro?les can [0017] Various transdermal drug delivery systems have be achieved. been described in the literature. For example, US. Pat. No. [0024] For a better understanding of the present invention, 4,559,222 describes a multi-layer non-adhesive matrix-type together With other and further objects thereof, reference is device having a reservoir layer Which comprises mineral oil, made to the folloWing description, taken in conjunction With colloidal silicon dioxide, a polyisobutylene adhesive and a the accompanying draWings, and its scope Will be pointed out drug, Which may be , at a concentration greater than in the appending claims. Further embodiments of the inven saturation. The system includes a drug release rate controlling tion include those described in the detailed description. layer through Which the drug may diffuse at a knoWn rate, an adhesive layer, Which may also contain a loading of drug, and BRIEF DESCRIPTION OF THE DRAWINGS a protective strippable coating. [0018] US. Pat. No. 5,762,952 describes a system compris [0025] FIG. 1 shoWs a schematic cross-sectional vieW of a ing a self-crosslinking acrylate adhesive into Which a drug, transdermal delivery device according to an embodiment of such as clonidine, is incorporated together With auxiliaries, the invention prior to use. such as solvents or absorption promoters, that are volatile at [0026] FIG. 2 is a graphic representation of the effects on relatively high temperatures. The patent discusses that the drug delivery of clonidine in a transdermal delivery device crosslinked acrylate adhesive is important to increase the With varying backing layers. consistency of the adhesive substance and to incorporate either a large amount of the active drug or a large amount of DETAILED DESCRIPTION OF THE PREFERRED an inactive solubiliZin EMBODIMENTS [0019] Thus, it Would therefore be desirable to provide a [0027] The foregoing and other objects are achieved by this system for use With many types of drugs, in Which the per invention Which provides a transdermal drug delivery system meation rate and pro?le can be easily adjusted by employing to provide an adhesive matrix composition Which effectively a backing layer to modulate ?ux of drug through the skirt or delivers drugs to a user over an extended period of time. mucosa and While providing an active agent-containing car [0028] Unless de?ned otherWise, all technical and scien rier composition formulated in a simple and cost effective ti?c terms used herein have the same meaning as commonly manner. It Would be further advantageous to avoid drug loss understood by one of ordinary skill in the art to Which the encountered in manufacturing methods requiring high tem invention pertains. perature heating or drying after addition of a drug to the carrier composition. [0029] As used herein, the term “pressure-sensitive adhe sive” refers to a viscoelastic material Which adheres almost SUMMARY OF THE INVENTION instantaneously to most substrates With the application of very slight pres sure and remains permanently tacky. A poly [0020] Based upon the foregoing, it is an object of the mer is a pressure-sensitive adhesive Within the meaning of the present invention to overcome the limitations of the prior term as used herein if it has the properties of a pressure transdermal systems, and to provide a transdermal drug deliv sensitive adhesive per se or functions as a pressure-sensitive ery system Which alloWs selective modulation of drug perme adhesive by admixture With tacki?ers, plasticiZers or other ation and delivery rates and pro?les. additives. The term pressure-sensitive adhesive also includes [0021] Another object is to provide a transdermal system, mixtures of different polymers and mixtures of polymers, Which is simple and inexpensive to manufacture. The present such as polyisobutylenes (PIB) of different molecular invention provides a transdermal drug delivery system for the Weights, the resultant mixtures being a pressure-sensitive topical application of one or more active agents contained in adhesive. In the last case, the polymers of loWer molecular US 2011/0097384 A1 Apr. 28, 2011

Weight in the mixture are not considered to be “tacki?ers,” the [0040] As used herein “non-functional acrylic-based poly term “tacki?er” being reserved for additives Which differ mer” is de?ned as an acrylic-based polymer that has no or other than in molecular Weight from the polymers to Which substantially no functional reactive moieties present in the they are added. acrylic. These are generally acrylic esters Which can be copo [0030] The term “topical” or “topically” is used herein in its lymeriZed With other monomers Which do not have functional conventional meaning as referring to direct contact With an groups, such as vinyl . anatomical site or surface area on a mammal including skin, [0041] The term “carrier” as used herein refers to any non teeth, nails and mucosa. aqueous material knoWn in the art as suitable for transdermal [0031] The term “mucosa” as used herein means any moist drug delivery administration, and includes any polymeric anatomical membrane or surface on a mammal such as oral, material into Which an active agent may be solubiliZed in buccal, vaginal, rectal, nasal or ophthalmic surfaces. combination or admixture With the other ingredients of the [0032] The term “transdermal” as used herein means pas composition. The polymeric materials preferably comprise sage into and/or through skin or mucosa for localiZed or adhesives and, in particular, pressure-sensitive adhesives. systemic delivery of an active agent. The carrier material is typically used in an amount of about [0033] As used herein, the terms “blend” and “mixture” are 40% to about 90%, and preferably from about 50% to about used herein to mean that there is no, or substantially no, 80%, by Weight based on the dry Weight of the total carrier chemical reaction or crosslinking (other than simple H-bond composition. ing) betWeen the different polymers in the polymer matrix. HoWever, crosslinking betWeen a single polymer component [0042] The term “carrier composition” may also refer to is fully contemplated to be Within the scope of the present enhancers, solvents, co-solvents and other types of addictives invention. useful for facilitating transdermal drug delivery. [0034] The term “adhesive” means a substance, inorganic [0043] The carrier compositions of the present invention or organic, natural or synthetic that is capable of surface can also contain one or more non-aqueous solvents and/or attachment at the intended topical application site by itself or co-solvents. Such solvents and/or co-solvents are those functions as an adhesive by admixture With tacki?ers, plasti knoWn in the art, and are non-toxic, pharmaceutically accept ciZers, cross-linking agents or other additives. able substances, preferably non-aqueous liquids, Which do [0035] In the most preferred embodiment, the carrier of the not substantially negatively affect the adhesive properties or present invention is a “pressure-sensitive adhesive” Which the solubility of the active agents at the concentrations used. refers to a viscoelastic material Which adheres instanta The solvent and/or co-solvent can be for the active agent or neously to most substrates With the application of very slight for the carrier materials, or both. pressure and remains permanently tacky. A polymer or der [0044] Suitable solvents include volatile processing liquids mal composition is a pressure-sensitive adhesive Within the such as (e.g., methyl, ethyl, isopropyl alcohols and meaning of the term as used herein if it has the adhesive methylene chloride); ketones (e.g., ); aromatic hydro properties of a pressure-sensitive adhesive per se or functions carbons such as derivatives (e.g., and tolu as a pressure- sensitive adhesive by admixture With tacki?ers, enes); loWer molecular Weight alkanes and cycloalkanes plasticiZers, cross-linking agents or other additives. (e.g., hexanes, heptanes and cyclohexanes); and alkanoic acid [0036] As used herein, a “polymer composition of tWo or esters (e.g., ethyl acetate, n-propyl acetate, isobutyl acetate, more polymers” is de?ned as a physical blend of at least tWo n-butyl acetate isobutyl isobutyrate, hexyl acetate, 2-ethyl polymers and can include 3 or more polymers. The tWo or hexyl acetate or butyl acetate); and combinations and mix more polymers may include the acrylic-based polymers tures thereof. Other suitable co-solvents include polyhydric described herein and can optionally include other polymers alcohols, Which include glycols, triols and polyols such as discussed more fully beloW. glycol, diethylene glycol, propylene glycol, dipro [0037] The term “acrylic-based” polymer is de?ned as any pylene glycol, trimethylene glycol, butylene glycol, polyeth polyacrylate, polyacrylic, acrylate and acrylic polymer. The ylene glycol, hexylene glycol, polyoxethylene, glycerin, tri acrylic-based polymers can be any of the homopolymers, methylpropane, , polyvinylpyrrolidone, and the like. copolymers, terpolymers, and the like of various acrylic acids Alternatively, co-solvents may include glycol ethers such as or esters. The acrylic-based polymers useful in practicing the ethylene glycol monoethyl ether, glycol esters, glycol ether invention are polymers of one or more monomers of acrylic esters such as ethylene glycol monoethyl ether acetate and acids and other copolymeriZable monomers. The acrylic ethylene glycol diacetate; saturated and unsaturated fatty based polymers also include copolymers of alkyl acrylates acids, mineral oil, silicone ?uid, , retinol derivatives and/or methacrylates and/or copolymeriZable secondary and the like, and ethers, esters and alcohols of fatty acids. As monomers. Acrylic-based polymers With functional groups Will be described in more detail hereafter, the solvents or as described more fully beloW, are copolymeriZed With func co-solvents used in accordance With the invention are desir tional monomers. ably a loW volatile solvent that does not require excessive [0038] As used herein, “functionality” is broadly de?ned as temperatures for evaporation thereof. a measure of the type and quantity of functional groups that a [0045] The term “solubiliZed” is intended to mean that in particular acrylic-based polymer has. the carrier composition there is an intimate dispersion or [0039] As used herein, “functional monomers or groups,” dissolution of the active agent at the crystalline, molecular or are monomer units in acrylic-based polymers Which have ionic level, such that crystals of the active agent cannot be reactive chemical groups Which modify the acrylic-based detected using a microscope having a magni?cation of 25x. polymers directly or provide sites for further reactions. As such, the active agent is considered herein to be in “non Examples of functional groups include carboxyl, epoxy and crystallized” form When in the compositions of the present hydroxy groups. invention. US 2011/0097384 A1 Apr. 28, 2011

[0046] As used herein “?ux” is de?ned as the percutaneous [0055] The term “active agent” (and its equivalents “agent,” absorption of drugs through the skin, and is described by “drug,” “medicament” and “pharmaceutical”) is intended to Fides ?rst laW of diffusion: have the broadest meaning and includes at least one of any therapeutic, prophylactic, pharmacological or physiological active substance, cosmetic and personal care preparations, Where J is the ?ux in g/cm2/ sec, D is the diffusion coef?cient and mixtures thereof, Which is delivered to a mammal to of the drug through the skin in cm2/sec and dCm/dx is the produce a desired, usually bene?cial, effect. More speci? concentration gradient of the active agent across the skirt or cally, any active agent that is capable of producing a pharma mucosa. cological response, localiZed or systemic, irrespective of [0047] As used herein, “therapeutically effective” means Whether therapeutic, diagnostic, cosmetic or prophylactic in an amount of an active agent that is suf?cient to achieve the nature, is Within the contemplation of the invention. Also desired local or systemic effect or result, such as to prevent, Within the invention are such bioactive agents as , cure, diagnose, mitigate or treat a disease or condition, When insect repellents, sun screens, cosmetic agents, etc. It should applied topically over the duration of intended use. The be noted that the drugs and/ or bioactive agents may be used amounts necessary are knoWn in the literature or may be singularly or as a mixture of tWo or more such agents, and in determined by methods knoWn in the art, but typically range amounts su?icient to prevent, cure, diagnose or treat a disease from about 0.1 mg to about 20,000 mg, and preferably from or other condition, as the case may be. The drugs and mixtures about 0.1 mg to about 1,000 mg, and most preferably from thereof can be present in the composition in different forms, about 0.1 to about 500 mg per human adult or mammal of depending on Which form yields the optimum delivery char about 75 kg body Weight per 24 hours. acteristics. Thus, in the case of drugs, the drug can be in its [0048] The term “about”, and the use of ranges in general free base or acid form, or in the form of salts, esters, amides, Whether or not quali?ed by the term about, means that the , enantiomers or mixtures thereof, or any other phar number comprehended is not limited to the exact number set macologically acceptable derivatives, or as components of forth herein, and is intended to refer to ranges substantially molecular complexes. Within the quoted range not departing from the scope of the [0056] The drug is used in a “pharmacologically effective invention. amount.” This term means that the concentration of the drug [0049] The term “user” or “subject” is intended to include is such that in the composition it results in a therapeutic level all Warm-blooded mammals, preferably humans. of drug delivered over the term that the transdermal dosage [0050] The phrase “substantially Zero-order” as used herein form is to be used, preferably With Zero order kinetics. Such means transdermal delivery of an active agent at a release rate delivery is dependent on a great number of variables includ Which is approximately constant once steady state is attained, ing the drug, the time period for Which the individual dosage typically Within 12 to 24 hours after topical application. unit is to be used, the ?ux rate of the drug from the system and While variability in blood levels of active agent are contem a number of other variables. The amount of drug needed can plated Within the scope of this meaning once steady state be experimentally determined based on the ?ux rate of the release is attained, the depletion rate of active agent over the drug through the system and through the skin When used With duration of use should typically not exceed about 20% to and Without enhancers. Having determined the ?ux rate about 25%. needed, the transdermal delivery system is designed so that [0051] As used herein, the term “rubber” refers to a vis the release rate over the period of time of therapeutic use Will coelastic material Which has the properties of a pressure be at least equal to the ?ux rate. Of course, the surface area of sensitive adhesive and Which contains at least one natural or the transdermal delivery system also affects the delivery of synthetic elastomeric polymer. Suitable rubbers include pol the drug from the system. ysiloxane, polyisobutylene and natural rubber. [0057] Drugs in general can be used in this invention. These [0052] Solubility parameter, also referred to herein as “SP,” drugs include those categories and species of drugs set forth has been de?ned as the sum of all the intermolecular attractive on page ther-5 to ther-29 of the , 11th Edition forces, Which are empirically related to the extent of mutual Merck & Co. RahWay, N]. (1989). solubility of many chemical species. A general discussion of [0058] 1. ot- such as Adra?nil, Adre solubility parameters is found in an article by Vaughan, nolone, , , BudralaZine, Cloni “Using Solubility Parameters in Cosmetics Formulation,” J. dine, , , , Dipivefrin, Soc. Cosmel. Chem, Vol. 36, pages 319-333 (1985). , Epinephrine, FenoxaZoline, , Guanfa [0053] The multiple polymer adhesive system is preferably cine, Hydroxyamphetamine, lbopamine, lndanaZoline, formulated so that it is a pressure-sensitive adhesive at room lsometheptene, , , Methoxam temperature and has other desirable characteristics for adhe ine Hydrochloride, Methylhexaneamine, MetiZolene, Mido sives used in the transdermal drug delivery art. Such charac drine, , , , Octo teristics include good adherence to skin, ability to be peeled drine, , , or otherWise removed Without substantial trauma to the skin, Hydrochloride, Hydrochloride, Phe retention of tack With aging, etc. In general, the multiple nylpropylmethylamine, , , Pseu polymer adhesive system should have a glass transition tem doephedrine, , , TetrahydroZoline, perature (Tg), measured using a differential scanning calo , TramaZoline, , TymaZoline, rimeter, of betWeen about —70° C. and 0° C. and . [0054] Further details and examples of silicone pressure [0059] 2. [3-Adrenergic agonists such as Albuterol, Bam sensitive adhesives Which are useful in the practice of this buterol, , , , Clorprenaline, invention are described in the following US. Pat. Nos. 4,591, , Dioxethedrine, , Ephedrine, Epi 622; 4,584,355; 4,585,836; and 4,655,767. These patents are nephrine, , Ethylnorepinephrine, , For incorporated herein by reference. moterol, , lbopamine, lsoetharine, lsoproter US 2011/0097384 A1 Apr. 28, 2011

enal, , Metaproterenol, , Salicylate, , , Clometacin, , , , , , Cropropamide, Crotethamide, , , , , , Soterenol, Terbuterol and Di?unisal, Dihydroxyaluminum Acetylsalicylate, Dipyro . cetyl, Dipyrone, EmorfaZone, Enfenamic Acid, , [0060] 3. ot-Adrenergic blockers such as , Aro Etersalate, , EthoxaZene, , , tinolol, , , Mesylates, Fen , , FlufenamicAcid, Fluoresone, Flu spiride, lndoramin, , , , Tera pirtine, , , Fosfosal, Gentisic Zosin, , and . Acid, , lbufenac, lmidaZole Salicylate, lndometha [0061] 4. [3-Adrenergic blockers such as , Alpre cin, lndoprofen, lsofeZolac, lsoladol, lsonixin, , nolol, Amosulalol, , , , Betax , p-Lactophenetide, , , olol, , , , , Befe Acetylsalicylate, Acetylsalicylate, Meth tolol, , , , otrimepraZine, , , , Morpho Hydrochloride, Buto?lolol, , , , , , , Dilevalol, , line Salicylate, , , , 5' Nitro-2' Esmolol, lndenolol, Labetalol, , , propoxyacetanilide, Parsalmide, Perisoxal, , Metipranalol, , , , , Hydrochloride, Phenocoll, PhenopyraZone, , , , , , Phenyl Acetylsalicylate, , Phenyramidol, , , , Sul?nalol, , Ter PipebuZone, , , , Propy tatolol, , and . , , Salicylate, RamifenaZone, [0062] 5. deterrents such as Cyanamide Metilsulfate, Salacetamide, , Salicyla Citrated, Disulfuram, Nadide and NitrefaZole. mide, O-, Salicylsulfuric Acid, Sal [0063] 6. Aldose reductase inhibitors such as Epalrestat, salte, Salverine, Simetride, , Sulfamipy Ponalrestat, Sorbinil and Tolrestat. rine, , Talni?umate, , Terofenamate, [0064] 7. Anabolics such as , Androstene Tetradrine, Tinoridine, , Tolpronine, Trama diol, , , , , dol, , Xenbucin and . Formyldienolone, 4-Hydroxy-19-nortestosterone, Meth [0068] 1 1 . such as Acetamidoeugenol, Alfado andriol, Methenolone, Methyltrienolone, , Nan lone Acetate, , Amucaine, Amolanone, Amylo drolone Decanoate, Nandrolone p-Hexyloxyphenylpropi calne Hydrochloride, Benoxinate, , Betoxycaine, onate, Nandrolone Phenpropionate, Norbolethone, Biphenamine, , , Butaben, Butanilic , PiZotyline, , and aine, Burethamine, Sodium, Butoxycaine, Cartic . aine, 2- Hydrochloride, , [0065] 8. (dental) such as , Clove , , Dibucaine Hydrochloride, and Eugenol. Dimethisoquin, , Diperadon Hydrochloride, [0066] 9. Analgesics () such as , Allyl Dyclonine, Ecgonidine, Ecgonine, Ethyl AminobenZoate, , Alphaprodine, , , BeZit Ethyl Chloride, , , [3-Eucaine, Euprocin, ramide, , , , , Fenalcomine, Fomocaine, , Hydro Codeine Methyl , Codeine , Codeine Sul chloride, Sodium, Hydroxyprocaine, Hydrox fate, , , , Diampro ytetracaine, lsobutyl p-AminobenZoate, Kentamine, Leuci mide, , Dihydrocodeinone Enol Acetate, nocaine Mesylate, Levoxadrol, , , , , , Dimeth Hydrochloride, Metabutoxycaine Hydrochlo ylthiambutene, , , EptaZo ride, Sodium, Methyl Chloride, , cine, , Ethylmethlythiambutene, Ethylmor Myrtecaine, Naepaine, Octacaine, , OXethaZaine, phine, , , , Hydrocodone Parethoxycaine, Phenacaine Hydrochloride, , Bitartrate, , , lsometha , , , Polidocanol, Pramoxine, done, , , , Meperidine, Prilocalne, , , Propanocaine, Propara , , Hydrochloride, Meto caine, Propipocaine, , Hydrochloride, pon, , Morphine Derivatives, , Nalbu Pseudococaine, Pyrrocaine, Quinine Urea Hydrochloride, phine, Narceine, , , Normetha , Salicyl Alcohol, Hydrochloride, Thial done, , , , , , Thimylal, , Thiopental Sodium, , , , , Tolycaine, and . , Pheoperidine, , , Pro [0069] 12. Anorexics such as , Amphecloral, heptaZine, Promedol, , , Propoxyphene, , BenZaphetamine, , and . , , , Cyclexedrine, Destro [0067] 10. Analgesics (non-narcotic) such as Acetami amphetamine Sulfate, Diethylpropion, Diphemethoxidine, nophen, Acetaminosalol, , Acetylsalicylsalicylic N-Ethylamphetamine, , Fen?uramine, Fenpro Acid, , , , Aluminum Bis porex, Furfurylmethylamphetamine, Levophacetoperate, (acetylsalicylate), AminochlorthenoxaZin, 2-Amino-4-pi , , Metamfeproamone, Methamphet coline, Aminopropylon, Aminopyrine, Ammonium Salicy amine, Norpseudoephedrine, , Phendime late, Antipyrine, Antipyrine Salicylate, , traZine Tartrate, PhenmetraZirte, Phenpentermine, Phenyl ApaZone, , Benorylate, , BenZpipery propanolamine Hydrochloride and . lon, , p-Bromoacetanilide, 5-Bromosalicylic [0070] 13. Anthelmintics (Cestodes) such as , Acid Acetate, , , BumadiZon, Butacetin, Aspidin, Aspidinol, Dichlorophen(e), Embelin, Kosin, Calcium Acetylsalicylate, , Carbetidine, Car Napthalene, Niclosamide, Pellertierine, Pellertierine Tannate biphene, Carsalam, Chloralantipyrine, ChlorthenoXaZin(e), and Quinacrine. US 2011/0097384 A1 Apr. 28, 2011

[0071] 14. Anthelmintics (Nematodes) such as Alantolac Lidocaine, , Lorcamide, Meobentine, Metipra tone, Amoscanate, Ascaridole, Bephenium, Bitoscanate, Car nolol, , MoriciZine, Nadoxolol, Nifenalol, Oxpre bon Tetrachloride, Carvacrol, CyclobendaZole, Diethylcar nolol, Penbutolol, Pindolol, Pirmenol, Practolol, Prajmaline, bamaZine, Diphenane, DithiaZanine Iodide, Dymanthine, Hydrochloride, Pronethalol, , Gentian Violet, 4-Hexylresorcinol, , Mebenda Propranolol, Pyrinoline, Sulfate, Quinidine, Zole, 2-Napthol, Oxantel, Papain, , piperaZine Adi Sotalol, Talinolol, Timolol, Tocamide, , Viquidil pate, piperaZine Citrate, piperaZine Edetate Calcium, pipera and Xibenolol. Zine Tartrate, , Pyrvinium Pamoate, a-Santonin, StilbaZium Iodide, Tetrachloroethylene, Tetramisole, thia [0081] 24. Antiarteriosclerotics such as Pyridinol Carbam bendaZole, , Thymyl N-lsoamylcarbamate, Tri ate. clofenol piperaZine and Urea Stibamine. [0082] 25. Antiarthritic/Antirheumatics such as Allocupre [0072] 15. Anthelmintics (Onchocerca) such as lvermectin ide Sodium, Aurano?n, Aurothio glucose, Aurothioglycanide, and Sodium. , Calcium 3-Aurothio-2-propanol-l-sulfonate, [0073] 16. Anthelmintics (Schistosoma) such as Amoscan , , ClobuZarit, Cuproxoline, , ate, Amphotalide, Antimony Potassium Tartrate, Antimony , Gold Sodium Thiomalate, Gold Sodium Thio Sodium Gluconate, Antimony Sodium Tartrate, Antimony sulfate, , , LobenZarit, Melit Sodium Thioglycollate, Antimony Thioglycollamide, Becan tin, , Myoral and Penicillamine. thone, Hycanthone, Lucanthone Hydrochloride, NiridaZole, [0083] 26. Antibacterial () drugs including: Oxamniquine, PraZiquantel, Stibocaptate, Stibophen and Urea Stibamine. [0084] such as Amikacin, Apramycin, [0074] 17. Anthelmintic (Trematodes) such as Anthi Arbekacin, Bambermycins, Butirosin, Dibekacin, Dihdros olimine and Tetrachloroethylene. treptomycin, Fortimicin(s), Gentamicin, lspamicin, Kana [0075] 18. Antiacne drugs such as Adapelene, mycin, Micronomicin, , Neomycin Undecylenate, Acetophenide, , BenZoyl Peroxide, Cyoctol, Netilmicin, , Ribostamycin, Sisomicin, Specti , Motretinide, Resorcinol, Retinoic Acid, Tetro nomycin, , StreptonicoZid and Tobramycin; quinone and Tretinonine. [0085] Amphenicols such as AZidamfenicol, Chloram [0076] 19. Antiallergics such as , , phenicol, Palmitate, Chloramphenicol , Cromolyn, , , lbudilast, Pantothenate, Florfenicol and ; , , Pentigetide, Poison Ivy Extract, [0086] Ansamycins such as Rifamide, Rifampin, Rifamy Poison Oak Extract, Poison Sumac Extract, Repirinast, Tra cin and ; nilast, Traxanox and Urushiol. [0087] [3-Lactams, including: [0077] 20. Antiamebics such as , Bialamicol, Car [0088] Carbapenems such as lmipenem; barsone, Cephaeline, Chlorbetamide, Chloroquine, Chlor phenoxamide, Chlortetracycline, , Dibro [0089] Cephalosporins such as Cefactor, Cefadroxil, Cefa mopropamidine, , Dephetarsone, , mandole, CefatriZine, CefaZedone, CefaZolin, Ce?xime, , Glaucarubin, , 8-Hydroxy-7-iodo Ce?nenoxime, CefodiZime, Cefonicid, CefoperaZone, Cefo S-quinolinesulfonic Acid, lodochlorhydroxyquin, ranide, Cefotaxime, Cefotiam, CefpimiZole, Cefpirimide, lodoquinol, Paromomycin, , Phearsone Sul Cefpodoxime Proxetil, Cefroxadine, Cefsulodin, CeftaZi foxylate, PolybenZarsol, , Quinfamide, Secnida dime, Cefteram, CefteZole, Ceftibuten, CeftiZoxime, Ceftri axone, Cefuroxime, CefuZonam, Cephacetrile Sodium, Zole, Sulfarside, , , ThiocarbamiZine, Cephalexin, Cephaloglycin, , Cephalosporin, Thiocarbarsone and TimidaZole. Cephalothin, Cephapirin Sodium, Cephradine and Pivcefal [0078] 21. such as Bi?uranol, Cyoctol, Cyproterone, Acetate, Flutimide, exin; and . [0090] Cephamycins such as CeibuperaZone, Ce?netaZole, [0079] 22. such as Acebutolol, , Cefminox, Cefetan and Cefoxitin; , , Arotinolol, Atenolol, , [0091] Monobactams such as AZtreonam, Carumonam and Bevantolol, Bucumolol, , Bufuralol, Bunitrolol, Tigemonam; Bupranolol, CaroZolol, Carteolol, Carvedilol, Celiprolol, [0092] Oxacephems such as Flomoxef and Moxolactam; Maleate, , Epanolol, , Gallo [0093] such as Amidinocillin, Amdinocillin pamil, lmolamine, lndenolol, lsosorbide Dinitrate, lsrad Pivoxil, , Ampicillan, Apalcillin, Aspoxicillin, ipine, Limaprost, Mepindolol, Metoprolol, , AZidocillan, AZlocillan, Bacampicillin, BenZylpenicillinic , , , Nifenalol, , Acid, BenZylpenicillin Sodium, Carbenicillin, Nipradilol, , Nitroglycerin, Oxprenolol, Oxy Sodium, Carindacillin, Clometocillin, Cloxacillin, Cyclacil fedrine, , Penbutolol, Pentaerythritol Tetranitrate, lin, , Diphenicillin Sodium, Epicillin, Fenbeni Pindolol, Pronethalol, Propranolol, Sotalol, , cillin, Floxicillin, , Lenampicillin, Metampicillin, Timolol, Toliprolol and Verapamil. Methicillin Sodium, MeZlocillin, Sodium, Oxacil [0080] 23. Antiarrhythmics such as Acebutol, Acecaine, lin, Penamecillin, Penethamate Hydriodide, G , , Alprenolol, Amiodarone, Amoproxan, Benethamine, Penicillin G BenZathine, Penicillin G BenZhy , Arotinolol, Atenolol, Bevantolol, To sy drylamine, Penicillin G Calcium, Penicillin G Hydrabamine, late, Bubumolol, Bufetolol, , Bunitrolol, Bupra Penicillin G Potassium, Penicillin G Procaine, Penicillen N, nolol, Butidrine Hydrochloride, Butobendine, Capobenic Penicillin O, Penicillin V, Penicillin V BenZathine, Penicillin Acid, CaraZolol, Carteolol, Cifenline, Cloranolol, Disopyra V Hydrabamine, Penimepicycline, Phenethicillin Potassium, mide, Encamide, Esmolol, Flecamide, , Hydro Piperacillin, Pivapicillin, Propicillin, Quinacillin, Sulbenicil quinidine, lndecamide, lndenolol, lpratropium Bromide, lin, Talampicillin, Temocillin and Ticarcillin; US 2011/0097384 A1 Apr. 28, 2011

[0094] Lincosamides such as and Lincomy enamine Mandelate, Methenamine Sulfosalicylate, Nitroxo cin; line and Xibomol, such as Adiphenine [0095] Macrolides such as AZithromycin, Carbomycin, Hydrochloride, , Ambutonomium Bromide, Amino , , Erythromycin Acistrate, pentamide, Amixetrine, Amprotropine Phosphate, Anisotro Erythromycin Estolate, Erythromycin Glucoheptonate, pine Methylbromide, Apoatropine, , Atropine N-OX Erythromycin Lactobionate, Erythromycin Propionate, ide, , BenapryZine, BenZetimide, BenZilonium Erythromycin Stearate, Josamycin, Leucomycins, Mideca Bromide, BenZtropine Mesylate, Methyl Sulfate, mycins, Miokamycin, Oleandomycin, Primycin, Rokitamy , Butropium Bromide, N-Butylscopolammonium cin, Rosaramicin, , Spiramycin and Trolean Bromide, BuZepide, Camylo?ne, Hydrochlo domycin; ride, , , Cimetropium [0096] Polypeptides such as Amphomycin, Bacitracin, Bromide, , Cyclodrine, Cyclonium Capreomycin, , Enduracidin, Enviomycin, lodide, Hydrochloride, , , Fusafungine, Gramicidin(s), Gramicidin S, Mikamycin, Polymyxin, -Methanesulfonic Acid, Pristina Dibutoline Sulfate, Dicyclomine Hydrochloride, DiethaZine, mycin, Ristocetin, Teicoplanin, Thiostrepton, Tuberactino , , Diphemanil Methylsulfate, N-(l, mycin, Tyrocidine, Tyrothricin, , Viomycin, Vio 2-Diphenylethyl), Dipiproverine, Diponium mycin Pantothenate, V1rginiamycin and Bacitracin; Bromide, , EndobenZyline Bromide, [0097] such asApicycline, Chlortetracycline, EthopropaZine, EthybenZtropine, EthylbenZhydramine, Eto Clomocycline, Demeclocycline, , Guamecy midoline, Eucatropine, Bromide, Fentonium cline, Lymecycline, Meclocycline, Methacycline, Minocy Bromide, Flutropium Bromide, Glycopyrrolate, Heteronium cline, , Penimepicycline, Pipacycline, Roli Bromide, Methyl Sulfate, , Hyos tetracycline, Sancycline, Senociclin and Tetracycline; and cyamine, lpratropium Bromide, lsopropamide, Levomepate, [0098] other such as , Mupirocin Mecloxamine, Bromide, Metcaraphen, Meth and Tuberin. antheline Bromide, Methixene, Methscopolamine Bromide, [0099] 27. Antibacterial drugs (synthetic), including: Octamylamine, Chloride, , Oxyphe [0100] 2,4-Diaminopyrimidines such as Brodimoprim, nonium Bromide, Pentapiperide, Bromide, Tetroxoprim and Trimethoprim; Phencarbamide, , , Pip eridolate, Piperilate, Methysulfate, , Pri [0101] such as Furaltadone, FuraZolium Chlo ?nium Bromide, , , Pro ride, Nifuradene, , Nifurfoline, Nifurpirinol, Nifur penZolate, PropyromaZine, , Scopolamine praZine, Nifurtoinol and Nitrofurantoin; N-Oxide, Stilonium lodide, Stramonium, Sultroponium, Thi [0102] Quinolones and Analogs such as Ami?oxacin, hexinol, Thiphenamil, Tiemonium lodide, Timepidium Bro Cinoxacin, Cipro?oxacin, Di?oxacin, Enoxacin, Fleroxacin, mide, TiquiZium Bromide, lodide, Trihex Flumequine, Lome?oxacin, Miloxacin, Nalidixic Acid, Nor yphenidyl Hydrochloride, Tropacine, TropenZile, ?oxacin, O?oxacin, , Pe?oxacin, Pipemidic , , Valethamate Bromide and Acid, Piromidic Acid, Rosoxacin, Tema?oxacin and Tosu Xenylropium Bromide. ?oxacin; [0105] 28. such as Acetylpheneturide, [0103] Sulfonamides such as Acetyl Sulfamethoxypyra Zine, Acetyl Sul?soXaZole, AZosulfamide, BenZylsulfamide, Albutoin, Aloxidone, , 4-Amino-3-hy Chloramine-B, Chloramine-T, Dichloramine T, Formosul droxybutyric Acid, Atrolactamide, , Buramate, fathiaZole, N2 Formylsul?somidine, Nz-a-D-Glucosylsulfa Calcium Bromide, CarbamaZepine, Cinromide, ClomethiaZ nilamide, Mafenide, 4'-(Methylsulfamoyl)sulfanilanilide, ole, , Decimemide, Diethadione, Dimethadione, Doxenitoin, , , , , p-NitrosulfathiaZole, Noprylsulfamide, Phthalylsulfaceta Fluoresone, Garbapentin, 5-Hydroxytryptophan, Lamot mide, , SalaZosulfadimidine, Succinyl rigine, Lomactil, Magnesium Bromide, Magnesium Sulfate, sulfathiaZole, SulfabenZamide, Sulfacetamide, Sulfachlorpy Mephenyloin, Mephobarbital, , Methetoin, ridaZine, Sulfachrysoidine, Sulfacytine, , Methsuximide, 5-Methyl-5-(3-phenanthryl), Sulfadicramide, Sulfadimethoxine, , Sulfaethi dole, , Sulfaguanol, , Sulfaloxic 3-Methyl-5-phenylhydantoin, , , , , , Phenetharbital, Acid, SulfameraZine, Sulfameter, SulfamethaZine, Sulfame , , Phenobarbital Sodium, Phen thiZole, Sulfamethomidine, SulfamethoXaZole, Sul famethoXypyridaZine, Sulfametrole, Sulfamidochrysoidine, suximide, Phenylmethylbarbituric Acid, Phenyloin, Pheth Sulfamoxole, Sulfanilamide, Sulfanilamidomethanesulfonic enylate Sodium, , Pregabatin, , Acid Triethanolamine Salt, 4-Sulfanilamidosalicylic Acid, , , Sodium , Solanum, N4-Sulfanilylsulfanilamide, Sulfanilylurea, N-Sulfanilyl-3, Bromide, Suclofenide, Sulthiame, Tetrantoin, 4-Xylamide, Sulfanitran, Sulfaperine, SulfaphenaZole, Sul , , Valproic Acid, , faproxyline, SulfapyraZine, Sulfapyridine, SulfasomiZole, and . SulfasymaZine, SulfathiaZole, Sulfathiourea, , [0106] 29. , including: Sul?somidine and Sul?soxaZole; [0107] Bicyclics such as Binedaline, , Citalo [0104] Sulfones such as Acedapsone, Acediasulfone, pram, , lndalpine, , lndeloXaZine Acetosulfone Sodium, , Diathymosulfone, Gluco Hydrochcloride, Nefopam, , Oxitriptan, sulfone Sodium, Solasulfone, Succisulfone, Sulfanilic Acid, , , , ThiaZesim, , p-SulfanilylbenZylamine, p,p'-Sulfonyldianiline-N,N' diga and Zometapine; lactoside, Sulfoxone Sodium and ThiaZolsulfone; and others [0108] / such as Benmoxine, lpro such as Clofoctol, Hexedine, Methenamine, Methenamine cloZide, lproniaZid, lsocarboXaZid, , Anhydromethylene-citrate, Methenamine Hippurate, Meth and ; US 2011/0097384 A1 Apr. 28, 2011

[0109] Pyrrolidones such as , Rolicyprine and tosine, HalethaZole, Hexetidine, Lo?ucarban, Nifuratel, ; , , Pyrithione, Salicylanilide, [0110] such as , , Sodium Propionate, , , , and . Tolindate, , Tricetin, Ujothion, [0111] such as , , Ami and Zinc Propionate. triptylinoxide, , , , [0129] 36. Antiglaucoma drugs such as , , , , Dimetracrine, Befunolol, , Bupranolol, Carteolol, DapipraZoke, Dothiepin, , , lmipramine, lmipramine Dichlorphenamide, Dipivefrin, Epinephrine, Levobunolol, N-Oxide, lprindole, , , , , , , Pindolol and , Noxiptilin, , PiZotyline, Timolol. , , , and [0130] 37. such as , ; and and . [0112] others such as Adra?nil, BenactyZine, , [0131] 38. Antigout drugs such as , , Butacetin, Deanol, Deanol Aceglumate, Deanol Acetamido , and Sul?npyraZone. benZoate, Dioxadrol, , , Femoxet [0132] 39. , including: ine, , , , Fluvoxamine [0133] Alkylamine derivatives such as , Bami Maleate, , Hypercinin, Levophacetoper pine, , Chlorpheniramine, Dimethindene, ane, , , , OXa?oZane, Metron S, , , Thenaldine, Tolpro , , Pyrisuccideanol, , pamine and ; , , , , , [0134] Aminoalkyl ethers such as Bietanautine, Bromo , , L-, V1loxaZine and , , , Diphenly Zimeldine. pyraline, , Embrammine, , [0113] 30. Antidiabetics, including: Mephenphydramine, p-Methyldiphenhydramine, [0114] such as Buforrnin, and Phen , , Piprinhydrinate and Seta formin; s1ne; [0115] such as Glucagon and Insulin; [0135] derivatives such as , [0116] Sulfonylurea derivatives such as , p-Bromtripelennamine, , , l-Butyl-3-metanilylurea, , , , Methafurylene, , Methapy , , , , Glisoxepid, rilene, , Pyrilamine, , Thenyl Glyburide, GlybuthiaZol(e), GlybuZole, Glyhexamide, Gly diamine, Hydrochloride, and midine, Glypinamide, Phenbutamide, , Tolbuta Zolamine; mide and Tolcyclamide; and [0136] such as , , Cin [0117] others such as Acarbose, Calcium Mesoxalate and nariZine, and ; Miglitol. [0137] Tricyclics, including: [0118] 31. Antidiarrheal drugs such as Acetyltannic Acid, [0138] such as Ahistan, , Albumin Tannate, Alkofanone, Aluminum SalicylatesiBa , N- Chloride, lso sic, , , , Lidamidine, Lomo , , PromethaZine, PyrathiaZine and til, , Mebiquine, Trillium and UZarin. ThiaZinamium Methyl Sulfate; and [0119] 32. Antidiuretics such as Desmopressin, Fely [0139] others such as , , Cyprohep pressin, Lypressin, Ornipressin, Oxycinchophen, Pituitaryi tadine, Deptropine, lsothipendyl, and Pro Posterior, Terlipressin and Vasopressin. thipendyl; and [0120] 33. such as , [0140] other antihistamines such as , Astemi , and . Zole, AZelastine, Cetoxime, , , [0121] 34. drugs (antibiotics), including: DiphenaZoline, Diphenhydramine, Propionate, [0122] Polyenes such as Amphotericin-B, , Der Mebhydroline, , and . mostatin, Filipin, Fungichromin, , , [0141] 40. Antihyperlipoproteinemics, including: Lucensomycin, , , , Pecilocin [0142] Aryloxyalkanoic acid derivatives such as Beclor and Perimycin; and brate, BaZa?brate, Bini?brate, Cipro?brate, Clino?brate, [0123] others such as AZaserine, , Oligomy Clo?brate, Clo?bric Acid, Eton?brate, Feno?brate, Gem? cins, Neomycin Undecylenate, Pyrrolnitrin, Siccanin, Tuber broZil, Nico?brate, Piri?brate, Roni?brate, Sim?brate and cidin and Viridin. Theo?brate; [0124] 35. Antifungal drugs (synthetic), including: [0143] acid sequesterants such as Cholestyramine [0125] such as Nafti?ne and Terbina?ne; Resin, and Polidexide; [0126] lmidaZoles such as , , [0144] HMG CoA reductase inhibitors such as , , , CloconaZole, , , Sodium and ; , EnilconaZole, , lsoconaZole, Keto [0145] Nicotinic acid derivatives Aluminum Nicotinate, conaZole, , , , , , , Nicoclonate, Nicomol and Oxiniacic and ; Acid; [0127] such as , ltraconaZole and [0146] and analogs such as Etiroxate, ; and Thyropropic Acid and Thyroxine; and [0128] others such as Acrisorcin, Amorol?ne, Biphe [0147] others such as Acifran, AZacosterol, Ben?uorex, namine, Bromosalicylchloranilide, Buclosamide, Calcium a-BenZalbutyramide, Carnitine, , Clom Propionate, Chlophenesin, , Cloxyquin, Coparaf estone, Detaxtran, Dextran Sulfate Sodium, 5,8,11,14,17 ?nate, DiamthaZole, Dihydrochloride, Exalamide, Flucy Eicosapentaenoic Acid, Eritadenine, FuraZbol, , US 2011/0097384 A1 Apr. 28, 2011

Melinamide, Mytatrienediol, Omithine, a-OryZanol, Pan , 3,5-Diiodotyrosine, Hinderin, , lothiouracil, tethine, Penataerythritol Tetraacetate, a-Phenylbutyramide, MethimaZole, Methylthiouracil, Propylthiouracil, Sodium PiroZadil, , a-Sitosterol, Sultosilic Acid, piperaZine Perchlorate, ThibenZaZoline, and 2-Thiouracil. Salt, , and Xenbucin. [0163] 43. Antihypotensive drugs such as AmeZinium [0148] 41.Antihypertensive drugs, including: Methyl Sulfate, Angiotensin Amide, Dimetofrine, Dopam [0149] Arylethanolamine derivatives such as Amosulalol, ine, Etifelmin, Etilefrin, , Metaraminol, , Bufuralol, Dilevalol, Labetalol, Pronethalol, Sotalol and Sul Norepinephrine, Pholedrinead and Synephrine. ?nalol; [0164] 44. Antihypothyroid drugs such as [0150] Aryloxypropanolamine derivatives such as Acebu Sodium, Liothyronine, Thyroid, Thyroidin, Thyroxine, tolol, Alprenolol, Arotinolol, Atenolol, Betaxolol, Bevan Tiratricol and TSH. tolol, Bisoprolol, Bopindolol, Bunitrolol, Bupranolol, Buto [0165] 45. Anti-In?ammatory (non-steroidal) drugs, ?lolol, CaraZolol, CarteZolol, Carvedilol, Celiprolol, including: Cetamolol, Epanolol, lndenolol, Mepindolol, Metipranolol, [0166] Aminoarylcarboxylic acid derivatives such as Enfe Metoprolol, Moprolol, Nadolol, Nipradilol, Oxprenolol, Pen namic Acid, , , lsonixin, butolol, Pindolol, Propranolol, Talinolol, Tetraolol, Timolol , Mefanamic Acid, Ni?umic Acid, Talni and Toliprolol; ?umate, Terofenamate and Tolfenamic Acid; [0151] BenZothiadiaZine derivatives such as AlthiaZide, [0167] Arylacetic acid derivatives such as , Bendro?umethiaZide, BenZthiaZide, BenZylhydrochlorothi Alclofenac, , Bufexamac, Cinmetacin, Clopirac, aZide, ButhiaZide, ChlorothiaZide, Chlorthalidone, Cyclo Sodium, Etodolac, Felbinac, , Fen penthiaZide, , , EpithiaZide, EthiaZ clorac, , , Glucametacin, lbufenac, ide, FenquiZone, , Hydro?umethiaZide, lndomethacin, lsofeZolac, lsoxepac, , MetiaZinic MethyclothiaZide, Meticrane, MetolaZone, Para?utiZide, Acid, Oxametacine, , , Tiaramide, PolythiaZide, TetrachlormethiaZide and TrichlormethiaZide; and Zomepirac; [0152] N-Carboxyalkyl (peptide/lactam) derivatives such [0168] Arylbutyric acid derivatives such as BumadiZon, asAlacepril, Captopril, CilaZapril, Delapril, Enalapril, Enala Butibufen, and Xenbucin; prilat, Fosinopril, Lisinopril, Moveltipril, Perindopril, [0169] Arylcarboxylic acids such as Clidanac, Ketorolac Quinapril and Ramipril; and Tinoridine; [0153] Dihydropyridine derivatives such as Amlodipine, [0170] Arylpropionic acid derivatives such as Alminopro Felodipine, lsradipine, Nicardipine, Nifedipine, Nilvadipine, fen, Benoxaprofen, Bucloxic Acid, Carprofen, Fenoprofen, Nisoldipine and ; , Flurbiprofen, , lbuproxam, [0154] derivatives such as , lndoprofen, Ketoprofen, Loxoprofen, Miroprofen, Debrisoquin, GuanabenZ, Guanacline, , GuanaZo Naproxen, , , , , dine, , , Guanochlor, ProtiZinic Acid, Suprofen and ; and ; [0171] such as DifenamiZole and EpiriZole; [0155] HydraZines and phthalaZines such as BudralaZine, [0172] such as ApaZone, BenZpiperylon, , , , HydracarbaZine, , , MoraZone, , , , and TodralaZine; PhenybutaZone, PipebuZone, , Ramifena [0156] lmidaZole derivatives such as Clonidine, Lofexi Zone, and ThiaZolinobutaZone; dine, , Phentolamine Mesylate, Tiamenidine [0173] derivatives such as Acetaminosalol, and ; Aspirin, Benorylate, Bromosaligenin, Calcium Acetylsalicy [0157] Quaternary ammonium compounds AZamethonium late, Di?unisal, Etersalate, Fendosal, Gentisic Acid, Glycol Bromide, Chloride, , Pen Salicylate, lmidaZole Salicylate, Lysine Acetylsalicylate, tacynium Bis(methyl sulfate), Pentamethonium Bromide, Mesalamine, Morpholine Salicylate, l-Naphthyl Salicylate, Tartate, Phenactopinium Chloride and Trime , Parsalmide, PhenylAcetylsalicylate, Phenyl Sali thidiunum Metho sulfate; cylate, Salacetamide, Salicylamine O-Acetic Acid, Salicyl [0158] derivatives such as , sulfuric Acid, and ; , DoxaZosin, Prasosin, and TrimaZosin; [0174] ThiaZinecarboXamides such as , lsoxi [0159] derivatives such as , Deser cam, and Tenoxicam; and pidine, , Reserpine and ; [0175] others such as e-Acetamidocaproic Acid, S-Adeno [0160] derivatives such as Ambuside, Clopa sylmethionine, 3-Amino-4-hydroxybutyric Acid, Amix mide, , lndapamide, QuinethaZone, Tripamide etrine, , BenZydamine, Bucolome, , and Xipamide; and DitaZol, EmorfaZone, GuaiaZulene, , Nime [0161] others such as Ajmaline, a-Aminobutyric Acid, sulide, Orgotein, , Paranyline, Perisoxal, Pifoxime, Bufeniode, Candesartan, Chlorthalidone, Cicletaine, Ciclosi , ProXaZole and . domine, Tannates, Eprosartan, , [0176] 46. Antimalarial drugs such as Acedapsone, Amo , lndoramin, lrbesartan, , , diaquin, Ar‘teether, , , Ar‘tesunate, Metbutamate, , , Methyl 4-Py Bebeerine, , Chirata, Chlorguanide, Chloroquine, ridyl Ketone ThiosemicarbarZone, MetolaZone, , Chlorproguanil, Cinchona, Cinchonidine, Cinchonine, MuZolimine, , , , , , Gentiopicrin, , Hydroxychloro Primaperone, Protoveratrines, Raubasine, Rescimetol, Ril quine, Me?oquine Hydrochloride, 3-Methylarsacetin, Pam menidene, Saralasin, , Ticrynafen, Tri aquine, Plasmocid, , , Quinacrine, methaphan Camsylate, Tyrosinase, and Valsartan. Quinine, Quinine Bisulfate, Quinine Carbonate, Quinine [0162] 42. Antihyperthyroids such as 2-Amino-4-meth Dihydrobromide, Quinine Dihydrochloride, Quinine Ethyl ylthiaZole, 2-AminothiaZole, CarbimaZole, 3,5-Dibromo-L carbonate, Quinine Formate, Quinine Gluconate, Quinine US 2011/0097384 A1 Apr. 28, 2011

Hydriodide, Quinine Hydrochloride, Quinine Salicylate, TenuaZonic Acid, TriaZiquone, 2,2',2"-Trichlorotriethy Quinine Sulfate, Quinine Tannate, Quinine Urea Hydrochlo lamine, Urethan, Vmblastine, Vmcristine, Vindesine and ride, Quinocide, and Sodium Arsenate Diabasic. Vinorelbine. [0177] 47. Antimigraine drugs such as Alpiropride, Dihy [0194] 50. Antineoplastic (hormonal) drugs, including: droergotamine, , Ergocomine, Ergocominine, [0195] such as , Dromostanolone Ergocryptine, , , acetate, Propionate, , and ; FonaZine, , Methysergid(e), , , [0196] Antiadrenals such as Amino , PiZotyline, and . and Trilo stane; [0178] 48. Antinauseant drugs such as Acetylleucine [0197] Antiandrogens such as and Nilutamide; Monoethanolamine, , , Bietanau tine, , , , , and , , Dipheniodol, , [0198] Antiestrogens such as Tamoxifen and Toremifene. , , Methalltal, , [0199] 51. Antineoplastic adjuncts including folic acid , , Ondansteron, Oxypendyl, Pipam replenishers such as Frolinic Acid. aZine, Piprinhydrinate, , Scopolamine, Tet [0200] 52. Antiparkinsonian drugs such as , rahydrocannabinols, , ThioproperZaine and , , Bietanautine, Biperiden, Bro . mocriptine, , , , Dexetimide, [0179] 49. Antineoplastic drugs, including: DiethaZine, Diphenhydramine, , EthopropaZine, [0180] Alkylating agents, including: EthylbenZhydramine, Levodopa, Naxagolide, , , , Pridinol, Prodipine, , [0181] Alkyl sulfonates such as Busulfan, lmprosulfan and , , , and Trihex Piposulfan; yphenidyl Hydrochloride. [0182] AZiridines such as BenZodepa, Carboquone, Meturedepa and Uredepa; [0201] 53. Antipheochromocytoma drugs such as Mety rosine, and Phentolamine. [0183] Ethylenimines and methylmelamines such as Altre tamine, Sulfosamide, Triethylenemelamine, Triethylene [0202] 54. Antipneumocystis drugs such as Efformithine, phosphoramide, Triethylenethiophosphoramide and Trim and SulfamethoxaZole. ethylolomelamine; [0203] 55. Antiprostatic hypertrophydrugs such as Gesto [0184] mustards such as Chlorambucil, Chlor norone Caproate, Mepartricin, Oxendolone and Proscar7. naphaZine, Chclophosphamide, , lfosfamide, [0204] 56. drugs (Leshmania) such as Anti Mechlorethamine, Mechlorethamine Oxide Hydrochloride, mony Sodium Gluconate, Ethylstibamine, Hydroxystilbami Melphalan, Novembichin, Phenesterine, , Tro dine, N-Methylglucamine, Pentamidine, Stilbamidine and fosfamide and Mustard; Urea Stibamine. [0185] Nitrosoureas such as Carmustine, ChloroZotocin, [0205] 57. AntiprotoZoal drugs (Trichomonas) such as Fotemustine, Lomustine, Nimustine and Ranimustine; and Acetarsone, AminitroZole, Anisomycin, , Form [0186] others such as Camptothecin, DacarbaZine, Manno initraZole, , Hachimycin, Lauroguadine, mustine, Mitobronitol, Mitolactol and Pipobroman; Mepartricin, , Nifuratel, Nifuroxime, Nimora [0187] Antibiotics such as Aclacinomycins, Actinomycin Zole, , Silver Picrate, TenonitroZole and Timida Ft, Anthramycin, AZaserine, Bleomycins, Cactinomycin, Zole. Carubicin, CarZinophilin, Chromomycins, Dactinomycin, [0206] 58. AntiprotoZoal drugs (Trypanosma) such as Ben Daunorubicin, 6-DiaZo-5-oXo-L-norleucine, Doxorubicin, ZnidaZole, E?ornithine, Melarsoprol, Nifurtimox, Oxophe Epirubicin, Mitomycins, , Nogalamycin, narsine, Hydrochloride, Pentamidine, Propamidine, Puromy Olivomycins, Peplomycin, , Por?romycin, Puro cin, Quinapyramine, Stilbamidine, Suramin Sodium, Trypan mycin, Rufocromomycin, Streptonigrin, StreptoZocin, Red and Tryparasmide. Tubercidin, Uhenimex, Zinostatin and Zorubicin; [0207] 59. Antipuritics such as , , [0188] Antimetabolites, including: , , , 3-Hydroxycamphor, [0189] Folic acid analogs such as Denopterin, Methotrex , Mesulphen, , Phenol, Polidocanol, ate, Pteropterin and ; Risocaine, Spirit of Camphor, Thenaldine, and [0190] analogs such as Fludarabine, 6-Mercaptopu TrimepraZine. rine, Thiamiprine and Thioguanaine; and [0208] 60. Antipsoriatic drugs such as Acitretin, Ammo [0191] analogs such asAncitabine, AZacitidine, nium Salicylate, Anthralin, 6-AZauridine, Bergapten(e), 6-AZauridine, Carmofur, Cytarabine, Doxi?, Enocit Chrysarobin, Etretinate and Pyrogallol. abine, Floxuridine, Fluoroouracil and Tegafur; [0209] 61. drugs, including: [0192] such as L-Asparaginase; and [0210] such as , , [0193] others such as Aceglatone, Amsacrine, Bestrabucil, properidol, , , , , Bisantrene, Bryostatin 1, Carboplatin, Cisplatin, Defofa , Sniperone, and Tri?uperidol; mide, , DiaZiquone, Dolastatins, Elfomithine, [0211] PhenothiaZines such as , Butapera Elliptinium Acetate, Etoglucid, Etoposide, Gallium Nitrate, Zine, CarphenaZine, , ChlorpromaZine, Hydroxyurea, Interferon-a, Interferon-a, Interferon-a, Inter ClospiraZine, , , , 1mi leukine-2, Lentinan, , , MitoguaZone, clopaZine, MepaZine, , MethoXypromaZine, Mitoxantrone, Mopidamol, Nitracrine, Pentostatin, Phe MetofenaZate, OXa?umaZine, , PericyaZine, namet, Pirarubicin, Podophyllinicc Acid, 2-EthylhydraZide, PerimethaZine, , , , Polynitrocubanes, , PSK7, RaZoXane, SiZofu ProchlorperaZine, , , , ran, Spirogermanium, Symplostatin 1, Taxol, Teniposide, , Tri?uoperaZine and Tri?upromaZine; US 2011/0097384 A1 Apr. 28, 2011

[0212] such as , Clo [0225] others such as Aluminum Acetate Solution, Alumi penthixol, and Thiothixene; num Subacetate Solution, Aluminum Sulfate, 3-Amino-4 [0213] other tricyclics such as BenZquinamide, hydroxybutyric Acid, Boric Acid, , ChloroaZo , , Clomacran, Clothiapine, din, m-Cresyl Acetate, Cupric Sulfate, Dibromopropamidine, , Opipramol, , , and lchthammol, Negatol7, Noxytiolin, OmidaZole, a-Propiolac ; and tone, a-Terpineol. [0226] 66. drugs such as Alibendol, Ambu [0214] others such as AliZapride, , Buramate, cetamide, AminopromaZine, Apoatropine, Bevonium Methyl , , Pen?uridol, , Spirilene Sulfate, Bietamiverine, Butaverine, Butropium Bromide, and Sulpiride. N-Butylscopolammonium Bromide, , [0215] 62. such as Acetaminophen, Acetami , , Clebopride, Coniine nosalol, Acetanilide, Aconine, Aconite, , Hydrobromide, Coniine Hydrochloride, Cyclonium lodide, Alclofenac, Aluminum Bis(acetylsalicylate), Aminochlorth Difemerine, , Dioxaphetyl Butyrate, Diponium enoXaZin, Aminopyrine, Aspirin, Benorylate, BenZydamine, Bromide, , Emepronium Bromide, Ethaverine, Berberine, p-Bromoacetanilide, Bufexamac, BumadiZon, Feclemine, Fenalamide, , Fenpiprane, Fenpiver Calcium Acetysalicylate, ChlorthenoXaZin(e), Choline Sali cylate, Clidanac, Dihydroxyaluminum Acetylsalicylate, inium Bromide, , , Flopropi , Dipyrone, EpiriZole, Etersalate, lmidaZole Sali one, Gluconic Acid, Guaiactamine, HydramitraZine, Hyme cromone, Leiopyrrole, , , Na?verine, cylate, lndomethacin, lsofeZolac, p-Lactophenetide, Lysine Octamylamine, Octaverine, Pentapiperide, Phenamacide Acetylsalicylate, Magnesium Acetylsalicylate, Meclofe Hydrochloride, , , Piperi namic Acid, MoraZone, Morpholine Salicylate, Naproxen, late, Pipoxolan Hydrochloride, Pramiverin, Pri?nium Bro NifenaZone, 5'-Nitro-2'-propoxyacetanilide, Phenacetin, mide, Properidine, Propivane, PropyromaZine, ProZapine, PhenicarbaZide, Phenocoll, PhenopyraZone, Phenyl Acetyl Racefemine, , Spasmolytol, Stilonium lodide, salicylate, Phenyl Salicylate, PipebuZone, Propacetamol, Sultroponium, Tiemonium lodide, TiquiZium Bromide, Tiro PropyphenaZone, RamifenaZone, Salacetamide, Salicyla pramide, , Tricromyl, Trifolium, , mide O-Acetic Acid, Sodium Salicylate, Sulfamipyrine, Tet N,N-1-Trimethyl-3,3-diphenyl-propylamine, TropenZile, randrine and Tinoridine. Trospium Chloride and Xenylropium Bromide. [0216] 63. Antirickettsial drugs such as p-AminobenZoic [0227] 67. drugs such as , Arga Acid, Chloramphenicol, Chloramphenicol Palmitate, troban, , Chrysoptin, Daltroban, De?brotide, Chloramphenicol Pantothenate and Tetracycline. Enoxaparin, Fraxiparine7, lndobufen, Lamoparan, Ozagrel, [0217] 64. Antiseborrheic drugs such as , 3-O , Pla?bride, Reviparin, Tedelparin, , Lauroylpyridoxol Diacetate, Piroctone, Pyrithione, Resorci Tri?usal and . nol, Sul?des and Tioxolone. [0228] 68. Antitussive drugs such as Allocamide, Amici [0218] 65. , including: bone, , , , [0219] such as Alexidine, AmbaZone, Chlo Bromoform, , Butethamate, Caramiphen rhexidine and Picloxydine; Ethanedisulfonate, Carbetapentane, Chlophedianol, Clobuti [0220] Halogens and halogen compounds such as nol, , Codeine, Codeine Methyl Bromide, lodide Oxide, Bismuth lodosubgallate, Bismuth Tribro Codeine N-Oxide, Codeine Phosphate, Codeine Sulfate, mophenate, Bornyl Chloride, Calcium lodate, Chlorinated Cyclexanone, , Sodium, Dihy Lime, Clo?ucarban, Fluorosalan, lodic Acid, lodine, Iodine drocodeine, Dihydrocodeinone Enol Acetate, , Monochloride, Iodine Trichloride, lodoform, Methenamine , a,a-Diphenyl-2-piperidinepropanol, pro Tetraiodine, oxychlorosene, PoVidone-lodine, Sodium propiZine, , , Ethyl Dibunate, Ethyl Hypochlorite, Sodium lodate, Symclosene, Thymol lodide, morphine, , Guiaiapate, Hydrocodone, lsoami , and Troclosene Potassium; nile, , , Narceine, [0221] Mercurial compounds such as Hydragaphen, Mera , , , , Pholcod lein Sodium, Merbromin, Mercuric Chloride, Mercuric Chlo ine, Picoperine, PipaZethate, , ride, Ammoniated, Mercuric Sodium p-Phenolsulfonate, Hydrochloride, Racemethorphan, TaZiprinone Hydrochlo Mercuric , Mercuric Sul?de, Red, Mercurophen, ride, and . Mercurous Acetate, Mercurous Chloride, Mercurous lodide, [0229] 69. Antiulcerative drugs such as Alu Nitromersol, Potassium Tetraiodomercurate(ll), Potassium minum Complex, e-Acetamidocaproic Acid Zinc Salt, Triiodomercurate(ll) Solution, Thimerfonate Sodium and , Arbaprostil, Benexate Hydrochloride, Bismuth Thimerosal; Subcitrate Sol (Dried), , , Cimeti [0222] Nitrofurans such as FuraZolidone, 2-(Methoxym dine, Enpro stil, EsapraZole, , Ftaxilide, Gefamate, ethyl)-5-, NidroXyZone, Nifuroxime, and GuaiaZulene, lrsogladine, , , Omepra ; Zole, Omoprostil, a-OryZanol, Pifamine, , [0223] such as Acetomeroctol, , Cad Plaunotol, , Rioprostil, Rosaprostol, Rotraxate, mium Salicylate, Carvacrol, Chloroxylenol, Clorophene, , , SpiZofurone, , Cresote, Cresol(s), p-Cresol, Fenticlor, Hexachlorophene, , Trimoprostil, ThrithioZine, and Zoli l-Napthyl Salicylate, 2-Napthyl Salicylate, 2,4,6-Tribromo midine. m-cresol, and 3',4',5-Trichlorosalicylanilide; [0230] 70. Antiurolithic drugs such as Acetohydroxamic [0224] such as Aminoquinuride, BenZoXiquine, Acid, Allopurinol, Potassium Citrate and Succinimide. , Chloroxine, , Cloxyquin, [0231] 71. Antivenin drugs such as Lyovac7 Antivenin. Ethylhydrocupreine, Euprocin, Halquinol, , 8-Hy [0232] 72. Antiviral drugs, including: droxquinoline, 8-Hydroxquinoline Sulfate and lodochlorhy [0233] and pyrimidinones such as Acyclovir, Cyt droxyquin; and arabine, Dideoxyadenosine, Dideoxycytidine, Dideoxyi US 2011/0097384 A1 Apr. 28, 2011

nosine, Edoxudine, Floxuridine, Ganciclovir, ldoxuridine, nin, Etidronic Acid, lpri?avone, Pamidronic Acid, Parathy lnosine Pranobex, MADU, Penciclovir, Tri?uridine, Vidrar roid and Teriparatide Acetate. bine and Zidovudiine; and [0252] 78. Cardiotonics such as , Acetyldigiti [0234] others such as Acetylleucine Monoethanolamine, toxins, 2-Amino-4-picoline, , Benfurodil Amantadine, Amidinomycin, Cosalane, Cuminaldehyde Thi Hemisuccinate, Buclasdesine, Cerberoside, Camphotamide, osemicarbZone, Foscarnet Sodium, lmiquimod, Interferon-a, Convallatoxin, Cymarin, Denopamine, Deslanoside, Ditalin, Interferon-a, Interferon-a, Kethoxal, LysoZyme, Methisa Digitalis, , Digoxin, , , Zone, Moroxydine, Podophyllotoxin, Ribavirin, Rimanta Dopexamine, , Erythrophleine, Fenalcomine, dine, Stallimycin, Statolon, Tromantadine and XenaZoic Gitalin, Gitoxin, Glycocyamine, , Hydrastinine, Acid. Dopamine, Lanotodises, Metamivam, , Neriifolin, [0235] 73. drugs, including: Oleandrin, Ouabain, Oxyfedrine, Prenalterol, Proscillaridin, [0236] ArylpiperaZines such as , , Isa Resibufogenin, Scillaren, Scillarenin, Strophanthin, Sulma pirone and Tondospirone. Zole, and Xamoterol. [0237] derivatives such as , [0253] 79. Chelating agents such as DeferoZmine, Ditio , , , , carb Sodium, Edetate Calcium Disodium, Edetate Disodium, , ChotiaZepam, , , Ethyl Edeate Sodium, Edetate Trisodium, Penicillamine, Pentetate Lo?aZepate, , FluidaZepam, , Fluto Calcium Trisodium, Pentectic Acid, Succimer and Trientine; , , , , , [0254] 80. Cholecystokinin antagonists such as Proglu , , , , mide. , , , PraZepam and To?so [0255] 81. Cholelitholytic agents such as Chenodiol, Pam; Methyl tert-Butyl Ether, Monooctanoin and Ursodiol. [0238] such as , , [0256] 82. Choleretics such as Alibendol, , , and Trithion, AZintamide, , Cicrotoic Acid, Clanobu ; and tin, , Cyclovalone, Cynarin(e), Dehydrocholic [0239] others such as , , Captodi Acid, , Dimecrotic Acid, a-EthylbenZyl amine, , , , Fluoresone, Alcohol, Exiproben, Feguprol, Fencibutirol, Fenipentol, Flo , HydroXyZine, , Mecloralurea, rantyrone, , Menbutone, 3-(o-Methoxyphe , MirtaZepine, , , nyl)-2-phenylacrylic Acid, Metochalcone, MoquiZone, and . Osalmid, Ox Bile Extract, 4,4'-OXydi-2-butanol, , [0240] 74. BenZodiaZepine antagonists such as . ProZapine, 4-Salicyloylmorpholine, Sincalide, Taurocholic [0241] 75. , including: Acid, Timonacic, Tocamphyl, Trepibutone and Vanitiolide. [0242] Ephedrine derivatives such as Albuterol, Bam [0257] 83. agents such as , Acetyl buterol, Bitolterol, Carbuterol, Clenbuterol, Clorprenaline, choline Bromide, Acetylcholide Chloride, Aclatonium Napa Dioxethedrine, Ephedrine, Epiniphrine, , disilate, BenZpyrinium Bromide, chloride, Car Etafedrine, Ethylnorepinephrine, Fenoterol, Hexoprenaline, bachol, Carpronium chloride, , lsoetharine, lsoproterenol, Mabuterol, Metaproterenol, Dexpanthenol, Diisopropyl , Iodide, N-Methylephedrine, Pirbuterol, Procaterol, Protokylol, Edrophomium chloride, Eseridine, Furtrethonium, lso?uo Reproterol, Rimiterol, , Soterenol, and rophate, chloride, , , ; Oxapropanium Iodide, and [0243] Quaternary ammonium compounds such as Bevo Bromide. nium Methyl Sulfate, Clutropium Bromide, lpratropium Bro [0258] 84. inhibitors such as Ambenonium mide and ; Chloride, Bromide and Galanthamine. [0244] derivatives such as Acefylline, Acefylline [0259] 85. Cholinesterase reactivators such as Obidox piperaZine, Ambuphylline, , , imine Chloride and Chloride. , , Dyphylline, Enprofyl [0260] 86. Central and agents line, Etamiphyllin, Etofylline, Guaithylline, , such as , Amphetimine, Amphetaminil, Beme Theobromine, l-Theobromineacetic Acid and ; gride, , Brucine, , Chlorphentermine, and , Clortermine, , Demanyl Phosphate, Dex [0245] others such as , MedibaZine, Monteku oxadrol, Sulfate, Diethlpropion, last, Methoxyphenanime, and Za?rkulast. N-Ethylamphetamine, Ethamivan, Etifelmin, Etryptamine, [0246] 76. blockers, including: Fencamfamine, , Fenosolone, Fluorothyl, Gal [0247] Arylalkylamines such as Bepridil, DitiaZem, anthamine, Sodium, Homocam?n, MaZindol, , Gallopanil, , Terodiline and Vera Megexamide, , , pamil; , , PentylenetetraZole, Phenidimetra [0248] Dihydropyridine derivatives such as Felodipine, Zine, , , , , lsradipine, Nicardipine, Nifedipine, Nilvadipine, Nimo Prolintane and . dipine, Nisoldipine and Nitrendipine; [0261] 87. Decongestants such as Amidephrine, Cafami [0249] PiperaZine derivatives such as , Flunar nol, Cyclopentamine, Ephedrine, Epinephrine, FenoxaZo isine and Lido?aZine; and line, lndanaZoline, MetiZoline, NaphaZoline, Nordefrin [0250] others such as , and Perhexy Hydrochloride, , OXymetaZoline, Phenylephrine line. Hydrochloride, Phenylpropanolamine Hydrochloride, Phe [0251] 77. Calcium regulators such as Calcifediol, Calcito nylpropylmethylamine, Propylhexedrine, , nin, Calcitriol, Clodronic Acid, Dihydrotachysterol, Elcato TetrahydroZoline, TymaZoline and XylometaZoline. US 2011/0097384 A1 Apr. 28, 2011

[0262] 88. Dental agents, including: , , , De?azacort, Des [0263] Bisphosphonates (anti-periodontal disease and onide, , , Di?orasone, Di?u bone resorption) such as Alendronate, Clodronate, Etidr cortolone, Di?uprednate, , , Flucloron onate, Pamidronate and Tiludronate; ide, Flumehtasone, , Acetonide, [0264] Carries Prophylactics such as Arginine and Sodium , Butyl, , Fluo Fluoride; Desensitizing Agents such as Potassium Nitrate and rometholone, Acetate, Acetate, Citrate . , Flurandrenolide, , Halcinon [0265] 89. Depigmentors such as Hydroquinine, Hydro ide, Halometasone, Acetate, , quinone and Monobenzone. , , hydrocortisone [0266] 90. , including: Phosphate, Hydrocortisone 21-Sodium Succinate, Hydrocor [0267] organomercurials such as Chlormerodrin, Merallu tisone Tebutate, , , , ride, Mercamphamide, Mercaptomerin Sodium, Mercumal Methyolprednisolone, Furoate, Parametha lylic Acid, Mercumatilin Sodium, Mercurous Chloride and sone, , , Prednisolone 21-Diethy Mersalyl; laminoacetate, Sodium Phosphate, Prednisolone [0268] Pteridines such as Furterene and ; Sodium Succinate, Prednisolone Sodium 21-m-Sulfoben [0269] Purines such as Acefylline, 7-Morpholinomethylth zoate, Prednisolone 21-Stearoylglycolate, Prednisolone eophylline, Pamabrom, Protheobromine and Theobromine; Tebutate, Prednisolone 21-Trimethylacetate, Prednisone, [0270] such as , Oleandrin and Prednival, , Prednylidene 21-Diethylaminoac ; etate, Tixocortal, , , [0271] Sulfonamide derivatives such as Acetazolmide, Triamcinolone Benetonide and Triamcinolone Hexac Ambuside, Azosemide, , Butazolamide, etonide. Chloraminophenamide, , Clopamide, Clorex [0286] 98. Gonad-Stimulating principles such as Buser olene, -4,4'-disulfonamide, Disulfamide, elin, Clomiphene, , , FSH, HCG and , Furosemide, lndapamide, Mefruside, Meth LH-RH. azolamide, , Quinethazone, Torsemide, Tripamide [0287] 99. Gonadotropic hormones such as LH and PMSG. and Xipamide; [0288] 100. GroWth hormone inhibitors such as [0272] such as Aminometradine and Amisometra and Somatostatin. dine; [0289] 101. GroWth hormone releasing factors such as [0273] others such as Amanozine, , Arbutin, Semorelin. Chlorazanil, Ethacrynic Acid, Etozolin, Hydracarbazine, [0290] 102. GroWth stimulants such as Somatotropin. lsosorbide, , Metochalcone, Muzolimine, Perhexy [0291] 103. Hemolytic agents such as and line, Ticrynafen and Urea. Phenylhydrazine Hydrochloride. [0274] 91 . Dopamine agonists such as Bromocrip [0292] 104. antagonists such as Hexadimethrine tine, Dopexamine, Fenoldopam, lbopamine, Lisuride, Nax Bromide and . agolide and Pergolide. [0293] 105. Hepatoprotectants such as S-Adenosylme [0275] 92. Ectoparasiticides such as , Benzyl Ben thionine, Betaine, Catechin, Citolone, Malotilate, Oraza zoate, , Crotamiton, DDT, Dixanthogen, lsobomyl mide, , Protoporphyrin IX, Silymarin ThiocyanoacetateiTechnical, Lime Sulfurated Solution, Group, Thiotic Acid and Tiopronin. , , Mercuric Oleate, Mesulphen and Sul [0294] 106. lmmunomodulators such as Amiprilose, Buci phuriPharmac eutical . llamine, Ditiocarb Sodium, lnosine Pranobex, Interferon-y, [0276] 93. Enzymes, including: Interleukin-2, Lentinan, Muroctasin, Platonin, Procodazole, [0277] Digestive enzymes such as a-Amylase (SWine Pan Tetramisole, Thymomodulin, Thymopentin and . creas), Lipase, Pancrelipase, Pepsin and Rennin; [0295] 107. lmmunosuppressants such as Azathioprine, [0278] Mucolytic enzymes such as Lysozyme; Cyclosporins and Mizoribine. [0279] Penicillin inactivating enzymes such as Penicilli [0296] 108. exchange resins such as Carbacrylic Res nase; and ins, Cholestyramine Resin, Colestipol, Polidexide, Resodec [0280] Proteolytic enzymes such as Collagenase, Chymo and Sodium Polystyrene Sulfonate. papain, Chymotrypsins, Papain and Trypsin. [0297] 109. Lactation stimulating hormone such as Prolac [0281] 94. inducers (hepatic) such as Flumecinol. tin. [0282] 95. (non-steroidal) such as , [0298] 110. LH-RH agonists such as Buserelin, , Broparoestrol, , , Diethylstil Goserelin Acetate, Leuprolide, Nafarelin, and Triptorelin. bestrol, Diproprionate, , Fos [0299] 111. Lipotropic agents such as N-Acetylmethion festrol, , and . ine, Choline Chloride, Choline Dehydrocholate, Choline [0283] Estrogens such as Conjugated Estrogenic Hor Dihydrogen Citrate, lnositol, Lecithin and . mones, , , Esteri?ed Estrogens, 17[3-Estra [0300] 1 12. Lupus erythematosus suppressants such as Bis diol, Benzoate, 17[3-, Estradiol muth Sodium Triglycollamate, , Chlo 17[3-Cypionate, , , , 17[3-Ethinyl roquine and Hydroxychloroquine. Estradiol and [0301] 113. Mineralcorticoids such as , [0284] 96. Gastric secretion inhibitors such as Enterogas Deoxycorticosterone, Deoxycorticosterone Acetate and trone and Octreotide. . [0285] 97. such as 21-Acetox [0302] 114. Miotic drugs such as , Physostig yprefnenolone, Aalclometasone, Algestone, Amicinonide, mine, Pilocarpine and Pilocarpus. Beclomethasone, , , Chloropred [0303] 115. inhibitors such as Depre nisone, , Blovetasone, , , nyl, lproclozide, lproniazid, lsocarboxazid, Moclobemide, US 2011/0097384 A1 Apr. 28, 2011

Octomoxin, Pargyline, PhenelZine, , Piva [0317] 128. Protease inhibitors such as Aprotinin, Camo lylbenZhydraZine, Prodipine, Toloxatone and Tranylcyprom stat, Gabexate and . me. [0318] 129. Respiratory stimulants such as , [0304] 116. Mucolytic agents such as , Bro , Carbon Dioxide, Cropropamide, Crotethamide, mhexine, Carbocysteine, , , LysoZyme, Dime?ine, Dimorpholamine, , Ethamivan, Fomi Hydrochloride, , , , Tio noben, , , Metamivam, Nikethamide, pronin and . Picrotoxin, , Pyridofylline, Sodium Succinate and [0305] 117. Muscle relaxants (skeletal) such as A?oqua . lone, Alcuronium, Atracurium Besylate, , BenZoc [0319] 130. Sclerosing agents such as , Ethy tamine, BenZoquinonium Chloride, C-Calebassine, Cariso lamine, 2-Hexyldecanoic Acid, Polidocanol, Quinine Bisul prodol, ChlormeZanone, Chlorphenesin , fate, Quinine Urea Hydrochloride, Sodium Ricinoleate, ChlorproethaZine, ChloZoXaZone, , Cyclarbamate, Sodium Tetradecyl Sulfate and Tribenoside. , , Bromide, [0320] 131. and , including: DiaZepam, , , Flumetramide, [0321] Acyclic ureides such as , Apronalide, , Hexacarbacholine Bromide, Bomisovalum, Capuride, and Ectylurea; Hexa?uorenium Bromide, ldrocilamide, Lauexium Methyl Sulfate, Leptodactyline, , , Mephe [0322] Alcohols such as Chlorhexadol, , noxalone, , , Iodide, Meparfynol, 4-Methyl-5-thiaZoleethanol, tert-Pentyl Alco NimetaZepam, Orphenadrine, , Phen hol and 2,2,2-Trichloroethanol; probamate, Phenyramidol, Pipecurium Bromide, Promox [0323] Amides such as Butoctamide, Diethylbromoaceta olane, Quinine Sulfate, , Succinylcholine Bromide, mide, lbrotamide, lsovaleryl Diethylamide, , Tric Succinylcholine Chloride, Succinylcholine Iodine, Suxetho etamide, , and ; nium Bromide, , , , [0324] Barbituric acid derivatives such as , , , , , Barbital, Brallabarbital, Butabar and Zoxolamine. bital Sodium, , , Butethal, , [0306] 118. Narcotic antagonists such as , , , Enallylpropymal, , , Nadide, Nalmfene, , 5-Ethyl-5-(1-piperidyl) barbituric Acid, 5-Furfuryl-5-isopro Nalorphine Dinicotinate, and . pylbarbituric Acid, Heptabarbital, Sodium, Hex [0307] 119. Neuroprotective agents such as . obarbital, Mephobarbital, , Narcobarbital, Neal [0308] 120. Nootropic agents such as Aceglutamide, Ace barbital, Sodium, Phenallymal, Phenobarbital, tylcamitine, , Bifematlane, Exifone, , Phenobarbital Sodium, Phenylmethylbarbituric Acid, ldebenone, lndeloXaZune Hydrochloride, NiZofenone, , , Proxibarbal, , Secobar , , , and bital Sodium, , , Sodium and Tacrine. ; [0309] 121. Ophthalmic agents such as 15-ketoprostaglan [0325] BenZodiaZepine derivatives such as , dins. , , , , [0310] 122. Ovarian hormone such as Relaxin. , , , NitraZepam, [0311] 123. Oxytocic drugs such as , Carguto , and ; cin, Deaminooxytocin, Ergonovine, , Methyler [0326] such as Ammonium Bromide, Calcium gonovine, Oxytocin, Pituitary (Posterior), E2, Bromide, Calcium Bromolactobionate, Bromide, Prostaglandin 132a and . Magnesium Bromide, Potassium Bromide and Sodium Bro [0312] 124. Pepsin inhibitors such as Sodium Amylosul mide; fate. [0327] Carbamates such as Amyl CarbamateiTertiary, [0313] 125. Peristaltic stimulants such as . , Hexaprpymate, Meparfynol Carbamate, [0314] 126. inhibitors such as . Novonal and Tricholorourethan; [0315] 127. and prostaglandin analogs such [0328] derivatives such as Carbocloral, Chloral as Arbaprostil, Carboprost; , Bemeprost, Limaprost, Betaine, Chloral Formamide, , Chloralan Misoprostol, Ornoprostil, , , tipyrine, , Pentaerythritol Chloral and , Prostagland in PM Rioprostil, Rosaprostol, ; and Trimoprostil. [0329] Piperidinediones such as Glutehimide, Methypry [0316] Progestational agents such as and lon, Piperidione, , Taglutimide and Thalido , , , Dime mide; thisterone, , Ethinylestrenol, , [0330] QuinaZolone derivatives such as , Ethynodiol and Ethynodiol Diacetate, , 170t-Hy and ; and droxyprogesterone, Hydroxygesterone Caproate, Medrox [0331] others such as Acetal, , Aldol, Ammo yprogesterone and Acetate, nium Valerate, Amphenidone, d-Bomyl a-Bromoisovalerate, Acetate, , Norethindrone and Norethidrone d-Bomyl lsovalerate, Bromoform, Calcium 2-Ethylbu Acetate, Norethynodrel, , , 19-Nor tanoate, Car?nate, a-Chlorolose, , Cypripe , Progesterone, and esters dium, Doxylamine, , , , thereof. Free base forms of drugs Which have a greater a?inity HomofenaZine, Hydrobromic Acid, Mecloxamine, Menthyl for the acid (carboxyl) functional group in a carboxyl func Valerate, Opium, , , , Ril tional acrylic-based polymer are preferred in some applica maZafone, , Sulfonethylmethane and Sul tions. fonmethane. US 2011/0097384 A1 Apr. 28, 2011

[0332] 132. Thrombolytic agents such as APSAC, Plasmin, memantine, pilocarpine, cyclobenZaprine, paroxetine, ?uox Pro-, , Tissue etine, , , decipramine, doxeprin, and Urokinase. nortriptylene, protriptylene, bupropion, aZelastine, chlorphe [0333] 133. Thyrotropic hormones such as TRH and TSH. namine, bisoprolol, pheniramine, alpraZolam, captopril, [0334] 134. such as , Ethe clonidine, clonaZepam, enalapril, ramipril, haloperidol, keto benecid, Orotic Acid, Oxycinchophen, Probenecid, Sul?n profen, loratadine, methimaZole (anti-hyperthyroid), meth pyraZone, Ticrynafen and . ylphenidate, methyl , , nitroglycerin, [0335] 135. Vasodilators (cerebral) such as Bencyclane, pramipexole, ropinirole, hydromorphone, scopolamine, test CinnariZine, , , , Diisopro osterone, methamphetamine, and phentermine. pylamine Dichloractetate, Ebumamonine, Fenoxedil, Fluna For desired therapeutic effect, it may be desirable certain riZine, , , Nafronyl, Nicametate, Nicer drugs, such as methylphenidate, d-amphetamine, metham goline, , , , Tinofedrine, phetamine and phentermine, be used in their base form. , V' inpocetine and Viquidil. [0344] The amount of drug to be incorporated in the com [0336] 136. Vasodilators (coronary) such as Amotriphene, position vanes depending on the particular drug, the desired BendaZol, Benfurodil Hemisuccinate, , Chloa therapeutic effect, and the time span for Which the device is to ciZine, Chromonar, Clobenfurol, Clonitrate, , Dipy provide therapy. For most drugs, the passage of the drugs ridamole, proprenilamine, E?oxate, Erythritol, Erythrityl through the skin Will be the rate-limiting step in delivery. Tetranitrate, Etafenone, Fendiline, Floredil, Ganglefene, Thus, the amount of drug and the rate of release is typically Hexestrol Bis([3-diethylaminoethyl ether), , selected so as to provide transdermal delivery characteriZed Itramin Tosylate, Khellin, Lido?aZine, Mannitol Hexanitrate, by a Zero order time dependency for a prolonged period of MedibaZine, , Nitroglycerin, Pentaerythritol Tet time. The minimum amount of drug in the system is selected ranitrate, Pentrinitrol, Perhexyline, Pimethylline, Preny based on the amount of drug Which passes through the skin in lamine, Propatyl Nitrate, Pyridofylline, , Tricromyl, the time span for Which the device is to provide therapy. , TroInitrate Phosphate and V1snadine. Normally, the amount of drug in the system can vary from [0337] 137. Vasodilators (peripheral) such as Aluminum about 0.1% to about 50%. HoWever, the composition of this Nicotinate, , Bencyclane, , Bradykinin, invention is particularly useful for drugs Which are used in Brovincamine, Bufoniode, Bu?omedil, , , relatively loW concentrations, especially 0.3% to 30% of the Ciclonicate, , CinnariZine, Cyclandelate, Diiso total composition, more preferably from about 0.5% to about propylamine Dichloracetate, Eledoisin, Fenoxidil, Flunar 15% of the total composition, most preferably from about 1% isine, Heronicate, Ifenprodil, Niacinate, , to about 10% of the total composition. Kallidin, Kallikrein, , Nafronyl, Nicametate, [0345] One preferred drug in clonidine. Clonidine is an Nicergoline, , , Nylidrin, Pen anti-sympathicotonic agent having an imidaZoline structure. tifylline, , , Protaglandin Et, It has af?nity for (x1 -adrenoceptors andimore stronglyifor and Xanthinal Niacinate. pre- and post-synaptic (x2-adrenoceptors and loWers periph [0338] 138. Vasoprotectants such as BenZarone, Bio?a eral sympathetic tone. It is believed that clonidine loWers vonoids, Chromocarb, Clobeoside, Diosmin, Dobesilate Cal blood pressure by decreasing cardiac output andiin the case cium, Escin, Rolescutol, Leucocyanidin, Metescufylline, of prolonged medicationiby reducing peripheral vascular , Rutin and Troxerutin. resistance. At the same time, it is believed that clonidine [0339] 139. Vitamins, vitamin sources, and vitamin reduces the release of renin With a decrease in angiotensin II extracts such as Vitamins A, B, C, D, E, and K and derivatives in the blood plasma, With aldosterone being released from the thereof, Calciferols, GlycyrrhiZa and Mecobalamin. adrenal cortex. [0340] 140. Vulnerary agents such as Acetylcysteine, [0346] Clonidine may be used, for example, in treating the Allantoin, Asiaticoside, Cadexomer Iodine, Chitin, Dextra folloWing indications: hypertension, migraine, states, nomer and Oxaceprol. hyperkinetic behavioural disorders, WithdraWal symptoms in [0341] 141. such as heparin. alcohol or drug WithdraWal, and menopausal symptoms. [0342] 142. Miscellaneous such as Erythropoietin (Hema [0347] Clonidine hydrochloride exists in the form of a tinic), Filgrastim, (Benign Prostate Hypertro mesomeric component. The chemical name is 2-(2,6-dichlo phy), Interferon Beta 1-Alpha (Multiple Sclerosis) and Tret rophenylamino)-2-imidaZoline hydrochloride. Clonidine has inonin (Urinary Incontinence). the folloWing molecular formula: C9H9Cl2N3HCl, and a [0343] Particular drugs that are usable in the present inven molecular Weight of 266.56. tion include loW molecular Weight drugs. Any drug Which is [0348] As used herein, the term “supersaturated” used in liquid at or about room temperature can be used according to reference to the drug means that the amount of drug present is the present invention. As used herein, the term “loW molecu in excess of its solubility or dispersability in a multiple poly lar Weight” is de?ned to include any drug and its equivalent mer adhesive system. forms that has a melting point such that it exists as a liquid at [0349] Referring to FIG. 1, the most preferred embodiment or about room temperatures. This term encompasses loW of the invention, transdermal drug delivery system 10 com molecular Weight drugs having a molecular Weight of less prises a carrier composition layer 12 incorporating the active than about 300 daltons. A drug Which is of loW molecular agent. Surface 14 of the adhesive carrier composition layer 12 Weight and liquid at or about room temperatures is generally is a?ixed to release liner 15 to protect the carrier composition in its free-base or free-acid form, and, as such, is encom layer prior to use but Which is removed upon topical applica passed by this term. Drugs usable in practicing the invention tion of the carrier composition layer to the skin or mucosa of include amphetamine, d-amphetamine, l-amphetamine, d,l the user. A non-drug containing backing layer 18 is a?ixed to amphetamine, methaphetamine, prilocalne, benZocaine, the other surface 20 of the carrier composition layer 12. As butacaine, , butanilicaine, corticaine, lidocaine, discussed in more detail beloW, backing layer 18 may be made US 2011/0097384 A1 Apr. 28, 2011

of any suitable material to tailor delivery of the active agent general, the acrylate polymer is composed of at least 50% by from the carrier composition layer 12 to the skin or mucosa of Weight of an acrylate or alkyl acrylate monomer, from 0 to the user. The backing layer 18 may be processed separately 20% of a functional monomer copolymeriZable With the acry from carrier layer 12 or may be processed together With the late, and from 0 to 40% of other monomers. carrier composition layer 12. [0354] Acrylate monomers Which can be used include [0350] Carrier composition layer 12 can comprise any acrylic acid, methacrylic acid, butyl acrylate, butyl methacry polymer or adhesive generally knoWn in the art for formulat late, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acry ing a drug carrier composition, and include all of the non late, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl toxic natural and synthetic polymers knoWn or suitable for methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacry use in transdermal systems including solvent-based, hot melt late, decyl acrylate, decyl methacrylate, dodecyl acrylate, and grafted adhesives, and may be used alone or in combina dodecyl methacrylate, tridecyl acrylate, and tridecyl meth tions, mixtures or blends. Examples include acrylic-based acrylate. polymer(s), silicone-based polymer(s), rubbers, gums, poly [0355] Functional monomers, copolymeriZable With the isobutylenes, polyvinylethers, polyurethanes, styrene block above alkyl acrylates or methacrylates, Which can be used copolymers, styrene/butadiene polymers, polyether block include acrylic acid, methacrylic acid, maleic acid, maleic amide copolymers, ethylene/vinyl acetate copolymers, and anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, vinyl acetate based adhesives, and bioadhesives as set forth in acrylamide, dimethylacrylamide, acrylonitrile, dimethylami US. Pat. No. 6,562,363 Which is expressly incorporated by noethyl acrylate, dimethylaminoethyl methacrylate, tert-bu reference in its entirety. tylaminoethyl acrylate, tert-butylaminoethyl methacrylate, [0351] The term “silicone-based” polymer is intended to be methoxyethyl acrylate and methoxyethyl methacrylate. used interchangeably With the terms siloxane, polysiloxane, [0356] Suitable acrylic-based polymers may also be a pres and silicones as used herein and as knoWn in the art. The sure- sensitive adhesive Which are commercially available and silicone-based polymer may also be a pressure-sensitive include the acrylic -based adhesives sold under the trademarks adhesive, With a polysiloxane adhesive prepared by cross Duro-Tak® by National Starch and Chemical Corporation, linking an elastomer, typically a high molecular Weight poly BridgeWater, N]. (such as 87-2287, -4098, -2852, -2196, diorganosiloxane, With a resin, to produce a three-dimen -2296, -2194, -2516, -2070, -2353, -2154, -2510, -9085 -9088 sional siloxane structure, via a condensation reaction in an and 73-9301). Other suitable acrylic-based adhesives include appropriate organic solvent. The ratio of resin to elastomer is those sold by Monsanto; St. Louis, Mo., under the trademarks a critical factor that can be adjusted in order to modify the Gelva® Multipolymer Solution (such as 2480, 788, 737, 263, physical properties of polysiloxane adhesives. Sobieski, et 1430, 1753, 1151, 2450, and 2495 and Eudragit® sold by al., “Silicone Pressure Sensitive Adhesives,” Handbook of Roehm Pharma GmbH, Darmstadt, Federal Republic of Ger Pressure-Sensitive Adhesive Technology. 2nd ed., pp. 508 many. 517 (D. Satas, ed.), Van Nostrand Reinhold, NeW York [0357] The carrier composition may comprise blends of (1989). Further details and examples of silicone pressure acrylic -based polymers, silicone-based polymers and rubbers sensitive adhesives Which are useful in the practice of this based upon their differing solubility parameters, alone or in invention are described in the following US. Pat. Nos. 4,591, combination With other polymers, for example polyvinylpyr 622; 4,584,355; 4,585,836; and 4,655,767, all expressly rolidone, as more fully described in US. Pat. Nos. 5,474,783; incorporated by reference in their entireties. Suitable silicone 5,656,286; 5,958,446; 6,024,976; 6,221,383; and 6,235,306; pressure-sensitive adhesives are commercially available and Which are incorporated herein in their entirety. The amount of include the silicone adhesives soldunder the trademarks BIO each polymer is selected to adjust the saturation concentra PSA® by Dow Corning Corporation, Medical Products, Mid tion of the drug in the multiple polymer system, and to result land, Mich. (such as -2685, -3027, -3122, -4101, -4102, in the desired rate of delivery of the drug from the system and -4203, -4301, -4302, -4303, -4401-4403, -4501, -4503, through the skin or mucosa. -4602, -4603 and -4919). Capped silicones With high resin [0358] Combinations of acrylic-based polymers based on content are preferred. their functional groups is also contemplated. Acrylic-based [0352] In the practice of the preferred embodiments of the polymers having functional groups are copolymers or ter invention, the carrier composition layer 12 includes an polymers Which contain in addition to nonfunctional mono acrylic-based polymer. The acrylic-based polymer can be any mer units, further monomer units having free functional of the homopolymers, copolymers, terpolymers, and the like groups. The monomers can be monofunctional or polyfunc of various acrylic acids. In such preferred embodiments, the tional. These functional groups include carboxyl groups, acrylic-based polymer constitutes from about 2% to about hydroxy groups, amino groups, amido groups, epoxy groups, 95% of the total dry Weight of the of the carrier composition, etc. Preferred functional groups are carboxyl groups and and preferably from about 2% to about 90%, and more pref hydroxy groups. Preferred carboxyl functional monomers erably from about 2% to about 85% of the carrier composi include acrylic acid, methacrylic acid, itaconic acid, maleic tion, Wherein the amount of the acrylic-based polymer is acid, and crotonic acid. Preferred hydroxy functional mono dependent on the amount and type of drug used. mers include 2-hydroxyethyl methacrylate, 2-hydroxyethyl [0353] The acrylic-based polymers usable in the invention acrylate, hydroxymethyl acrylate, hydroxymethyl methacry are polymers of one or more monomers of acrylic acids and late, hydroxyethyl acrylate, hydroxyethyl methacrylate, other copolymeriZable monomers. The acrylate polymers hydroxypropyl acrylate, hydroxypropyl methacrylate, also include copolymers of alkyl acrylates and/or methacry hydroxybutyl acrylate, hydroxybutyl methacrylate, lates and/ or copolymeriZable secondary monomers or mono hydroxyamyl acrylate, hydroxyamyl methacrylate, hydroxy mers With functional groups. By varying the amount of each hexyl acrylate, hydroxyhexyl methacrylate. Non-functional type of monomer added, the cohesive properties of the result acrylic-based polymers can include any acrylic based poly ing acrylate polymer can be changed as is knoWn in the art. In mer having no or substantially no free functional groups. The US 2011/0097384 A1 Apr. 28, 2011

acrylic based polymer can include homopolymers, copoly backing can comprise additional polymeric layers, for mers and terpolymers. The monomers used to produce the example, a second layer having a high Water vapor transmis polymers can include alkyl acrylic or methacrylic esters such sion rate, as Well as additional layers. The additional layers as methyl methacrylate, ethyl acrylate, propyl acrylate, amyl can be placed on one or both sides of the ?rst layer. Suitable acrylate, butyl acrylate, 2-ethylbutyl acrylate, hexyl acrylate, backings are disclosed in Us. Pat. No. 4,994,278 Which is heptyl acrylate, octyl acrylate, nonyl acrylate, 2-ethylhexyl herein incorporated by reference in its entirety. acrylate, decyl acrylate, dodecyl acrylate, tridecyl acrylate, [0365] Basically, the backing material is constructed of a glycidyl acrylate and the corresponding methacrylic esters. barrier polymer or resin or other permeable material. The [0359] Both the acrylic-basedpolymer having substantially term “barrier” is used here in reference to a material’s resis no functional groups and acrylic-based polymers having tance to absorption, diffusion, and desorption of gases, mois functional groups can optionally include further modifying ture and other chemicals. By the use of certain barrier mate monomers. These modifying monomers can include any con rials, a ?lm can be made selectively permeable to Water or ceivable monomer that is capable of undergoing vinyl poly other liquid vapor rather than gas or vice versa. The backing meriZation. For example, the incorporation of styrene mono layer 18 has a thickness from about 0.2 mm to about 3 mm. mers can be used to increase the glass transition temperature [0366] The permeability to gas and moisture vapor is and are sometimes used to improve the cohesive strength. The knoWn or can be computed using standardized tests. A com copolymeriZation of vinyl acetate monomers With acrylic parison of different plastics is found in “Barrier Resins Key esters are also used to form acrylic-based polymers. Ethylene NeW Package Development”, Plastics Packaging, July/Au can also be copolymeriZed With acrylic esters and vinyl gust 1988, pp. 17-21. acetate to give suitable acrylic-based polymers. [0360] For example, a composition Will require less of a TABLE 1 functional acrylic that contains 20% by Weight of functional Comparison of Barrier Properties for Commercial polymers groups as opposed to one that contains 0.5% by Weight of functional groups to achieve the same effect required for Oxygen Trans Moisture Vapor solubility and ?ux. Broadly speaking, the amount of func mission Rate Transmission Rate, tional acrylic is generally Within the range of about 1 to 99 25° C., 65/RH (cc 40° C., 90/RH (cc Weight % and preferably 5 to 95 Weight %, more preferably 20 Material mil/100 in2—24 hours) mil/100 in2 2 hours) to 75 Weight %, even more preferably 30 to 65 Weight %, Ethylene vinyl alcohol 0.05 to 0.18 1.4 to 5.4 based on the total polymer content of the transdermal com Polyvinylidene chloride 0.15 to 0.90 0.1 to 0.2 Acrylonitrile 0.80 5.0 position. The amount of non-functional acrylic or acrylic With Amorphous nylon 0.74 to 2.0 a functional group Which does not have as great of an a?inity Oriented polyester 2.60 1.2 for the drug, is Within the range of about 99 to 1 Weight %, terephthalate preferably 95 to 5 Weight %, more preferably 75 to 20 Weight Oriented nylon 2.10 9.0 Rigid polyvinyl chloride 14.0 3.0 % and even more preferably 30 to 65 Weight %, based on the LoW density 420 1.0 to 1.5 total polymer content of the composition. polyethylene [0361] Further details and examples of acrylic-based adhe High density 150 0.4 sives, functional monomers, and polymers Which have no polyethylene Polypropylene 150 0.69 functional groups and Which are suitable in the practice of the Polystyrene 350 7 to 10 invention are described in Satas, “Acrylic Adhesives,” Hand book of Pressure-SensitiveAdhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, N.Y. (1989); [0367] In the above table, oxygen transmission rate is “Acrylic and Methacrylic Ester Polymers,” Polymer Science expressed in cubic centimeters of oxygen of 1 mil ?lm per 100 and Engineering, Vol. 1, 2nd ed., pp 234-268, John Wiley & square inches surface area per 24 hours at 65% relative Sons, (1984); Us. Pat. No. 4,390,520; and Us. Pat. No. humidity (RH) and 250 Celsius (0 C.) and moisture vapor 4,994,267 all of Which are expressly incorporated by refer transmission rate is expressed in cubic centimeters per 100 ence in their entireties. square inches of surface area of 1 mil ?lm per 24 hours at 40 [0362] The required proportions of acrylic-based or other degrees Celsius (0 C.) and 90% relative humidity polymers used are generally dependant on the speci?c drug, [0368] Additional moisture vapor transmission rates are: its desired delivery rate and the desired duration of drug delivery. In general, proportions of acrylic-based polymers TABLE 2 also depend on the content of the functional monomer units in Moisture Vapor Transmission the functional acrylic. Rate 400 C./90% R.H. [0363] When the drug carrier composition is intended to g 30 microns/ g. mil/100 function as the face layer, that is the layer 14 that comes in {112/24 Hrs m2/24 Hrs contact With the topical site of application as depicted in FIG. 1, it is preferable that the carrier composition comprise a Biaxially Oriented 5 0.38 pressure-sensitive adhesive or bioadhesive. Polypropylene High Density 5 0.38 [0364] The backing layer 18 comprises at least one layer, Polyethylene the primary layer having a high Water vapor transmission rate Polypropylene 9 0. 69 and a moderate to loW gas transmission rate. Thus, the back LoW Density 15 1.14 Polyethylene ing has a Water vapor transmission rate about equal to or in Biaxially Oriented 15 1.2 excess of that of ethylene vinyl alcohol copolymer (EVOH) Polyester Terephthalate and a gas transmission rate about equal to or less than EVOH, Rigid Polyvinyl Chloride 40 3.1 in Which the EVOH is of about 0.2 to 3 mil thickness. The