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USOO6465.004B1 (12) United States Patent (10) Patent No.: US 6,465,004 B1 Rossi-Montero et al. (45) Date of Patent: Oct. 15, 2002

(54) SOLUBILITY ENHANCEMENT OF DRUGS 5,716,609 A 2/1998 Jain et al. IN TRANSIDERMAL DRUG DELIVERY 5,810,786 A 9/1998 Jackson et al. SYSTEMS AND METHODS OF USE 5,885,612 A 3/1999 Meconi et al. 5,906,814 A 5/1999 Epstein (75) Inventors: Sylvia Rossi-Montero, Miami, FL 5. A : E. E. et al. (US); Juan Mantelle, Miami, FL (US); 6024,974. A 2.2000 p O David Kanios, Miami, FL (US); David 6,231.885 B1 * 5/2001 Carrara Houze, Coconut Grove, FL (US) FOREIGN PATENT DOCUMENTS (73) ASSignee: Nyneharmaceuticals, Inc., Miami, EP 156 080 A1 10/1985 ( ) EP 262 422 A1 4/1998 EP 913 158 A1 5/1999 (*) Notice: Subject to any disclaimer, the term of this WO WO92/15289 A1 SE patent is extended or adjusted under 35 WO WO96/OOO72 A1 1/1996 U.S.C. 154(b) by 0 days. WO WO98/39042 A1 9/1998 WO WO99/15156 A1 4/1999 (21) Appl. No.: 09/586,906 WO PCT/USOO/15538 12/2000 (22) Filed: Jun. 5, 2000 OTHER PUBLICATIONS O O Eastman, Eastman Cellulose Esters for Pharmaceutical Drug Related U.S. Application Data Delivery, Publication EFC-223C, Oct. 1997, Eastman (60) Provisional application No. 60/137.827, filed on Jun. 5, Chemical Co., Kingsport, Tennessee.* 1999. John Wiley & Sons, Inc., Kirk-Othmer, “Cellulose (51) Int. Cl." ...... A61F 13/02; A61L 15/16 and Triacetate Fibers/Cellulose Derivatives, Esters,” pp. (52) U.S. Cl...... 424/448; 424/449 82-129, 1979, Encyclopedia of Chemical Technology, 3rd (58) Field of Search ...... 424/449,448, Ed, Vol. 5. 424/443 Eastman, Eastman Cellulose Esters for Pharmaceutical Drug Delivery, Oct. 1997, Publ. EFC-223C, Eastman (56) References Cited Chemical Co., Kingsport, Tennessee. U.S. PATENT DOCUMENTS * cited by examiner 4,668.232 A 5/1987 Cordes et al. Primary Examiner Thurman K. Page 4.883.669 A 11/1989 Chien et al. ASSistant Examiner-Isis Ghali 4,900,554 A * 2/1990 Yanagibashi et al. (74) Attorney, Agent, or Firm-Jay G. Kolman 4,994.267 A 2/1991 Sablotsky 5,028,435 A * 7/1991 Katz et al. (57) ABSTRACT 5,120,546 A * 6/1992 Hansen et al. A composition and method for the continuous and controlled 5. E. A to: R al. transdermal delivery of an active agent comprising a phar 5474783 A 12/1995 Miranda et all maceutically acceptable active agent carrier and cellulose 5523005 A 6/1996 Wilson et al. derivative which provides a Solubilizing and Stabilizing 5589.498 A 12/1996 Mohr et al. effect on the active agents incorporated therein. 5,656.286 A 8/1997 Miranda et al. 5,662.923 A * 9/1997 Roreger 14 Claims, 2 Drawing Sheets

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US 6,465,004 B1 1 2 SOLUBILITY ENHANCEMENT OF DRUGS active agent is available for delivery out of the transdermal IN TRANSIDERMAL DRUG DELIVERY System, the carrier composition must not promote crystal SYSTEMS AND METHODS OF USE growth or formation, especially during Storage of the System prior to use. Generally, active agents have been found to be This application claims benefit of provisional No. 5 readily Soluble in acrylic polymers. However, in order to 60/137,827 filed Jun. 5, 1999. deliver a therapeutically effective amount to the System's user, and to also achieve the desired adhesive Strength BACKGROUND OF THE INVENTION required for topical application in a matrix-type System, This invention relates generally to transdermal drug deliv additional polymers and ingredients are often added to the ery Systems, and more particularly, to pressure-Sensitive carrier composition (for example, incorporating a rubber, adhesive compositions for continuous and controlled deliv polysiloxane or polyvinylpyrrolidone polymer). Such addi ery of active agents over a prolonged period of time that tional polymers and ingredients can affect the recrystalliza incorporate a cellulose derivative, and in particular esterified tion of the active agent in the carrier composition. The or acylated cellulose, to Stabilize the concentration of the tendency for crystal formation or growth is known, for active agent in the composition and to inhibit crystal for 15 example, in the case of . mation of the active agent. Formulation of transdermal Systems is further frequently The use of transdermal drug delivery Systems as a means hampered by poor Solubility of certain active agents in the to topically administer an active agent is well known. Such carrier composition, which in turn also Severely limits its Systems incorporate the active agent into a carrier therapeutic application. This formulating aspect is particu composition, Such as a polymeric and/or pressure-Sensitive larly difficult in matrix-type Systems because the carrier adhesive composition, from which the active agent is deliv composition has to be optimized not only for the desired ered through the Skin or mucosa of the user. active agents but also for the carrier's pressure-Sensitive In general, transdermal drug delivery Systems are either adhesive properties. While using low concentrations in order reservoir-type or matrix-type. Both types of Systems include to incorporate the active agent into the carrier may not 25 deleteriously affect the carrier's adhesive properties, low a backing layer that forms the protective outer Surface of the active agent concentration can result in difficulties in achiev finished transdermal device and which is exposed to the ing an acceptable delivery rate. Poor or inadequate Solubility environment during use, and a release liner or protective of the active agent further gives rise to crystal formation or layer that forms the inner Surface and which covers the growth. adhesive means for affixing the device to the Skin or mucosa of a user. The release liner or protective layer is removed Generally, concentrations of the active agent up to the prior to application, eXposing the adhesive means, which is Saturation Solubility, and even SuperSaturated (i.e., an typically a pressure-Sensitive adhesive. The active agent is amount of active agent at a concentration greater than the located between the release liner and backing layer, usually Solubility of the active agent in the carrier composition at Solubilized or dispersed in a Solvent or carrier composition. room temperature) are Sought in order to increase or maxi 35 mize delivery rates. Such Systems also allow for continuous In a reservoir-type device, the active agent, typically in administration of the active drug in therapeutically effective fluid or gel form, is isolated from the adhesive means used amounts for prolonged periods of time, Such as greater than to affix the device to the user. Traditionally, a reservoir 24 hours, and even up to 7 days or more. In Such Systems, System referred to a device having a pocket or “reservoir' however, the active agent can recrystallize unpredictably, which served to hold the active agent and which was formed 40 especially during Storage. This gives rise to Stability prob in or by the backing layer itself. A peripheral adhesive layer lems. was then used to affix the device to the user. While Such Active agent that is present in crystalline form cannot be devices are still in use today, the term reservoir has become delivered through skin or mucosa. Inadequate delivery of the known as a device which employs one or more permeable active agent in turn leads to blood levels falling below that layers, Such as rate controlling membranes and drug perme 45 able adhesives layers, laminated over the reservoir (which is which are therapeutically effective. Some transdermal SyS typically nothing more than another layer containing the tems rely upon both solubilized and crystalline forms of drug in a carrier composition), in order to more effectively active agent to achieve the desired drug loading in the carrier control the delivery rate of the active agent and attachment composition. Although the drug crystals in Such Systems are of the device to the user. intended to dissolve later, for example after application, Such 50 a proceSS is unpredictable and interferes with achieving a A matrix-type device generally comprises the active agent controlled delivery rate, especially a Zero-order kinetic Solubilized or dispersed in an adhesive carrier composition, delivery rate. typically a pressure-Sensitive adhesive or bioadhesive, Failure to control crystal formation and growth can fur which functions as both the drug carrier and the adhesive ther interfere with the physical properties of the transdermal means of applying the System to the skin or mucosa. Such 55 System. The presence of crystals, particularly in excessive devices are described, for example, in U.S. Pat. Nos. 4,994, amounts, can interfere with the carrier composition's adhe 267, 5,446,070, 5,474,783 and 5,656,286, all of which are Sive properties in matrix-type transdermal Systems. assigned to Noven Pharmaceuticals, Inc., Miami, Fla. Furthermore, Surface crystals can come into direct contact A particular advantage over other forms of drug delivery, with the Skin or mucosa and promote irritation. The presence Such as oral administration, is that the transdermal System 60 of drug crystals is therefore generally undesirable. can provide a continuous and controlled release of the active agent over a prolonged period of time So that the resulting SUMMARY OF THE INVENTION blood levels remain constant. It is therefore an object of this invention to provide a It has been shown that the degree of Saturation and transdermal drug delivery System that can Substantially Solubility of the active agent in the carrier composition are 65 SuppreSS or prevent crystallization of active agents incorpo determining factors in controlling delivery of the active rated therein for the delivery of a therapeutically effective agent from the transdermal System. Since only Solubilized amount. US 6,465,004 B1 3 4 It is another object of this invention to provide a trans dermal drug delivery System that can Substantially SuppreSS Where J is the flux in g/cm2/sec, D is the diffusion coeffi or prevent crystallization formation or growth of the active cient of the drug through the skin or mucosa in cm2/sec and agents incorporated in a preSSure-Sensitive adhesive carrier Dcm/dx is the concentration gradient of the drug acroSS the composition while retaining good physical adhesive prop skin or mucosa. erties. The term “about', and the use of ranges in general It is also an object of this invention to provide a trans whether or not qualified by the term about, means that the dermal drug delivery System that can incorporate Saturated number comprehended is not limited to the exact number Set and SuperSaturated concentrations of the active agent, and forth herein, and is intended to refer to ranges Substantially deliver the same at a controlled and predictable release rate. 1O within the quoted range not departing from the Scope of the It is a further object of this invention to provide for invention. transdermal drug delivery Systems that can incorporate The term “user” or “subject' is intended to include all active agents that are insoluble or sparingly Soluble in warm-blooded mammals, preferably humans. preSSure-Sensitive adhesives in amounts necessary to deliver The phrase “substantially zero-order” as used herein a therapeutically effective amount without resulting in 15 means transdermal delivery of an active agent at a release recrystallization of the active agent, and deliver the same at rate which is approximately constant once Steady State is attained, typically within 12 hours or less after topical a controlled and predictable release rate. application. While variability in blood levels of active agent It is still another object of this invention to provide a are contemplated within the Scope of this meaning once method for increasing the Solubilizing and Stabilizing of Steady State release is attained, the depletion rate of active active agents in transdermal delivery Systems. agent over the duration of use should typically not exceed It is additionally an object of this invention to provide a about 20% to about 25%. method for making a transdermal drug delivery System that Unless defined otherwise, all technical and Scientific achieves a Substantially Zero-order kinetic rate of drug terms used herein have the same meaning as commonly delivery for a prolonged period of time without crystalliza 25 understood by one of ordinary skill in the art to which the tion of the active agent therein. invention pertains. Although any methods and materials Similar or equivalent to those described herein can be used BRIEF DESCRIPTION OF DRAWINGS in the practice for testing of the present invention, the FIG. 1 is a Schematic illustration of a matrix-type trans preferred materials and methods are described herein. dermal drug delivery System of the present invention. The cellulose derivatives of the present invention prefer FIG. 2 is a graphical representation of the Steady State flux ably have at least 2 anhydroglucose rings and most prefer rate of through cadaver Skin from ably have from about 2 to about 5,000 anhydroglucose rings. pressure-sensitive adhesive carrier compositions of the In addition, the degree of Substitution for acetyl per anhy present invention comprising cellulose esters as compared to droglucose unit of the cellulose derivative is preferably from a pressure-Sensitive adhesive carrier composition compris 35 about 0.1 to about 2.9, more preferably from about 0.1 to ing polyvinylpyrrollidone. about 2.0, and optimally from about 0.1 to about 0.5. Moreover, the acetyl content is from about 2% to about 45% DETAILED DESCRIPTION OF THE and more preferably from about 2% to about 30%. INVENTION In accordance with one aspect of the invention, an 40 improved preSSure-Sensitive adhesive carrier composition The foregoing and other objects are achieved by this which is suitable for controlled and continuous delivery of invention which provides a transdermal drug delivery Sys an active agent from a matrix-type transdermal System tem wherein the use of a cellulose derivative provides a comprises one or more preSSure-Sensitive adhesives and an Solubilizing and Stabilizing effect on the active agents incor esterified or acylated cellulose. porated into the carrier composition. 45 Exemplary esterified or acylated cellulose derivatives The term “topical” or “topically” is used herein in its Suitable for use in practicing this invention include those conventional. meaning as referring to direct contact with an which are Substituted by one to three acetyl groups or by one anatomical Site or Surface area on a mammal including skin, or two acetyl groupS and a further acyl radical other than teeth, nails and mucosa. acetyl, Such as cellulose acetate dimethylamino acetate, The term "mucosa” as used herein means any moist 50 cellulose acetate ethyl and methyl carbonate, cellulose anatomical membrane or Surface on a mammal Such as oral, acetate phthalate, cellulose acetate Succinate, cellulose buccal, vaginal, rectal, nasal or ophthalmic Surfaces. acetate chloroacetate, cellulose diacetate, cellulose triacetate, cellulose acetate ethyl oxalate, cellulose acetate The term “transdermal” as used herein means passage of methyl and butyl Sulfonate, cellulose acetate octate, cellu an active agent into and/or through skin or mucosa for 55 lose acetate laurate, cellulose acetate p-toluene Sulfonate, localized or Systemic delivery. cellulose acetate ethyl and methyl carbomate, cellulose The term "solubilized” is intended to mean that in the acetate Valerate, cellulose acetate maleate, and the like, and carrier composition there is an intimate dispersion or disso combinations and mixtures thereof. lution of the active agent at the crystalline, molecular or Preferred cellulose esters are cellulose acetate, cellulose ionic level, Such that crystals of the active agent cannot be 60 acetate propionate, cellulose acetate butyrate, cellulose detected using a microscope having a magnification of 25X. acetate phthalate, cellulose propionate butyrate, and the like, AS Such, the active agent is considered herein to be in and combinations and mixtures thereof. Such cellulose “non-crystallized” form when in the compositions of the derivatives can be prepared by any known technique in the present invention. art (for example, see Kirk-Othmer, Encyclopedia of Chemi As used herein, the term “flux' is defined as the absorp 65 cal Technology, 3rd Edition, Vol. 5, John Wiley & Sons, tion of the drug through the skin or mucosa, and is described New York, N.Y., 1979, p. 89-129; and Libscomb, A. G., by Fick's first law of diffusion: Cellulose Acetate: Its Manufacture and Applications, Ernest US 6,465,004 B1 S 6 Benn, Ltd. London, GB, 1933), or can be obtained com one or more additional polymeric materials and ingredients mercially (for example, from Eastman Chemical Products, in the carrier composition, and on the amount and type of Inc., Kingsport, Tenn.). active agent. Generally, the amount to be used is an amount The particularly preferred cellulose esters are those that sufficient to deliver a therapeutically effective amount of the do not exhibit pH-dependent solubility characteristics are active agent at a Substantially Zero-order kinetic rate of insoluble in water and are Soluble in the carrier material. delivery for a prolonged period of time (i.e., greater than 24 Examples include cellulose acetate butyrates (CAB) and hours), and to Substantially Suppress or prevent recrystalli cellulose acetate propionates (CAP). Particularly preferred Zation of the active agent during Storage. Typically, the cellulose acetate butyrates are CAB-171-15PG, CAB-381 0.1, CAB-500-5, and CAB-553-0.4, which are all commer amount of the esterified or acylated cellulose to be used cially available from Eastman Chemical Products, Inc., ranges from about 0.5% to about 50%, preferably from Kingsport, Tenn.). In the foregoing description, the first two about 0.5% to 40%, and more preferably from about 2.5% digits indicate the approximate butyryl content at the triester to 30% by weight based on the dry weight of the total carrier Stage, the third digit indicates the number of hydroxyl composition. groups for each four anhydroglucose units, and the last AS used herein, “therapeutically effective' means an digit(s) indicate the viscosity of the ester. CABs with higher 15 amount of an active agent that is Sufficient to achieve the butyryl content, such as greater than 30%, tend to be more desired local or Systemic effect or result, Such as to prevent, effective in Suppressing crystal formation. cure, diagnose, mitigate or treat a disease or condition, when CABS are particularly Suitable to SuppreSS crystallization applied topically over the duration of intended use. The in pressure-Sensitive adhesive carrier compositions contain amounts necessary are known in the literature or may be ing Steroidal hormones, Such as methyltestosterone, and determined by methods known in the art, but typically range allow for the delivery of a desired dose continuously. FIG. from about 0.1 mg to about 20,000 mg, and preferably from 2 graphically demonstrates the in vitro flux results through about 0.1 mg to about 1,000 mg, and most preferably from cadaver skin from matrix-type transdermal Systems com about 0.1 to about 500 mg per human adult or mammal of prising preSSure-Sensitive carrier compositions incorporat about 75 kg body weight per 24 hours. ing CABs and soluble polyvinylpyrrollidone (PVP). The use 25 The term “active agent” (and its equivalents "agent,” of soluble PVP as a drug crystallization inhibitor and solu “drug,” “medicament” and “pharmaceutical”) is intended to bility enhancer is known in the art. have the broadest meaning and includes at least one of any Five formulations were prepared using the method of therapeutic, prophylactic, pharmacological or physiological Example I to yield compositions having the ingredient active Substance, cosmetic and personal care preparations, concentrations, by weight based on the dry weight of the and mixtures thereof, which is delivered to a mammal to total carrier composition, set forth in TABLE I. produce a desired, usually beneficial, effect. More Specifically, any active agent that is capable of producing a TABLE I pharmacological response, localized or Systemic, irrespec WEIGHT 2% tive of whether therapeutic, diagnostic, cosmetic or prophy 35 lactic in nature, is within the contemplation of the invention. INGREDIENT Ex. A Ex. B Ex. C Ex. D. Ex. E It should be noted that the active agents can be used Polysiloxane Adhesive 50.9 50.9 50.9 SO.9 42.9 Singularly or in combinations and mixtures. (BIO-PSA (R) Q7-4502) There is no limitation on the type of active agent that can Polyacrylate Adhesive 2O.O 2O.O 2O.O 2O.O 20.O be used in this invention. However, active agents that are (DURO-TAK (R87-2510) 40 CAB 381-01 1.O.O 7.0 Solid at room temperature are preferred. CAB SOO-5 3.0 10.0 - The active agents contained in the carrier composition can CAB 553-0.4 1O.O be in different forms depending on the Solubility and release Soluble PVP 2O.O characteristics desired, for example as neutral molecules, (KOLLIDON (R 30)* Oleyl Alcohol 6.O 6.O 6.O 6.O 6.O components of molecular complexes, and pharmaceutically Dipropylene Glycol 8.O 8.0 8.0 8.0 8.0 45 acceptable Salts, free acids or bases, or quaternary Salts of 1.1 1.1 1.1 1.1 1.1 the same. Simple derivatives of the drugs. Such as pharma Methyltestosterone 4.0 4.0 4.0 4.0 2.0 ceutically acceptable , esters, amides and the like which have desirable retention and release characteristics *(BASF AG, Ludwigshafen, ). but which are easily metabolized at body pH, and enzymes, The particular soluble PVP was selected based on its 50 pro-active forms, pro-drugs and the like, can also be respective Solubility in Similar volatile Solvents and its employed. similar molecular weight to the two CABs to which it was Steroidal hormones and active agents that generally tend compared. AS Seen in FIG. 2, the carrier compositions to be poorly Soluble or insoluble in pressure-Sensitive adhe containing CABS were able to incorporate twice as much Sive carrier compositions are preferred and include, for drug and yield flux rates as much as 47% greater than the 55 example, Estrogenically effective Steroid hormones Such as carrier composition containing the soluble PVP. In terms of Colpormon, Conjugated , Estradiol (173- and drug crystallization, the soluble PVP concentration used in C.-)and its Esters (e.g., Acetate, Benzoate, Cypionate, Dipro Example E, which is double the corresponding weight pionate Diacetate, Enanthate, Undecylate and Valerate), percent of CABS, was necessitated in order to SuppreSS drug Estriol, Estrone, Ethinyl Estradiol, Equilenin, Equilin, crystal growth. Moreover, large drug crystals were observed 60 Mestranol, Moxestrol, Mytatrienediol, Quinestradiol and when using 20% soluble PVP (stored 25 days at room QuineStrol; ProgeStagenically effective Steroid hormones temperature and a relative humidity of 60–75%) with 4% Such as , , Acetate, methyltestosterone. It was therefore necessary to addition Acetate, , , 3-Keto ally halve the methyltestosterone weight percent (i.e., to De Soge Strel, Dime this terone, , 2%). 65 Ethinylestrenol, , Ethynodiol (and Diacetate), The amount and type of the esterified or acylated cellulose Flurogestone Acetate, , , required in the practice of the invention will depend on the , (17-Hydroxy- and 17-Acetate-) US 6,465,004 B1 7 8 16-Methylene-, 17C.-Hydroxyprogesterone 13. Anti-Hyperlipoproteinemic agents Such as (Acetate and Caproate), , , Atorvastatin, Cerivastatin, Lovastatin, Pravastatin and , (and Acetate), Mege Simvastatin. Strol Acetate, , Norethindrone (Acetate and 14. Anti-Hyperthyroid agents Such as Methimazole. Enanthate), , Norethynodrel, , 15. Anti-Inflammatory and/or Corticoid agents Such as Norge Stimate, Norge Strel, Norge Strie none, Beclomethasone, (and Acetate, Diprop 19-Norprogesterone, , , rionate and Valerate), , , Progesterone, , and Trenge Deoxycortocosterone (and Acetate), , Stone; Androgenically effective Steroid hormones Such as Diclofenac, Fenoprofen, Flucinolone (and Acetonide), Aldosterone, , , , 1O , , , , , , Fluradrenolide, Flurbiprofen, , Hydrocor , Methandrostenolone, Methyl , tisone (and Acetate), Ibuprofen, Ibuproxam, 17C.-Methyl testeosterone, 17C.-Methyl testosterone Indoprofen, Ketoprofen, Ketorolac, Naproxen, 3 - Cyclope nty 1 Enol , Nore thandrolone, OXame tacine, Oxyphen but a Zone, Piro Xicam, Nor methandrone, , Oxyme Sterone, 15 , , Stanlolone, , Test , , Suprofen and osterone (Acetate, Enanthate, Isobutyrate, Propionate and (and Acetonide). Undecanoate), Testosterone 17-Chloral Hemiacetal, Test 16. Anti-Malarial agents Such as Pyrimethamine. osterone 17B-Cypionate and . 17. Anti-Parkinson's and/or Anti-Alzhiemer's agents Such Other specific drugs for which cellulose derivatives can as Biperiden, Bromocriptine, Cabergoline, 1-Hydroxy be particularly usefully employed according to the invention Tacrine, Levodopa, LiSuride, Pergolide, Pramipexole, include: Quinpirole, Ropinirole, Rivastigmine, PhySOstigimine, 1. C.-Adrenergic Agonist agents Such as Phenylpropano Selegiline (Deprenyl and L-Deprenyl), Tacrine and lamine and Talipexole. Teruride. 2. Analgesics and/or Anti-Migraine Such as 25 18. Anti-Psychotic and/or Anti-Anxiety and/or Anti Acetaminophen, Acetylsalicylic Acid, Buprenorphine, Depressant agentS Such as Acetophena Zine, Codeine, Fentanyl, Hydomorphone, Lisuride, Salicylic Bromperidol, Chlorproethazine, , Acid derivatives, Sufentanil and Sumatriptan. Clomipramine, Clozapine, Fluoxetine, Fluphenazine, 3. Anti-Allergic agents Such as Amlexanox, AStemizole, , Loxapine, MeSoridazine, Molindone, AZelastine, Cromolyn, Fenpiprane, Ibudilast, Paroxetine, Perphenazine, Piperacetazine, Sertraline, Nedocromil, Oxatomide, Pentigetide, Repirinast, Tra Thiopropa Zate, Thiorida Zine, Thiothixene, nilast and TraxanoX. Trifluoperazine, Triflupromazine and Venlafaxine. 4. Anesthetic agents Such as Benzocaine, Bupivicaine, 19. Anti-Ulcerative agents Such as Enprostil and Miso Cocaine, Dibucaine, Dyclonine, Etidocaine, Lidocaine, prostol. Mepivacaine, Prilocaine, Procaine and Tetracaine. 35 20. Anti-Viral agents Such as Acyclovir, Rimantadine and 5. Anoretic agents Such as Fenfluramine, Mazindol and Vidarabine. Phentermine. 21. Anxiolytic agents Such as AZapirones Such as Bus 6. Anti-Bacterial (antibiotic) agents including pirone and Ipsapirone, BenZodiazepines Such as Aminoglycosides, B-Lactams, Cephamycins, Alprazolam, Chlordiazepoxide, Clonazepam, Macrollides, Penicillins, Polypeptides and Tetracy 40 CloraZepate, Diazepam, Flurazepam, Halazepam, clines. Lorazepam, Oxazepam, Oxazolam, Prazepam and Tria 7. Anti-Cancer agents Such as Aminolevulinic Acid, Zolam. 5-Fluouracil, Methotrexate, and Taxol. 22. B-Adrenergic agonist agents Such as Albuterol, 8. Anti-Cholinergic agents Such as Atropine, Eucatropine Carbuterol, Fenoterol, Metaproterenol, Mirtazapine, and Procyclidine. 45 Rimiterol, Quinterenol, Salme famol, Soterenol, 9. Anti-Diabetic agents such as Glipizide, Glyburide, Tratoquinol, Terbutaline and Terbuterol. Glypinamide, Insulins, Repaglinide, RosiglitaZone and 23. Bronchodilators such as Ephedrine derivatives includ TroglitaZone. ing Epiniphrine and Isoprote renol, Albute rol, 10. Anti-Emetic agentS Such as Acetylleucine 50 Salbutanol, Clenbuterol and Theophylline. Monoethanolamine, Alizapride, BenZquinamide, 24. Cardioactive agentS Such as Ate no lol, Bietanautine, Bromopride, Buclizine, Chlorpromazine, Benzydroflu methiazide, Bendroflu methiazide, Clebopride, Cyclizine, Dimenhydrinate, Dipheniodol, Calcitonin, Captopril, Chlorothiazide, Clonidine, , Granisetron, Meclizine, Methalltal, Clopamide, Dobutamine, Dopamine, Diltia Zem, , Metop imazine, Nabilone, 55 Enalapril, Enalaprilat, Gallopamil, Indomethacin, ISOS On dan Steron, OXype ndy 1, Pip amazine, orbide (Dinitrate and Mononitrate), Monoxidil, Piprinhydrinate, Prochlorperazine, Scopolamine, Nicardipine, Nifedipine, Nitroglycerin, Papaverine, Tetrahydrocannabinols, Thiethylp era Zine, Prazosin, Procainamide, Propranolol, Prostaglandin ThioproperZaine, Trimethobenzamide and Tropisetron. (E and E), Quinidine Sulfate, Timolol, and Vera 11. Anti-Fungal agents Such as Clortrima Zole, 60 pamil. , , NyStatin and Triacetin. 25. Central Nervous System Stimulants and agents Such as 12. Antihistamine agents Such as TricyclicS Such as Dextroamphetamine, Methylphenidate (and each Enan A histan, Ety me ma Zine, Fene tha Zine, tiomer and Free Base Form) and Nicotine. N-Hydroxyethylpro me tha Zine Chloride, 26. Cholinergic agents Such as Acetylcholine, Arecoline, Isoprometha Zine, Mequita Zine, Prometha Zine, 65 Bethanechol, Carbachol, Choline, Methacoline, Mus Pyrathiazine, and Thiazinamium Methyl Sulfate, and carine and Pilocarpine. Loratadine and Clobenzepam. 27. Muscle relaxants Such as Baclofen. US 6,465,004 B1 10 28. Narcotic antagonist agents Such Nalmfene and Nalox The carrier compositions of the present invention can also OC. contain one or more Solvents and/or co-Solvents. Such The amount of active agent to be incorporated in the Solvents and/or co-Solvents are those known in the art, and carrier composition will vary depending on the particular are non-toxic, pharmaceutically acceptable Substances, pref active agent, the desired therapeutic effect, and the time Span erably liquids, which do not Substantially negatively affect for which the transdermal System is to provide therapy. the adhesive properties or the Solubility of the active agents Normally, the amount of active agent in the transdermal at the concentrations used. The Solvent and/or co-Solvent can system can vary from about 0.1% to about 50%, and preferably from about 0.1% to about 30% by weight based be for the active agent or for the carrier materials, or both. on the dry weight of the total carrier composition. For lower Suitable solvents include volatile liquids such as alcohols dose concentrations permitted by this invention, Such as (e.g., methyl, ethyl, isopropyl alcohols and methylene with Steroidal hormones, the preferred amount is from about chloride), ketones (e.g., acetone); aromatic hydrocarbons 0.1% to about 10%. Such as benzene derivatives (e.g., Xylenes and toluenes); While not essential, it is preferred that the androgenic lower molecular weight alkanes and cycloalkanes (e.g., hormones be incorporated near, at or above Saturation with hexanes, heptanes and cyclohexanes); and alkanoic acid respect to its concentration in the carrier composition. 15 esters (e.g., ethyl acetate, n-propyl acetate, isobutyl acetate, The term “carrier” as used herein refers to any non n-butyl acetate isobutyl isobutyrate, hexyl acetate, aqueous material known in the art as Suitable for transdermal 2-ethylhexyl acetate or butyl acetate); and combinations and drug delivery administration, and includes any polymeric mixtures thereof. material into which an active agent may be Solubilized in Suitable co-solvents include polyhydric alcohols, which combination or admixture with the other ingredients of the include glycols, triols and polyols Such as ethylene glycol, composition. The polymeric materials preferably comprise diethylene glycol, propylene glycol, dipropylene glycol, adhesives and, in particular, pressure-Sensitive adhesives. trimethylene glycol, butylene glycol, polyethylene glycol, The carrier material is typically used in an amount of about he Xylene glycol, poly o X ethylene, glycerin, 10% to about 90%, and preferably from about 10% to about trimethylpropane, Sorbitol, polyvinylpyrrollidone, and the 75%, by weight based on the dry weight of the total carrier 25 like. composition. Further Suitable co-Solvents include glycol etherS Such as The term “carrier composition” may also refer to ethylene glycol monoethyl ether, glycol esters, glycol ether enhancers, Solvents, co-Solvents and other types of addic esterS Such as ethylene glycol monoethyl ether acetate and tives useful for facilitating transdermal drug delivery. An ethylene glycol diacetate; Saturated and unsaturated fatty “adhesive” as used herein means any natural or Synthetic acids, mineral oil, Silicone fluid, lecithin, retinol derivatives Substance that is capable of Surface attachment to the topical and the like, and ethers, esters and alcohols of fatty acids. Site of the transdermal drug delivery System. Although the exact amount of co-Solvents that may be CABS have been found to be highly effective in prevent used in the carrier composition depends on the nature and ing crystallization of active agents in pressure-Sensitive amount of the other ingredients, Such amount typically adhesive carrier compositions. An adhesive is a pressure 35 ranges from about 0.1% to about 40%, and preferably from Sensitive adhesive within the meaning of the term as used about 0.1% to about 30% by weight, and more preferably herein if it has the properties of a preSSure-Sensitive adhesive from about 1% to about 20%, by weight based on the dry per Se or if it functions as a preSSure-Sensitive adhesive by weight of the total carrier composition. admixture with tackifiers, plasticizers, croSS-linking agents In certain embodiments of the invention, an enhancer is or other additives. 40 incorporated into the carrier composition. The term Pressure-sensitive adhesives include all of the non-toxic "enhancers' as used herein refers to Substances used to natural and Synthetic polymers known or Suitable for use in increase permeability and/or accelerate the delivery of an transdermal Systems as adhesives, Such as polyacrylates, active agent through the skin or mucosa, and include mon polysiloxanes, Silicones, rubbers, gums, polyisobutylenes, hydric alcohols Such as ethyl, isopropyl, butyl and benzyl polyvinylethers, polyurethanes, Styrene block copolymers, 45 alcohols, or dihydric alcohols Such as ethylene glycol, Styrene/butadiene polymers, polyether block amide diethylene glycol, or propylene glycol dipropylene glycol copolymers, ethylene/vinyl acetate copolymers, and Vinyl and trimethylene glycol, or polyhydric alcohols Such as acetate based adhesives. glycerin, Sorbitol and polyethylene glycol, which enhance The pressure-Sensitive adhesives particularly useful in drug Solubility; polyethylene glycol ethers of aliphatic alco practicing this invention include polyacrylates of one or 50 hols (Such as cetyl, lauryl, oleyl and Stearly) including more monomers of acrylic acids or other copolymerizable polyoxyethylene (4) lauryl ether, polyoxyethylene (2) oleyl monomers. Polyacrylate adhesives also include polymers of ether and polyoxyethylene (10) oleyl ether commercially alkyl acrylates and/or methacrylates and/or copolymerizable available under the trademark BRIJCR 30, 93 and 97 from ICI Secondary monomers, or monomers with functional groups, Americas, Inc., and BRIJCR 35, 52,56,58, 72, 76, 78,92, 96, and in particular hydroxy functional groups. The term “poly 55 700 and 721; vegetable, animal and fish fats and oils such as acrylate” is intended to be used interchangeably with the cotton Seed, corn, Safflower, olive and castor oils, Squalene, terms acrylic, acrylate and polyacrylic as used herein and as and lanolin; fatty acid esterS Such as propyl oleate, decyl known in the art. Suitable preSSure-Sensitive acrylic adhe oleate, isopropyl palmitate, glycol palmitate, glycol laurate, Sives are commercially available and include those Sold dodecyl myristate, isopropyl myristate and glycol Stearate under the trademark DURO-TAKCR) by National Starch and 60 which enhance drug diffusibility; fatty acid alcohols Such as Chemical Company, Bridgewater, N.J., and GELVACR) Mul oleyl alcohol and its derivatives, fatty acid amides Such as tipolymer Solution by Solutia, Inc., St. Louis, Mo. oleamide and its derivatives, urea and urea derivatives Such The pressure-Sensitive adhesives useful in practicing the as allantoin which affect the ability of keratin to retain invention include Solvent-based, hot melt and grafted moisture; polar Solvents Such as dimethyldecylphosphoxide, adhesives, and may be used alone or in combinations, 65 methyloctylsulfoxide, dimethyl laury lamide, mixtures or blends. Particularly preferred blends include dodecylpyrrollidone, isosorbitol, dimethylacetonide, blends of polyacrylates and polysiloxanes. dimethylsulfoxide, decylmethylsulfoxide and dimethylfor US 6,465,004 B1 11 12 mamide which affect keratin permeability; Salicylic acid and excipients used in the composition. These factors can be which Softens the keratin; amino acids which are penetration adjusted by those skilled in the art, while keeping in mind assistants, benzyl nicotinate which is a hair follicle opener; the objects of achieving a Solubilized active agent and and higher molecular weight aliphatic Surfactants Such as providing a uniform product that will also give desirable lauryl Sulfate Salts which change the Surface State of the skin results. and drugs administered and esters of Sorbitol and Sorbitol Further details and examples of pressure-Sensitive anhydride Such as polySorbate 20 commercially available adhesives, enhancers, Solvents, co-Solvents, and other under the trademark Tween(E) 20 from ICI Americas, Inc., as additives, as well as transdermal Systems generally, Suitable well as other polysorbates such as 21, 40,60, 61, 65,80, 81, in practicing the invention are described in U.S. Pat. Nos. and 85. Other Suitable enhancers include oleic and linoleic 5,474,787, 5,656,286 and 60/115,987, all of which are acids, triacetin, ascorbic acid, panthenol, butylated assigned to Noven Pharmaceuticals, Inc. and incorporated hydroxytoluene, tocopherol, tocopherol acetate, tocopheryl herein by reference. linoleate. If enhancers are incorporated into the carrier A particularly preferred Structure for the transdermal drug composition, the amount typically ranges up to about 30%, delivery System useful in practicing this invention is a and preferably from about 0.1% to about 15%, by weight 15 matrix-type system. Reference to FIG. 1 shows a matrix based on the dry weight of the total carrier composition. type transdermal drug delivery System 10 comprising a In addition to enhancers, there may also be incorporated preSSure-Sensitive adhesive carrier composition layer 11, a various pharmaceutically acceptable additives and excipi release liner 12, and a backing layer 13. Removal of the ents available to those skilled in the art. These additives release liner 12 exposes the pressure-Sensitive adhesive include tackifying agents Such as aliphatic hydrocarbons, carrier composition for topical application to the user. mixed aliphatic and aromatic hydrocarbons, aromatic It is understood that a reservoir-type System, provided hydrocarbons, Substituted aromatic hydrocarbons, hydroge with a separate pressure-Sensitive adhesive layer or adhesive nated esters, polyterpenes, Silicone fluid, mineral oil and means of attachment, is contemplated in practicing the hydrogenated wood rosins. Additional additives include invention and may well be of advantage in certain cases. The binders such as lecithin which “bind” the other ingredients, 25 reservoir-type System may further consist of one or more or rheological agents (thickeners) containing Silicone Such layerS or membranes. Regardless of the type of transdermal as fumed Silica, reagent grade Sand, precipitated Silica, System used to practice the invention, the carrier composi amorphous Silica, colloidal Silicon dioxide, fused Silica, tion is preferably non-aqueous (i.e., Substantially free of Silica gel, quartz and particulate Siliceous materials com water). mercially available as Syloid(R), Cabosil(R), Aerosil(F), and Whitelite(R), for purposes of enhancing the uniform consis EXAMPLES tency or continuous phase of the final composition. Other The above description and following Specific examples additives and excipients include diluents, stabilizers, fillers, are hereby illustrative of pharmaceutically acceptable active clayS, buffering agents, biocides, humectants, anti-irritants, agent carrier compositions and transdermal drug delivery antioxidants, preservatives, plasticizing agents, croSS 35 Systems, and methods of making Same, within the contem linking agents, flavoring agents, colorants, pigments and the plation of the invention. The description and examples are in like. Such Substances can be present in any amount Sufficient no way intended to be, or should be considered, limiting of to impart the desired properties to the carrier composition. the scope of the invention. And while efforts have been made Such additives or excipients are typically used in amounts to ensure accuracy with respect to numbers used (Such as up to 25%, and preferably from about 0.1% to about 10%, 40 by weight based on the dry weight of the total carrier amounts and temperatures), Some experimental error and composition. deviation should be accounted for and/or allowed. The carrier compositions according to the present inven Example 1 tion can be prepared by first mixing appropriate amounts of the cellulose derivative(s) in Volatile polar and/or non-polar 45 An estradiol/methyltestosterone pressure-Sensitive adhe organic liquids Such as those previously described as Suit Sive mixture was prepared by combining 4.0 parts of meth able Volatile Solvents. Appropriate amounts of active agent yltestosterone and 1.1 parts of estradiol in a Solution of 42.3 (S) are then added to the mixture together with appropriate parts of CAB-381-0.1 with 38.0 parts each of isopropyl amounts of pressure-sensitive adhesive(s), Solvent(s) and/or alcohol and ethyl acetate. Then 76.5 parts of a polysiloxane co-Solvent(s), with or without enhancer(s), and thoroughly 50 adhesive (BIO-PSACR Q7-4502, a silicone in ethyl acetate; mixed. The mixture of the carrier composition is next Dow Corning Corporation, Medical Products, Midland, formed into a film at ambient temperature, preferably by Mich.), 48.8 parts of a polyacrylate adhesive (DURO-TAKCR) coating or casting at a controlled Specified thickness onto a 87-2510, an acrylate copolymer in ethyl acetate and hexane, flexible sheet material, Such as a release liner, followed by National Starch and Chemical Corporation, Bridgewater, evaporation of the Volatile Solvents at elevated temperatures 55 N.J.), 8.0 parts of dipropylene glycol and 6.0 parts of oleyl (e.g., by passing through an oven). The non-volatile or alcohol were added and thoroughly mixed in an appropriate higher boiling point Solvents and/or co-Solvents, Such as the container until the mixture was completely homogeneous. polyols, used in the carrier composition remain therein. The The resulting composition had the ingredient concentrations carrier composition has been coated or cast on the flexible on a dry weight percent basis (i.e., after evaporation of sheet material, is then laminated to another flexible sheet 60 volatile solvents) as shown below. material preferably a backing layer. Appropriate size and shape individual transdermal drug delivery Systems are cut and then packaged (e.g., pouched). The order of Steps, the amount of the ingredients, and the INGREDIENT WEIGHT 2% amount and time of mixing may be important proceSS 65 Polysiloxane Adhesive 45.9 variables which will depend on the Specific polymers, active (BIO-PSA (R) Q7-4502) agents, Solvents and/or co-Solvents, enhancers and additives US 6,465,004 B1 14 polyurethanes, Styrene block copolymers, Styrene/ -continued butadiene polymers, polyether block amide copoly INGREDIENT WEIGHT 2% mers, ethylene/vinyl acetate copolymers, and vinyl acetate based adhesives, Polyacrylate Adhesive 2O.O (ii) cellulose acetate butyrafe which is insoluble in (DURO-TAK (R) 87-2510) Cellulose Acetate Butyrate 15.O water and Substantially Soluble in the adhesive car CAB 381-0.1) rier composition, and having a butyryl content of at Dipropylene Glycol 8.0 Estradiol 1.1 least 30%, as a recrystallization inhibitor, and Methyl testosterone 4.0 (iii) a therapeutically effective amount of one or more active agents. 1OO.O 2. The System according to claim 1, wherein the pressure Sensitive adhesive includes a hydroxy functional polyacry Examples 2-5 late adhesive. 15 3. The System according to claim 1, wherein the cellulose In the following examples, the method of Example 1 was acetate butyrate is present in an amount from about 0.5% to used with the appropriate amounts of Starting materials to about 20%. yield compositions having the following ingredient concen 4. The System according to claim 1, wherein the pressure trations set forth in tabular form in TABLE II. Example 2 is Sensitive adhesive carrier composition further includes one presented as a control formulation to demonstrate the effect or more Solvents and enhancers. that CABS have on reducing drug crystallization formation. 5. The System according to claim 1, wherein the one or more active agents is Selected from the group consisting of TABLE II Steroidal hormones, analgesics, anti-inflammatory agents, WEIGHT 2% 25 central nervous System agents, cardioactive agents, anti Parkinson's agents and anti-Alzhiemer's agents. INGREDIENT Ex. 2 EX. 3 Ex. 4 Ex. 5 6. The system according to claim 5, wherein the steroidal Polysiloxane Adhesive 60.9 45.9 45.9 is Selected from the group consisting of estradiol, (BIO-PSA (R) Q7-4502) Polysiloxane Adhesive * 49.9 ethinyl estradiol, progesterone, norethindrone, methyltest (BIO-PSA (R) Q7-4302) osterone and testosterone. Polyacrylate Adhesive 2O.O 2O.O 2O.O 2O.O 7. A method of Suppressing recrystallization of active (DURO-TAK (R) 87-2510) CAB 171-15 PG 15.O agents in an adhesive carrier composition of a transdermal CAB 5OO-5 15.O drug delivery System during Storage comprising: CAB 553-0.4 15.O (a) preparing a pharmaceutically acceptable non-aqueous Oleyl Alcohol 6.O 6.O 6.O 35 Dipropylene Glycol 5.0 1.O.O 8.0 8.O adhesive carrier composition comprising one or more Estradiol 1.1 1.1 1.1 1.1 active agents, and Methyltestosterone 4.0 4.0 4.0 4.0 (b) mixing into the adhesive carrier composition a cellu * Methylated trimethylated silica in ethyl acetate lose ester which is insoluble in water and substantially 40 Soluble in the adhesive carrier composition. The rate of crystallization formation of the two active 8. The method according to claim 7, wherein the adhesive ingredients in the matrix-type Systems of Examples 1-5 was carrier composition is a pressure-Sensitive adhesive. compared and the incidence of crystal formation Set forth in 9. The method according to claim 8, wherein the pressure tabular form in TABLE III. Comparison of the examples SensitiVe adhesive includes a hydroxy functional polyacry after 25 days, maintained at 25 C.t5 C. and a relative 45 late adhesive. humidity of 65–70%, demonstrates the distinct reduction in 10. The method according to claim 7, wherein the cellu the number of crystals in the adhesive carrier composition. lose ester is Selected from the group consisting of cellulose acetate butyrate, cellulose acetate propionate and cellulose TABLE III acetate phthalate. Effect of CABS On Crystal formation 50 11. The method according to claim 7, wherein the cellu lose ester is present in an amount from about 0.5% to about Example # of crystals in patch 20% by weight based on the dry weight of the total adhesive 1. 23 6 carrier composition. 2 >5OO 12. The method according to claim 10, wherein the 3 30 6 55 4 2 - 1 cellulose ester is cellulose acetate butyrate. 5 2 - 1 13. The method according to claim 7, wherein the one or more active agents is Selected from the group consisting of * Approximate number of crystals visible in a 10 cm2 patch. Steroidal hormones, analgesics, anti-inflammatory agents, What is claimed is: 60 central nervous System agents, cardioactive agents, anti 1. A transdermal drug delivery System comprising Parkinson's agents and anti-Alzhiemer's agents. a pharmaceutically acceptable non-aqueous pressure 14. The method according to claim 13, wherein the Sensitive adhesive carrier composition comprising a Steroidal hormone is Selected from the group consisting of blend of, estradiol, ethinyl estradiol, progesterone, norethindrone, (i) one or more adhesives Selected from the group 65 methyltestosterone and testosterone. consisting of polyacrylates, polysiloxanes, Silicones, rubbers, gums, polyisobutylenes, polyvinylethers, UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 6,465,004 B1 Page 1 of 1 DATED : October 15, 2002 INVENTOR(S) : Rossi-Montero et al.

It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Column 14, Line 5, delete “butyrafe' and insert therefor--butyrate --.

Signed and Sealed this Thirty-first Day of August, 2004 WDJ

JON W. DUDAS Director of the United States Patent and Trademark Office