USOO6835392B2 (12) United States Patent (10) Patent No.: US 6,835,392 B2 Hsu et al. (45) Date of Patent: Dec. 28, 2004

(54) DUAL ENHANCER COMPOSITION FOR 5,071,657. A 12/1991 Oloff et al. TOPCAL AND TRANSIDERMAL DRUG 5,152.997 A 10/1992 Ebert et al. DELIVERY 5,318,960 A 6/1994 Toppo 5,432,192 A 7/1995 Sawanishi et al. (75) Inventors: Tsung-Min Hsu, San Diego, CA (US); (List continued on next page.) Eric C. Jacobson, San Diego, CA (US); Rose C. LoBello, San Diego, CA FOREIGN PATENT DOCUMENTS (US); Eric C. Luo, Plano, TX (US) EP O276561 8/1988 (73) Assignee: Dermatrends, Inc., San Diego, CA EP O316065 5/1989 (US) (List continued on next page.) (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S. patent application Ser. No. 09/465,098, Luo et al., filed

(21) Appl. No.: 10/389,143 (List continued on next page.) (22) Filed: Mar 13, 2003 Primary Examiner Thurman K. Page 9 ASSistant Examiner-Isis Ghali (65) Prior Publication Data (74) Attorney, Agent, or Firm-Reed & Eberle LLP, US 2003/0161870 A1 Aug. 28, 2003 Dianne E. Reed; Shelley P. Eberle Related U.S. ApplicationO O Data (57) ABSTRACT A permeation enhancer composition is provided for increas (60) Division of application No. 09/972,008, filed on Oct. 4, ing the permeability of skin or mucosal tissue to topically or nowR.E.7. Pat. No. 6,586,000, which is aSSS"'5, continuation-in-part of ceuticallytransdermally active administered agents. The compositionpharmacologically is comprised or cosme: of a application No. 09/569,889, filed on May 11, 2000, now hydroxide-releasing agent and a lipophilic co-enhancer Such abandoned, which is a continuation-in-part of application as a fatty alcohol, a fatty ether, or a fatty acid ester, including No. 09/465,098, filed on Dec. 16, 1999, now abandoned. fatty acid esters of polyols Such as propylene glycol and (51) Int. Cl...... A61F 13/00; A61L 15/00 glycerol. Also provided are pharmaceutical formulations (52) U.S. Cl...... 424/449, 424/443; 424/445, containing a therapeutically effective amount of an active 424/447: 424/44s. 514/946. 514/944 agent in addition to the aforementioned enhancer (58) Field of Search s s 424A49, 443 composition, methods for administering active agents topi 424,445,447,448. 514/946, 9 47.944 cally or transdermally with enhanced permeation, and drug s Y-s s 1 s delivery Systems for application to an individual’s skin or (56) References Cited mucosal tissue, wherein the Systems are formulated So as to contain an active agent to be administered and an effective U.S. PATENT DOCUMENTS permeation enhancing amount of an enhancer composition of the invention. 4,704,282 A 11/1987 Campbell et al. 4,789,547 A 12/1988 Song et al. 4,837,027 A 6/1989 Lee et al. 48 Claims, 1 Drawing Sheet

Human Skin Permeation of testosterone from a Matrix Patch

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O), 3 est-180 0.254 mg.cm2 ,2 5

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0.15

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U.S. PATENT DOCUMENTS 6,004,577 A 12/1999 Murdock 6,019,988 A 2/2000 Parab et al. 5,446,070 A 8/1995 Mantelle 6,019.997 A 2/2000 Scholz et al. 5,460.820 A 10/1995 Ebert et al. 6,123,961 A 9/2000 Aberg 5,462,744. A 10/1995 Gupte et al. 6,132,760 A 10/2000 Hedenstrom et al. 5,462,746 A 10/1995 Wolter et al. 6,139,866 A 10/2000 Chono et al. 5,474,783 A 12/1995 Miranda et al. 6,174,546 B1 1/2001 Therriault et al. 5,498,417 A 3/1996 Lhila et al. 6,204.268 B1 3/2001 Scarborough et al. 5,500.222 A 3/1996 Lee et al. 6.214.374 B1 4/2001 Schmirler et al. 5,527,832 A 6/1996 Chi et al. 6,316,011 B1 11/2001 Ron et al. 5.532.278 A 7/1996 Aberg et al. 5,534,496 A 7/1996 Lee et al. FOREIGN PATENT DOCUMENTS 5,562.917. A 10/1996 Durif et al. 5,573,778 A 11/1996 Therriault et al. EP O709088 5/1996 5,599,554 A 2/1997 Majeti EP O842662 5/1998 5,614,211 A 3/1997 Gale et al. FR 2692145 12/1993 5,674,895 A 10/1997 Guittard et al. JP 218O835 7/1990 5,807,568 A 9/1998 Cody et al. JP 6092843 4/1994 5,817,332 A 10/1998 Urtti et al. KR 9507098 6/1995 5.830,497 A 11/1998 Yamanaka et al. WO WO 94/21271 9/1994 5,834,513 A 11/1998 Ptchelintsev et al. WO WO 99/49844 10/1999 5,847,003 A 12/1998 Ptchelintsev et al. 5,879,690 A 3/1999 Perricone OTHER PUBLICATIONS 5,939,094. A 8/1999 Durif et al. 5.962,018 A 10/1999 Curtis et al. U.S. patent application Ser. No. 09/569,889, Luo et al., filed 5,985,317 A 11/1999 Venkateshwaran et al. May 11, 2000. A A. Toppo Aungst et al. (1990), “Contributions of Drug Solubilization, 5.990,1132- Y - 2 A 11/1999f1999 YamazakiHsu et al. et al. Partitioning, Barrier Disruption, and Solvent Permeation to 5.990,179 A 11/1999 Gyory et al. the Enhancement of Skin Permeation of Various Compounds 5,993,851 A 11/1999 Foldvari with Fatty Acids and Amines, Pharmaceutical Research 5,994,372 A 11/1999 Yaksh 7(7):712-718. U.S. Patent Dec. 28, 2004 US 6,835,392 B2

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cN 2 Y. ed o o (zuoyfu) euouasosal go unouw aaen uno US 6,835,392 B2 1 2 DUAL ENHANCER COMPOSITION FOR skin permeability include: Sulfoxides Such as dimethylsul TOPCAL AND TRANSIDERMAL DRUG foxide (DMSO) and decylmethylsulfoxide (CMSO); DELIVERY ethers such as diethylene glycol monoethyl ether (available commercially as TranscutolCE) and diethylene glycol CROSS-REFERENCE TO RELATED monomethyl ether, Surfactants Such as Sodium laurate, APPLICATIONS Sodium lauryl Sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween This is a divisional of U.S. patent application Ser. No. (20, 40, 60,80) and lecithin (U.S. Pat. No. 4,783,450); the 09/972,008, filed Oct. 4, 2001, and now issued as U.S. Pat. 1-Substituted azacycloheptan-2-ones, particularly 1-n- No. 6,582,724; which is a continuation-in-part of U.S. patent dodecyl-cyclazacycloheptan-2-one (available under the application Ser. No. 09/738,410, filed Dec. 14, 2000, and trademark AZone(R) from Nelson Research & Development now issued as U.S. Pat. No. 6,586,000; which was a continuation-in-part of U.S. patent application Ser. No. Co., Irvine, Calif.; see U.S. Pat. Nos. 3,989.816, 4,316,893, 09/569,889, filed May 11, 2000, now abandoned; which was 4,405,616 and 4,557,934); alcohols such as ethanol, a continuation-in-part of U.S. patent application Ser. No. propanol, octanol, benzyl alcohol, and the like; fatty acids 15 Such as lauric acid, oleic acid and Valeric acid; fatty acid 09/465,098, filed Dec. 16, 1999, now abandoned; the dis esterS Such as isopropyl myristate, isopropyl palmitate, closures of which are incorporated by reference. methylpropionate, and ethyl oleate; polyols and esters thereof Such as propylene glycol, ethylene glycol, glycerol, TECHNICAL FIELD butanediol, polyethylene glycol, and polyethylene glycol This invention relates generally to the topical and trans monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); dermal administration of pharmacologically active agents, amides and other nitrogenous compounds Such as urea, and more particularly relates to permeation enhancer com dimethylacetamide (DMA), dimethylformamide (DMF), positions for enhancing the permeability of skin or mucosal 2-pyrrollidone, 1-methyl-2-pyrrollidone, ethanolamine, tissue to topically applied pharmacologically active agents. diethanolamine and triethanolamine; terpenes, alkanones, 25 and organic acids, particularly Salicylic acid and Salicylates, BACKGROUND ART citric acid and Succinic acid. Percutaneous Penetration Skin is a structurally complex, relatively thick membrane. Enhancers, eds. Smith et al. (CRC Press, 1995) provides an In order to deliver a drug into and through the skin, i.e., excellent overview of the field and further background “transdermally, drug molecules must first penetrate the information on a number of chemical and physical enhanc Stratum corneum and any material on its Surface. They must CS. then penetrate the viable epidermis, the papillary dermis, Although many chemical permeation enhancers are and the capillary walls into the blood stream or lymph known, there is an ongoing need for enhancers that are channels. To be So absorbed, molecules must overcome a highly effective in increasing the rate at which a drug different resistance to penetration in each type of tissue. permeates the skin, do not result in Skin damage, irritation, Transport across the Skin membrane is thus a complex 35 Sensitization, or the like, and can be used to effect transder phenomenon. However, it is the cells of the Stratum corneum mal delivery of even high molecular weight drugs. Such as that present the primary barrier to absorption of topical peptides, proteins, and nucleic acids. Furthermore, it would compositions or transdermally administered drugs. The Stra be a clear advantage commercially if a Single enhancer tum corneum is a thin layer of dense, highly keratinized cells composition could be used to enhance both hydrophilic and approximately 10-15 microns thick over most of the body. 40 hydrophobic drugs. Currently, the enhancers that are used It is believed to be the high degree of keratinization within with hydrophilic drugs are not generally effective with these cells as well as their dense packing which creates in hydrophobic drugs, and, conversely, the enhancers that are most cases a Substantially impermeable barrier to drug used with hydrophobic drugs are not generally effective with penetration. With many drugs, the rate of permeation hydrophilic drugs. It has now been discovered that a com 45 bination enhancer, comprised of both a hydrophilic compo through the skin is extremely low without the use of Some nent and a lipophilic component, wherein the hydrophilic means to enhance the permeability of the skin. component is a hydroxide-releasing agent, is a highly effec In order to increase the rate at which a drug penetrates tive permeation enhancer, provide all of the aforementioned through the skin, various approaches have been followed, advantages relative to known permeation enhancers, and is each of which-involves the use of either a chemical pen 50 equally effective with hydrophilic and lipophilic drugs. etration enhancer or a physical penetration enhancer. Meth ods for physically enhancing skin permeation include, for SUMMARY OF THE INVENTION example, electrophoretic techniqueS Such as iontophoresis. The use of ultrasound (or "phonophoresis) as a physical It is thus a primary object of the invention to address the penetration enhancer has also been researched. Chemical 55 above-described need in the art by providing a novel per enhancers are compounds that are administered along with meation enhancer composition for enhancing the rate at the drug (or in Some cases used to pretreat the skin, prior to which an active agent administered to a patient's body drug administration) in order to increase the permeability of Surface permeates into and/or through the body Surface. the Stratum corneum, and thereby provide for enhanced It is another object of the invention to provide Such an penetration of the drug through the skin. Ideally, Such 60 enhancer composition, wherein the composition contains a chemical penetration enhancers (or “permeation enhancers,” hydroxide-releasing agent and a lipophilic co-enhancer. as the compounds are referred to herein) are compounds that It is still another object of the invention to provide such are innocuous and Serve merely to facilitate diffusion of the an enhancer composition, where in the lipophilic drug through the Stratum corneum. co-enhancer comprises a fatty acid ester, a fatty alcohol, a Various compounds for enhancing the permeability of 65 fatty ether, or a derivative and/or combination thereof. skin are known in the art and described in the pertinent texts It is yet another object of the invention to provide a and literature. Compounds that have been used to enhance pharmaceutical formulation containing a therapeutically US 6,835,392 B2 3 4 effective amount of a pharmacologically active agent and an In another aspect of the invention, a pharmaceutical effective permeation enhancing amount of an enhancer formulation is provided containing a therapeutically effec composition of the invention. tive amount of a pharmacologically active agent, an effective It is a further object of the invention to provide a drug permeation enhancing amount of a permeation enhancer delivery System for application to a patient's body Surface, composition as just described, and a pharmaceutically containing a therapeutically effective amount of a pharma acceptable carrier Suitable for topical or transdermal drug cologically active agent and an effective permeation administration. The formulation may be in any form suitable enhancing amount of an enhancer composition of the inven for application to the body Surface, and may comprise, for tion. example, a cream, lotion, Solution, gel, ointment, paste or It is still a further object of the invention to provide a the like, and/or may be prepared So as to contain lipoSomes, method for enhancing the flux of an active agent through a micelles, and/or microSpheres. The formulation may be body Surface, wherein the method involves administering directly applied to the body Surface or may involve use of a the agent to a localized region of a human patient's body drug delivery device. It is preferred although not essential Surface in combination with an effective permeation enhanc that water be present in order for the hydroxide-releasing 15 agent to generate hydroxide ions and thus assist in enhanc ing amount of an enhancer composition of the invention. ing the flux of the active agent through a patient's body It is yet a further object of the invention to provide such Surface. Thus, a formulation or drug reservoir may be a method wherein the active agent is intended for local aqueous, i.e., contain water, or may be nonaqueous and used delivery, and drug administration is topical. in combination with an occlusive overlayer So that moisture It is an additional object of the invention to provide such evaporating from the body Surface is maintained within the a method wherein the active agent is intended for Systemic formulation or transdermal System during drug administra delivery, and drug administration is transdermal. tion. Additional objects, advantages and novel features of the The amount of the hydroxide-releasing agent in the phar invention will be set forth in part in the description that maceutical formulation is preferably the total of (a) the follows, and in part will become apparent to those skilled in 25 amount required to neutralize any acidic species in the the art upon examination of the following, or may be learned formulation plus (b) an amount equal to approximately 0.5 by practice of the invention. wt % to 4.0 wt % of the formulation. When the active agent In one aspect of the invention, then, a permeation is an acid addition Salt of a basic compound, the amount in enhancer composition is provided that is comprised of a (a) is the amount required to neutralize the acid addition Salt hydroxide-releasing agent and a lipophilic co-enhancer, and any other acidic species in the formulation. When the wherein the weight ratio of the hydroxide-releasing agent to active agent is an acidic drug in the form of a free acid, the the lipophilic co-enhancer is generally in the range of amount in (a) is the amount required to neutralize the acidic approximately 1:99 to approximately 99:1, preferably in the drug and any other acidic species in the formulation. With range of approximately 1:20 to approximately 20:1, and basic drugs present in the formulation as a neutral, free base, most preferably in the range of approximately 1:2 to 35 and with basic Salts of acidic drugs, the amount in (a) is approximately 2:1. The hydroxide-releasing agent is gener Simply the amount necessary to neutralize inactive compo ally Selected from the group consisting of inorganic nents that are acidic, Since Such drugs are not, clearly, hydroxides, inorganic oxides, metal Salts of weak acids, and susceptible to neutralization with base. Preferably, although mixtures thereof, although inorganic hydroxides, i.e., not necessarily, the pharmaceutical formulation has a pH in ammonium hydroxide, alkali metal hydroxides, and alkaline 40 the range of approximately 8.0 to approximately 13.0, more earth metal hydroxides, are preferred. The lipophilic preferably in the range of approximately 8.0 to 11.5, and co-enhancer has a molecular weight in the range of about optimally in the range of approximately 8.0 to approxi 150 to 1000 and an aqueous solubility of less than about 1 mately 11.5. wt %. Preferably, the co-enhancer also has a Hildebrand In a further aspect of the invention, a drug delivery System Solubility parameter O in the range of about 2.5 to about 12, 45 is provided for the topical or transdermal administration of preferably in the range of about 5 to about 10. Preferred a drug using the dual enhancer composition of the invention. co-enhancers have the molecular structure (CH-L-X).R., The System will generally comprise: at least one drug in which: reservoir containing the drug and the enhancer composition n is 1 or 2, in an amount effective to enhance the flux of the drug 50 through the body Surface; a means for maintaining the L is alkylene or alkenylene containing 1 to 3 double bonds System in drug and enhancer transmitting relationship to the and from about 6 to about 22 carbon atoms; body Surface; and a backing layer that Serves as the outer X is Selected from the group consisting of COO-, Surface of the device during use. The backing layer may be CHO- and -CH-O-(CO)-; and occlusive or nonocclusive, although it is preferably occlu R is Selected from the group consisting of H, lower alkyl, 55 Sive. The drug reservoir may be comprised of a polymeric and lower alkyl substituted with one or two hydroxyl adhesive, which may serve as the basal Surface of the System groups, with the proviso that if R is H, X is necessarily during use and thus function as the means for maintaining -CHO-, the System in drug and enhancer transmitting relationship to wherein when n is 2, R contains at least two carbon atoms. the body Surface. The drug reservoir may also be comprised Preferred lipophilic co-enhancers are fatty acid esters, 60 of a hydrogel, or it may be a Sealed pouch within a particularly lower alkyl esters of a Co-Cs fatty acid, and "patch'-type structure wherein the drug and hydroxide Co-Cs fatty acid mono- and di-esters of polyols Such as releasing agent are present in the pouch as a liquid or propylene glycol and glycerol. Preferably, although not Semi-Solid formulation. necessarily, the enhancer composition has a pH in the range In an additional aspect of the invention, a method is of approximately 8.0 to approximately 13.0, more preferably 65 provided for increasing the rate at which an active agent in the range of approximately 8.0 to 11.5, and optimally in permeates through the body Surface of a patient. The method the range of approximately 8.0 to approximately 11.5. involves administering the agent to a predetermined area of US 6,835,392 B2 S 6 the patient’s body surface in combination with an effective The term "hydroxide-releasing agent” as used herein is permeation-enhancing amount of a permeation enhancer intended to mean an agent that releases free hydroxide ions composition of the invention. The effective permeation in an aqueous environment. The agent may contain hydrox enhancing amount of the enhancer composition is preferably ide ions and thus release the ions directly (e.g., an alkali an amount effective to provide a pH at the body Surface, i.e., metal hydroxide), or the agent may be one that is acted upon during drug administration, in the range of about 8.0 to 13, chemically in an aqueous environment to generate hydrox ide ions (e.g., a metal carbonate). preferably about 8.0 to 11.5, most preferably about 8.5 to The terms “active agent,” “drug” and “pharmacologically 11.5. If a skin patch is used, this is the preferred pH at the active agent” are used interchangeably herein to refer to a interface between the basal Surface of the patch (i.e., the chemical material or compound that induces a desired effect, skin-contacting or mucosa-contacting Surface of the patch) and include agents that are therapeutically effective, and the body Surface. The optimal amount (or concentration) prophylactically effective, or cosmeceutically effective. of the enhancer composition will, however, depend on the Also included are derivatives and analogs of those com Specific hydroxide-releasing agent, i.e., on the Strength or pounds or classes of compounds Specifically mentioned that weakness of the base, its molecular weight, and other factors also induce the desired effect. as will be appreciated by those of ordinary skill in the art of 15 By “therapeutically effective” amount is meant a nontoxic transdermal drug delivery. This optimal amount may be but Sufficient amount of an active agent to provide the determined using routine experimentation to ensure that the desired therapeutic effect. pH at the body Surface is within the aforementioned ranges, By “transdermal” drug delivery is meant administration of i.e., in the range of about 8.0 to 13, preferably about 8.0 to a drug to the skin Surface of an individual So that the drug 11.5, most preferably about 8.5 to 11.5. A conventional passes through the skin tissue and into the individual’s blood transdermal drug delivery device or “patch' may be used to Stream, thereby providing a Systemic effect. The term “trans administer the active agent, in which case the drug and dermal” is intended to include “transmucosal” drug hydroxide-releasing agent are generally present in a drug administration, i.e., administration of a drug to the mucosal reservoir or reservoirs. However, the drug and hydroxide (e.g., Sublingual, buccal, vaginal, rectal) Surface of an indi releasing agent may also be administered to the body Surface 25 vidual So that the drug passes through the mucosal tissue and using a liquid or Semisolid formulation. Alternatively, or in into the individual's blood stream. addition, the body surface may be pretreated with the The term “topical administration” is used in its conven enhancer, i.e., prior to transdermal drug administration. tional Sense to mean delivery of a topical drug or pharma cologically active agent to the skin or mucosa, as in, for BRIEF DESCRIPTION OF THE DRAWING example, the treatment of various skin disorders. Topical FIG. 1 is a graph illustrating the cumulative amount of administration, in contrast to transdermal administration, testosterone permeated through the skin with a dual provides a local rather than a systemic effect. Unless oth enhancer composition of the invention, a composition con erwise Stated or implied, the terms “topical drug adminis taining only one of the enhancers, and a composition con tration' and "transdermal drug administration' are used taining no enhancers, as described in detail in the Example. 35 interchangeably. The term “body surface” is used to refer to skin or DETAILED DESCRIPTION OF THE mucosal tissue. INVENTION By “predetermined area of skin or mucosal tissue, which I. Definitions and Overview refers to the area of Skin or mucosal tissue through which a Before describing the present invention in detail, it is to 40 drug-enhancer formulation is delivered, is intended a be understood that this invention is not limited to particular defined area of intact unbroken living skin or mucosal tissue. drugs or drug delivery Systems, as Such may vary. It is also That area will usually be in the range of about 5 cm° to about to be understood that the terminology used herein is for the 200 cm, more usually in the range of about 5 cm to about purpose of describing particular embodiments only, and is 100 cm, preferably in the range of about 20 cm to about not intended to be limiting. 45 60 cm'. However, it will be appreciated by those skilled in It must be noted that, as used in this specification and the the art of drug delivery that the area of skin or mucosal tissue appended claims, the singular forms “a,” “an” and “the” through which drug is administered may vary Significantly, include plural referents unless the context clearly dictates depending on patch configuration, dose, and the like. otherwise. Thus, for example, "a pharmacologically active “Penetration enhancement' or “permeation enhance agent” refers not only to a Single active agent but also to a 50 ment” as used herein relates to an increase in the perme mixture of two or more active agents, reference to “a ability of the skin or mucosal tissue to the Selected pharma hydroxide-releasing agent' includes mixtures of two or cologically active agent, i.e., So that the rate at which the more hydroxide-releasing agents, the term "a lipophilic agent permeates therethrough (i.e., the "flux' of the agent co-enhancer' can refer to two or more lipophilic compo through the body Surface) is increased relative to the rate that nents in combination, and the like. 55 would be obtained in the absence of permeation enhance In describing and claiming the present invention, the ment. The enhanced permeation effected through the use of following terminology will be used in accordance with the Such enhancers can be observed by measuring the rate of definitions set out below. diffusion of drug through animal or human skin using, for The terms “treating” and “treatment” as used herein refer example a Franz diffusion apparatus as known in the art and to reduction in Severity and/or frequency of Symptoms, 60 as employed in the Examples herein. elimination of Symptoms and/or underlying cause, preven An “effective amount” or “an effective permeation tion of the occurrence of Symptoms and/or their underlying enhancing amount of a permeation enhancer refers to a cause, and improvement or remediation of damage. The nontoxic, nondamaging but Sufficient amount of the present method of “treating a patient, as the term is used enhancer composition to provide the desired increase in skin herein, thus encompasses both prevention of a disorder in a 65 permeability and, correspondingly, the desired depth of predisposed individual and treatment of the disorder in a penetration, rate of administration, and amount of drug clinically Symptomatic individual. delivered. US 6,835,392 B2 7 8 “Carriers' or “vehicles” as used herein refer to carrier metaborate, Sodium carbonate, Sodium bicarbonate, Sodium materials Suitable for transdermal drug administration. Car phosphate (tribasic), Sodium phosphate (dibasic), potassium riers and vehicles useful herein include any Such materials carbonate, potassium bicarbonate, potassium citrate, potas known in the art, which are nontoxic and do not interact with sium acetate, potassium phosphate (dibasic), potassium other components of a pharmaceutical formulation or drug phosphate (tribasic), ammonium phosphate (dibasic), and delivery System in a deleterious manner. the like. Preferred hydroxide-releasing agents are metal Accordingly, the invention pertains to an enhancer hydroxides Such as Sodium hydroxide and potassium composition, pharmaceutical formulation, drug delivery Sys hydroxide. tem and method for increasing the rate at which an active It is important that the amount of hydroxide-releasing agent permeates through the body Surface of a patient, agent in any patch or formulation is optimized So as to wherein the method involves administering the agent to a increase the flux of the drug through the body surface while predetermined area of the patient's body Surface in combi minimizing any possibility of skin damage. In general, this nation with an effective permeation enhancing amount of an means that the pH at the body Surface in contact with a enhancer composition comprised of a hydroxide-releasing formulation or drug delivery System of the invention (i.e., agent and a lipophilic co-enhancer. 15 the interface between the body surface and the formulation II. The Enhancer Composition or delivery System) should be in the range of approximately The enhancer composition is comprised of a hydroxide 8.0 to 13, preferably about 8.0 to 11.5, more preferably about releasing agent and a lipophilic co-enhancer, wherein the 8.5 to 11.5. This will typically although not necessarily mean weight ratio of the hydroxide-releasing agent to the lipo that the pH of a pharmaceutical formulation containing the philic co-enhancer is generally in the range of approximately enhancer composition and the active agent, or a drug com 1:99 to approximately 99:1, preferably in the range of position contained within a delivery System, will be in the approximately 1:20 to approximately 20:1, and most pref range of approximately 8.0 to 13, preferably about 8.0 to erably in the range of approximately 1:2 to approximately 11.5, more preferably about 8.5 to 11.5. 2:1. The presence of the hydrophilic component, i.e., the For inorganic hydroxides, the amount of hydroxide hydroxide-releasing agent, ensures that the enhancer com 25 releasing agent in a drug-containing pharmaceutical formu position will be effective with hydrophilic drugs, while the lation for application to a patient's body Surface will typi presence of the lipophilic co-enhancer ensures that the cally represent about 0.5 wt % to 4.0 wt %, preferably about enhancer composition will also be effective with hydropho 0.5 wt % to 3.0 wt %, more preferably about 0.75 wt % to bic (lipophilic) drugs. Further, the inventors herein have 2.0 wt % and optimally about 1.0 wt %, of a topically discovered that there is a Synergistic effect in combining the applied formulation or of a drug reservoir of a drug delivery two enhancer components, in that greater enhancement is System, or “patch.” The aforementioned amount applies to observed with the combination of the hydroxide-releasing formulations and patches in which the active agent is (1) in agent and the lipophilic co-enhancer than with the use of nonionized, free base form, (2) a basic Salt of an acidic drug, either enhancer component alone. or (3) there are no additional Species in the formulation or Preferably, although not necessarily, the enhancer com 35 patch that could react with or be neutralized by the inorganic position has a pH in the range of approximately 8.0 to hydroxide. approximately 13.0, more preferably in the range of approxi More generally, however, the amount of the hydroxide mately 8.0 to 11.5, and optimally in the range of approxi releasing agent in the formulation will be the total of (a) the mately 8.0 to approximately 11.5. amount required to neutralize any acidic species in the A. The Hydroxide-Releasing Agent 40 formulation plus (b) an amount equal to approximately 0.5 The “hydroxide-releasing agent' is a chemical compound wt % to 4.0 wt %, preferably about 0.5 wt % to 3.0 wt %, that releases free hydroxide ions in the presence of an more preferably about 0.75 wt % to 2.0 wt % and optimally aqueous fluid. The aqueous fluid may be natural moisture at about 1.0 wt %, of the formulation. Thus, when the active the skin Surface, or a patch or composition that is used may agent is an acid addition Salt of a basic compound, the contain added water, and/or be used in connection with an 45 amount in (a) is the amount required to neutralize the acid occlusive backing. Similarly, any liquid or Semisolid formu addition Salt and any other acidic species in the formulation. lation that is used is preferably aqueous or used in conjunc When the active agent is an acidic drug in the form of a free tion with an overlayer of an occlusive material. acid, the amount in (a) is the amount required to neutralize Any hydroxide-releasing agent may be used provided that the acidic drug and any other acidic species in the formu the compound releases free hydroxide ions in the presence 50 lation. AS pointed out above, neither basic drugs in the form of an aqueous fluid. Hydroxide-releasing agents useful as of a neutral, free base nor acidic drugs are affected by a permeation enhancers are described in detail in co-pending hydroxide-releasing agent, and thus for these drugs, the U.S. patent application Ser. No. 09/738,410, filed Dec. 14, amount in (a) is simply the amount necessary to neutralize 2000, for “Hydroxide-Releasing Agents as Skin Permeation inactive components that are acidic. Enhancers' by Luo et al., assigned to Dermatrends, Inc. (San 55 For other hydroxide-releasing agents Such as inorganic Diego, Calif.). AS described in the aforementioned patent oxides and metal Salts of weak acids, the amount of application, hydroxide-releasing agents that are Suitable hydroxide-releasing agent in the formulation or drug deliv permeation enhancers include, but are not limited to, inor ery System may be Substantially higher, as high as 20 wt %, ganic hydroxides, inorganic oxides, and alkali metal or in Some cases as high as 25 wt % or higher, but will alkaline earth metal Salts of weak acids. Inorganic hydrox 60 generally be in the range of approximately 2 wt % to 20 wt ides include, for example, ammonium hydroxide, alkali %. metal hydroxide and alkaline earth metal hydroxides, Such Still greater amounts of hydroxide-releasing agent may be as Sodium hydroxide, calcium hydroxide, potassium used by-controlling the rate and/or quantity of release of the hydroxide, magnesium hydroxide, and the like. Inorganic hydroxide-releasing agent preferably during the drug deliv oxides include, for example, magnesium oxide, calcium 65 ery period itself. oxide, and the like. Metal Salts of weak acids include, for However, for all hydroxide-releasing agents herein, the example, Sodium acetate, Sodium borate, Sodium optimum amount of any particular agent will depend on the US 6,835,392 B2 10 Strength or weakness of the base, the molecular weight of the is -CHO-(CO)- and R is lower alkyl or lower alkyl base, and other factorS Such as the number of ionizable Sites Substituted with one or two hydroxyl groups); L may also be in the drug administered and any other acidic Species in the alkenylene, in which case 1 to 3, preferably 1 or 2, double formulation or patch. One skilled in the art may readily bonds may be present, although one double bond (as in oleic determine the optimum amount for any particular agent by acid) is typical. ensuring that a formulation or drug delivery System should Preferred lipophilic co-enhancers herein are fatty acid in all cases be effective to provide a pH at the skin Surface, esters, particularly lower alkyl esters of Saturated or unsat during drug delivery, in the range of about 8.5 to 13, urated Co-Cs fatty acids, as noted above. Of the Saturated preferably in the range of about 8.5 to 11.5. This in turn Co-C1s fatty acids, most preferred are the Co., C2 and Ca ensures that the degree of enhancement is optimized while acids, i.e., capric acid, lauric acid, and myristic acid, respec the possibility of damage to the body Surface is eliminated tively. Unsaturated Co-Cs fatty acids include oleic acid, or at least Substantially minimized. palmitolcic acid, vaccenic acid, petroSelenic acid, linoleic B. The Lipophilic Co-Enhancer acid, linolenic acid, and linolaidic acid, with oleic acid being The lipophilic co-enhancer is Selected from those enhanc the most common and preferred herein. It will be appreci erS typically referred to as "plasticizing” enhancers, i.e., 15 ated from the definition of “n” that the fatty acid ester may enhancers that have a molecular weight in the range of about comprise a Single -X-L-CH chain or two -X-L- 150 to 1000, an aqueous solubility of less than about 1 wt %, CH chains. In the latter case, the compound is a di-esterified preferably less than about 0.5 wt %, and most preferably less dial or triol, with di-esterified C-C alkane diols and triols than about 0.2 wt %. The Hildebrand solubility parameter O preferred. For example, R may be Selected from the group of plasticizing enhancers is in the range of about 2.5 to about consisting of structures (II) through (V) 10, preferably in the range of about 5 to about 10. As is known in the art, the Hildebrand solubility parameter mea (II) Sures the cohesive forces and Sum of all intermolecular attractive forces related to the extent of mutual solubility of -"2 many chemical Species. See, e.g., the CRC Handbook of 25 fl. Solubility Parameters and other Cohesion Parameters, CRC HC-L-X-CH Press, Inc., Boca Raton, Fla. (1985). Relative hydrophilicity (III) increases with the value of the Hildebrand solubility param eter. For example, the skin has a O value of 10, while water --2 has a O value of 23.4. This in turn means enhancers with lo-fi, solubility parameters of <10 will intervene with the lipid HC-L-X-CH components of the skin, but those with solubility parameters (IV) of >10 will selectively partition into the polar components of o t2 the skin. Such enhancers are distinguishable from “Solvent HC-L-X- t type' enhancers, which are lower molecular weight hydro 35 philic compounds having a higher Solubility parameter O (as HO-CH high as 18–20, or even higher). (V) The lipophilic co-enhancer preferably comprises a com o CH2 pound having the structure (CH-L-X),R, in which: HC-L-X-CH 40 n is 1 or 2, CH L is alkylene or alkenylene containing 1 to 3 double bonds and from about 6 to about 22 carbon atoms; Examples of Specific and most preferred fatty acid esters X is Selected from the group consisting of -COO-, for use as lipophilic co-enhancers herein include, but are not CHO-, and -CHO-(CO)-; and 45 limited to, methyl laurate, ethyl oleate, propylene glycol R is Selected from the group consisting of H, lower alkyl, monolaurate, propylene glycerol dilaurate, glycerol and lower alkyl substituted with one or two hydroxyl monolaurate, glycerol monooleate, isopropyl n-decanoate, groups, with the proviso that if R is H, X is necessarily and octyldodecyl myristate, and the like. -CH-O-, The lipophilic co-enhancer may also be a fatty alcohol, in wherein when n is 2, R contains at least two carbon atoms. 50 which case X is -CHO- and R is H, a fatty ether, in By “lower alkyl,” applicants intend an alkyl group of 1 to which case X is -CHO- and R is other than H, or an ester 7 carbon atoms, typically 1 to 3 carbon atoms. of a lower carboxylic acid with a fatty ether, in which case Preferred L. moieties are alkylene linkers containing about X is -CH-O-(CO)- and R is other than H. Fatty alcohols 6 to about 22 carbon atoms, preferably about 8 to about 18 include, for example, Stearyl alcohol and oleyl alcohol, carbon atoms, more preferably about 8 to about 16 carbon 55 while fatty ethers include compounds wherein a diol or triol, atoms, and, for Saturated aliphatic L. moieties, most prefer preferably a C-C alkane diol or triol, are Substituted with ably 8 to 12 carbon atoms. It will be appreciated by those one or two fatty ether substituents. Such fatty ethers include, skilled in the art that Since two additional carbon atoms are for example, compounds wherein R is any one of Structures present within the entire compound (in “X” as well as in the (II) through (V), above. methyl group bound to L), the most preferred compounds 60 C. Other Components of the Enhancer Composition are actually: lower alkyl esters of Co-Cs fatty acids (X is In addition to the hydroxide-releasing agent and the -COO- and R is lower alkyl or lower alkyl substituted lipophilic co-enhancer, the enhancer composition may also with one or two hydroxyl groups); lower alkyl ethers of include conventional additives Such as opacifiers, Co-Cs fatty acids (X is -CHO- and R is lower alkyl antioxidants, fragrance, colorant, gelling agents, thickening or lower alkyl Substituted with one or two hydroxyl groups); 65 agents, Stabilizers, Surfactants and the like. Other agents Co-Cs fatty alcohols (X is -CHO- and R is H); and may also be added, Such as antimicrobial agents, to prevent esters of CoCs fatty ethers and “lower carboxylic acids (X Spoilage upon Storage, i.e., to inhibit growth of microbes US 6,835,392 B2 11 12 Such as yeasts and molds. Suitable antimicrobial agents are rations that are typically based on petrolatum or other typically Selected from the group consisting of the methyl petroleum derivatives. The Specific ointment base to be and propyl esters of p-hydroxybenzoic acid (i.e., methyl and used, as will be appreciated by those skilled in the art, is one propyl paraben), Sodium benzoate, Sorbic acid, imidurea, that will provide for optimum drug delivery, and, preferably, and combinations thereof. The enhancer composition may will provide for other desired characteristics as well, e.g., also contain one or more topical carriers, as described in emolliency or the like. AS with other carriers or vehicles, an Section IV, infra. ointment base should be inert, stable, nonirritating and The enhancer composition may also contain irritation nonsensitizing. AS explained in Remington. The Science mitigating additives to minimize or eliminate the possibility and Practice of Pharmacy, 19th Ed. (Easton, Pa.; Mack of skin irritation or skin damage resulting from the enhancer, Publishing Co., 1995), at pages 1399–1404, ointment bases the drug to be administered, or other components of the may be grouped in four classes: oleaginous bases, emulsi composition. Suitable irritation-mitigating additives fiable bases, emulsion bases, and water-Soluble bases. Ole include, for example: C-tocopherol, monoamine oxidase aginous ointment bases include, for example, vegetable oils, inhibitors, particularly phenyl alcohols Such as 2-phenyl-1- fats obtained from animals, and Semisolid hydrocarbons ethanol, glycerin; Salicylic acids and Salicylates, ascorbic 15 obtained from petroleum. Emulsifiable ointment bases, also acids and ascorbates, ionophores Such as monensin; known as absorbent ointment bases, contain little or no amphiphilic amines, ammonium chloride, N-acetylcysteine; water and include, for example, hydroxyStearin Sulfate, cis-urocanic acid; capsaicin; and chloroquine. The irritant anhydrous lanolin and hydrophilic petrolatum. Emulsion mitigating additive, if present, may be incorporated into the ointment bases are either water-in-oil (W/O) emulsions or present enhancer compositions at a concentration effective oil-in-water (O/W) emulsions, and include, for example, to mitigate irritation or skin damage, typically representing cetyl alcohol, glyceryl monoStearate, lanolin and Stearic not more than about 20 wt %, more typically not more than acid. Preferred water-Soluble ointment bases are prepared about 5 wt %, of the composition. from polyethylene glycols of varying molecular weight; III. Pharmaceutical Formulations again, see Remington. The Science and Practice of Phar In another embodiment, a pharmaceutical formulation is 25 macy for further information. provided containing an effective permeation enhancing Creams, as also well known in the art, are Viscous liquids amount of the above-described enhancer composition, a or Semisolid emulsions, either oil-in-water or water-in-oil. therapeutically effective amount of a pharmacologically Cream bases are water-washable, and contain an oil phase, active agent, and a pharmaceutically acceptable carrier Suit an emulsifier and an aqueous phase. The oil phase, also able for topical or transdermal drug administration. The called the “internal' phase, is generally comprised of pet formulation may be in any form Suitable for application to rolatum and a fatty alcohol Such as cetyl or Stearyl alcohol. the body Surface, and may comprise, for example, a cream, The aqueous phase usually, although not necessarily, lotion, Solution, gel, ointment, paste or the like, and/or may exceeds the oil phase in Volume, and generally contains a be prepared So as to contain liposomes, micelles, and/or humectant. The emulsifier in a cream formulation is gener microSpheres. It is preferred although not essential that 35 ally a nonionic, anionic, cationic or amphoteric Surfactant. water be present in order for the hydroxide-releasing agent As will be appreciated by those working in the field of to generate hydroxide ions and thus assist in enhancing the pharmaceutical formulation, gels are Semisolid, Suspension flux of the active agent through a patient's body Surface. type Systems. Single-phase gels contain organic macromol Thus, the formulation may be acqueous, i.e., contain water, or ecules distributed Substantially uniformly throughout the may be nonaqueous and optionally used in combination with 40 carrier liquid, which is typically aqueous, but also, an occlusive overlayer So that moisture evaporating from the preferably, contain an alcohol and, optionally, an oil. Pre body Surface is maintained within the formulation or trans ferred “organic macromolecules, i.e., gelling agents, are dermal System during drug administration. crosslinked acrylic acid polymerS Such as the “carbomer' The amount of the hydroxide-releasing agent in the phar family of polymers, e.g., carboxypolyalkylenes that may be maceutical formulation is preferably the total of (a) the 45 obtained commercially under the CarbopolE) trademark. amount required to neutralize any acidic species in the Also preferred are hydrophilic polymerS Such as polyethyl formulation plus (b) an amount equal to approximately 0.5 ene oxides, polyoxyethylene-polyoxypropylene copolymers wt % to 4.0 wt % of the formulation. When the active agent and polyvinylalcohol, cellulosic polymerS Such as hydrox is an acid addition Salt of a basic compound, the amount in ypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl (a) is the amount required to neutralize the acid addition Salt 50 methylcellulose, hydroxypropyl methylcellulose phthalate, and any other acidic species in the formulation. When the and methylcellulose, gums Such as tragacanth and Xanthan active agent is an acidic drug in the form of a free acid, the gum, Sodium alginate; and gelatin. In order to prepare a amount in (a) is the amount required to neutralize the acidic uniform gel, dispersing agents Such as alcohol or glycerin drug and any other acidic species in the formulation. With can be added, or the gelling agent can be dispersed by basic drugs present in the formulation as a neutral, free base, 55 trituration, mechanical mixing, Stirring, or combinations and with basic Salts of acidic drugs, the amount in (a) is thereof. Simply the amount necessary to neutralize inactive compo Lotions, which are preferred for delivery of cosmetic nents that are acidic, Since Such drugs are not, clearly, agents, are preparations to be applied to the Skin Surface Susceptible to neutralization with base. Like the enhancer without friction, and are typically liquid or Semiliquid prepa composition, the pharmaceutical formulation preferably has 60 rations in which Solid particles, including the active agent, a pH in the range of approximately 8.0 to approximately are present in a water or alcohol base. Lotions are usually 13.0, more preferably in the range of approximately 8.0 to Suspensions of Solids, and preferably, for the present 11.5, and optimally in the range of approximately 8.0 to purpose, comprise a liquid oily emulsion of the oil-in-water approximately 11.5. type. Lotions are preferred formulations herein for treating Suitable formulations include ointments, creams, gels, 65 large body areas, because of the ease of applying a more lotions, pastes, and the like. Ointments, as is well known in fluid composition. It is generally necessary that the insoluble the art of pharmaceutical formulation, are Semisolid prepa matter in a lotion be finely divided. Lotions will typically US 6,835,392 B2 13 14 contain Suspending agents to produce better dispersions as further permeation enhancer in the formulation, although in well as compounds useful for localizing and holding the a preferred embodiment the hydroxide-releasing agent and active agent in contact with the skin, e.g., methylcellulose, lipophilic co-enhancer are administered without any other Sodium carboxymethylcellulose, or the like. permeation enhancers. Any other enhancers should, like the Pastes are Semisolid dosage forms in which the active hydroxide-releasing agent and the lipophilic co-enhancer, agent is Suspended in a Suitable base. Depending on the minimize the possibility of Skin damage, irritation, and nature of the base, pastes are divided between fatty pastes or Systemic toxicity. Examples of Suitable additional enhancers those made from a single-phase aqueous gel. The base in a include, but are not limited to, etherS Such as diethylene fatty paste is generally petrolatum or hydrophilic petrolatum glycol monoethyl ether (available commercially as or the like. The pastes made from Single-phase aqueous gels Transcutolf) and diethylene glycol monomethyl ether, Sur generally incorporate carboxymethylcellulose or the like as factants Such as Sodium laurate, Sodium lauryl Sulfate, a base. cetyltrimethyl-ammonium bromide, benzalkonium chloride, Formulations may also be prepared with liposomes, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80) and micelles, and microSpheres. Liposomes are microscopic lecithin (U.S. Pat. No. 4,783,450); alcohols such as ethanol, vesicles having a lipid wall comprising a lipid bilayer, and 15 propanol, octanol, benzyl alcohol, and the like; polyethylene can be used as drug delivery Systems herein as well. glycol and esters thereof Such as polyethylene glycol mono Generally, liposome formulations are preferred for poorly laurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides Soluble or insoluble pharmaceutical agents. Liposomal and other nitrogenous compounds Such as urea, dimethy preparations for use in the instant invention include cationic lacetamide (DMA), dimethylformamide (DMF), (positively charged), anionic (negatively charged) and neu 2-pyrrollidone, 1-methyl-2-pyrrollidone, ethanolamine, tral preparations. Cationic liposomes are readily available. diethanolamine and triethanolamine; terpenes, alkanones, For example, N1-2,3-dioleyloxy)propyl-N,N,N- and organic acids, particularly citric acid and Succinic acid. triethylammonium (DOTMA) liposomes are available under AZone(R) and sulfoxides such as DMSO and CMSO may the tradename Lipofectin(R) (GIBCO BRL, Grand Island, also be used, but are leSS preferred. AS noted earlier herein, N.Y.). Similarly, anionic and neutral liposomes are readily 25 Percutaneous Penetration Enhancers, eds. Smith et al. available as well, e.g., from Avanti Polar Lipids (CRC Press, 1995) provides an excellent overview of the (Birmingham, Ala.), or can be easily prepared using readily field and further information concerning possible Secondary available materials. Such materials include phosphatidyl enhancers for use in conjunction with the present invention. choline, cholesterol, phosphatidyl ethanolamine, dio The concentration of the active agent in the formulation leoylphosphatidyl choline (DOPC), dioleoylphosphatidyl can vary a great deal, and will depend on a variety of factors, glycerol (DOPG), dioleoylphoshatidyl ethanolamine including the disease or condition to be treated, the nature (DOPE), among others. These materials can also be mixed and activity of the active agent, the desired effect, possible with DOTMA in appropriate ratios. Methods for making adverse reactions, the ability and Speed of the active agent liposomes using these materials are well known in the art. to reach its intended target, and other factors within the Micelles are known in the art as comprised of Surfactant 35 particular knowledge of the patient and physician. Preferred molecules arranged So that their polar headgroups form an formulations will typically contain on the order of about 0.5 outer spherical shell, while the hydrophobic, hydrocarbon wt % to 50 wt %, optimally about 10 wt % to 30 wt %, active chains are oriented towards the center of the Sphere, forming agent. a core. Micelles form in an aqueous Solution containing IV. The Active Agent Surfactant at a high enough concentration So that micelles 40 The active agent administered may be any compound that naturally result. Surfactants useful for forming micelles is Suitable for topical, transdermal or transmucosal delivery include, but are not limited to, potassium laurate, Sodium and induces a desired local or Systemic effect. Such Sub octane Sulfonate, Sodium decane Sulfonate, Sodium dode stances include the broad classes of compounds normally cane Sulfonate, Sodium lauryl Sulfate, docusate Sodium, delivered through body Surfaces and membranes, including decyltrimethylammonium bromide, dodecyltrimethyl 45 skin. In general, this includes: analgesic agents, anesthetic ammonium bromide, tetradecyltrimethylammonium agents, antiarthritic agents, respiratory drugs, including anti bromide, tetradecyltrimethyl-ammonium chloride, dodecy asthmatic agents, anticancer agents, including antineoplastic lammonium chloride, polyoxyl 8 dodecyl ether, polyoxyl 12 drugs, anticholinergics, anticonvulsants, antidepressants, dodecyl ether, nonoxynol 10 and nonoxynol 30. Micelle antidiabetic agents, antidiarrheals, antihelminthics, antihis formulations can be used in conjunction with the present 50 tamines, antihyperlipidemic agents, antihypertensive invention either by incorporation into the reservoir of a agents, anti-infective agents Such as antibiotics and antiviral topical or transdermal delivery System, or into a formulation agents, antiinflammatory agents, antimigraine preparations; to be applied to the body Surface. antinauseants, antineoplastic agents, antiparkinsonism MicroSpheres, Similarly, may be incorporated into the drugs, antipruritics, antipsychotics, antipyretics, antispas present formulations and drug delivery Systems. Like lipo 55 modics, antitubercular agents, antiulcer agents, antiviral Somes and micelles, microSpheres essentially encapsulate a agents, anxiolytics, appetite Suppressants, attention deficit drug or drug-containing formulation. They are generally disorder (ADD) and attention deficit hyperactivity disorder although not necessarily formed from lipids, preferably (ADHD) drugs, cardiovascular preparations including cal charged lipids Such as phospholipids. Preparation of lipidic cium channel blockers, CNS agents, beta-blockers and anti microSpheres is well known in the art and described in the 60 arrhythmic agents, central nervous System Stimulants, cough pertinent texts and literature. and cold preparations, including decongestants, diuretics, Various additives, known to those skilled in the art, may genetic materials; herbal remedies, hormonolytics, hypnot be included in the topical formulations. For example, ics, hypoglycemic agents, immunosuppressive agents, leu Solvents, including relatively Small amounts of alcohol, may kotriene inhibitors, mitotic inhibitors, muscle relaxants, be used to Solubilize certain drug Substances. For those 65 narcotic antagonists, nicotine; nutritional agents, Such as drugs having an unusually low rate of permeation through Vitamins, essential amino acids and fatty acids, ophthalmic the skin or mucosal tissue, it may be desirable to include a drugS Such as antiglaucoma agents, parasympatholytics; US 6,835,392 B2 15 16 peptide drugs, psychoStimulants, Sedatives, Steroids, Sym Examples of Specific primary amines include, but are not pathomimetics, tranquilizers, and vasodilators including limited to, amphetamine, norepinephrine, phenylpropanola general coronary, peripheral and cerebral. mine (including any of the four isomers, individually or in The active agent administered also may be one that is combination, i.e., (+)-norephedrine, (-)-norephedrine, (+)- cosmetically or "cosmeceutically effective rather than phar norpseudoephedrine, and (-)-norpseudoephedrine), and macologically active. Such agents include, for example, pyrithiamine. compounds that can reduce the appearance of aging or Examples of Secondary and tertiary amines include, but photodamaged skin, e.g., alpha hydroxyacids, alpha are not limited to, amiodarone, amitryptyline, azithromycin, ketoacids, polymeric hydroxyacids, moisturizers, collagen, ben Zphetamine, bromopheniramine, chlorambucil, marine extract, and antioxidants Such as ascorbic acid chloroprocaine, chloroquine, chlorpheniramine, chlorothen, (vitamin C), C-tocopherol (Vitamin E), f-tocopherol, chlorpromazine, cinnarizine, clarthromycin, clomiphene, Y-tocopherol, 8-tocopherol, e-tocopherol, -tocopherol, cyclobenzaprine, cyclopentolate, cyclophosphamide, 2-tocopherol, m-tocopherol, and retinol (vitamin A), and/or dacarbazine, demeclocycline, dibucaine, dicyclomine, cosmetically acceptable Salts, esters, amides, or other diethylproprion, diltia Zem, dime nhy drinate, derivatives thereof. A preferred tocopherol compound is 15 diphenhydramine, diphenylpyraline, disopyramide, C-tocopherol. Additional cosmetic agents include those that doxepin, doxycycline, doxylamine, dypyridamine, are capable of improving oxygen Supply in Skin tissue, as ephedrine, epinephrine, ethylene diamine tetraacetic acid described, for example, in International Patent Publication (EDTA), erythromycin, flurazepam, gentian violet, Nos. WO94/00098 and WO94/00109. Sunscreens may also hydroxychloroquine, imipramine, isoprote renol, be included. isothipendyl, levomethadyl, lidocaine, loXarine, The active agent may be administered, if desired, in the mechlorethamine, melphalan, methadone, methafurylene, form of a Salt, ester, amide, prodrug, derivative, or the like, methapheniline, methalpy rilene, methdila Zine, provided the Salt, ester, amide, prodrug or derivative is methotimeperazine, methotrexate, metoclopramide, Suitable pharmacologically. Salts, esters, amides, prodrugs minocycline, naftifine, nicardipine, nicotine, nizatidine, and other derivatives of the active agents may be prepared 25 orphenadrine, oxybutynin, oxytetracycline, phenindamine, using Standard procedures known to those skilled in the art pheniramine, phenoxyben Zamine, phentolamine, of Synthetic organic chemistry and described, for example, phenylephrine, phenyltoloxamine, procainamide, procaine, by J. March, Advanced Organic Chemistry. Reactions, promazine, promethazine, proparacaine, propoxycaine, Mechanisms and Structure, 4th Ed. (New York: Wiley propoxyphene, pyrilamine, ranitidine, Scopolamine, Interscience, 1992). tamoxifen, terbinafine, tetracaine, tetracy cline, For those active agents that are chiral in nature and can thonzylamine, tramadol, triflu promazine, trimeprazine, thus be in enantiomerically pure form or in a racemic trimethylbenzamide, trimipramine, tripelennamine, mixture, the drug may be incorporated into the present troleandomycin, uracil mustard, Verapamil and vonedrine. dosage units either as the racemate or in enantiomerically Examples of non-aromatic heterocyclic amines include, pure form. 35 but are not limited to, alprazolam, amoxapine, arecoline, The amount of active agent administered will depend on astemizole, atropine, azithromycin, benazepril, benztropine, a number of factors and will vary from subject to subject and bupre norphine, buSpirone, butorphanol, caffeine, depend on the particular drug administered, the particular capriomycin, ceftriaxone, chloraZepate, chlorcyclizine, disorder or condition being treated, the Severity of the chlordiazepoxide, chlorpromazine, chlorthiazide, Symptoms, the Subjects age, weight and general condition, 40 ciprofloxacin, cladarabine, cle mastine, cle mizole, and the judgment of the prescribing physician. Other factors, clindamycin, clofa Zamine, clonazepam, clonidine, Specific to transdermal drug delivery, include the Solubility clozapine, cocaine, codeine, cyclizine, cyproheptadine, and permeability of the carrier and adhesive layer in a drug dacarb Zine, dactinomycin, desipramine, diaZoxide, delivery device, if one is used, and the period of time for dihydroergotamine, diphen idol, diphenoxylate, which such a device will be fixed to the skin or other body 45 dipyridamole, doxapram, ergotamine, esta Zolam, Surface. The minimum amount of drug is determined by the famciclovir, fentanyl, flavoxate, fludarabine, fluphenazine, requirement that Sufficient quantities of drug must be present flurazepam, fluvastatin, folic acid, ganciclovir, granisetron, in a device or composition to maintain the desired rate of guane thidine, halazepam, haloperidol, homatropine, release over the given period of application. The maximum hydrocodone, hydromorphone, hydroxy Zine, hyoscyamine, amount for Safety purposes is determined by the requirement 50 imipramine, itraconazole, ketorolac, ketoconazole, that the quantity of drug present cannot exceed a rate of levocarbustine, levorphan, lincomycin, lomefloxacin, release that reaches toxic levels. Generally, the maximum loperamide, lorazepam, losartan, loxapine, maZindol, concentration is determined by the amount of agent that can meclizine, meperidine, mepivacaine, mesoridazine, be received in the carrier without producing adverse histo meth dila Zine, me the namine, me thima Zole, logical effects Such as irritation, an unacceptably high initial 55 methotrimeperazine, methy Sergide, metronidazole, pulse of agent into the body, or adverse effects on the midazolam, minoxidil, mitomycin c, molindone, morphine, characteristics of the delivery device Such as the loss of naftaZone, nalbuphine, naldixic acid, nalmefene, naloxone, tackiness, Viscosity, or deterioration of other properties. naltrexone, naphazoline, nedocromil, nicotine, norfloxacin, Preferred classes of active agents are described in the ofloxacin, on dansetron, oxazepam, oxycodone, following Sections. 60 oxymetazoline, oxymorphone, pemoline, pentazocine, A. Pharmacologically Active Amines pentostatin, pentoxyfylline, perphenazine, phentolamine, The active agent may be a pharmacologically active phySOStigmine, pilocarpine, pimozide, pramoxine, praZosin, nitrogen-containing base, for example, a primary amine, a prochlorperazine, promazine, promethazine, pyrrobutamine, Secondary amine, or a tertiary amine, or it may be an quazepam, quinidine, quinine, rauwolfia alkaloids, aromatic or non-aromatic nitrogen-containing heterocycle, 65 riboflavin, rifabutin, risperidone, rocuronium, Scopolamine, an azo compound, an imine, or a combination of any of the Sufentanil, tacrine, temazepam, teraZosin, terconazole, foregoing. terfenadine, tetrahydrazoline, thioridazine, thiothixene, US 6,835,392 B2 17 18 ticlodipine, timolol, tolazoline, tolaZamide, tolmetin, well as higher potency corticosteroids Such as clobetasol traZodone, triazolam, triethylperazine, trifluopromazine, propionate, betamethasone benzoate, betamethasone trihexylphenidyl, trimeprazine, trimipramine, tubocurarine, diproprionate, diflorasone diacetate, fluocinonide, mometa vecuronium, Vidarabine, vinblastine, Vincristine, Vinorelbine Sone furoate, triamcinolone acetonide, and the like, local and Xylometazoline. anesthetic agents Such as phenol, benzocaine, lidocaine, Examples of aromatic heterocyclic amines include, but prilocaine and dibucaine; topical analgesicS Such as glycol are not limited to, acetazolamide, acyclovir, adenosine Salicylate, methyl Salicylate, 1-menthol, d.1-camphor and phosphate, allopurinal, alprazolam, amoxapine, amrinone, capsaicin; and antibiotics. Preferred additional agents are apraclonidine, azatadine, aztreonam, bisacodyl, bleomycin, antibiotic agents, discussed in Section F, infra. brompheniramine, buSpirone, butoconazole, carbinoxamine, The aforementioned compounds may be administered cefamandole, cefazolin, cefixime, cefimetazole, cefonicid, transdermally using the compositions, System and method of cefopera Zone, cefotaXime, cefotetan, cefpodoxime, the invention to treat any patient with an NSAID-responsive ceftriaxone, cephapirin, chloroquine, chlorpheniramine, condition or disorder. Typically, NSAMDs are employed as cimetidine, cladarabine, clotrima Zole, cloxacillin, anti-inflammatory and/or analgesic agents, and accordingly did anoSine, dipyridamole, doxa Zosin, doxylamine, 15 may be used to treat individuals Suffering from rheumatic or econazole, enoxacin, estazolam, ethionamide, famciclovir, arthritic disorders, including, for example: rheumatoid famotidine, fluconazole, fludarabine, folic acid, ganciclovir, arthritis (RA), degenerative joint disease (also known as hydroxychloroquine, iodoquinol, isoniazid, isothipendyl, DJD and “osteoarthritis”); juvenile rheumatoid arthritis itraconazole, ketoconazole, lamotrigine, lanSoprazole, (JRA), psoriatic arthritis; gouty arthritis, ankylosing lorce tadine, losartan, mebendazole, mercaptopurine, spondylitis, and lupus erythematoses Such as Systemic lupus methafurylene, methapyriline, methotrexate, metronidazole, erythematosus and discoid lupus erythematosus. miconazole, midazolam, minoxidil, naldixic acid, niacin, Other potential uses of NSAIDs include, but are not nicotine, nifedipine, nizatidine, omeperazole, Oxaprozin, limited to, treating fever (via the anti-pyretic property of OXiconazole, papaverine, pentostatin, phenaZopyridine, NSAIDs) or myocardial infarction (MI), transient ischemic pheniramine, pilocarpine, piroXicam, praZosin, primaquine, 25 attacks, and acute Superficial thrombophlebitis (via inhibi pyrazinamide, pyrilamine, pyrimethamine, pyrithiamine, tion of platelet aggregation). Further non-limiting uses for pyridoxamine, quinidine, quinine, ribaverin, rifampin, NSAIDs include either single or adjuvant therapy for anky Sulfadia Zine, Sulfame thiZole, Sulfame thoxazole, losing spondylitis, burSitis, cancer-related pain, SulfaSalazine, SulfaSoxazole, teraZosin, thiabendazole, dySmenorrhea, gout, headaches, muscular pain, tendonitis, thiamine, thioguanine, thonzylamine, timolol, traZOdone, and pain associated with medical procedures Such as dental, triampterene, triazolam, trimethadione, trimethoprim, gynecological, oral, orthopedic, post-partum and urological trimetrexate, triplenamine, tropicamide and vidarabine. procedures. Examples of azo compounds are phenaZopyridine and The amount of active agent administered will depend on SulfaSalazine, while examples of imines include cefixime, a number of factors and will vary from Subject to Subject, as cimetidine, clofazimine, clonidine, dantrolene, famotidine, 35 noted above. Generally, however, and by way of example, a furazolidone, nitrofurantoin, nitrofuraZone and oxiconazole. daily dosage of ketorolac using the present formulations and Combinations of the aforementioned drugs and/or com Systems will be in the range of approximately 10 mg to 40 binations of one or more of the aforementioned drugs with mg, a daily dosage of piroXicam using the present formu different type of active agent may also be delivered using the lations and Systems will be in the range of approximately 10 methodology of the present invention. 40 mg to 40 mg, and a daily dosage of ibuprofen using the B. Nonsteroidal Antiinflammatory Agents (NSAIDS) present formulations and Systems will be in the range of Suitable nonsteroidal antiinflammatory agents that may approximately 200 mg/day to 1600 mg/day. be used in the formulations of the present invention include, C. Steroids but are not limited to: propionic acid derivatives Such as 1. EStrogens and Progestins ketoprofen, flurbiprofen, ibuprofen, naproxen, fenoprofen, 45 Suitable estrogens that may be administered using the benoxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, compositions and drug delivery Systems of the invention pranoprofen, Suprofen, alminoprofen, butibufen, fenbufen include Synthetic and natural estrogens Such as: estradiol and tiaprofenic acid, acetylsalicylic acid; apaZone; (i.e., 1,3,5-estratriene-3,17B-diol, or “17B-estradiol”) and its diclofenac; difenpiramide, diflunisal, etodolac, flufenamic esters, including estradiol benzoate, Valerate, cypionate, acid; indomethacin, ketorolac, meclofenamate, mefenamic 50 heptanoate, decanoate, acetate and diacetate, 17C.-estradiol; acid, nabumetone; phenylbutaZone, piroXicam, Salicylic ethinylestradiol (i.e., 17O-ethinylestradiol) and esters and acid; Sulindac, tolmetin; and combinations of any of the ethers thereof, including ethinylestradiol 3-acetate and ethi foregoing. Preferred NSAIDs are ibuprofen, diclofenac nylestradiol 3-benzoate, estriol and estriol Succinate; poly Sodium, ketoprofen, ketorolac and piroXicam. estrol phosphate, estrone and its esters and derivatives, The NSAID or NSAIDs may be co-administered with one 55 including estrone acetate, estrone Sulfate, and piperazine or more additional active agents, e.g.: antihistaminic agents estrone Sulfate; quineStrol; mestranol; and conjugated Such as diphenhydramine and chlorphe niramine equine estrogens. 17B-Estradiol, ethinylestradiol and (particularly diphenhydramine hydrochloride and chlorphe meStranol are particularly preferred Synthetic estrogenic niramine maleate); corticosteroids, including lower potency agents for use in conjunction with the present invention. corticosteroids Such as hydrocortisone, hydrocortisone-21 60 Suitable progestins that can be delivered using the com monoe Sters (e.g., hydrocort is one-21-acetate, positions and Systems of the invention include, but are not hydrocortisone-21-butyrate, hydrocortisone-21-propionate, limited to, acetoxypregnenolone, allylestrenol, anageStone hydrocortisone-21-Valerate, etc.), hydrocortisone-17,21 acetate, chlormadinone acetate, cyproterone, cyproterone die Sters (e.g., hydrocortisone - 17,21-diacetate, acetate, desogeStrel, dihydrogesterone, dimethisterone, hydrocortisone-17-acetate-21-butyrate, hydrocortisone-17, 65 ethisterone (17O-ethinyl testosterone), ethynodiol diacetate, 21-dibutyrate, etc.), alclometaSone, dexamethasone, flurogestone acetate, gestadene, hydroxyprogesterone, flumethasone, prednisolone, and methylprednisolone, as hydroxyprogesterone acetate, hydroxyprogesterone US 6,835,392 B2 19 20 caproate, hydroxymethyl-progesterone, hydroxymethyl deterioration of other properties. However, preferred trans progesterone acetate, 3-ketodesogestrel, levonorgestrel, dermal compositions and Systems for hormone replacement lynestrenol, medrogestone, medroxyprogesterone acetate, therapy are capable of delivering about 0.5 to 10.0 mg megestrol, mege Strol acetate, melengestrol acetate, progestin, e.g., norethindrone, norethindrone acetate or the norethindrone, norethindrone acetate, norethisterone, nore like, and about 10 to 200 ug estrogen, e.g., 173-estradiol, thisterone acetate, norethynodrel, norgestimate, norgestrel, ethinyl estradiol, mestranol or the like, over a period of norgestrienone, norme thisterone, and progesterone. about 24 hours. However, it will be appreciated by those Progesterone, medroxyprogesterone, nore thindrone, skilled in the art that the desired dose of each individual norethynodrel, d.1-norgestrel and 1-norgestrel are particu active agent will depend on the Specific active agent as well larly preferred progestins. as on other factors, the minimum effective dose of each It is generally desirable to co-administer a progestin along active agent is of course preferred. with an estrogen in female HRT So that the estrogen is not 2. Androgenic Drugs “unopposed.” AS is well known, estrogen-based therapies Suitable androgenic agents that may be administered are known to increase the risk of endometrial hyperplasia using the compositions, System and method of the invention and cancer, as well as the risk of breast cancer, in treated 15 include, but are not limited to: the naturally occurring individuals. Co-administration of estrogenic agents with a androgens and derivatives thereof, including androsterone, progestin has been found to decrease the aforementioned androsterone acetate, androsterone propionate, androsterone risks. Preferred Such combinations include, without limita benzoate, androstenediol, androstenediol-3-acetate, tion: 173-estradiol and medroxyprogesterone acetate, 17B androstenediol-17-acetate, androstenediol-3,17-diacetate, estradiol and norethindrone, 17B-estradiol and norethyno androstenediol-17-benzoate, androstenediol-3-acetate-17 drel; ethinyl estradiol and d, 1-norgestrel; ethinyl estradiol benzoate, androstenedione, dehydroepiandrosterone and 1-norgestrel; and megestrol and medroxyprogesterone (DHEA; also termed “prasterone'), sodium dehydroepi acetate. androsterone sulfate, 4-dihydrotestosterone (DHT; also For female HRT, it may be desirable to co-administer a termed “stanolone”), 5 C.-dihydrotestosterone, Small amount of an androgenic agent along with the proges 25 dromoStanolone, dromoStanolone propionate, ethyleStrenol, tin and the estrogen, in order to reproduce the complete nandrolone phenpropionate, nandrolone decanoate, nan hormone profile of the premenopausal woman, Since low drolone furylprop io nate, in and rolone levels of certain androgens are present in premenopausal cyclohexanepropionate, nandrolone benzoate, nandrolone WOC. cyclohexanecarboxylate, Oxandrolone, Stanozolol and test Any of the aforementioned Steroid drugs may be naturally osterone, pharmaceutically acceptable esters of testosterone occurring Steroids, Synthetic Steroids, or derivatives thereof. and 4-dihydrotestosterone, typically esters formed from the As alluded to above, administration of a combination of hydroxyl group present at the C-17 position, including, but Steroidal active agents is useful in a variety of contexts, as not limited to, the enanthate, propionate, cypionate, will be readily appreciated by those skilled in the art. For phenylacetate, acetate, isobutyrate, buciclate, heptanoate, example, the transdermal administration of a progestin with 35 decanoate, undecanoate, caprate and isocaprate esters, and an estrogen may be used in female hormone replacement pharmaceutically acceptable derivatives of testosterone Such therapy, So that the Symptoms or conditions resulting from as methyl testosterone, testolactone, oxymetholone and flu altered hormone levels is mitigated or Substantially pre oxymesterone. Testosterone and testosterone esters, Such as vented. The present compositions and drug delivery Systems testosterone enanthate, testosterone propionate and testoster are in addition useful to administer progestins and estrogens 40 one cypionate, are particularly preferred androgenic agents to treat other conditions and disorders that are responsive to for use in conjunction with the present invention. The transdermal administration of the combination of active aforementioned testosterone esters are commercially avail agents. For example, the aforementioned combination is able or may be readily prepared using techniques known to useful to treat the Symptoms of premenstrual StreSS and for those skilled in the art or described in the pertinent literature. female contraception, as noted above. For female hormone 45 The aforementioned androgenic agents are Selected from replacement therapy, the woman undergoing treatment will the group consisting of naturally occurring androgens, Syn generally be of childbearing age or older, in whom ovarian thetic androgens, and derivatives thereof. The active agents estrogen, progesterone and androgen production has been may be incorporated into the present dosage units and thus interrupted either because of natural menopause, Surgical administered in the form of a pharmaceutically acceptable procedures, radiation, chemical ovarian ablation or 50 derivative, analog, ester, Salt, or amide, or the agents may be extirpation, or premature ovarian failure. For hormone modified by appending one or more appropriate functional replacement therapy, and for the other indications described ities to enhance Selected biological properties Such as pen herein including female contraception, the compositions or etration through mucosal tissue. In general, with regard to drug delivery Systems are preferably used consecutively So androgenic agents, esters are preferred relative to Salts or that administration of the active agentS is Substantially 55 other derivatives. Preparation of esters, as noted in the continuous. Transdermal drug administration according to preceding Section, involves functionalization of hydroxyl the invention provides highly effective female hormone and/or carboxyl groups that may be present, as will be replacement therapy. That is, the incidence and Severity of appreciated by those skilled in the arts of pharmaceutical hot flashes and night Sweats are reduced, postmenopausal chemistry and drug delivery. For example, to prepare test loSS of calcium from bone is minimized, the risk of death 60 osterone esters, the 17-hydroxyl group of the testosterone from ischemic heart disease is reduced, and the vascularity molecule is generally caused to react with a Suitable organic and health of the Generally, the maximum concentration is acid under esterifying conditions, Such conditions typically determined by the amount of agent that can be received in involving the use of a Strong acid Such as Sulfuric acid, the carrier without producing adverse histological effects hydrochloric acid, or the like, and a temperature Sufficient to Such as irritation, an unacceptably high initial pulse of agent 65 allow the reaction to proceed at reflux. Esters can be into the body, or adverse effects on the characteristics of the reconverted to the free acids, if desired, by using conven delivery device Such as the loSS of tackiness, Viscosity, or tional hydrogenolysis or hydrolysis procedures. US 6,835,392 B2 21 22 Androgenic drugs such as testosterone (17f8 Simply Serve as a means for organization. AS will be hydroxyandrost-4-en-3-one) are required for Sperm produc appreciated, a peptidyl drug may fall into more than one tion and promote general growth of body tissues. The category. primary clinical use of androgens is to replace or augment Coagulation modulators include, for example, androgen Secretion in hypogonadal men. Androgens may C-antitrypsin, C-macroglobulin, antithrombin III, factor I also be used to treat certain gynecologic disorders, Such as (fibrinogen), factor II (prothrombin), factor III (tissue to reduce breast engorgement during the postpartum period. prothrombin), factor V (proaccelerin), factor VII Androgens may also be used to reduce protein loSS after (proconvertin), factor VIII (antihemophilic globulin or trauma, Surgery, or prolonged immobilization, or in the AHG), factor IX (Christmas factor, plasma thromboplastin treatment of anemia and hereditary angioedema. Androgens component or PTC), factor X (Stuart-Power factor), factor may additionally be used in the treatment of male osteoporo XI (plasma thromboplastin antecedent or PTA), factor XII sis or as metabolic growth Stimulators in prepubertal boys. (Hageman factor), heparin cofactor II, kallikrein, plasmin, Testosterone and its derivatives are compounds that are plasminogen, prekallikrein, protein C, protein S, thrombo therapeutically effective at fairly low doses, generally in the modulin and combinations thereof. When applicable, both range of approximately 5 to 10 mg/day. 15 the “active” and “inactive” versions of these proteins are D. Peptidyl Drugs included. Peptidyl drugs that can be administered according to the Preferred cytokines include, without limitation, colony invention include any pharmacologically active peptides, Stimulating factor 4, heparin binding neurotrophic factor polypeptides or proteins. Once chosen, the peptidyl drug (HBNF), interferon-C, interferon C-2a, interferon C-2b, must be prepared or obtained from commercial Suppliers for interferon C.-n3, interferon-B, interferon-Y, interleukin-1, incorporation into a composition or delivery System. The interleukin-2, interleukin-3, interleukin-4, interleukin-5, peptidyl drug may be prepared using Standard Synthetic interleukin-6, interleukin-7, interleukin-8, interleukin-9, techniques, recombinant technology or extraction from natu interleukin-10, interleukin-11, interleukin-12, interleukin ral Sources. 13, interleukin-14, interleukin-15, interleukin-16, Synthetic production of peptides, polypeptides and pro 25 interleukin-17, tumor necrosis factor, tumor necrosis factor teins generally employs techniques of Standard Solid phase C., granuloycte colony-stimulating factor (G-CSF), peptide Synthesis well known in the art. In Such a method, granulocyte-macrophage colony-stimulating factor (GM the Synthesis is Sequentially carried out by incorporating the CSF), macrophage colony-stimulating factor, midkine desired amino acid residues one at a time onto a growing (MD), thymopoietin and combinations thereof. peptide chain according to the general principles of Solid Preferred endorphins include, but are not limited to, phase Synthesis as described, for example, by Merrifield dermorphin, dynorphin, C.-endorphin, B-endorphin, (1963) J. Amer: Chem. Soc. 85:2149-2154. Common to Y-endorphin, O-endorphin Leulenkephalin, Met chemical Syntheses of peptides, polypeptides and proteins is enkephalin, Substance P, and combinations thereof. the protection of reactive Side chain groups of the various Preferred peptidyl hormones include activin, amylin, amino acid moieties with Suitable protecting groups that will 35 angiotensin, atrial natriuretic peptide (ANP), calcitonin prevent a chemical reaction from occurring at that Site until (derived from chicken, eel, human, pig, rat, Salmon, etc.), the protecting group is ultimately removed. It is also well calcitonin gene-related peptide, calcitonin N-terminal flank known to protect the C-amino group on an amino acid while ing peptide, cholecystokinin (CCK), ciliary neurotrophic that entity reacts at the carboxyl group, followed by the factor (CNTF), corticotropin (adrenocorticotropin hormone, Selective removal of the O.-amino protecting group to allow 40 ACTH), corticotropin-releasing factor (CRF or CRH), epi a Subsequent reaction to take place at that Site. Examples of dermal growth factor (EGF), follicle-stimulating hormone Suitable O.-amino and Side chain protecting groups are well (FSH), gastrin, gastrin inhibitory peptide (GIP), gastrin known in the art. releasing peptide, ghrelin, glucogon, gonadotropin-releasing Alternatively, the peptide, polypeptide or protein may be factor (GnRF or GNRH), growth hormone releasing factor prepared by employing recombinant technology via tech 45 (GRF, GRH), human chorionic gonadotropin (hCH), inhibin niques well known in the art. That is, conventional recom A, inhibin B, insulin (derived from beef, human, pig, etc.), binant techniques may be used, which, as will be appreciated leptin, lipotropin (LPH), luteinizing hormone (LH), lutein by those skilled in the art, involves constructing DNA izing hormone-releasing hormone (LHRH), C.-melanocyte encoding the desired amino acid Sequence, cloning the DNA Stimulating hormone, B-melanocyte-stimulating hormone, into an expression vector, transforming a host cell, e.g., a 50 Y-melanocyte-stimulating hormone, melatonin, motilin, bacterial, yeast, or mammalian cell, and expressing the DNA oxytocin (pitocin), pancreatic polypeptide, parathyroid hor to produce the desired peptide, polypeptide or protein. mone (PTH), placental lactogen, prolactin (PRL), prolactin Additionally, peptides, polypeptides or proteins can be release inhibiting factor (PIF), prolactin-releasing factor obtained from natural Sources Such as a human or other (PRF), Secretin, Somatotropin (growth hormone, GH), Soma animal, and may be extracted from either a living organism 55 tostatin (SIF, growth hormone-release inhibiting factor, or from a cadaver. The material is separated and purified GIF), thyrotropin (thyroid-stimulating hormone, TSH), prior to incorporation into a drug delivery System or dosage thyrotropin-releasing factor (TRH or TRF), thyroxine, form. Techniques of Separation and purification are well triiodothyronine, vasoactive intestinal peptide (VIP), vaso known in the art and include, for example, centrifugation pressin (antidiuretic hormone, ADH) and combinations and 60 thereof. Although any peptidyl drug may be incorporated into the Particularly preferred analogues of LHRH include delivery Systems of the present invention, the drug is gen buSerelin, deslorelin, fertirelin, goserelin, histrelin, leupro erally Selected from coagulation modulators, cytokines, lide (leuprorelin), lutrelin, nafarelin, tryptorelin and combi endorphins, kinins, hormones, LHRH (luteinizing hormone nations thereof. releasing hormone) analogs and other peptidyl drugs that 65 Particularly preferred kinins include bradykinin, poten provide a desired pharmacological activity. Of course, the tiator B, bradykinin potentiator C, kallidin and combinations categories provided are not intended to be limiting and thereof. US 6,835,392 B2 23 24 Still other peptidyl drugs that provide a desired pharrna methylprednisolone, or may be a higher potency corticos cological activity can be incorporated into the delivery teroid Such as clobetasol propionate, betametbaSone Systems of the invention. Examples include abarelix, benzoatc., betamethasone diproprionate, difloraSone adenosine deaminase, anakinra, ancestim, altep lase, diacetate, fluocinonide, niometasone furoate, triamcinolone alglucerase, asparaginase, bivalirudin, bleomycin, acetonide, or the like. bombesin, desmopressin acetate, des-Q14-ghrelin, dornase F. Other Active Agents and Analogs C, enterostatin, erythropoietin, eXendin-4, fibroblast growth Still other examples of active agents with which the novel factor-2, filgrastim, B-glucocerebrosidase, gonadorelin, enhancer compositions may be advantageously employed hyaluronidase, insulinotropin, lepirudin, magainin I, magai include, but are not limited to, the following: analgesic and anesthetic agents-hydrocodone, nin II, nerve growth factor, pentigetide, thrombopoietin, hydromorphone, le V orphanol, oxycodone, thymosin C-1, thymidin kinase (TK), tissue plasminogen Oxymorphone, codeine, morphine, alfentanil, fentanyl, activator, tryptophan hydroxylase, urokinase, urotensin II meperidine, Sufentanil, buprenorphine, and nicomor and combinations thereof. phine; E. Locally Administered Active Agents antidepressant drugs-Selective Serotonin reuptake Preferred agents for local, topical administration are 15 inhibitorS Such as Sertraline, paroxetine, fluoxetine, within the broad classes of compounds known to be topi fluvoxamine, citalopram, Venlafaxine and nefazodone; cally administrable, including, but not limited to, topical tricyclic anti-depressants Such as amitriptyline, antibiotics and other anti-acne agents, anti-fungal agents, doxepin, nortriptyline, imipramine, trimipramine, anti-pSoriatic agents, antipruritic agents, antihistamines, amoxapine, desipramine, protriptyline, clomipramine, antineoplastic agents, local anesthetics, anti-inflammatory mirtazapine and maprotiline; other anti-depressants agents and the like. Suitable topical antibiotic agents Such as traZOdone, buSpirone and bupropion; include, but are not limited to, antibiotics of the lincomycin attention deficit disorder and attention deficit hyperactiv family (referring to a class of antibiotic agents originally ity disorder drugS-methylphenidate and pemoline; recovered from Streptomyces lincolnensis), antibiotics of the cardiovascular preparations-angiotensin converting tetracycline family (referring to a class of antibiotic agents 25 enzyme (ACE) inhibitors such as enalapril, originally recovered from Streptomyces aureofaciens), and 1-carboxymethyl-3-1-carboxy-3-phenyl-(1S)- Sulfur-based antibiotics, i.e., Sulfonamides. Exemplary anti propylamino-2,3,4,5-tetrahydro-1H-(3S)-1- biotics of the lincomycin family include lincomycin itself benzazepine-2-one, 3-(5-amino-1-carboxy-1S-pentyl) (6,8-dideoxy-6-( 1-methyl-4-propyl-2-pyrrollidinyl)- a mino-2,3,4,5-tetrahydro-2-oxo-3S-1H-1- carbonyl amino-1-thio-L-threo-C.-D-galacto benzazepine-1-acetic acid or 3-(1-ethoxycarbonyl-3- octopyranoside), clindamycin, the 7-deoxy, 7-chloro deriva phenyl-(1S)-propylamino)-2,3,4,5-tetrahydro-2-oxo tive of lincomycin (i.e., 7-chloro-6,7,8-trideoxy-6-(1- (3S)-benzazepine-1-acetic acid monohydrochloride; methyl-4-propyl-2-pyrrolidinyl)carbonyl-amino-1-thio-L- diuretics, pre- and afterload reducers, cardiac glyco threo-C-D-galacto-Octopyranoside), related compounds as SideS Such as digoxin and digitoxin; inotropes Such as described, for example, in U.S. Pat. Nos. 3,475,407, 3,509, 35 amrinone and milrinone, calcium channel blockers 127, 3,544,551 and 3,513,155, and pharmacologically Such as Verapamil, nifedipine, nicardipene, felodipine, acceptable Salts and esters thereof Exemplary antibiotics of isradipine, nimodipine, bepridil, amlodipine and dilt the tetracycline family include tetracycline itself iazem; beta-blockerS Such as metoprolol, pindolol, 4-(dimethylamino)-1,4,4C.5,5C,6,11,12C-octahydro-3,6,12, propafenone, propranolol, eSmolol, Sotalol and acebu 12C-pentahydroxy-6-m ethyl-1,11-dioxo-2-naphthacene 40 tolol, antiarrhythmicS Such as moricizine, ibutilide, carboxamide), chiorite tracycline, oxytetracycline, procainamide, quinidine, disopyramide, lidocaine, tetracycline, demeclocycline, rollitetracycline, methacycline phenytoin, tocainide, mexiletine, flecainide, encainide, and doxycycline and their pharmaceutically acceptable Salts bretylium and amiodarone; cardioprotective agents and esters, particularly acid addition Salts. Such as the hydro Such as deXraZOxane and leucovorin; vasodilatorS Such chloride Salt. Exemplary Sulfur-based antibiotics include, 45 as nitroglycerin; cholinergic agents Such as arecoline; but are not limited to, the Sulfonamides Sulfacetamide, CNS agents-bromocriptine, it trans-1,3,4,4C.,5,103 Sulfabenzamide, Sulfadiazine, Sulfadoxine, Sulfamerazine, hexahydro-4-propyl-2H-1-benzopyrano-3,4-bipyridine-9-ol Sulfamethazine, Sulfamethizole, Sulfamethoxazole, and monohydrochloride; pharmacologically acceptable Salts and esters thereof, e.g., muscle relaxants-baclofen; Sulfacetamide Sodium. Topical anti-acne agents include 50 keratolytics Such as Salicylic acid, retinoic acid (“Retin-A), nicotine; and organic peroxides, while topical antifungal agents narcotic antagonists-naloxone, particularly naloxone include amphotericin B, benzoic acid, butoconazole, hydrochloride; caprylic acid, econazole, fluconazole, itraconazole, peripheral vascular dilators-cyclandelate, isOXSuprine ketoconazole, miconazole, nyStatin, Salicylic acid, and 55 and papaverine; terconazole, and topical antipsoriatic agents include ophthalmic drugs-physostigmine Sulfate; anthralin, azathioprine, calcipotriene, calcitriol, coichicine, respiratory drugs-Such as albute rol, formoterol, cyclosporine, retinoids, and Vitamin A. The active agent may nikethamide, theophylline, terbutaline, Oxytriphylline, also be a topical corticosteroid, and may be one of the lower aminophylline and other Xanthine derivatives, and potency corticosteroids Such as hydrocortisone, 60 topoimerase inhibitors-topotecan and irinotecan. hydrocortisone-2-monoesters (e.g., hydrocortisone-21 Genetic material may also be delivered using the acetate, hydrocortisone-21-butyrate, hydrocortisone-2- methods, formulations and transdermal Systems of the prop io nate, hydrocortis one-2-Vale rate, etc.), invention, e.g., a nucleic acid, RNA, DNA, recombinant hydrocortisone-17,21-diesters (e.g., hydrocortisone- 17,21 RNA, recombinant DNA, antisense RNA, antisense DNA, a diacetate, hydrocortisone - 17-acetate-21-butyrate, 65 ribooligonucleotide, a deooxyriboonucleotide, an anti Sense hydrocortisone- 17,21-dibutyrate, etc.), alclometaSone, ribooligonucleotide, or an antisense deoxyriboooligonucle de Xame thaSone, flume thaSone, prednisolone, or otide. US 6,835,392 B2 25 26 Particularly preferred Systemically active agents that can is removed from the device so that the system may be affixed be administered transdermally in conjunction with the to the skin. The release liner should be made from a present invention are as follows: buprenorphine, fentanyl, drug/vehicle impermeable material, and is a disposable Sufentanil, terbutaline, formoterol, albuterol, theophylline, element that Serves only to protect the device prior to e Stradiol, proge Sterone, Scopolamine, enalapril, 1-carboxymethyl-3-1-carboxy-3-phenyl-(1S)-propylamino application. Typically, the release liner is formed from a 2,3,4,5-tetrahydro-1H-(3S) 1 3-(5-amino-1-carboxy-1S material impermeable to the pharmacologically active agent pentyl)amino-2,3,4,5-tetrahydro-2-oxo-3S-1H-1- and the hydroxide-releasing agent, and which is easily benzazepine 1-acetic acid, 3-(1-ethoxycarbonyl-3-phenyl Stripped from the transdermal patch prior to use. (1S)-propylamino)-2,3,4,5-tetrahydro-2-oxo-(3S)- In an alternative embodiment, the drug-containing reser benzazepion-1-acid monohydrochloride, nitroglycerin, voir and Skin contact adhesive are present as Separate and trip rollidine, tripe le namine, diphenhydramine, distinct layers, with the adhesive underlying the reservoir. In phySOStigmine, arecoline, and nicotine. Uncharged, nonion Such a case, the reservoir may be a polymeric matrix as izable active agents are preferred, as are acid addition Salts described above. Alternatively, the reservoir may be com of basic drugs. Of the latter group, the hydrochloride Salt is prised of a liquid or Semisolid formulation contained in a most preferred. 15 closed compartment or "pouch,” or it may be a hydrogel V. Drug Delivery Systems: reservoir, or may take Some other form. Hydrogel reservoirs An alternative and preferred method involves the use of a are particularly preferred herein. AS will be appreciated by drug delivery System, e.g., a topical or transdermal "patch,' those skilled in the art, hydrogels are macromolecular net wherein the active agent is contained within a laminated works that absorb water and thus Swell but do not dissolve Structure that is to be affixed to the skin. In Such a structure, in water. That is, hydrogels contain hydrophilic functional the drug and enhancer composition is contained in a layer, groups that provide for water absorption, but the hydrogels or “reservoir, underlying an upper backing layer. The are comprised of crosslinked polymers that give rise to laminated Structure may contain a single reservoir, or it may aqueous insolubility. Generally, then, hydrogels are com contain multiple reservoirs. prised of crosslinked hydrophilic polymerS Such as a In one embodiment, the reservoir comprises a polymeric 25 polyurethane, a polyvinyl alcohol, a polyacrylic acid, a matrix of a pharmaceutically acceptable adhesive material polyoxyethylene, a polyvinylpyrrollidone, a poly that Serves to affix the System to the Skin during drug (hydroxyethyl methacrylate) (poly(HEMA)), or a copoly delivery; typically, the adhesive material is a pressure mer or mixture thereof. Particularly preferred hydrophilic sensitive adhesive (PSA) that is suitable for long-term skin polymers are copolymers of HEMA and polyvinylpyrroli contact, and which should be physically and chemically done. compatible with the active agent, hydroxide-releasing agent, Additional layers, e.g., intermediate fabric layers and/or and any carriers, vehicles or other additives that are present. rate-controlling membranes, may also be present in any of Examples of Suitable adhesive materials include, but are not these drug delivery Systems. Fabric layerS may be used to limited to, the following: polyethylenes, polysiloxanes, facilitate fabrication of the device, while a rate-controlling polyisobutylenes, polyacrylates, polyacrylamides, polyure 35 membrane may be used to control the rate at which a thanes, plasticized ethylene-Vinyl acetate copolymers, and component permeates out of the device. The component may tacky rubberS Such as polyisobutene, polybutadiene, be a drug, a hydroxide-releasing agent and/or the lipophilic polystyrene-isoprene copolymers, polystyrene-butadiene co-enhancer, an additional enhancer, or Some other compo copolymers, and neoprene (polychloroprene). Preferred nent contained in the drug delivery System. adhesives are polyisobutylenes. 40 A rate-controlling membrane, if present, will be included The backing layer functions as the primary Structural in the System on the skin Side of one or more of the drug element of the transdermal System and provides the device reservoirs. The materials used to form Such a membrane are with flexibility and, preferably, occlusivity. The material Selected to limit the flux of one or more components used for the backing layer should be inert and incapable of contained in the drug formulation. Representative materials absorbing drug, hydroxide-releasing agent or components of 45 useful for forming rate-controlling membranes include poly the formulation contained within the device. The backing is olefins Such as polyethylene and polypropylene, preferably comprised of a flexible elastomeric material that polyamides, polyesters, ethylene-ethacrylate copolymer, Serves as a protective covering to prevent loSS of drug and/or ethylene-Vinyl acetate copolymer, ethylene-Vinyl methylac vehicle Via transmission through the upper Surface of the etate copolymer, ethylene-Vinyl ethylacetate copolymer, patch, and will preferably impart a degree of occlusivity to 50 ethylene-Vinyl propylacetate copolymer, polyisoprene, the System, Such that the area of the body Surface covered by polyacrylonitrile, ethylene-propylene copolymer, and the the patch becomes hydrated during use. The material used like. for the backing layer should permit the device to follow the It will also be appreciated by those skilled in the art that contours of the skin and be worn comfortably on areas of the enhancer composition and the drug(s) may be contained skin Such as at joints or other points of flexure, that are 55 in Separate patches each applied to the patient's body normally Subjected to mechanical Strain with little or no Surface. Alternatively, the drug delivery device may com likelihood of the device disengaging from the Skin due to prise two or more patch Segments each containing different differences in the flexibility or resiliency of the skin and the components (e.g., one may contain the drug and the other device. The materials used as the backing layer are either may contain the enhancer composition) that are assembled occlusive or permeable, as noted above, although occlusive 60 immediately prior to use. backings are preferred, and are generally derived from Generally, the underlying Surface of the transdermal Synthetic polymers (e.g., polyester, polyethylene, device, i.e., the skin contact area, has an area in the range of polypropylene, polyurethane, polyvinylidine chloride, and about 5 cm to 200 cm, preferably 5 cm to 100 cm, more polyether amide), natural polymers (e.g., cellulosic preferably 20 cm to 60 cm. That area will vary, of course, materials), or macroporous woven and nonwoven materials. 65 with the amount of drug to be delivered and the flux of the During Storage and prior to use, the laminated Structure drug through the body Surface. Larger patches will necessary includes a release liner. Immediately prior to use, this layer to accommodate larger quantities of drug, while Smaller US 6,835,392 B2 27 28 patches can be used for Smaller quantities of drug and/or Surface throughout the drug delivery period established for drugs that exhibit a relatively high permeation rate. a particular active agent. Such drug delivery Systems may be fabricated using The invention accordingly provides a novel and highly conventional coating and laminating techniques known in effective means for increasing the flux of an active agent the art. For example, adhesive matrix Systems can be pre through the body Surface (skin or mucosal tissue) of a human pared by casting a fluid admixture of adhesive, drug and or animal. The enhancer compositions discussed herein may be used as permeation enhancers with a wide variety of vehicle onto the backing layer, followed by lamination of the drugs and drug types, including both hydrophilic and hydro release liner. Similarly, the adhesive mixture may be cast phobic drugs. The increase in permeation is not accompa onto the release liner, followed by lamination of the backing nied by any noticeable tissue damage, irritation, or Sensiti layer. Alternatively, the drug reservoir may be prepared in Zation. The invention thus represents an important advance the absence of drug or excipient, and then loaded by in the field of drug delivery. “Soaking in a drug/vehicle mixture. In general, transdermal It is to be understood that while the invention has been systems of the invention are fabricated by solvent described in conjunction with the preferred specific embodi evaporation, film casting, melt extrusion, thin film ments thereof, the foregoing description is intended to lamination, die cutting, or the like. The enhancer composi 15 illustrate and not limit the scope of the invention. Other tion will generally be incorporated into the device during aspects, advantages and modifications will be apparent to patch manufacture rather than Subsequent to preparation of those skilled in the art to which the invention pertains. the device. Thus, for acid addition Salts of basic drugs (e.g., Furthermore, the practice of the present invention will hydrochloride Salts of amine drugs, Such as phenylpropano employ, unless otherwise indicated, conventional techniques lamine hydrochloride), the hydroxide-releasing agent of drug formulation, particularly topical and transdermal present in the enhancer composition will neutralize the drug drug formulation, which are within the skill of the art. Such during manufacture of the drug delivery System, resulting in techniques are fully explained in the literature. See Reming a final drug delivery System in which the drug is present in ton. The Science and Practice of Pharmacy, cited Supra, as nonionized, neutral form along with an excess of hydroxide well as Goodman & Gilman's The Pharmacological Basis of releasing agent. For nonionized acidic drugs, the hydroxide 25 Therapeutics, 9th Ed. (New York: McGraw-Hill, 1996). releasing agent will neutralize Such drugs by converting All patents, patent applications, patent publications, jour nal articles and other references cited herein are incorpo them to the ionized drug in Salt form. rated by reference in their entireties. In a preferred delivery System, an adhesive overlayer that The following example is put forth So as to provide those also serves as a backing for the delivery System is used to of ordinary skill in the art with a complete disclosure and better secure the patch to the body surface. This overlayer is description of how to make and use the compounds of the sized Such that it extends beyond the drug reservoir So that invention, and is not intended to limit the Scope of what the adhesive on the overlayer comes into contact with the body inventors regard as their invention. Efforts have been made Surface. The overlayer is useful because the adhesive/drug to ensure accuracy with respect to numbers (e.g., amounts, reservoir layer may lose its adhesion a few hours after temperature, etc.) but Some errors and deviations should be application due to hydration. By incorporating Such adhe 35 accounted for. Unless indicated otherwise, parts are parts by Sive overlayer, the delivery System remains in place for the weight, temperature is in C. and pressure is at or near required period of time. atmospheric. Other types and configurations of transdermal drug deliv ery Systems may also be used in conjunction with the present EXAMPLE invention, as will be appreciated by those skilled in the art 40 An in-vitro skin permeation Study was conducted using of transdermal drug delivery. See, for example, Ghosh, four testosterone transdermal Systems. The formulations Transdermal and Topical Drug Delivery Systems used to prepare these Systems are listed in Table 1, which (Interpharm Press, 1997), particularly Chapters 2 and 8. include weight and weight percent of each ingredient in the As with the topically applied formulations of the formulations. Formulation Test-P 178 contained no oleic invention, the composition that contains the drug and per 45 acid and no NaOH. Formulation Test-P179 contained both meation enhancer composition within the drug reservoir(s) NaOH and oleic acid. Formulation Test-P180 contains of these laminated System may contain a number of addi NaOH without oleic acid. Formulation Test-181 contained tional components. In Some cases, the drug and hydroxide oleic acid without NaOH. releasing agent may be delivered "neat, i.e., in the absence Each formulation was coated on a release liner and dried of additional liquid. In most cases, however, the drug will be 50 in an oven at 55 C. for two hours to remove water and other dissolved, dispersed or Suspended in a Suitable pharmaceu Solvents. The dried drug-in-adhesive/release liner film was tically acceptable vehicle, typically a Solvent or gel. Other laminated to a backing film. The backing/drug-in-adhesive/ components that may be present include preservatives, release liner laminate was then cut into round discS with a Stabilizers, Surfactants, and the like. diameter of 1/16 inch. VI. Method of Use 55 The in-vitro permeation of testosterone through human The method of delivery of the active agent may vary, but cadaver Skin from these discS was performed using Franz necessarily involves application of a drug and the enhancer type diffusion cells with a diffusion area of 1 cm. The composition of the invention to a predetermined area of the volume of receiver Solution was 8 ml. Human cadaver skin skin or other tissue for a period of time Sufficient to provide was cut to desired size and placed on a flat Surface with the the desired local or systemic effect. The method may involve 60 Stratum corneum Side facing up. The release liner was peeled pretreatment of the body surface with the enhancer away from the disc laminate. The backing/drug-in-adhesive composition, followed by application of a pharmaceutical film was placed and pressed on the skin with the adhesive formulation or drug delivery device. More commonly, the Side facing the Stratum corneum. The Skin/adhesive/backing method of drug delivery will involve direct application of laminate was clamped between the donor and receiver the pharmaceutical formulation as an ointment, gel, cream, 65 chambers of the diffusion cell with the skin side facing the or the like, or may involve use of a drug delivery device. The receiver Solution. Three diffusion cells were used for each delivery device is generally maintained in place on the body formulation. US 6,835,392 B2 29 30 The receiver solution was completely withdrawn and (i) a compound having a molecular weight in the range of replaced with fresh Solution at each time point. The Samples about 150 to 1000 and an aqueous solubility of less than taken were analyzed by an HPLC for the concentration of about 1 wt %, and the structure (CH-L-X),R, testosterone in the receiver Solution. The cumulative amount wherein: n is 1 or 2, L is alkylene or alkenylene of testosterone acroSS human cadaver skin was calculated containing 1 to 3 double bonds, and from about 6 to using the measured testosterone concentrations in the about 22 carbon atoms, X is Selected from the group receiver Solutions, which were shown in Table 2 and FIG. 1. consisting of COO-, -CH2O-, and -CHO (CO)-; and R is selected from the group consisting of TABLE 1. H, lower alkyl, and lower alkyl substituted with one or two hydroxyl groups, with the proviso that if R is H, X Weight and Weight Percent of Each Ingredient Based on Total 1O is necessarily -CH-O-, and wherein when n is 2, R Solution Weight for Four Testosterone Transdermal Systems contains at least two carbon atoms, Component Test-P178 Test-P179 Test-P180 Test-P181 (ii) a lower alkyl ester of a Co-Cs fatty acid; and (iii) an esterified polyol selected from the group consist Polymer 0.25 g 0.25 g 0.25 g 0.25 g ing of propylene glycol mono- or di-Substituted with a THF 1.25 g 1.25 g 1.25 g 1.25 g 15 Benzyl alcohol 0.7 g 0.7g 0.7g 0.7g Co-Cs fatty acid and glycerol mono- or di-Substituted Glycerin 0.7 g 0.7g 0.7g 0.7g with a Co-Cs fatty acid; Oleic acid O 0.2g O 0.2g wherein the composition is effective to provide a pH in the Protalan 0.15g 0.15g 0.15g 0.15g range of approximately 8.0 to 13.0 at the localized Vitamin E 0.3g 0.3g 0.3g 0.3g Urea 0.2g 0.2g 0.2g 0.2g region of the body Surface, and the amount of NaOH O 0.09 g 0.09 g O hydroxide-releasing agent in the composition is the Water O 0.09 g 0.09 g O total of (a) the amount required to neutralize any acidic Testosterone 0.5g 0.5g 0.5g 0.5g Species in the composition plus (b) an amount equal to approximately 0.5 wt % to 25 wt % of the composition. 2. The method of claim 1, wherein the pH is in the range 25 of approximately 8.0 to 11.5. TABLE 2 3. The method of claim 1, wherein the body surface is Cumulative Amount of testosterone across human cadaver skin for skin. Testosterone Transdermal Systems (mg/cm 4. The method of claim 1, wherein the body surface is mucosal tissue. Measurement 5. The method of claim 1, wherein the composition is time Test-P178 Test-P179 Test-P180 Test-P181 aqueous. 4.75 hours O.OO5 0.027 O.036 OOO6 6. The method of claim 5, wherein the composition is 15.5 hours O.O22 O.1.89 O.167 0.027 Selected from the group consisting of a cream, a gel, a lotion, 19.5 hours O.O33 O.258 O.209 O.O38 24 hours O.O44 O.346 O.254 O.O51 and a paste. 35 7. The method of claim 1, wherein the composition is nonaqueous. The cumulative amount of testosterone acroSS human 8. The method of claim 7, wherein the composition is an cadaver skin at 24 hours for Test-P179 (contained dual ointment. enhancers, NaOH and oleic acid) was 0.346 mg/cm, which 9. The method of claim 1, wherein the hydroxide was higher than that for Test-P180 (0.254 mg/cm, contain 40 releasing agent releases free hydroxide ions in the presence ing NaOH without oleic acid) or that for Test-P181 (0.051 of an aqueous fluid. mg/cm, containing oleic acid without NaOH). The cumu 10. The method of claim 1, wherein the hydroxide lative amount of testosterone acroSS human cadaver skin at releasing agent is Selected from the group consisting of 24 hours for Test-P178 containing no NaOH and no oleic inorganic hydroxides, inorganic oxides, metal Salts of weak acid is the lowest among these four formulations, which is 45 acids, and mixtures thereof. 0.044 mg/cm. The results are illustrated in graph form in 11. The method of claim 10, wherein the hydroxide FIG. 1. releasing agent is an inorganic hydroxide. The method may be repeated using other pharmacologi 12. The method of claim 11, wherein the inorganic cally active agents (e.g., other Steroids, NSAIDs, peptidyl hydroxide is Selected from the group consisting of ammo drugs, etc.; see Section IV), permeation enhancing bases 50 nium hydroxide, alkali metal hydroxides, alkaline earth (e.g., other inorganic hydroxides, inorganic oxides, and metal hydroxides, and mixtures thereof. alkali metal or alkaline earth metal Salts of weak acids, See 13. The method of claim 12, wherein the inorganic Section IIA), and lipophilic co-enhancers (e.g., methyl hydroxide is Selected from the group consisting of ammo laurate, ethyl oleate, propylene glycol monolaurate, propy nium hydroxide, Sodium hydroxide, calcium hydroxide, lene glycerol dilaurate, glycerol monolaurate, glycerol 55 potassium hydroxide, magnesium hydroxide, and mixtures monooleate, isopropyl n-decanoate, and octyldodecyl thereof. myristate; see Section IIB) as described herein, and Substan 14. The method of claim 13, wherein the inorganic tially the same results will be obtained. hydroxide is sodium hydroxide. We claim: 15. The method of claim 13, wherein the inorganic 1. A method for enhancing the flux of a drug through a 60 hydroxide is potassium hydroxide. body Surface, comprising administering the drug to a local 16. The method of claim 11, wherein the amount of ized region of a human patient's body Surface in combina inorganic hydroxide in the composition is the total of(a) the tion with an effective permeation enhancing amount of amount required to neutralize any acidic species in the permeation enhancer composition comprised of a composition plus (b) an amount equal to approximately 0.5 hydroxide-releasing agent and a lipophilic co-enhancer, Said 65 wt % to 4.0 wt % of the composition. lipophilic co-enhancer being Selected from the group con 17. The method of claim 16, wherein the amount of Sisting of: inorganic hydroxide in the composition is the total of(a) the US 6,835,392 B2 31 32 amount required to neutralize any acidic species in the 37. The method of claim 1, wherein X is -CHO composition plus (b) an amount equal to approximately 0.5 (CO)- and R is lower alkyl. wt.% to 3.0 wt.% of the composition. 38. The method of claim 1, wherein X is -CHO 18. The method of claim 17, wherein the amount of (CO)- and R is lower alkyl substituted with one or two inorganic hydroxide in the composition is the total of a) the 5 hydroxyl groups. amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.75 39. The method of claim 1, wherein the weight ratio of the wt.% to 2.0 wt.% of the composition. hydroxide-releasing agent to the lipophilic co-enhancer is in 19. The method of claim 10, wherein the hydroxide the range of approximately 1:99 to approximately 99:1. releasing agent is an inorganic oxide. 40. The method of claim 39, wherein the weight ratio of 20. The method of claim 19, wherein the inorganic oxide the hydroxide-releasing agent to the lipophilic co-enhancer is Selected from the group consisting of magnesium oxide, is in the range of approximately 1:20 to approximately 20:1. calcium oxide, and mixtures thereof. 41. The method of claim 40, wherein the weight ratio of 21. The method of claim 19, wherein the composition the hydroxide-releasing agent to the lipophilic co-enhancer contains up to approximately 20 wt.% of the hydroxide is in the range of approximately 1:2 to approximately 2:1. releasing agent. 15 42. The method of claim 1, wherein the drug and the 22. The method of claim 10, wherein the hydroxide permeation enhancer composition are administered by releasing agent is a metal Salt of a weak acid. applying a drug delivery device to the localized region of the 23. The method of claim 22, wherein the hydroxide patient's body Surface thereby forming a body Surface releasing agent is Selected from the group consisting of delivery device interface, the device comprising the drug Sodium acetate, Sodium carbonate, tribasic Sodium and the permeation enhancer composition, and having an phosphate, dibasic Sodium phosphate, Sodium borate, potas outer backing layer that Serves as the outer Surface of the sium carbonate, potassium acetate, dibasic potassium device during use. phosphate, tribasic potassium phosphate, Sodium 43. The method of claim 1, wherein the drug is selected metaborate, and mixtures thereof. from the group consisting of analgesic agents, anesthetic 24. The method of claim 22, wherein the composition 25 contains up to approximately 20 wt.% of the hydroxide agents, antiarthritic agents, respiratory drugs, anticancer releasing agent. agents, anticholinergics, anticonvulsants, antidepressants, 25. The method of claim 1, wherein L is alkylene. antidiabetic agents, antidiarrheals, antibelminthics, antihis 26. The method of claim 25, wherein Lhas a total of from tamines, antihyperlipidemic agents, antihypertensive about 8 to about 12 carbon atoms. agents, anti-infective agents, antiinflammatory agents, anti 27. The method of claim 1, wherein L is alkenylene. migraine preparations, antinauseants, antiparkinsonism 28. The method of claim 27, wherein Lhas a total of from drugs, antipruritics, antipsychotics, antipyretics, antispas about 8 to about 18 carbon atoms. modics, antitubercular agents, antiulcer agents, antiviral 29. The method of claim 28, wherein Lhas a total of from agents, anxiolytics, appetite Suppressants, attention deficit about 8 to about 16 carbon atoms. disorder and attention deficit hyperactivity disorder drugs, 30. The method of claim 1, wherein X is -COO-. 35 calcium channel blockers, beta-blockers, antiarrhythmic 31. The method of claim 30, wherein n is 1 and R is lower agents, central nervous System Stimulants, decongestants, alkyl. diuretics, genetic materials; herbal remedies, hormonolytics, 32. The method of claim 30, wherein n is 1 and R is lower hypnotics, hypoglycemic agents, immunosuppressive alkyl Substituted with one or two hydroxyl groups. agents, leukotriene inhibitors, mitotic inhibitors, muscle 33. The method of claim 30, wherein n is 2 and R is lower 40 relaxants, narcotic antagonists, nicotine; nutritional agents, alkyl Substituted with one or two hydroxyl groups. ophthalmic drugs, parasympatholytics, peptide drugs, psy 34. The method of claim 30, wherein R is selected from chostimulants, Sedatives, Steroids, Sympathomimetics, tran the group consisting of quilizers, vasodilators, and combinations thereof. 44. The method of claim 1, wherein the drug is an acid 45 -CH -CH addition Salt of a basic compound, and the amount in (a) is the amount required to neutralize the acid addition Salt and CH2 HO-CH any other acidic species in the composition. 45. The method of claim 1, wherein the drug is an acidic HC-L-X-CH, HC-L-X-CH, drug in the form of a free acid, and the amount in (a) is the -CH -CH 50 amount required to neutralize the acidic drug and any other HC-L-X-CH and HC-L-X-CH . acidic Species in the composition. 46. The method of claim 1, wherein the drug is a basic HO-CH CH drug is the form of a free base. 47. The method of claim 1, wherein the drug is a basic 35. The method of claim 1, wherein X is -CHO- and 55 addition Salt of an acidic compound. R is lower alkyl or lower alkyl substituted with one or two 48. The method of claim 1, wherein the drug is nonion hydroxyl groups. izable. 36. The method of claim 1, wherein X is -CHO- and R is H.