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(12) Patent Application Publication (10) Pub. No.: US 2002/0192302 A1 Hsu Et Al

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US 2002O1923O2A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0192302 A1 Hsu et al. (43) Pub. Date: Dec. 19, 2002 (54) TRANSDERMAL AND TOPICAL which is a continuation-in-part of application No. ADMINISTRATION OF ANTIDEPRESSANT 09/569,889, filed on May 11, 2000, which is a con DRUGS USING BASIC ENHANCERS tinuation-in-part of application No. 09/465,098, filed on Dec. 16, 1999, and which is a continuation-in-part (76) Inventors: Tsung-Min Hsu, San Diego, CA (US); of application No. 09/738,395, filed on Dec. 14, 2000, Alan T. J. Hickey, San Diego, CA which is a continuation-in-part of application No. (US); Eric C. Luo, Plano, TX (US); 09/607,892, filed on Jun. 30, 2000, now abandoned. Jane Obara, San Diego, CA (US) Publication Classification Correspondence Address: REED & ASSOCATES (51) Int. Cl." .......................... A61K 33/02; A61K 33/00 800 MENLO AVENUE (52) U.S. Cl. ............................................ 424/719, 424/722 SUTE 210 MENLO PARK, CA 94025 (US) (57) ABSTRACT (21) Appl. No.: 10/175,769 Methods are provided for enhancing the permeability of skin (22) Filed: Jun. 19, 2002 or mucosal tissue to topical or transdermal application of antidepressant drugs. The methods entail the use of a base in Related U.S. Application Data order to increase the flux of the drug through a body Surface while minimizing the likelihood of skin damage, irritation or (63) Continuation-in-part of application No. 09/972,008, Sensitization. The permeation enhancer can be an inorganic filed on Oct. 4, 2001, which is a continuation-in-part or organic base. Compositions and transdermal Systems are of application No. 09/738,410, filed on Dec. 14, 2000, also described. US 2002/0192302 A1 Dec. 19, 2002 TRANSIDERMAL AND TOPICAL Ideally, Such chemical penetration enhancers or “permeation ADMINISTRATION OF ANTIDEPRESSANT DRUGS enhancers,” as the compounds are referred to herein, are USING BASIC ENHANCERS compounds that are innocuous and Serve merely to facilitate diffusion of the drug through the stratum corneum. The CROSS-REFERENCE TO RELATED permeability of many therapeutic agents with diverse physi APPLICATIONS cochemical characteristics may be enhanced using these 0001. This application is a continuation in part of U.S. chemical enhancement means. However, there are skin Ser. No. 09/972,008 filed on Oct. 4, 2001, which is a irritation and Sensitization problems associated with high continuation in part of U.S. Ser. No. 09/738,410 filed on levels of certain enhancers. Dec. 14, 2000, which is a continuation in part of U.S. Ser. 0006 There are many potential uses for topical and No. 09/569,889 filed on May 11, 2000, which is a continu transdermal delivery of antidepressant drugs. Such uses ation in part of U.S. Ser. No. 09/465,098 filed on Dec. 16, include the treatment of depressive disorderS Such as major 1999; and is a continuation in part of U.S. Ser. No. 09/738, depression and bipolar disorder or manic-depressive illness. 395 filed on Dec. 14, 2000, which is a continuation in part Major depression is a significant mental illness, and is of U.S. Ser. No. 09/607,892 filed on Jun. 30, 2000, now characterized by feelings of persistent and intense Sadness, abandoned. feelings of hopelessness and pessimism, difficulty concen trating, decreased energy and fatigue, restleSSneSS or agita FIELD OF THE INVENTION tion, Suicidal tendencies and Self-deprecation. In addition, 0002 This invention relates generally to the topical and physical changes can also occur that affect the patient's transdermal administration of antidepressant drugs, and ability to function normally. These include insomnia, early more particularly relates to methods and compositions for morning awakening or OverSleeping, an increase or decrease enhancing the flux of antidepressant drugs through a body in appetite or weight, and decreased libido. Treatment of the underlying depression can also serve to alleviate these Surface utilizing a basic permeation enhancer. asSociated problems. BACKGROUND OF THE INVENTION 0007 Accordingly, there is a need for a method that is 0003. The delivery of drugs through the skin provides highly effective in increasing the rate at which antidepres many advantages, primarily, Such a means of delivery is a Sant drugs permeate the Skin, does not result in skin damage, comfortable, convenient and noninvasive way of adminis irritation, Sensitization, or the like, and can be used to effect tering drugs. The variable rates of absorption and metabo transdermal delivery of a wide range of compounds within lism encountered in oral treatment are avoided, and other the class of antidepressant drugs. It has now been discovered inherent inconveniences, e.g., gastrointestinal irritation and that basic permeation enhancers as described herein are the like, are eliminated as well. Transdermal drug delivery highly effective permeation enhancers, and provide all of the also makes possible a high degree of control over blood aforementioned advantages relative to known permeation concentrations of any particular drug. enhancers. Furthermore, in contrast to many conventional enhancers, transdermal administration of antidepressant 0004 Skin is a structurally complex, relatively thick drugs with basic permeation enhancers, employed at the membrane. Molecules moving from the environment into appropriate levels, does not result in Systemic toxicity. and through intact skin must first penetrate the Stratum corneum and any material on its Surface. They must then SUMMARY OF THE INVENTION penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To 0008 One aspect of the invention pertains to a method be So absorbed, molecules must overcome a different resis for enhancing the flux of an antidepressant drug through a tance to penetration in each type of tissue. Transport acroSS body Surface, comprising: (a) administering the antidepres the skin membrane is thus a complex phenomenon. How Sant drug to a localized region of a human patient's body ever, it is the cells of the Stratum corneum, which present the Surface; and (b) administering a basic permeation enhancer primary barrier to absorption of topical compositions or to the localized region, the enhancer comprising a pharma transdermally administered drugs. The Stratum corncum is a ceutically acceptable base and being present in an amount thin layer of dense, highly keratinized cells approximately effective to provide a pH within the range of about 8.0-13.0 10-15 microns thick over most of the body. It is believed to at the localized region of the body Surface during adminis be the high degree of keratinization within these cells as well tration of the drug and to enhance the flux of the drug as their dense packing which creates in most cases a Sub through the body Surface without causing damage thereto. stantially impermeable barrier to drug penetration. With The pharmaceutically acceptable base can be an inorganic or many drugs, the rate of permeation through the Skin is an organic base. extremely low without the use of Some means to enhance the 0009. Another aspect of the invention relates to a com permeability of the skin. position for the enhanced delivery of an antidepressant drug 0005 Numerous chemical agents have been studied as a through a body Surface, comprising a formulation of: (a) a means of increasing the rate at which a drug penetrates therapeutically effective amount of the antidepressant drug, through the skin. AS will be appreciated by those in the field, (b) a pharmaceutically acceptable base in an amount effec chemical enhancers are compounds that are administered tive to provide a pH within the range of about 8.0-13.0 at the along with the drug (or in Some cases the skin may be body Surface during administration of the drug and to pretreated with a chemical enhancer) in order to increase the enhance the flux of the drug through the body Surface permeability of the Stratum corneum, and thereby provide without causing damage thereto, and (c) a pharmaceutically for enhanced penetration of the drug through the skin. acceptable carrier Suitable for topical or transdermal drug US 2002/0192302 A1 Dec. 19, 2002 administration. In one aspect of the invention the pH is about applications by these inventors or assigned to common 8.0-11.5 and in another aspect, the pH is about 8.5-10.5. The owners. Additionally, when examples are given, they are formulation is typically aqueous. The pharmaceutically intended to be exemplary only and not to be restrictive. acceptable base can be an inorganic or an organic base. 0015. It must be noted that, as used in this specification 0.010 Yet another aspect of the invention pertains to a and the appended claims, the Singular forms “a,”“an and System for the enhanced topical or transdermal administra “the' include plural referents unless the context clearly tion of an antidepressant drug, comprising: (a) at least one dictates otherwise. Thus, for example, reference to “a phar drug reservoir containing the antidepressant drug and a macologically active agent' includes a mixture of two or pharmaceutically acceptable base, in an amount effective to more Such compounds, reference to “a base' includes mix enhance the flux of the antidepressant drug through the body tures of two or more bases, and the like. Surface without causing damage thereto; (b) a means for maintaining the System in drug and base transmitting rela 0016. In describing and claiming the present invention, tionship to the body Surface and forming a body Surface the following terminology will be used in accordance with System interface; and (c) a backing layer that serves as the the definitions set out below. outer Surface of the device during use, wherein the base is 0017 “Active agent,”“pharmacologically active agent” effective to provide a pH within the range of about 8.0-13.0 and "drug” are used interchangeably herein to refer to at the body Surface-system interface during administration antidepressant drugs.
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