US 20090317453A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0317453 A1 Hsu et al. (43) Pub. Date: Dec. 24, 2009 (54) TRANSDERMAL AND TOPICAL now abandoned, which is a continuation-in-part of ADMINISTRATION OF DRUGS USING BASIC application No. 09/972,008, filed on Oct. 4, 2001, now PERMEATION ENHANCERS Pat. No. 6,582,724, which is a continuation-in-part of application No. 09/738,410, filed on Dec. 14, 2000, (75) Inventors: Tsung-Min Hsu, Minneapolis, MN now Pat. No. 6,586,000, which is a continuation-in (US); Nicole T. Gricenko, St. Louis part of application No. 09/569,889, filed on May 11, Park, MN (US); Alan T.J. Hickey, 2000, now abandoned, which is a continuation-in-part Eden Prairie, MN (US); Eric C. of application No. 09/465,098, filed on Dec. 16, 1999, Jacobson, San Diego, CA (US); now abandoned, said application No. 10/860,887 is a Rose C. LoBello, San Diego, CA continuation-in-part of application No. 09/738,395, (US); Jane Obara, San Diego, CA filed on Dec. 14, 2000, now Pat. No. 6,719,997, which (US); Eric C. Luo, Plano, TX (US) is a continuation-in-part of application No. 09/607, 892, filed on Jun. 30, 2000, now abandoned. Correspondence Address: INTELLECTUAL PROPERTY GROUP Publication Classification FREDRIKSON & BYRON, PA. (51) Int. Cl. 200 SOUTH SIXTH STREET, SUITE 4000 A 6LX 9/70 (2006.01) MINNEAPOLIS, MN 55402 (US) A6II 3L/24 (2006.01) (73) Assignee: DERMATRENDS, INC., (52) U.S. Cl. ......................................... 424/449; 514/536 Minneapolis, MN (US) (57) ABSTRACT (21) Appl. No.: 12/343,000 Methods are provided for enhancing the permeability of skin or mucosal tissue to topical or transdermal application of (22) Filed: Dec. 23, 2008 pharmacologically or cosmeceutically active agents. The methods entail the use of a base in order to increase the flux of Related U.S. Application Data the active agent through a body Surface while minimizing the (60) Continuation of application No. 10/860,887, filed on likelihood of skin damage, irritation or sensitization. The Jun. 3, 2004, now abandoned, which is a division of permeation enhancer can be an inorganic or organic base. application No. 10/177,436, filed on Jun. 20, 2002, Compositions and transdermal systems are also described. US 2009/0317453 A1 Dec. 24, 2009 TRANSIDERMAL AND TOPCAL treated with a chemical enhancer) in order to increase the ADMINISTRATION OF DRUGS USING BASIC permeability of the stratum corneum, and thereby provide for PERMEATION ENHANCERS enhanced penetration of the drug through the skin. Ideally, Such chemical penetration enhancers or “permeation enhanc CROSS-REFERENCE TO RELATED ers, as the compounds are referred to herein, are compounds APPLICATIONS that are innocuous and serve merely to facilitate diffusion of the drug through the stratum corneum. The permeability of 0001. This application is a divisional of U.S. Ser. No. many therapeutic agents with diverse physicochemical char 10/177,436 filed on Jun. 20, 2002. U.S. Ser. No. 10/177,436 is acteristics may be enhanced using these chemical enhance a continuation in part of U.S. Ser. No. 09/972,008 filed on ment means. However, there are skin irritation and sensitiza Oct. 4, 2001 and now issued as U.S. Pat. No. 6,582,724, tion problems associated with high levels of certain which is a continuation in part of U.S. Ser. No. 09/738,410 enhancers. filed on Dec. 14, 2000 and now issued as U.S. Pat. No. 0006. Accordingly, although there are many chemical 6,586,000, which is a continuation in part of U.S. Ser. No. methods of enhancing permeation, there remains an ongoing 09/569,889 filed on May 11, 2000 and now abandoned, which need for a method that is highly effective in increasing the rate is a continuation in part of U.S. Ser. No. 09/465,098 filed on at which a drug permeates the skin, does not result in skin Dec. 16, 1999 and now abandoned; and is a continuation in damage, irritation, sensitization, or the like, and can be used part of U.S. Ser. No. 09/738,395 filedon Dec. 14, 2000, which to effect transdermal delivery of even high molecular weight is a continuation in part of U.S. Ser. No. 09/607,892 filed on drugs such as peptides, proteins, and nucleic acids. It has now Jun. 30, 2000, now abandoned, the disclosures of which are been discovered that basic permeation enhancers as described incorporated herein by reference. hereinare highly effective permeation enhancers, and provide FIELD OF THE INVENTION all of the aforementioned advantages relative to known per meation enhancers. Furthermore, in contrast to many conven 0002 This invention relates generally to the topical and tional enhancers, transdermal administration of drugs with transdermal administration of pharmacologically or cosme basic permeation enhancers, employed at the appropriate lev ceutically active agents, and more particularly relates to els, does not result in Systemic toxicity. methods and compositions for enhancing the flux of pharma cologically active agents through a body Surface by treatment SUMMARY OF THE INVENTION with a basic permeation enhancer. 0007. One aspect of the invention pertains to a method for enhancing the flux of a drug through a body Surface, compris BACKGROUND OF THE INVENTION ing: (a) administering the drug to a localized region of a 0003. The delivery of drugs through the skin provides human patient's body Surface; and (b) administering a basic many advantages; primarily, such a means of delivery is a permeation enhancer to the localized region, the enhancer comfortable, convenient and noninvasive way of administer comprising a pharmaceutically acceptable base and being ing drugs. The variable rates of absorption and metabolism present in an amount effective to provide a pH within the encountered in oral treatment are avoided, and other inherent range of about 8.0-13.0 at the localized region of the body inconveniences, e.g., gastrointestinal irritation and the like, Surface during administration of the drug and to enhance the are eliminated as well. Transdermal drug delivery also makes flux of the drug through the body Surface without causing possible a high degree of control over blood concentrations of damage thereto. The pharmaceutically acceptable base can be any particular drug. an inorganic or an organic base. 0004 Skin is a structurally complex, relatively thick mem 0008 Another aspect of the invention relates to a compo brane. Molecules moving from the environment into and sition for the enhanced delivery of a drug through a body through intact skin must first penetrate the stratum corneum Surface, comprising a formulation of: (a) a therapeutically and any material on its surface. They must then penetrate the effective amount of the drug; (b) a pharmaceutically accept viable epidermis, the papillary dermis, and the capillary walls able base, in an amount effective to provide a pH within the into the blood stream or lymph channels. To be so absorbed, range of about 8.0-13.0 at the body surface during adminis molecules must overcome a different resistance to penetra tration of the drug and to enhance the flux of the drug through tion in each type of tissue. Transport across the skin mem the body Surface without causing damage thereto; and (c) a brane is thus a complex phenomenon. However, it is the cells pharmaceutically acceptable carrier Suitable for topical or of the stratum corneum, which present the primary barrier to transdermal drug administration. In one aspect of the inven absorption of topical compositions or transdermally admin tion the pH is about 8.0-11.5 and in another aspect, the pH is istered drugs. The stratum corneum is a thin layer of dense, about 8.5-10.5. The formulation is typically aqueous. The highly keratinized cells approximately 10-15 microns thick pharmaceutically acceptable base can be an inorganic or an over most of the body. It is believed to be the high degree of organic base. keratinization within these cells as well as their dense packing 0009. Yet another aspect of the invention pertains to a which creates in most cases a Substantially impermeable bar system for the enhanced topical or transdermal administra rier to drug penetration. With many drugs, the rate of perme tion of a drug, comprising: (a) at least one drug reservoir ation through the skin is extremely low without the use of containing the drug and a pharmaceutically acceptable base, Some means to enhance the permeability of the skin. in an amount effective to enhance the flux of the drug through 0005 Numerous chemical agents have been studied as a the body Surface without causing damage thereto; (b) a means means of increasing the rate at which a drug penetrates for maintaining the system in drug and base transmitting through the skin. As will be appreciated by those in the field, relationship to the body Surface and forming a body Surface chemical enhancers are compounds that are administered system interface; and (c) a backing layer that serves as the along with the drug (or in some cases the skin may be pre outer surface of the device during use, wherein the base is US 2009/0317453 A1 Dec. 24, 2009 effective to provide a pH within the range of about 8.0-13.0 at and analogs of those active agents specifically mentioned the body Surface-system interface during administration of herein, including, but not limited to, salts, esters, amides, the drug. In one aspect of the invention the pH is about prodrugs, active metabolites, inclusion complexes, analogs, 8.0-11.5 and in another aspect, the pH is about 8.5-10.5.