US 2005.0020552A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0020552 A1 Aschkenasy et al. (43) Pub. Date: Jan. 27, 2005 (54) PHARMACEUTICAL COMPOSITION AND Related U.S. Application Data METHOD FORTRANSIDERMAL DRUG DELIVERY (60) Provisional application No. 60/487.278, filed on Jul. 16, 2003. Provisional application No. 60/487,248, (76) Inventors: Chaim Aschkenasy, Yerucham (IL); filed on Jul. 16, 2003. Provisional application No. Oren Chen, Beer Sheva (IL); Rami 60/487.277, filed on Jul. 16, 2003. Provisional appli Boochnik, Yerucham (IL); Eilon cation No. 60/581,458, filed on Jun. 22, 2004. Asculai, Lehavim (IL); Chalil Abu-Gnim, Beer Sheva (IL); Amira Publication Classification Zeevi, Omer (IL) (51) Int. Cl. ................................................. A61K 31/57 Correspondence Address: (52) U.S. Cl. .............................................................. 514/177 MARTIN MOYNHAN c/o ANTHONY CASTORINA SUTE 207 (57) ABSTRACT 2001 JEFFERSON DAVIS HIGHWAY ARLINGTON, VA 2.2202 (US) A pharmaceutical composition for transdermal administra tion of a hormone (e.g., testosterone), which includes isos (21) Appl. No.: 10/891,487 tearic acid as a penetration enhancer, and methods utilizing Same for treating medical conditions in which elevating a (22) Filed: Jul. 15, 2004 hormone Serum level is beneficial are disclosed. US 2005/0020552 A1 Jan. 27, 2005 PHARMACEUTICAL COMPOSITION AND 0009. An additional disadvantage of oral administration METHOD FORTRANSIDERMAL DRUG DELIVERY is that many drugs almost immediately experience metabo lism or inactivation. The veins from the stomach and the 0001. This application claims the benefit of priority from Small and large intestines pass directly through the liver. U.S. Provisional Patent Applications Nos. 60/487.278, Thus, drugs entering the bloodstream must first pass though 60/487,248, and 60/487.277, filed Jul. 16, 2003, and U.S. the liver before distribution into the general blood circula Provisional Patent Application No. 60/581,458, filed Jun. tion. More than Sixty percent of most drugs (and essentially 22, 2004, all of which are incorporated by reference as if one hundred percent of certain drugs) are removed from the filly set forth herein. patients bloodstream during this “first pass' through the liver, resulting in poor bioavailability. FIELD AND BACKGROUND OF THE INVENTION 0010 Furthermore, additional stress is placed on the liver as it removes the exceSS drug from the bloodstream. This is 0002 The present invention relates to novel composi particularly Severe if the drug treatment has been occurring tions for the transdermal administration of testosterone over an extended period of time. The liver may become and/or other hormones and to methods utilizing these com overloaded with the drugs metabolite, which must then be positions. excreted. As a result, there is an increased risk of hepatic or 0.003 Drugs are ideally administered in Such a way as to renal disorders. enable an optimal concentration of active agent to be deliv 0011 Transdermal delivery of drugs provides many ered to the intended target Site. Conventional routes of advantages over conventional oral administration. Advan administration include ingestion, injection, inhalation, and tages of transdermal Systems include bypassing the portal topical application. circulation, thereby eliminating first-pass metabolism in the 0004 Oral administration is the most prevalent method of liver, convenience, non-interrupted therapy, improved administering pharmacological medicaments. The medica patient compliance, reversibility of treatment (by removal of ment is generally incorporated into a tablet, capsule, or a the transdermal System from the skin), and delivery of liquid base, and then Swallowed. The oral administration medication directly into the System circulation at a constant modality is often preferred because of its convenience. In rate. addition, oral administration is generally non-threatening, 0012 Although transdermal systems have many advan painless, and Simple to accomplish for most patients. tages over oral administration, most drugs are not amenable 0005 Nevertheless, oral administration of drugs suffers to this mode of administration due to the well-known barrier from Several disadvantages. One disadvantage is that pedi properties of the skin. Skin is a structurally complex, rela atric and geriatric patients frequently have difficulty Swal tively thick membrane. Molecules moving from the envi lowing pills and other Solid dosage forms, and Such patients ronment into and through intact skin must first penetrate the often refuse to cooperate in Swallowing a liquid medication. Stratum corneum and any material on its Surface. The In addition, for many medicaments, the act of Swallowing molecule must then penetrate the viable epidermis, the the medicament often requires fluids and increases gastric papillary dermis, and then the capillary walls into the blood Volume and the likelihood of nausea and Vomiting. Stream or lymph channels. 0006 Furthermore, drugs with short half-lives require 0013 The stratum corneum, the outer horny layer of the repeated daily dosing (2 to 4 times daily), which can lead to skin, is a complex Structure composed of dead, keratinized, inadequate compliance. The short plasma half life of the metabolically inactive cells, which are closely packed drug and frequent dosing regimen may result in “peaks” and together, and consist of an amorphous matrix of mainly “valleys' in the plasma concentration profile, which lipoid and non-fibrous protein within which keratin fila increases the likelihood of adverse side effects associated ments are distributed. The cells of the stratum corneum with the peak concentration, as well as decreased therapeutic generally contain 20% water, while the cells of the stratum effectiveness towards the end of the dosing interval. germinativum, Situated below the Stratum corneum, contain 70% water. The high degree of keratinization within these 0007 A further problem associated with oral administra cells, as well as their dense packing, creates a Substantially tion is that the rate of absorption of the drug into the impermeable barrier to drug penetration, presenting a rate bloodstream after Swallowing varies from patient to patient. limiting barrier to absorption of topical compositions or The absorption of the drug is dependent upon the movement transdermally administered drugs. of the drug from the Stomach to the Small and large intestines and the effects of Secretions from these organs and on the 0014. In order to improve the penetration of drugs into resulting pH within the Stomach and intestines. Anxiety and the Skin, a variety of techniques and materials have been StreSS can dramatically reduce these movements and Secre developed. These include iontophoresis and ultrasound to tions, prevent or reduce the final effects of the drug, and improve penetration of drugs into the skin, and the use of delay onset of the drug's effects. formulations containing penetration enhancing compounds, Surfactants, lipids and other aliphatic compounds and lipo 0008 An additional disadvantage associated with oral administration is the filet that there is normally a Substantial SOCS. delay between the time of oral administration and the time 0015 Penetration enhancers are materials that have a that the therapeutic effect of the drug begins. AS mentioned direct effect on the permeability of the skin barrier. Chemical above, the drug is must pass through the gastrointestinal penetration enhancers are believed to operate mainly in the System in order to enter the bloodstream, which typically intercellular spaces of the Stratum corneum. The exact takes forty-five minutes or longer. mechanisms by which many chemical penetration enhancers US 2005/0020552 A1 Jan. 27, 2005 function have not been clearly elucidated; it is almost certain osterone production will also cause growth promoting or that they will have multiple effects once absorbed into the “anabolic' changes in the body, including an enhanced rate Stratum corneum. Effects that have been documented of protein Synthesis (leading to muscle accumulation). include an alteration of the Solvent potential of the Stratum 0021 Testosterone also has a number of secondary corneum’s biochemical environment, and a disordering of effects, which are of great importance for the StreSSability the intercellular lipid matrix following insertion of the and performance characteristics of the human organism. enhancer into the bilayer store “Percutaneous Penetration These include the maintaining of an anabolic metabolic Enhancers”, E. W. Smith and H. I. Maibach, Eds., CRC Situation, the restoration of the performance of man follow Press, 1995). Modern investigative techniques have shown ing exhausting exercise and increasing is the psychophysi that many enhancers may operate via a disruption of the ological StreSSability and StreSS resistance. ordered Structure of the intercellular lipid regions of the Stratum corneum. The insertion of the enhancer molecule 0022. Over 90% of the testosterone in the blood is bound between the parallel carbon chains of the fatty acids is to protein and the biologically active component is free believed to enhance the fluidity of this environment, thereby testosterone representing 4 to 8% of the total concentration facilitating the diffusion of the coadministered drug “Per in the blood. The testosterone concentration in the blood is cutaneous Penetration Enhancers', E. W. Smith and