Episodic Transdermal Delivery of Testosterone Ritu Malik, † K. S. Venkatesh, ‡ Anil Kumar Dwivedi, † and Amit Misra* ,† † Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow, 226001, India ‡ ACES and Department of Electrical Engineering, Indian Institute of Technology, Kanpur, 208016, India ABSTRACT: Film-forming lotions, precast films and adhesive patches containing testosterone (T) were prepared by compounding vinylic, acrylic and cellulosic polymers with a variety of excipients in order to achieve distribution of T in domains of heterogeneity within multicomponent matrices. The feasibility of this approach in achieving episodic transdermal delivery of testosterone (T) was investigated. Composition-dependent differences in extent of in vitro drug release and periodicity were observed. Representative formulations showing the most pronounced episodic T release in vitro were tested in female rats. Whereas intravenously administered T decayed exponentially, three maxima of T in serum were observed upon application of selected formulations. Thus, peak serum concentrations of 240, 36, and 29 ng/dL were observed at 0.2, 5, and 16.8 h after application of the preferred lotion formulation, and 89, 65, and 64 ng/dL at 1, 16.4, and 48.8 h after patches. Deconvolution, noncompartment pharmacokinetic analysis and multiple peak fitting also indicated episodicity. These results suggest the feasibility of using transdermal systems for pulsatile T delivery in a variety of clinical applications, including hormone supplementation and male contraception. KEYWORDS: nanoparticles, adhesive-dispersion, dermatopharmaceutics, skin permeation ■ INTRODUCTION Testosterone (T) is a crucial androgen mediating varied anabolic and reproductive effects. Exogenous administration of T is indicated for androgen replacement therapy in male hypogonadism, erectile dysfunction, type 2 diabetes and treatment of female androgen deficiency. 1-3 T also has potential as a stand-alone, noninvasive and user-friendly hormonal male contraceptive. 4 Design of T delivery systems requires attention to the time course of T secretion in healthy, fertile adult males. The male reproductive endocrine axis in fertile men displays a 24 h biorhythm evocative of the 28 day menstrual cycle in women. The hypothalamus secretes gonadotrophin-releasing hormone in synchronous bursts, which stimulate episodic secretion of gonadotrophins by the anterior pituitary. Luteinizing hormone from the pituitary acts on Leydig cells in the testes, stimulating T production required to support spermatogenesis. T crosses the blood-testis barrier and feedback-inhibits secretion of hypothalamic and pituitary hormones. 5 Ideally, therefore, exogenous replacement of T should mimic the transient rises and falls in blood levels observed in normal physiology. Episodic T delivery, rather than maintenance of a high, inhibitory concentration of T, additionally has the potential to feedback-inhibit the episodic secretion of reproductive hormones necessary for male fertility. 6 The present report describes transdermal formulations capable of delivering T in an episodic manner. The pharmacokinetics of conventional transdermal T are beneficial in androgen supplementation, but are not effective as stand-alone male contraceptives, probably because the serum T levels generated are inadequate for suppression of the reproductive endocrine axis. 7-10 Transdermal androgen gels, including those providing sustained and higher serum T levels, are associated with incomplete suppression of spermatogenesis along with other adverse effects of T, 11 and are additionally liable to accidentally virilize contacts of their users. 12,13 Transdermal T has been formulated as patches, 14-17 film- forming lotions and sprays, 18 and supersaturated liquid-crystal gels, 19,20 but episodic T delivery is addressed by none of these. Received: May 4, 2011 Revised: April 17, 2012 Accepted: April 25, 2012 Published: April 25, 2012 Article pubs.acs.org/molecularpharmaceutics © 2012 American Chemical Society 1537 dx.doi.org/10.1021/mp200558a | Mol. Pharmaceutics 2012, 9, 1537-1543