FORMULATION AND DEVELOPMENT OF TRANSDERMAL DRUG DELIVERY SYSTEM OF ETHINYLESTRADIOL AND TESTOSTERONE: IN VITRO EVALUATION
Objective: The combination therapy of ethinylestradiol and testosterone in post-menopausal females has shown improved sexual response and libido. The present studies were designed to develop a suitable matrix-type transdermal drug delivery system (TDDS) of ethinylestradiol and testosterone using the polymer chitosan.
Methods: Five formulations (ET1 to ET5) were developed by varying the concentration of polymer and keeping the drug load constant. Physical parameters and drug excipient interaction studies were evaluated in all the formulations. In vitro skin permeation profiles of ethinylestradiol and testosterone from various formulations were simultaneously characterized in a thermostatically controlled modified Franz Diffusion cell using HPLC. Based on the physical parameters and in vitro skin permeation profile formulation ET3 containing 30 mg/ml of chitosan was found to be the best and chosen for further studies. Optimized formulation was subjected to in vivo pharmacokinetic analysis in rats using ELISA.
Results: Stability profile of patch formulation ET3 depicted stability up to 3 mo. One week skin irritation evaluation in rats indicated that formulation ET3 was nonirritating. Combination transdermal patch across rat skin showed a maximum release of 92.936 and 95.03 % in 60 h with a flux of 2.088 and 21.398 Âµg/cm2h for ethinylestradiol and testosterone respectively.
Conclusion: The net result of this study is the formulation of a stable, non-irritating transdermal patch of ethinylestradiol and testosterone, with good bioavailability and can be used as Estrogen Replacement Therapy (ERT) in postmenopausal women.
2. Kusum Devi V, Saisivam S, Maria GR, Deepti PU. Design and evaluation of matrix diffusion controlled transdermal patches of verapamil. Drug Dev Ind Pharm 2003;29:495-503.
3. Sherwin BB, Gelfand MM, Brender W. Androgen enhances sexual motivation in females: a prospective, crossover study of sex steroid administration in the surgical menopause. Psychosom Med 1985;47:339-45.
4. Mahmoud MS, Diamond MP, Balon R. Androgen therapy for low female libido. Sex Reprod Menopause 2006;4:52-9.
5. Hollingsworth M, Berman J. The role of androgens in female sexual dysfunction. Sex Reprod Menopause 2006;4:27-32.
6. Basson R. Female sexual response: the role of drugs in the management of sexual dysfunction. Obstet Gynecol 2001;98:350-3.
7. Kingsberg S. Testosterone treatment for hypoactive sexual desire disorder in postmenopausal women. J Sex Med 2007;4:227-34.
8. Kingsberg S, Shifren J, Wekselman K, Rodenberg C, Koochaki P, De Rogatis L. Evaluation of the clinical relevance of benefits associated with transdermal testosterone treatment in postmenopausal women with hypoactive sexual desire disorder. J Sex Med 2007;4:1001-8.
9. Buster JE, Kingsberg SA, Aguirre O, Brown C, Breaux JG, Buch A, Rodenberg CA, et al. Testosterone patch for low sexual desire in surgically menopausal women: a randomized trial. Obstet Gynecol 2005;105:944-52.
10. Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, et al. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:682-8.
11. Sherwin BB. Randomized clinical trials of combined estrogen-androgen preparations: effects on sexual functioning. Fertil Steril 2002;77:49-54.
12. Ganz PA, Greendale GA. Female sexual desire-beyond testosterone. J Natl Cancer Inst 2007;99:659-61.
13. Ganz PA, Greendale GA, Petersen L, Zibecchi L, Kahn B, Belin TR. Managing menopausal symptoms in breast cancer survivors: results of a randomized controlled trial. J Natl Cancer Inst 2000;92:1054-64.
14. Bancroft J, Loftus J, Long JS. Distress about sex: a national survey of women in heterosexual relationships. Arch Sex Behav 2003;32:193-208.
15. Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol 2000;96:351-8.
16. Nelson HD, Haney EM, Humphrey L, Miller J, Nedrow A, Nicolaidis C, et al. Management of menopause-related symptoms; 2005.
17. Shen WW, Urosevich Z, Clayton DO. Sildenafil in the treatment of female sexual dysfunction induced by selective serotonin reuptake inhibitors. J Reprod Med 1999;44:535-42.
18. Sherwin B. Use of combined estrogen-androgen preparations in the postmenopause: evidence from clinical studies. Int J Fertility Womens Med 1998;43:98-103.
19. Sarrel PM. Effects of hormone replacement therapy on sexual psychophysiology and behavior in postmenopause. J Women's Health Gender-Based Med 2000;9(1, Suppl 1):25-32.
20. Davis SR, Burger HG. Clinical review 82: androgens and the postmenopausal woman. J Clin Endocrinol Metab 1996;81:2759-63.
21. Sarrel P, Dobay B, Wiita B. Estrogen and estrogen-androgen replacement in postmenopausal women dissatisfied with estrogen-only therapy. Sexual behavior and neuroendocrine responses. J Reprod Med 1998;43:847-56.
22. Davis SR, McCloud P, Strauss BJ, Burger H. Testosterone enhances estradiol's effects on postmenopausal bone density and sexuality. Maturitas 1995;21:227-36.
23. LL Brunton, JS Lazo, KL Parker. Eds. Goodman and Gillman's Manual of pharmacology and therapeutics, the McGraw-hill companies. New York; 2006. p. 15.
24. Mukherjee B, Mahapatra S, Gupta R, Patra B, Tiwari A, Arora P. A comparison between povidone-ethylcellulose and povidone-eudragit transdermal dexamethasone matrix patches based on in vitro skin permeation. Eur J Pharm Biopharm 2005;59:475-83.
25. Dornish M, Domard A, Roberts GAF, Varum KM.1 Advances in chitin science. In: Eds. Elsevier Applied Science Publication; 1997. p. 664-70.
26. Dodane V, Khan MA, Merwin JR. Effect of chitosan on epithelial permeability and structure. Int J Pharm 1999;182:21-32.
27. Park YJ, Lee YM, Lee JY, Seol YJ, Chung CP, Lee SJ. Controlled release of platelet-derived growth factor-BB from chondroitin sulfateâ€“chitosan sponge for guided bone regeneration. J Controlled Release 2000;67:385-94.
28. Ramanathan S, Block LH. The use of chitosan gels as matrices for electrically-modulated drug delivery. J Controlled Release 2001;70:109-23.
29. Arora P, Mukherjee B. Design, development, physicochemical, and in vitro and in vivo evaluation of transdermal patches containing diclofenac diethylammonium salt. J Pharm Sci 2002;91:2076-89.
30. Guideline IH. Stability testing of new drug substances and products Q1A (R2). Curr Step 2003;4:1-24.
31. Mutalik S, Udupa N. Pharmacological evaluation of the membraneâ€moderated transdermal system of glipizide. Clin Exp Pharmacol Physiol 2006;33:17-26.
32. Siepmann J, Ainaoui A, Vergnaud JM, Bodmeier R. Calculation of the dimensions of drug-polymer devices based on diffusion parameters. J Pharm Sci 1998;87:827-32.
33. Brochard F, Degennes PG. Kinetics of polymer dissolution. Physicol Chem Hydrodynamics 1983;4:313-22.
34. Bonferoni MC, Caramella C, Sangalli ME, Conte U, Hernandez RM, Pedraz JL. Rheological behavior of hydrophilic polymers and drug release from erodible matrices. J Controlled Release 1992;18:205-12.
35. Ju RT, Nixon PR, Patel MV, Tong DM. Drug release from hydrophilic matrices. 2. A mathematical model based on the polymer disentanglement concentration and the diffusion layer. J Pharm Sci 1995;84:1464-77.
36. Ouano AC, Tu XO, Carothers JA. Dynamics of polymer dissolution. In: FW Harish, RB Seymour. EDs. Structure solubility relationships in polymers, Academic Press: New York, NY; 1997. p. 11-20.
37. Yum SL, Wright RM. Drug delivery based on diffusion and osmosis. In: SD Bruck. ed. Controlled drug deliveryâ€“basic concepts. Vol. II. CRC Press: Boca Raton, FL; 1983. p. 65-88.
38. Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes.
J Pharmacol Exp Ther 1944;82:377-90.
39. Das A, Ahmed AB. Formulation and evaluation of transdermal patch of indomethacin containing patchouli oil as natural penetration enhancer. Asian J Pharm Clin Res 2017;10:320-5.
40. Sadhasivam LI, Dey N, Francis AP, Devasena T. Transdermal patches of chitosan nanoparticles for insulin delivery. Int J Pharm Pharm Sci 2015;7:84-8.
41. Jadhav JK, Sreenivas SA. Formulation and in vitro evaluation of indomethacin transdermal patches using polymers HPMC E5 and ethyl cellulose. Int J Pharm Pharm Sci 2012;4:550-6.
42. Allena RT, Yadav HK, Sandina S, Sarat Chandra Prasad M. Preparation and evaluation of transdermal patches of metformin hydrochloride using natural polymer for sustained release. Int J Pharm Pharm Sci 2012;4:297-305.