Development of finasteride polymer microspheres for systemic application in androgenic alopecia

Kim,Ju   Hee; Na,Jungtae; Bak,Dong‑Ho; Lee,Byung   Chul; Lee,Esther; Choi,Mi   Ji; Ryu,Choong  Ho; Lee,Sangno; Mun,Seog‑Kyun; Park,Byung   Cheol; Kim,Beom   Joon; Lee,Hyun‑Shik

doi:10.3892/ijmm.2019.4149

Development of finasteride polymer microspheres for systemic application in androgenic alopecia

Authors:
- Ju Hee Kim
- Jungtae Na
- Dong‑Ho Bak
- Byung Chul Lee
- Esther Lee
- Mi Ji Choi
- Choong Ho Ryu
- Sangno Lee
- Seog‑Kyun Mun
- Byung Cheol Park
- Beom Joon Kim
- Hyun‑Shik Lee
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Affiliations: KNU‑Center for Nonlinear Dynamics, CMRI, School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, College of Natural Science Kyungpook National University, Daegu 41566, Republic of Korea, Department of Dermatology, College of Medicine, Chung‑Ang University, Seoul 06973, Republic of Korea, Headquarter, Inventage Lab, Inc., Seongnam, Gyeonggi 13403, Republic of Korea, Department of Otorhinolaryngology‑Head and Neck Surgery, College of Medicine, Chung‑Ang University, Seoul 06973, Republic of Korea , Department of Dermatology, Dankook Medical College, Cheonan, Chungcheongnam 31116, Republic of Korea
Published online on: March 28, 2019 https://doi.org/10.3892/ijmm.2019.4149
Pages: 2409-2419
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The use of finasteride for alleviating hair loss has been investigated, and it has been applied as an oral dose medication. However, due to the inconvenience of daily drug administration over long period of time, novel controllable finasteride delivery has been actively investigated. As a novel method of finasteride delivery, the development of finasteride‑loaded microspheres for subcutaneous administration is becoming increasingly pharmaceutically important. Therefore, the present study aimed to use finasteride‑loaded microspheres in a controlled manner in an attempt to overcome the limitations of the oral administration of finasteride and to cause fewer adverse effects. Finasteride‑loaded microspheres containing poly(lactic‑co‑glycolic acid) and finasteride at a ratio of 4:1 were prepared, and a testosterone‑induced androgenic alopecia mouse model was used. Following observation for 10 weeks, the percentage hair growth was 86.7% (total hair growth 60%, partial hair growth 26.7%) in the orally‑applied finasteride‑treated group as a positive control, and 93.3% (total hair growth 60%, partial hair growth 33.3%) in the finasteride‑loaded microspheres‑treated group. Serum dihydrotestosterone levels began to decrease at week 6 in the orally‑applied finasteride‑ and finasteride‑loaded microsphere‑treated groups. In addition, the finasteride‑loaded microspheres‑treated group exhibited similar follicular number, follicular length, anagen/telogen ratio and hair bulb diameter values to those of the orally‑applied finasteride‑treated group. Furthermore, the finasteride‑loaded microspheres increased the activities of phosphoinositide 3‑kinase/protein kinase B and Wnt/β‑catenin in relation to hair follicle cell growth signaling in mouse skin, and suppressed the apoptosis of hair follicle cells by reducing the expression of transforming growth factor‑β2 and caspase‑3, which are indicators of apoptosis. In conclusion, the administration of a single injection of finasteride‑loaded microspheres was effective in treating testosterone‑induced alopecia. Furthermore, it led to equivalent hair growth effects when compared with orally‑applied finasteride, thus revealing the possibility of effective treatment via different routes of administration.

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1	Sinclair R: Male pattern androgenetic alopecia. BMJ. 317:865–869. 1998. View Article : Google Scholar : PubMed/NCBI
2	Cash TF: The psychology of hair loss and its implications for patient care. Clin Dermatol. 19:161–166. 2001. View Article : Google Scholar : PubMed/NCBI
3	Whiting DA: Possible mechanisms of miniaturization during androgenetic alopecia or pattern hair loss. J Am Acad Dermatol. 45(Suppl 3): S81–S86. 2001. View Article : Google Scholar : PubMed/NCBI
4	Urysiak-Czubatka I, Kmieć ML and Broniarczyk-Dyła G: Assessment of the usefulness of dihydrotestosterone in the diagnostics of patients with androgenetic alopecia. Postepy Dermatol Alergol. 31:207–215. 2014. View Article : Google Scholar : PubMed/NCBI
5	Aggarwal S, Thareja S, Verma A, Bhardwaj TR and Kumar M: An overview on 5alpha-reductase inhibitors. Steroids. 75:109–153. 2010. View Article : Google Scholar
6	Azzouni F, Godoy A, Li Y and Mohler J: The 5 alpha-reductase isozyme family: A review of basic biology and their role in human diseases. Adv Urol. 2012:5301212012. View Article : Google Scholar : PubMed/NCBI
7	McConnell JD, Wilson JD, George FW, Geller J, Pappas F and Stoner E: Finasteride, an inhibitor of 5 alpha-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyperplasia. J Clin Endocrinol Metab. 74:505–508. 1992.PubMed/NCBI
8	Gormley GJ, Stoner E, Bruskewitz RC, Imperato-McGinley J, Walsh PC, McConnell JD, Andriole GL, Geller J, Bracken BR, Tenover JS, et al: The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group. N Engl J Med. 327:1185–1191. 1992. View Article : Google Scholar : PubMed/NCBI
9	Drake L, Hordinsky M, Fiedler V, Swinehart J, Unger WP, Cotterill PC, Thiboutot DM, Lowe N, Jacobson C, Whiting D, et al: The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. J Am Acad Dermatol. 41:550–554. 1999.PubMed/NCBI
10	Kaufman KD, Olsen EA, Whiting D, Savin R, DeVillez R, Bergfeld W, Price VH, Van Neste D, Roberts JL, Hordinsky M, et al: Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group. J Am Acad Dermatol. 39:578–589. 1998. View Article : Google Scholar : PubMed/NCBI
11	Finasteride Male Pattern Hair Loss Study Group: Long-term (5-year) multinational experience with finasteride 1 mg in the treatment of men with androgenetic alopecia. Eur J Dermatol. 12:38–49. 2002.PubMed/NCBI
12	Whiting DA, Olsen EA, Savin R, Halper L, Rodgers A, Wang L, Hustad C and Palmisano J; Male Pattern HairLoss Study Group: Efficacy and tolerability of finasteride 1 mg in men aged 41 to 60 years with male pattern hair loss. Eur J Dermatol. 13:150–160. 2003.PubMed/NCBI
13	Mella JM, Perret MC, Manzotti M, Catalano HN and Guyatt G: Efficacy and safety of finasteride therapy for androgenetic alopecia: A systematic review. Arch Dermatol. 146:1141–1150. 2010. View Article : Google Scholar : PubMed/NCBI
14	Peng D, Huang K, Liu Y and Liu S: Preparation of novel polymeric microspheres for controlled release of finasteride. Int J Pharm. 342:82–86. 2007. View Article : Google Scholar : PubMed/NCBI
15	Caon T, Porto LC, Granada A, Tagliari MP, Silva MA, Simões CM, Borsali R and Soldi V: Chitosan-decorated polystyrene-b-poly(acrylic acid) polymersomes as novel carriers for topical delivery of finasteride. Eur J Pharm Sci. 52:165–172. 2014. View Article : Google Scholar
16	Freiberg S and Zhu X: Polymer microspheres for controlled drug release. Int J Pharm. 282:1–18. 2004. View Article : Google Scholar : PubMed/NCBI
17	Nojehdehian H and Ekrami M: Loading of gentamicin sulfate into poly (lactic-co-glycolic acid) biodegradable microspheres. Shahid Beheshti University. J Dent Sch. 33:145–151. 2015.
18	Sinha V, Bansal K, Kaushik R, Kumria R and Trehan A: Poly-ϵ-caprolactone microspheres and nanospheres: An overview. Int J Pharma. 278:1–23. 2004. View Article : Google Scholar
19	Burns SA, Hard R, Hicks WL Jr, Bright FV, Cohan D, Sigurdson L and Gardella JA Jr: Determining the protein drug release characteristics and cell adhesion to a PLLA or PLGA biodegradable polymer membrane. J Biomed Mater Res A. 94:27–37. 2010. View Article : Google Scholar : PubMed/NCBI
20	Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A and Préat V: PLGA-based nanoparticles: An overview of biomedical applications. J Control Release. 161:505–522. 2012. View Article : Google Scholar : PubMed/NCBI
21	Corrigan OI and Li X: Quantifying drug release from PLGA nanoparticulates. Eur J Pharm Sci. 37:477–485. 2009. View Article : Google Scholar : PubMed/NCBI
22	Mu L and Feng S: A novel controlled release formulation for the anticancer drug paclitaxel (Taxol): PLGA nanoparticles containing vitamin E TPGS. J Control Release. 86:33–48. 2003. View Article : Google Scholar
23	Wang ZD, Feng Y, Ma LY, Li X, Ding WF and Chen XM: Hair growth promoting effect of white wax and policosanol from white wax on the mouse model of testosterone-induced hair loss. Biomed Pharmacother. 89:438–446. 2017. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
25	Kim YJ, Choi MJ, Bak DH, Lee BC, Ko EJ, Ahn GR, Ahn SW, Kim MJ, Na J and Kim BJ: Topical administration of EGF suppresses immune response and protects skin barrier in DNCB-induced atopic dermatitis in NC/Nga mice. Sci Rep. 8:118952018. View Article : Google Scholar : PubMed/NCBI
26	Hibino T and Nishiyama T: Role of TGF-beta2 in the human hair cycle. J Dermatol Sci. 35:9–18. 2004. View Article : Google Scholar : PubMed/NCBI
27	Chen W, Zouboulis CC and Orfanos CE: The 5-alpha reductase system and its inhibitors. Recent development and its perspective in treating androgen-dependent skin disorders. Dermatology. 193:177–184. 1996. View Article : Google Scholar
28	Thornton MJ, Messenger AG, Elliott K and Randall VA: Effect of androgens on the growth of cultured human dermal papilla cells derived from beard and scalp hair follicles. J Invest Dermatol. 97:345–348. 1991. View Article : Google Scholar : PubMed/NCBI
29	Sato A and Takeda A: Evaluation of efficacy and safety of finasteride 1 mg in 3,177 Japanese men with androgenetic alopecia. J Dermatol. 39:27–32. 2012. View Article : Google Scholar
30	Mysore V and Shashikumar B: Guidelines on the use of finasteride in androgenetic alopecia. Indian J Dermatol Venereol Leprol. 82:128–134. 2016. View Article : Google Scholar : PubMed/NCBI
31	Hirshburg JM, Kelsey PA, Therrien CA, Gavino AC and Reichenberg JS: Adverse effects and safety of 5-alpha reductase inhibitors (finasteride, dutasteride): A systematic review. J Clin Aesthet Dermatol. 9:56–62. 2016.PubMed/NCBI
32	Wessells H, Roy J, Bannow J, Grayhack J, Matsumoto AM, Tenover L, Herlihy R, Fitch W, Labasky R, Auerbach S, et al: Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia. Urology. 61:579–584. 2003. View Article : Google Scholar : PubMed/NCBI
33	Moinpour CM, Darke AK, Donaldson GW, Thompson IM Jr, Langley C, Ankerst DP, Patrick DL, Ware JE Jr, Ganz PA, Shumaker SA, et al: Longitudinal analysis of sexual function reported by men in the prostate cancer prevention trial. J Natl Cancer Inst. 99:1025–1035. 2007. View Article : Google Scholar : PubMed/NCBI
34	Carbone D Jr and Hodges S: Medical therapy for benign prostatic hyperplasia: Sexual dysfunction and impact on quality of life. Int J Impot Res. 15:299–306. 2003. View Article : Google Scholar : PubMed/NCBI
35	Peng D, Huang K, Liu Y, Liu S, Wu H and Xiao H: Preparation of carbon dioxide/propylene oxide/ε-caprolactone copolymers and their drug release behaviors. Polymer Bull. 59:117–125. 2007. View Article : Google Scholar
36	Ahmed OA, Hussein AK and Mady FM: Optimisation of microstructured biodegradable finasteride formulation for depot parenteral application. J Microencapsul. 33:229–238. 2016. View Article : Google Scholar : PubMed/NCBI
37	Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB and Hobbs S: Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5α-reductase inhibitor. J Clin Endocrinol Metab. 89:2179–2184. 2004. View Article : Google Scholar : PubMed/NCBI
38	Tsai TF, Choi GS, Kim BJ, Kim MB, Ng CF, Kochhar P, Jasper S, Brotherton B, Orban B and Lulic Z: Prospective randomized study of sexual function in men taking dutasteride for the treatment of androgenetic alopecia. J Dermatol. 45:799–804. 2018. View Article : Google Scholar : PubMed/NCBI
39	Fertig R, Shapiro J, Bergfeld W and Tosti A: Investigation of the plausibility of 5-alpha-reductase inhibitor syndrome. Skin Appendage Disord. 2:120–129. 2017. View Article : Google Scholar : PubMed/NCBI
40	Wilt TJ, MacDonald R, Hagerty K, Schellhammer P, Tacklind J, Somerfield MR and Kramer BS: 5-α-reductase inhibitors for prostate cancer chemoprevention: An updated Cochrane systematic review. BJU Int. 106:1444–1451. 2010. View Article : Google Scholar : PubMed/NCBI
41	Wu XJ, Zhi Y, Zheng J, He P, Zhou XZ, Li WB and Zhou ZS: Dutasteride on benign prostatic hyperplasia: A meta-analysis on randomized clinical trials in 6,460 patients. Urology. 83:539–543. 2014. View Article : Google Scholar
42	Arif T, Dorjay K, Adil M and Sami M: Dutasteride in androge-netic alopecia: An update. Curr Clin Pharmacol. 12:31–35. 2017. View Article : Google Scholar