Drug Delivery and Translational Research

, Volume 8, Issue 1, pp 140–149 | Cite as

Germacrone and sesquiterpene-enriched extracts from Curcuma aeruginosa Roxb. increase skin penetration of minoxidil, a hair growth promoter

  • Jukkarin Srivilai
  • Neti Waranuch
  • Anothai Tangsumranjit
  • Nantaka Khorana
  • Kornkanok Ingkaninan
Original Article
First Online:
  • 186 Downloads

Abstract

Minoxidil is approved for topical treatment of androgenic alopecia but hampered by poor cutaneous absorption. Recently, the randomized control trial showed that hair loss treatment of minoxidil was improved by co-application of the anti-androgen, Curcuma aeruginosa Roxb. extract. Here, we aimed to show that the apparent synergism arises from improved cutaneous penetration of minoxidil by bioactive compound, germacrone or C. aeruginosa (as an n-hexane extract, or essential oil). The partition coefficient of germacrone was determined by HPLC. Skin penetration was measured ex vivo on Franz diffusion cells using full thickness human foreskin as membranes. The receiver solution was sampled hourly for 8 h after which the skin was removed, the stratum corneum separated, and minoxidil assayed in this and in the remaining viable skin layer by HPLC. Skin penetration of minoxidil with 0.2 and 2% extract was increased ~ 4-fold (accumulated amount in receiver + skin viable layer after 8 h). Furthermore, germacrone enhanced minoxidil flux by ~ 10-fold and C. aeruginosa essential oil by ~ 20-fold. This work suggests three clinical consequences: (i) minoxidil efficacy is promoted, (ii) lower doses of minoxidil suffice, and (iii) C. aeruginosa extract/essential oil or germacrone can supplement treatment outcomes by acting as anti-androgen, thereby introducing a more effective topical treatment strategy for androgenic alopecia.

Keywords

Skin penetration enhancer Germacrone Minoxidil Curcuma aeruginosa Roxb. Hair loss 

Abbreviations

CA-ext

Curcuma aeruginosa hexane extract

CA-oil

Curcuma aeruginosa essential oil

ERsol

solubility enhancement ratio

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Notes

Acknowledgements

We thank Dr. C. Norman Scholfield, Faculty of Pharmaceutical Sciences, Naresuan University for his help in the manuscript preparation. Dr. Wudticha Wisutriport, Ms. Prattana Khehaluna, Ms. Matusorn Wong-ona, and Ms. Ratchaprapa Sinlapasakkajohna are thanked for their help in the preliminary study.

Funding information

The authors are grateful for the financial supports received from the Royal Golden Jubilee Program (RGJ-Ph.D., grant no. PHD/0205/2556), the Thailand Research Fund (the grant nos. DBG608005 and IRN58W0005), the Center of Excellence for Innovation in Chemistry (PERCH-CIC), Office of the Higher Education Commission, Ministry of Education, and Naresuan University, Thailand.

Compliance with ethical standards

The investigational protocol was approved by Naresuan University Institutional Review Board (Approval No. HE-55-Ex-0134).

Conflict of interest

The authors declare that there are no conflicts of interest.

Supplementary material

13346_2017_447_MOESM1_ESM.docx (130 kb)
ESM 1 (DOCX 130 kb)

References

  1. 1.
    Dinh QQ, Sinclair R. Female pattern hair loss: current treatment concepts. Clin Interv Aging. 2007;2(2):189–99.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Sinclair RD. Male androgenetic alopecia. J Men’s Health Gender. 2004;1(4):319–27.  https://doi.org/10.1016/j.jmhg.2004.09.016.CrossRefGoogle Scholar
  3. 3.
    Varothai S, Bergfeld WF. Androgenetic alopecia: an evidence-based treatment update. Am J Clin Dermatol. 2014;15(3):217–30.  https://doi.org/10.1007/s40257-014-0077-5.CrossRefPubMedGoogle Scholar
  4. 4.
    Balakrishnan P, Shanmugam S, Lee WS, Lee WM, Kim JO, Oh DH, et al. Formulation and in vitro assessment of minoxidil niosomes for enhanced skin delivery. Int J Pharm. 2009;377(1-2):1–8.  https://doi.org/10.1016/j.ijpharm.2009.04.020.CrossRefPubMedGoogle Scholar
  5. 5.
    Irwig MS, Kolukula S. Persistent sexual side effects of finasteride for male pattern hair loss. J Sex Med. 2011;8(6):1747–53.  https://doi.org/10.1111/j.1743-6109.2011.02255.x.CrossRefPubMedGoogle Scholar
  6. 6.
    Mysore V. Finasteride and sexual side effects. Indian Dermatol Online J. 2012;3(1):62–5.  https://doi.org/10.4103/2229-5178.93496.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Tosti A, Pazzaglia M, Soli M, Rossi A, Rebora A, Atzori L, et al. Evaluation of sexual function with an international index of erectile function in subjects taking finasteride for androgenetic alopecia. Arch Dermatol. 2004;140(7):857–8.  https://doi.org/10.1001/archderm.140.7.857.CrossRefPubMedGoogle Scholar
  8. 8.
    Srivastava, S, Chitranshi, N, Srivastave, S, Dan, M, Rawat, A, Pushpangadan, P. Pharmacognostic evaluation of Curcuma aeurigenosa Roxb. Nat Prod Sci. 2006;12(3):162–5.Google Scholar
  9. 9.
    Reanmongkol W, Subhadhirasakul S, Khaisombat N, Khaisombat N, Fuengnawakit P, Jantasila S, et al. Investigation the antinociceptive, antipyretic and anti-inflammatory activities of Curcuma aeruginosa Roxb. Extracts in experimental animals. Songklanakarin J Sci Technol. 2006;5:999–1008.Google Scholar
  10. 10.
    Pumthong G, Asawanonda P, Varothai S, Jariyasethavong V, Triwongwaranat D, Suthipinittharm P, et al. Curcuma aeruginosa, a novel botanically derived 5alpha-reductase inhibitor in the treatment of male-pattern baldness: a multicenter, randomized, double-blind, placebo-controlled study. J Dermatol Treat. 2012;23(5):385–92.  https://doi.org/10.3109/09546634.2011.568470.
  11. 11.
    Srivilai J, Khorana N, Waranuch N, Suphrom N, Ingkaninan K. Conformational analysis of an anti-androgenic, (E,E)-8-hydroxygermacrene B, using NOESY and dynamic NMR spectroscopy. Bioorg Med Chem Lett. 2014;24(15):3526–9.  https://doi.org/10.1016/j.bmcl.2014.05.057.CrossRefPubMedGoogle Scholar
  12. 12.
    Srivilai J, Khorana N, Waranuch N, Ingkaninan K. Anti-androgenic activity of furanodiene isolated from Curcuma aeruginosa Roxb. extract. Naresuan Univ J. 2011;Specual issue:33–7.Google Scholar
  13. 13.
    Suphrom N, Pumthong G, Khorana N, Waranuch N, Limpeanchob N, Ingkaninan K. Anti-androgenic effect of sesquiterpenes isolated from the rhizomes of Curcuma aeruginosa Roxb. Fitoterapia. 2012;83(5):864–71.  https://doi.org/10.1016/j.fitote.2012.03.017.
  14. 14.
    Bianchi F, Careri M, Mangia A, Musci M. Retention indices in the analysis of food aroma volatile compounds in temperature-programmed gas chromatography: database creation and evaluation of precision and robustness. J Sep Sci. 2007;30(4):563–72.  https://doi.org/10.1002/jssc.200600393.CrossRefPubMedGoogle Scholar
  15. 15.
    Shah VP, Flynn GL, Yacobi A, Maibach HI, Bon C, Fleischer NM, et al. Bioequivalence of topical dermatological dosage forms--methods of evaluation of bioequivalence. Pharm Res. 1998;15(2):167–71.  https://doi.org/10.1023/A:1011941929495.
  16. 16.
    Roberts MS, Pugh WJ, Hadgraft J. Epidermal permeability: penetrant structure relationships. 2. The effect of h-bonding groups in penetrants on their diffusion through the stratum corneum. Int J Pharm. 1996;132(1-2):23–32.  https://doi.org/10.1016/0378-5173(95)04278-4.CrossRefGoogle Scholar
  17. 17.
    Zhu H, Jung EC, Hui X, Maibach H. Proposed human stratum corneum water domain in chemical absorption. J Appl Toxicol. 2015;38:991–6.Google Scholar
  18. 18.
    Hansch C, Leo A, Hoekman D. Exploring QSAR: volume 1: hydrophobic, electronic, and steric constants. 1st ed. Washington D.C.: American Chemistry Society; 1995.Google Scholar
  19. 19.
    Chia-Ming C, Flynn G, Weiner N, Szpunar GJ. Bioavailability assessment of topical delivery systems: effect of vehicle evaporation upon in vitro delivery of minoxidil from solution formulations. Int J Pharm. 1989;2:229–36.CrossRefGoogle Scholar
  20. 20.
    Moser K, Kriwet K, Naik A, Kalia YN, Guy RH. Passive skin penetration enhancement and its quantification in vitro. Eur J Pharm Biopharm. 2001;52(2):103–12.  https://doi.org/10.1016/S0939-6411(01)00166-7.CrossRefPubMedGoogle Scholar
  21. 21.
    Kwak S, Brief E, Langlais D, Kitson N, Lafleur M, Thewalt J. Ethanol perturbs lipid organization in models of stratum corneum membranes: an investigation combining differential scanning calorimetry, infrared and (2)H NMR spectroscopy. Biochim Biophys Acta. 1818;2012:1410–9.Google Scholar
  22. 22.
    Herman A, Herman AP. Essential oils and their constituents as skin penetration enhancer for transdermal drug delivery: a review. J Pharm Pharmacol. 2015;67(4):473–85.  https://doi.org/10.1111/jphp.12334.CrossRefPubMedGoogle Scholar
  23. 23.
    Sapra B, Jain S, Tiwary AK. Percutaneous permeation enhancement by terpenes: mechanistic view. AAPS J. 2008;10(1):120–32.  https://doi.org/10.1208/s12248-008-9012-0.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Vaddi HK, Ho PC, Chan SY. Terpenes in propylene glycol as skin-penetration enhancers: permeation and partition of haloperidol, Fourier transform infrared spectroscopy, and differential scanning calorimetry. J Pharm Sci. 2002;91(7):1639–51.  https://doi.org/10.1002/jps.10160.CrossRefPubMedGoogle Scholar
  25. 25.
    Femenia-Font A, Balaguer-Fernandez C, Merino V, Rodilla V, Lopez-Castellano A. Effect of chemical enhancers on the in vitro percutaneous absorption of sumatriptan succinate. Eur J Pharm Biopharm. 2005;61(1-2):50–5.  https://doi.org/10.1016/j.ejpb.2005.02.014.CrossRefPubMedGoogle Scholar
  26. 26.
    Narishetty ST, Panchagnula R. Transdermal delivery of zidovudine: effect of terpenes and their mechanism of action. J Control Release. 2004;95(3):367–79.  https://doi.org/10.1016/j.jconrel.2003.11.022.CrossRefPubMedGoogle Scholar
  27. 27.
    Narishetty ST, Panchagnula R. Effect of L-menthol and 1,8-cineole on phase behavior and molecular organization of SC lipids and skin permeation of zidovudine. J Control Release. 2005;102(1):59–70.  https://doi.org/10.1016/j.jconrel.2004.09.016.CrossRefPubMedGoogle Scholar
  28. 28.
    Williams AC, Barry BW. Terpenes and the lipid-protein-partitioning theory of skin penetration enhancement. Pharm Res. 1991;8(1):17–24.  https://doi.org/10.1023/A:1015813803205.CrossRefPubMedGoogle Scholar
  29. 29.
    Okabe H, Obata Y, Takayama K, Nagai T. Percutaneous absorption enhancing effect and skin irritation of monocyclic monoterpenes. Drug Des Deliv. 1990;6(3):229–38.PubMedGoogle Scholar
  30. 30.
    Suphrom N, Srivilai J, Pumthong G, Khorana N, Waranuch N, Limpeanchob N, et al. Stability studies of antiandrogenic compounds in Curcuma aeruginosa Roxb. extract. J Pharm Pharmacol. 2014;66(9):1282–93.  https://doi.org/10.1111/jphp.12216.CrossRefPubMedGoogle Scholar
  31. 31.
    Nokhodchi A, Sharabiani K, Rashidi MR, Ghafourian T. The effect of terpene concentrations on the skin penetration of diclofenac sodium. Int J Pharm. 2007;335(1-2):97–105.  https://doi.org/10.1016/j.ijpharm.2006.10.041.CrossRefPubMedGoogle Scholar
  32. 32.
    Lucky AW, Piacquadio DJ, Ditre CM, Dunlap F, Kantor I, Pandya AG, et al. A randomized, placebo-controlled trial of 5% and 2% topical minoxidil solutions in the treatment of female pattern hair loss. J Am Acad Dermatol. 2004;50(4):541–53.  https://doi.org/10.1016/j.jaad.2003.06.014.CrossRefPubMedGoogle Scholar
  33. 33.
    Kaufman KD, Olsen EA, Whiting D, Savin R, DeVillez R, Bergfeld W, et al. Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group. J Am Acad Dermatol. 1998;39(4):578–89.  https://doi.org/10.1016/S0190-9622(98)70007-6.CrossRefPubMedGoogle Scholar

Copyright information

© Controlled Release Society 2017

Authors and Affiliations

  1. 1.Bioscreening Unit, Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences and Center of Excellence for Innovation in ChemistryNaresuan UniversityPhitsanulokThailand
  2. 2.Cosmetics and Natural Products Research Center, Department of Pharmaceutical Technology, Faculty of Pharmaceutical SciencesNaresuan UniversityPhitsanulokThailand
  3. 3.Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences and Center of Excellence for Innovation in ChemistryNaresuan UniversityPhitsanulokThailand

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