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Production and characterization of newly developed alcohol-free topical liposome-gel transdermal drug delivery systems containing estradiol (E2)/ estriol (E3) for post-menopausal women

Yıl 2023, Cilt: 27 Sayı: 5, 2190 - 2198, 28.06.2025

İsmail Aslan , Ali Fuat Aytekin

Öz

The aim of the research was to develop alcohol-free and relatively safe liposome-gel formulations containing Estradiol (E2)/Estriol (E3) combinations for menopausal women. Herewith, we purposed to solve problems some of the transdermal products containing ethanol by preparing liposome-gel formulations. The purpose of this research was the develop of liposome-gel formulations including Estradiol (E2) /Estriol (E3) hormones. Mean particle size, zeta potential, FT-IR spectrum, rheological behaviour studies were evaluated in transdermal non-invasive formulation. The optimum formulation (LH5) was concluded to be the negatively charged liposomes, which exhibited high physical characteristics, and relatively optimum particle size for transdermal penetration as 153.3 nm ± 1.1. Mean particle size distribution of empty liposome dispersion was smaller than E2/E3 loaded liposomes (LH6) because of encapsulation of them. So, the best E2/E3 loaded formulation (LH6) was selected according to the mean particle size distribution analysis, PDI values (< 0.5 PDI value) PDI value was found as 0.371 ± 0.01 for LH6. Moreover, since the zeta potential was found to be -54.9 mV± 0.25, it is predicted to be more stable than other E2/E3 loaded liposomes according to DLVO theory. When U21 and U30 used as gelling agent were compared, it was observed that U21 showed a more stable rheological behavior with approximately 25500 cP at skin pH. For this reason, U21 was preferred as a gelling agent for liposome dispersions in the second step. Considering the liposome-gel formulations, the LHG6 formulation, which is not excessively viscous in skin application compared to the other three formulations in terms of ease of transdermal application, was found to have a value of 34500 cP and was selected as the optimum liposome-gel formulation. Formulation and characterization studies supported that liposome gel delivery system is suitable for topical applications. All results supported that liposome-gel delivery system is more appropriate for transdermal applications. Since the liposome-gel transdermal drug delivery system is suitable and safer than oral administration in all characterization studies, efficacy studies of E2/E3 loaded liposome-gel formulations will soon be possible with in- vivo studies in human volunteers.

Anahtar Kelimeler

Liposome transdermal estradiol estriol menopause

Kaynakça

  • [1] Gregoriadis G, Florence AT. Liposomes in drug delivery. Clinical, diagnostic and ophthalmic potential. Drugs. 1993; 45(1): 15-28. https://doi.org/10.2165/00003495-199345010-00003
  • [2] Allen TM, Cullis PR. Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev. 2013; 65(1): 36-48. https://doi.org/10.1016/j.addr.2012.09.037
  • [3] Keller BC. Liposomes in nutrition. Trends in Food Science & Technology. 2001; 12(1): 25-31. https://doi.org/10.1016/S0924-2244(01)00044-9
  • [4] Maherani B, Arab-Tehrany E, Mozafari M, Gaiani C, M L. Liposomes: A Review of Manufacturing Techniques and Targeting Strategies. Current Nanoscience. 2011; 7(436-452). https://doi.org/10.2174/157341311795542453
  • [5] Akbarzadeh A, Rezaei-Sadabady R, Davaran S, Joo SW, Zarghami N, Hanifehpour Y, Samiei M, Kouhi M, Nejati-Koshki K. Liposome: classification, preparation, and applications. Nanoscale Research Letters. 2013; 8(1): 102. https://doi.org/10.1186/1556-276X-8-102
  • [6] Jesorka A, Orwar O. Liposomes: technologies and analytical applications. Annu Rev Anal Chem (Palo Alto Calif). 2008; 1(801-832). https://doi.org/10.1146/annurev.anchem.1.031207.112747
  • [7] Sharma A, Sharma US. Liposomes in drug delivery: Progress and limitations. International Journal of Pharmaceutics. 1997; 154(2): 123-140. https://doi.org/10.1016/S0378-5173(97)00135-X
  • [8] Aslan I, Kurt A, In-vitro comparison release study of novel liposome and conventional formulation containing Rosmarinus officinalis extract, 2021. https://doi.org/10.38093/cupmap.848115
  • [9] Aslan I, Kurt A. Characterization and Optimization of Phytosome Formulation Containing Alcohol-free Umckalin from Pelargonium sidoides. Current Perspectives on Medicinal and Aromatic Plants (CUPMAP). 2020; 49-53. https://doi.org/10.38093/cupmap.737878
  • [10] Laouini A, Jaafar-Maalej C, Blouza I, Sfar S, Charcosset C, Fessi H. Preparation, Characterization and Applications of Liposomes: State of the Art. Journal of Colloid Science and Biotechnology. 2012; 1(147-168). https://doi.org/10.1166/jcsb.2012.1020
  • [11] Petersen AL, Hansen AE, Gabizon A, Andresen TL. Liposome imaging agents in personalized medicine. Adv Drug Deliv Rev. 2012; 64(13): 1417-1435. https://doi.org/10.1016/j.addr.2012.09.003
  • [12] Duman G, Aslan İ, Özer AY, İnanç İ, Taralp A. Liposome, gel and lipogelosome formulations containing sodium hyaluronate. J Liposome Res. 2014; 24(4): 259-269. https://doi.org/10.3109/08982104.2014.907305
  • [13] Torchilin V. Multifunctional and stimuli-sensitive pharmaceutical nanocarriers. Eur J Pharm Biopharm. 2009; 71(3): 431-444. https://doi.org/10.1016/j.ejpb.2008.09.026
  • [14] Huang Z, Li X, Zhang T, Song Y, Zhennan S, Li J, Deng Y. Progress involving new techniques for liposome preparation. Asian Journal of Pharmaceutical Sciences. 2014; 9. https://doi.org/10.1016/j.ajps.2014.06.001
  • [15] Weissig V. Liposomes - A Practical Approach, 2nd Edition, Vladimir P. Torchilin, Volkmar Weissig (Eds), Oxford University Press, 396 pages (2003). 2003
  • [16] Jahn A, Vreeland WN, Gaitan M, Locascio LE. Controlled vesicle self-assembly in microfluidic channels with hydrodynamic focusing. J Am Chem Soc. 2004; 126(9): 2674-2675. https://doi.org/10.1021/ja0318030
  • [17] Emaminia F, Rezaei A, Badehnoosh B, Ramezani R, Shabani M. The effects of Elaeagnus angustifolia L. whole fruit on the sex hormone profile in menopausal women: A double-blind, randomized, placebo-controlled study. J Ethnopharmacol. 2020; 246(112229). https://doi.org/10.1016/j.jep.2019.112229
  • [18] Burger HG, Dudley EC, Robertson DM, Dennerstein L. Hormonal changes in the menopause transition. Recent Prog Horm Res. 2002; 57(257-275). https://doi.org/10.1210/rp.57.1.257
  • [19] Huber TJ, Rollnik J, Wilhelms J, von zur Mühlen A, Emrich HM, Schneider U. Estradiol levels in psychotic disorders. Psychoneuroendocrinology. 2001; 26(1): 27-35. https://doi.org/10.1016/s0306-4530(00)00034-2
  • [20] Shirtcliff EA, Granger DA, Schwartz EB, Curran MJ, Booth A, Overman WH. Assessing estradiol in biobehavioral studies using saliva and blood spots: simple radioimmunoassay protocols, reliability, and comparative validity. Horm Behav. 2000; 38(2): 137-147. https://doi.org/10.1006/hbeh.2000.1614
  • [21] Huidrom S, Beg MA, Masood T. Post-menopausal Osteoporosis and Probiotics. Curr Drug Targets. 2021; 22(7): 816-822. https://doi.org/10.2174/1389450121666201027124947
  • [22] Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. Bmj. 2011; 343(d6423). https://doi.org/10.1136/bmj.d6423
  • [23] Muijsers RB, Wagstaff AJ. Transdermal fentanyl: an updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control. Drugs. 2001; 61(15): 2289-2307. https://doi.org/10.2165/00003495-200161150-00014
  • [24] Peltola S, Saarinen-Savolainen P, Kiesvaara J, Suhonen TM, Urtti A. Microemulsions for topical delivery of estradiol. International Journal of Pharmaceutics. 2003; 254(2): 99-107. https://doi.org/10.1016/S0378-5173(02)00632-4
  • [25] Lachenmeier DW. Safety evaluation of topical applications of ethanol on the skin and inside the oral cavity. J Occup Med Toxicol. 2008; 3(26). https://doi.org/10.1186/1745-6673-3-26
  • [26] Maier A, Ovesen JL, Allen CL, York RG, Gadagbui BK, Kirman CR, Poet T, Quiñones-Rivera A. Safety assessment for ethanol-based topical antiseptic use by health care workers: Evaluation of developmental toxicity potential. Regul Toxicol Pharmacol. 2015; 73(1): 248-264. https://doi.org/10.1016/j.yrtph.2015.07.015
  • [27] Baert, B., Annavarapu, S., Burvenich, C., & De Spiegeleer, B. (2009). Analytical, biopharmaceutical and regulatory evaluation of topical testosterone preparations. European journal of pharmaceutics and biopharmaceutics, 72(1), 275-281. https://doi.org/10.1016/j.ejpb.2008.10.014
  • [28] Laohavisuti N, Boonchom B, Boonmee W, Chaiseeda K, Seesanong S. Simple recycling of biowaste eggshells to various calcium phosphates for specific industries. Scientific Reports. 2021; 11(1): 15143. https://doi.org/10.1038/s41598-021-94643-1
  • [29] Pereira A, Mallya R. Formulation and evaluation of a photoprotectant cream containing Phyllanthus emblica extract- phospholipid complex. Journal of Pharmacognosy and Phytochemistry. 2015; 4(232-240).
  • [30] Zidan AS, Spinks C, Fortunak J, Habib M, Khan MA. Near-infrared investigations of novel anti-HIV tenofovir liposomes. Aaps J. 2010; 12(2): 202-214. https://doi.org/10.1208/s12248-010-9177-1
  • [31] Toopkanloo SP, Tan TB, Abas F, Alharthi FA, Nehdi IA, Tan CP. Impact of Quercetin Encapsulation with Added Phytosterols on Bilayer Membrane and Photothermal-Alteration of Novel Mixed Soy Lecithin-Based Liposome. Nanomaterials (Basel). 2020; 10(12): https://doi.org/10.3390/nano10122432
  • [32] Abdella S, Afinjuomo F, Song Y, Upton R, Garg S. Mucoadhesive Buccal Film of Estradiol for Hormonal Replacement Therapy: Development and In-Vivo Performance Prediction. Pharmaceutics. 2022; 14(3): https://doi.org/10.3390/pharmaceutics14030542
  • [33] Seçilmiş Canbay H, Polat M, Doğantürk M. Study of Stability and Drug-Excipient Compatibility of Estriol. Bilge International Journal of Science and Technology Research. 2019; 3 https://doi.org/10.30516/bilgesci.582054
  • [34] Holtorf, K. (2009). The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy?. Postgraduate medicine, 121(1), 73-85. https://doi.org/10.3810/pgm.2009.01.1949. PMID: 19179815.
  • [35] Girgert, R., Emons, G., & Gründker, C. (2014). Inhibition of GPR30 by estriol prevents growth stimulation of triple-negative breast cancer cells by 17β-estradiol. BMC Cancer, 14, 1-12. https://doi.org/10.1186/1471-2407-14-935. PMID: 25496649; PMCID: PMC4364648.

Yıl 2023, Cilt: 27 Sayı: 5, 2190 - 2198, 28.06.2025

İsmail Aslan , Ali Fuat Aytekin

Öz

Kaynakça

  • [1] Gregoriadis G, Florence AT. Liposomes in drug delivery. Clinical, diagnostic and ophthalmic potential. Drugs. 1993; 45(1): 15-28. https://doi.org/10.2165/00003495-199345010-00003
  • [2] Allen TM, Cullis PR. Liposomal drug delivery systems: from concept to clinical applications. Adv Drug Deliv Rev. 2013; 65(1): 36-48. https://doi.org/10.1016/j.addr.2012.09.037
  • [3] Keller BC. Liposomes in nutrition. Trends in Food Science & Technology. 2001; 12(1): 25-31. https://doi.org/10.1016/S0924-2244(01)00044-9
  • [4] Maherani B, Arab-Tehrany E, Mozafari M, Gaiani C, M L. Liposomes: A Review of Manufacturing Techniques and Targeting Strategies. Current Nanoscience. 2011; 7(436-452). https://doi.org/10.2174/157341311795542453
  • [5] Akbarzadeh A, Rezaei-Sadabady R, Davaran S, Joo SW, Zarghami N, Hanifehpour Y, Samiei M, Kouhi M, Nejati-Koshki K. Liposome: classification, preparation, and applications. Nanoscale Research Letters. 2013; 8(1): 102. https://doi.org/10.1186/1556-276X-8-102
  • [6] Jesorka A, Orwar O. Liposomes: technologies and analytical applications. Annu Rev Anal Chem (Palo Alto Calif). 2008; 1(801-832). https://doi.org/10.1146/annurev.anchem.1.031207.112747
  • [7] Sharma A, Sharma US. Liposomes in drug delivery: Progress and limitations. International Journal of Pharmaceutics. 1997; 154(2): 123-140. https://doi.org/10.1016/S0378-5173(97)00135-X
  • [8] Aslan I, Kurt A, In-vitro comparison release study of novel liposome and conventional formulation containing Rosmarinus officinalis extract, 2021. https://doi.org/10.38093/cupmap.848115
  • [9] Aslan I, Kurt A. Characterization and Optimization of Phytosome Formulation Containing Alcohol-free Umckalin from Pelargonium sidoides. Current Perspectives on Medicinal and Aromatic Plants (CUPMAP). 2020; 49-53. https://doi.org/10.38093/cupmap.737878
  • [10] Laouini A, Jaafar-Maalej C, Blouza I, Sfar S, Charcosset C, Fessi H. Preparation, Characterization and Applications of Liposomes: State of the Art. Journal of Colloid Science and Biotechnology. 2012; 1(147-168). https://doi.org/10.1166/jcsb.2012.1020
  • [11] Petersen AL, Hansen AE, Gabizon A, Andresen TL. Liposome imaging agents in personalized medicine. Adv Drug Deliv Rev. 2012; 64(13): 1417-1435. https://doi.org/10.1016/j.addr.2012.09.003
  • [12] Duman G, Aslan İ, Özer AY, İnanç İ, Taralp A. Liposome, gel and lipogelosome formulations containing sodium hyaluronate. J Liposome Res. 2014; 24(4): 259-269. https://doi.org/10.3109/08982104.2014.907305
  • [13] Torchilin V. Multifunctional and stimuli-sensitive pharmaceutical nanocarriers. Eur J Pharm Biopharm. 2009; 71(3): 431-444. https://doi.org/10.1016/j.ejpb.2008.09.026
  • [14] Huang Z, Li X, Zhang T, Song Y, Zhennan S, Li J, Deng Y. Progress involving new techniques for liposome preparation. Asian Journal of Pharmaceutical Sciences. 2014; 9. https://doi.org/10.1016/j.ajps.2014.06.001
  • [15] Weissig V. Liposomes - A Practical Approach, 2nd Edition, Vladimir P. Torchilin, Volkmar Weissig (Eds), Oxford University Press, 396 pages (2003). 2003
  • [16] Jahn A, Vreeland WN, Gaitan M, Locascio LE. Controlled vesicle self-assembly in microfluidic channels with hydrodynamic focusing. J Am Chem Soc. 2004; 126(9): 2674-2675. https://doi.org/10.1021/ja0318030
  • [17] Emaminia F, Rezaei A, Badehnoosh B, Ramezani R, Shabani M. The effects of Elaeagnus angustifolia L. whole fruit on the sex hormone profile in menopausal women: A double-blind, randomized, placebo-controlled study. J Ethnopharmacol. 2020; 246(112229). https://doi.org/10.1016/j.jep.2019.112229
  • [18] Burger HG, Dudley EC, Robertson DM, Dennerstein L. Hormonal changes in the menopause transition. Recent Prog Horm Res. 2002; 57(257-275). https://doi.org/10.1210/rp.57.1.257
  • [19] Huber TJ, Rollnik J, Wilhelms J, von zur Mühlen A, Emrich HM, Schneider U. Estradiol levels in psychotic disorders. Psychoneuroendocrinology. 2001; 26(1): 27-35. https://doi.org/10.1016/s0306-4530(00)00034-2
  • [20] Shirtcliff EA, Granger DA, Schwartz EB, Curran MJ, Booth A, Overman WH. Assessing estradiol in biobehavioral studies using saliva and blood spots: simple radioimmunoassay protocols, reliability, and comparative validity. Horm Behav. 2000; 38(2): 137-147. https://doi.org/10.1006/hbeh.2000.1614
  • [21] Huidrom S, Beg MA, Masood T. Post-menopausal Osteoporosis and Probiotics. Curr Drug Targets. 2021; 22(7): 816-822. https://doi.org/10.2174/1389450121666201027124947
  • [22] Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. Bmj. 2011; 343(d6423). https://doi.org/10.1136/bmj.d6423
  • [23] Muijsers RB, Wagstaff AJ. Transdermal fentanyl: an updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control. Drugs. 2001; 61(15): 2289-2307. https://doi.org/10.2165/00003495-200161150-00014
  • [24] Peltola S, Saarinen-Savolainen P, Kiesvaara J, Suhonen TM, Urtti A. Microemulsions for topical delivery of estradiol. International Journal of Pharmaceutics. 2003; 254(2): 99-107. https://doi.org/10.1016/S0378-5173(02)00632-4
  • [25] Lachenmeier DW. Safety evaluation of topical applications of ethanol on the skin and inside the oral cavity. J Occup Med Toxicol. 2008; 3(26). https://doi.org/10.1186/1745-6673-3-26
  • [26] Maier A, Ovesen JL, Allen CL, York RG, Gadagbui BK, Kirman CR, Poet T, Quiñones-Rivera A. Safety assessment for ethanol-based topical antiseptic use by health care workers: Evaluation of developmental toxicity potential. Regul Toxicol Pharmacol. 2015; 73(1): 248-264. https://doi.org/10.1016/j.yrtph.2015.07.015
  • [27] Baert, B., Annavarapu, S., Burvenich, C., & De Spiegeleer, B. (2009). Analytical, biopharmaceutical and regulatory evaluation of topical testosterone preparations. European journal of pharmaceutics and biopharmaceutics, 72(1), 275-281. https://doi.org/10.1016/j.ejpb.2008.10.014
  • [28] Laohavisuti N, Boonchom B, Boonmee W, Chaiseeda K, Seesanong S. Simple recycling of biowaste eggshells to various calcium phosphates for specific industries. Scientific Reports. 2021; 11(1): 15143. https://doi.org/10.1038/s41598-021-94643-1
  • [29] Pereira A, Mallya R. Formulation and evaluation of a photoprotectant cream containing Phyllanthus emblica extract- phospholipid complex. Journal of Pharmacognosy and Phytochemistry. 2015; 4(232-240).
  • [30] Zidan AS, Spinks C, Fortunak J, Habib M, Khan MA. Near-infrared investigations of novel anti-HIV tenofovir liposomes. Aaps J. 2010; 12(2): 202-214. https://doi.org/10.1208/s12248-010-9177-1
  • [31] Toopkanloo SP, Tan TB, Abas F, Alharthi FA, Nehdi IA, Tan CP. Impact of Quercetin Encapsulation with Added Phytosterols on Bilayer Membrane and Photothermal-Alteration of Novel Mixed Soy Lecithin-Based Liposome. Nanomaterials (Basel). 2020; 10(12): https://doi.org/10.3390/nano10122432
  • [32] Abdella S, Afinjuomo F, Song Y, Upton R, Garg S. Mucoadhesive Buccal Film of Estradiol for Hormonal Replacement Therapy: Development and In-Vivo Performance Prediction. Pharmaceutics. 2022; 14(3): https://doi.org/10.3390/pharmaceutics14030542
  • [33] Seçilmiş Canbay H, Polat M, Doğantürk M. Study of Stability and Drug-Excipient Compatibility of Estriol. Bilge International Journal of Science and Technology Research. 2019; 3 https://doi.org/10.30516/bilgesci.582054
  • [34] Holtorf, K. (2009). The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy?. Postgraduate medicine, 121(1), 73-85. https://doi.org/10.3810/pgm.2009.01.1949. PMID: 19179815.
  • [35] Girgert, R., Emons, G., & Gründker, C. (2014). Inhibition of GPR30 by estriol prevents growth stimulation of triple-negative breast cancer cells by 17β-estradiol. BMC Cancer, 14, 1-12. https://doi.org/10.1186/1471-2407-14-935. PMID: 25496649; PMCID: PMC4364648.
Toplam 35 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular İlaç Dağıtım Teknolojileri
Bölüm Articles
Yazarlar

İsmail Aslan 0000-0001-7075-7103

Ali Fuat Aytekin 0009-0007-5143-4270

Yayımlanma Tarihi 28 Haziran 2025
Yayımlandığı Sayı Yıl 2023 Cilt: 27 Sayı: 5

Kaynak Göster

APA Aslan, İ., & Aytekin, A. F. (2025). Production and characterization of newly developed alcohol-free topical liposome-gel transdermal drug delivery systems containing estradiol (E2)/ estriol (E3) for post-menopausal women. Journal of Research in Pharmacy, 27(5), 2190-2198.
AMA Aslan İ, Aytekin AF. Production and characterization of newly developed alcohol-free topical liposome-gel transdermal drug delivery systems containing estradiol (E2)/ estriol (E3) for post-menopausal women. J. Res. Pharm. Temmuz 2025;27(5):2190-2198.
Chicago Aslan, İsmail, ve Ali Fuat Aytekin. “Production and Characterization of Newly Developed Alcohol-Free Topical Liposome-Gel Transdermal Drug Delivery Systems Containing Estradiol (E2)/ Estriol (E3) for Post-Menopausal Women”. Journal of Research in Pharmacy 27, sy. 5 (Temmuz 2025): 2190-98.
EndNote Aslan İ, Aytekin AF (01 Temmuz 2025) Production and characterization of newly developed alcohol-free topical liposome-gel transdermal drug delivery systems containing estradiol (E2)/ estriol (E3) for post-menopausal women. Journal of Research in Pharmacy 27 5 2190–2198.
IEEE İ. Aslan ve A. F. Aytekin, “Production and characterization of newly developed alcohol-free topical liposome-gel transdermal drug delivery systems containing estradiol (E2)/ estriol (E3) for post-menopausal women”, J. Res. Pharm., c. 27, sy. 5, ss. 2190–2198, 2025.
ISNAD Aslan, İsmail - Aytekin, Ali Fuat. “Production and Characterization of Newly Developed Alcohol-Free Topical Liposome-Gel Transdermal Drug Delivery Systems Containing Estradiol (E2)/ Estriol (E3) for Post-Menopausal Women”. Journal of Research in Pharmacy 27/5 (Temmuz 2025), 2190-2198.
JAMA Aslan İ, Aytekin AF. Production and characterization of newly developed alcohol-free topical liposome-gel transdermal drug delivery systems containing estradiol (E2)/ estriol (E3) for post-menopausal women. J. Res. Pharm. 2025;27:2190–2198.
MLA Aslan, İsmail ve Ali Fuat Aytekin. “Production and Characterization of Newly Developed Alcohol-Free Topical Liposome-Gel Transdermal Drug Delivery Systems Containing Estradiol (E2)/ Estriol (E3) for Post-Menopausal Women”. Journal of Research in Pharmacy, c. 27, sy. 5, 2025, ss. 2190-8.
Vancouver Aslan İ, Aytekin AF. Production and characterization of newly developed alcohol-free topical liposome-gel transdermal drug delivery systems containing estradiol (E2)/ estriol (E3) for post-menopausal women. J. Res. Pharm. 2025;27(5):2190-8.