Intravaginal administration of metformin HCL loaded nanoemulgel for treatment of PCOS: in-vitro and in-vivo study
DOI:
https://doi.org/10.1590/s2175-97902026e24725Palavras-chave:
Metformin hydrochloride, Nanoemulsion gel, In-vitro release, In-vivo study, Intravaginal delivery, Polycystic ovary syndrome (PCOS)Resumo
Metformin HCL (MET-HCL), is a Biguanide derivative, most effective agent in treatment of PCOS. The focus of the present study was on developing and optimizing a nanoemulsion formulation. of MET-HCL and convert into intravaginal MET-HCL Nanoemulsion Gel (MET-HCLNE GEL) To enhance the therapeutic efficacy in managing PCOS. The nanoemulsion was formulated using water titration method and evaluated for droplet size, zeta potential, polydispersity index (PDI), drug content, viscosity, and morphology. Then incorporated into gel and evaluated for pH, drug content, viscosity, in-vitro release & in-vivo study. The formulation MET-HCLNE 1 showed the desired droplet size (45.60 ± 1.7 nm), PDI (0.198 ± 0.2), zeta potential (22.4 ± 0.3), drug content (89.19 ± 0.2 %) and viscosity (42.85 ± 2.1 cp). In in-vitro release, MET-HCLNEGEL showed significant prolonged release over MET-HCL solution. Intravaginal MET-HCLNE GEL showed significant efficiency against PCOS compared to oral administration in female Wistar rats. No significant changes were found in the values of viscosity, drug content and pH over the period of 120 days. Thus, MET-HCLNE GEL was found to have good potential to function as an Intravaginal formulation & having great PCOS activity and good storage stability.
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Al-Suwayeh SA, Badran MM, Alhumoud GO, Taha EI, Ashri LY, Kazi M. Design and dermatokinetic appraisal of lornoxicam-loaded ultrafine self-nanoemulsion hydrogel for the management of inflammation: In vitro and in vivo studies. Saudi Pharm J. 2023 Jun 1;31(6):889-903.
Anjali CH, Sharma Y, Mukherjee A, Chandrasekaran N. Neem oil (Azadirachta indica) nanoemulsion—a potent larvicidal agent against Culex quinquefasciatus. Pest Manage Sci. 2012 Feb;68(2):158-63.
Balpande HM, Raut NS, Umekar MJ, Kotagale NR. Compatibility study of metformin with pharmaceutical excipients. Int J Chem Tech Res. 2013;5(1684): e1693.
Bassi P, Kaur G. Innovations in bio adhesive vaginal drug delivery system. Expert Opinion on Therapeutic Patents. 2012 Sep 1;22(9):1019-32.
Chellapa P, Eid AM, Elmarzugi NA. Preparation and characterization of virgin coconut oil nanoemulgel. J Chem Pharm Res. 2015;7(9):787-93.
Cook MT, Brown MB. Polymeric gels for intravaginal drug delivery. J Controlled Release. 2018 Jan 28;270:145-57.
De Lima JA, Paines TC, Motta MH, Weber WB, Dos Santos SS, Cruz L, da Silva CD. Novel Pemulen/Pullulan blended hydrogel containing clotrimazole-loaded cationic nanocapsules: Evaluation of mucoadhesion and vaginal permeation. J Controlled Release: C. 2017 Oct 1;79:886-93.
Deore SK, Surawase RK, Maru A. Formulation and evaluation of o/w nanoemulsion of ketoconazole. Res J Pharm Dosage Forms Technol. 2019;11(4):269-4.
Divyashree S, Janhavi P, Ravindra PV, Muthukumar SP. Experimental models of polycystic ovary syndrome: An update. Life sciences. 2019 Nov 15;237:116911.
Diwedi R, Alexandar A, Chandrasekar MJ. Preparation and in vitro evaluation of sustained release tablet formulations of metformin HCL. Asian J Pharm Clin Res. 2012;5(1):45-8.
Ghosh V, Mukherjee A, Chandrasekaran N. Ultrasonic emulsification of food-grade nanoemulsion formulation and evaluation of its bactericidal activity. Ultrasonics Sonochem. 2013 Jan;20(1):338-44.
Gundogdu N, Cetin M. Chitosan-poly (lactide-co-glycolide) (CS-PLGA) nanoparticles containing metformin HCl: Preparation and in vitro evaluation. Pak J Pharm Sci. 2014 Nov;27(6):1923-9.
Gupta SK. Formulation and evaluation of nanoemulsion based nanoemulgel of aceclofenac. J Pharm Sci Res. 2020 Apr 1;12(4):524-32.
Heidarpour M, Mojarad M, Mazaheri-Tehrani S, Kachuei A, Najimi A, Shafie D, Rezvanian H. Comparative Effectiveness of Antidiabetic Drugs as an Additional Therapy to Metformin in Women with Polycystic Ovary Syndrome: A Systematic Review of Metabolic Approaches. Int J Endocrinol. 2024;2024(1):9900213.
Jhawat V, Gulia M, Sharma AK. Pseudo ternary phase diagrams used in emulsion preparation. Chemoinf Bioinf Pharm Sci. 2021 Jan 1 (pp. 455-481). Academic Press.
Kawarkhe S, Poddar SS. Designing of the mucoadhesive intravaginal spermicidal films. Indian J Pharm Sci. 2010 Sep;72(5):652.
Khan RU, Shah SU, Rashid SA, Naseem F, Shah KU, Farid A, et al. Lornoxicam-loaded chitosan-decorated nanoemulsion: preparation and in vitro evaluation for enhanced transdermal delivery. Polymers. 2022 May 9;14(9):1922.
Kumar M, Pathak K, Misra A. Formulation and characterization of nanoemulsion-based drug delivery system of risperidone. Drug Dev Ind Pharm. 2009 Apr 1;35(4):387-95.
Larik MO, Ahmed A, Khan L, Iftekhar MA. Effects of resveratrol on polycystic ovarian syndrome: a systematic review and meta-analysis of randomized controlled trials. Endocrine. 2024 Jan;83(1):51-9.
Machado RM, Palmeira-De-Oliveira A, Martinez-De-Oliveira J, Palmeira-De-Oliveira R. Vaginal films for drug delivery. J Pharm Sci. 2013 Jul 1;102(7):2069-81.
Moghimipour E, Salimi A, Leis F. Preparation and evaluation of tretinoin microemulsion based on pseudo-ternary phase diagram. Adv Pharm Bull. 2012 Dec;2(2):141.
Mallipeddi R, Rohan LC. Nanoparticle-based vaginal drug delivery systems for HIV prevention. Expert Opinion Drug Delivery. 2010 Jan 1;7(1):37-48.
Matanović MR, Kristl J, Grabnar PA. Thermoresponsive polymers: Insights into decisive hydrogel characteristics, mechanisms of gelation, and promising biomedical applications. Int J Pharm. 2014 Sep 10;472(1-2):262-75.
Nasr A, Gardouh A, Ghorab M. Novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for oral delivery of olmesartan medoxomil: design, formulation, pharmacokinetic and bioavailability evaluation. Pharmaceutics. 2016 Jun 27;8(3):20.
Nilsuwan K, Benjakul S, Prodpran T. Emulsion stability and properties of fish gelatin-based films as affected by palm oil and surfactants. J Sci Food Agric. 2016 May;96(7):2504-13.
Paarakh MP, Jose PA, Setty CM, Peterchristoper GV. Release kinetics–concepts and applications. Int J Pharm Res Technol (IJPRT). 2018;8(1):12-20.
Patel RP, Joshi JR. An overview on nanoemulsion: a novel approach. Int J Parm Sci Res. 2012 Dec 1;3(12):4640.
Pathan IB, Setty CM. Stability evaluation of tamoxifen citrate nanoemulsion containing Cremophor RH 40 as surfactant. ACTA Pharm Sci. 2011;53(1).
Peng Q, Chen X, Liang X, Ouyang J, Wang Q, Ren S, et al. Metformin improves polycystic ovary syndrome in mice by inhibiting ovarian ferroptosis. Front Endocrinol. 2023 Jan 23;14:1070264.
Prajapati DP, Patel M, Dharamsi A. Beneficial effect of polyherbal formulation in letrozole induced polycystic ovarian syndrome (PCOS). J Tradit Complementary Med. 2022 Nov 1;12(6):575-83.
Saini N, Sodhi RK, Bajaj L, Pandey RS, Jain UK, Katare OP, Madan J. Intravaginal administration of metformin hydrochloride loaded cationic niosomes amalgamated with thermosensitive gel for the treatment of polycystic ovary syndrome: In vitro and in vivo studies. Colloids Surf B. 2016 Aug 1;144:161-9.
Shaikh NM, Swamy SV, NARSING NS, Kulkarni KB. Formulation and evaluation of nanoemulsion for topical application. J Drug Delivery Ther. 2019 Aug 15;9(4-s):370-5.
Shapiro RL, DeLong K, Zulfiqar F, Carter D, Better M, Ensign LM. In vitro and ex vivo models for evaluating vaginal drug delivery systems. Adv Drug Delivery Rev. 2022 Dec 1;191:114543.
Shukat R, Bourgaux C, Relkin P. Crystallisation behaviour of palm oil nanoemulsions carrying vitamin E: DSC and synchrotron X-ray scattering studies. J Thermal Analysis Calorimetry. 2012 Apr 1;108(1):153-61.
Siavash M, Tabbakhian M, Sabzghabaee AM, Razavi N. Severity of gastrointestinal side effects of metformin tablet compared to metformin capsule in type 2 diabetes mellitus patients. J Research Pharm Pract. 2017 Apr 1;6(2):73-6.
Smoleński M, Karolewicz B, Gołkowska AM, Nartowski KP, Małolepsza-Jarmołowska K. Emulsion-based multicompartment vaginal drug carriers: from nanoemulsions to nanoemulgels. International J Mol Sci. 2021 Jun 16;22(12):6455.
Sreelakshmi C, Sivakumar R, Giridas S, Fathima R, Vijaykumar B. In situ gel of Nifedipine: an approach for extended release with Zero order kinetics. Res J Pharm Technol. 2018;11(4):1293-7.
Srikrishna S, Cardozo L. The vagina as a route for drug delivery: a review. Int Urogynecol J. 2013 Apr;24:537-43.
Stoica RA, Ştefan DS, Rizzo M, Suceveanu AI, Suceveanu AP, Serafinceanu C, Pantea-Stoian A. Metformin indications, dosage, adverse reactions, and contraindications. In Metformin 2019 Aug 28. London, UK: IntechOpen.
Tang B, Tan T, Huang Y, Zhang M, Li M, Lei X, Nong W. A bibliometric analysis of global research trends in polycystic ovary syndrome and metformin. Clin Exp Obstet Gynecol. 2024 Mar 27;51(4):86.
Valamla B, Thakor P, Phuse R, Dalvi M, Kharat P, Kumar A, et al. Engineering drug delivery systems to overcome the vaginal mucosal barrier: Current understanding and research agenda of mucoadhesive formulations of vaginal delivery. J Drug Delivery Sci Technol. 2022 Apr 1;70:103162.
Yakubu MT, Olawepo FJ, Olayaki LA, Ibrahim OO. Mifepristone (RU486) induces polycystic ovarian syndrome in female Wistar rats with features analogous to humans. J Endocrinol Reprod. 2015;19(1):40-51.
Zhao B, Li Z, He Z, Zhou X, Yu Y, Ren K, Yan P. Metformin and Lactic Acidosis in Diabetic Patients. J Endocrinol Res. 2021 Apr 2;3(1):21-6.
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