METFORMIN HCl CONTROLLED RELEASE MICROPARTICLES: DoE- BASED FORMULATION DEVELOPMENT AND IN-VIVO PROOF OF CONCEPT STUDY
Keywords:
controlled drug delivery system, microparticles, Optimization
Abstract
Conventional drug delivery systems deal with side effects caused by fluctuating plasma levels. However, controlled drug delivery systems face another challenge since big dosing results in voluminous dosage forms. The drug delivery system is only suitable for some patients. A sustained-release drug delivery system in microparticles is proposed to conquer the problems. This research proposed to develop and optimize sustained-release microparticles consisting of metformin HCl as a drug model and a mixture of Eudragit RS and Kollidon SR as a polymeric matrix using a Box-Behnken design. The evaluation was conducted regarding drug loading, entrapment efficiency, and particle size to determine the optimal formulation. Metformin HCl concentration and drug-polymer ratio were dominant increased particle size, drug loading, entrapment efficiency, and particle size distribution. Particle size testing showed that the optimized formulation had a microparticle size of 1.363 ± 0.03 µm with a particle size distribution of 1.131 ± 0.028. In vitro evaluation showed that the release of metformin HCl microparticles followed Weibull kinetics within 24 hours. In contrast, in vivo evaluation confirmed the ability of microparticles to control blood glucose levels in mice for up to 24 hours with a 59% reduction. The microparticle effectively controlled drug release and reduced blood glucose levels in the rats.
References
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Ainurofiq, A., & Choiri, S. (2018). Development and Optimization of a Meloxicam/β-Cyclodextrin Complex for Orally Disintegrating Tablet using Statistical Analysis. Pharmaceutical Development and Technology, 23(5), 464–475. https://doi.org/10.1080/10837450.2016.1264418
Ainurofiq, A., Hidayat, Y., Lestari, E. Y. P., Kumalasari, M. M. W., & Choiri, S. (2022). Resveratrol Nanocrystal Incorporated into Mesoporous Material: Rational Design and Screening through Quality-by-Design Approach. Nanomaterials, 12(2). https://doi.org/10.3390/nano12020214
Alipour, S., Montaseri, H., & Tafaghodi, M. (2010). Preparation and Characterization of Biodegradable Paclitaxel loaded Alginate Microparticles for Pulmonary Delivery. Colloids and Surfaces B: Biointerfaces, 81(2), 521–529. https://doi.org/10.1016/j.colsurfb.2010.07.050
Baryakova, T. H., Pogostin, B. H., Langer, R., & McHugh, K. J. (2023). Overcoming Barriers to Patient Adherence: The Case for Developing Innovative Drug Delivery Systems. Nature Reviews Drug Discovery, 22(5), 387–409. https://doi.org/10.1038/s41573-023-00670-0
Bouriche, S., Cózar-Bernal, M. J., Rezgui, F., Rabasco Álvarez, A. M., & González-Rodríguez, M. L. (2019). Optimization of Preparation Method by W/O/W Emulsion for Entrapping Metformin Hydrochloride into Poly (lactic acid) Microparticles using Box-Behnken design. Journal of Drug Delivery Science and Technology, 51(September 2018), 419–429. https://doi.org/10.1016/j.jddst.2019.03.011
Choiri, S., Sulaiman, T. N. S., & Rohman, A. (2019). Characterization of Eudragit Types and Kollidon SR Inter-polymer Complexes and Their Effects on the Drug Release. Journal of Applied Pharmaceutical Science, 9(7), 058–068. https://doi.org/10.7324/JAPS.2019.90708
Daniel, A. I., Gara, T. Y., Ibrahim, Y. O., Muhammad, F. M., Salisu, F. E., & Tsado, R. (2022). In Vivo Antidiabetic and Antioxidant Activities of Chloroform Fraction of Nelsonia canescens Leaf in Alloxan-induced Diabetic Rats. Pharmacological Research - Modern Chinese Medicine, 3(2021), 100106. https://doi.org/10.1016/j.prmcm.2022.100106
De, A., Kuppuswamy, G., & Jaiswal, A. (2019). Implementation of Two Different Experimental Designs for Screening and Optimization of Process Parameters for Metformin-loaded Carboxymethyl Chitosan Formulation. Drug Development and Industrial Pharmacy, 45(11), 1821–1834. https://doi.org/10.1080/03639045.2019.1665060
Dhakar, R. C. (2012). From Formulation Variables To Drug Entrapment Efficiency of Microspheres: a Technical Review. Journal of Drug Delivery and Therapeutics, 2(6), 128–133. https://doi.org/10.22270/jddt.v2i6.160
Djukaj, S., Kolář, J., Lehocký, R., Zadražil, A., & Štěpánek, F. (2022). Design of Particle Size Distribution for Custom Dissolution Profiles by Solving the Inverse Problem. Powder Technology, 395, 743–757. https://doi.org/10.1016/j.powtec.2021.10.023
Dora, C. P., Singh, S. K., Kumar, S., Datusalia, A. K., & Deep, A. (2010). Development and Characterization of Nanoparticles of Glibenclamide by Solvent Displacement Method. Acta Poloniae Pharmaceutica - Drug Research, 67(3), 283–290.
Ekenna, I. C., & Abali, S. O. (2022). Comparison of the Use of Kinetic Model Plots and DD Solver Software to Evaluate the Drug Release from Griseofulvin Tablets. Journal of Drug Delivery and Therapeutics, 12(2-S), 5–13. https://doi.org/10.22270/jddt.v12i2-s.5402
Elkateb, H., Cauldbeck, H., Niezabitowska, E., Hogarth, C., Arnold, K., Rannard, S., & McDonald, T. O. (2023). High Drug Loading Solid Lipid Nanoparticles, Nanostructured Lipid Carriers and Nanoemulsions for the Dual Drug Delivery of the HIV Drugs Darunavir and Ritonavir. JCIS Open, 11(May), 100087. https://doi.org/10.1016/j.jciso.2023.100087
Giridhar Reddy, S., & Thakur, A. (2019). Drug Entrapment Efficiency of Silver Nanocomposite Hydrogel. IOP Conference Series: Materials Science and Engineering, 577(1). https://doi.org/10.1088/1757-899X/577/1/012176
Gracia-Vásquez, S. L., González-Barranco, P., Camacho-Mora, I. A., González-Santiago, O., & Vázquez-Rodríguez, S. A. (2017). Medications That Should Not Be Crushed. Medicina Universitaria, 19(75), 50–63. https://doi.org/10.1016/j.rmu.2017.03.001
Haramkar, S. S., Thombre, G. N., Jadhav, S. V., & Thorat, B. N. (2021). The Influence of Particle(s) Size, Shape and Distribution on Cake Filtration Mechanics-A Short Review. Comptes Rendus Chimie, 24(2), 255–265. https://doi.org/10.5802/CRCHIM.84
Öztürk, A. A., Yenilmez, E., Arslan, R., Şenel, B., & Yazan, Y. (2017). Dexketoprofen Trometamol-loaded Kollidon® SR and Eudragit® RS 100 Polymeric Nanoparticles: Formulation and In Vitro-In Vivo Evaluation. Latin American Journal of Pharmacy, 36(11), 2153–2165.
Park, H., Otte, A., & Park, K. (2022). Evolution of Drug Delivery Systems: From 1950 to 2020 and Beyond. Journal of Controlled Release, 342(December 2021), 53–65. https://doi.org/10.1016/j.jconrel.2021.12.030
Sarwar, M. S., & Hossain, M. S. (2012). Development and Evaluation of Sustained Release Losartan Potassium Matrix Tablet using Kollidon SR as Release Retardant. Brazilian Journal of Pharmaceutical Sciences, 48(4), 621–628. https://doi.org/10.1590/S1984-82502012000400005
Singh, P., Shrivastava, A. K., Kumar, S., & Dwivedi, M. D. (2021). Formulation and Evaluation of Sustained Release Matrix Tablets of Aceclofenac. Borneo Journal of Pharmacy, 4(2), 99–109. https://doi.org/10.33084/bjop.v4i2.1854
Steyerberg, E. W., Vickers, A. J., Cook, N. R., Gerds, T., Gonen, M., Obuchowski, N., Pencina, M. J., & Kattan, M. W. (2010). Assessing the Performance of Prediction Models A Framework for Traditional and Novel Measures. Epidemiology, 21(1), 128–138. https://doi.org/10.1097/EDE.0b013e3181c30fb2
Sung, Y. K., & Kim, S. W. (2020). Recent Advances in Polymeric Drug Delivery Systems. Biomaterials Research, 24(12), 1–12.
Thong, M. Y., Manrique, Y. J., & Steadman, K. J. (2018). Drug Loss while Crushing Tablets: Comparison of 24 Tablet Crushing Devices. PLoS ONE, 13(3), 5–7. https://doi.org/10.1371/journal.pone.0193683
Vo, A., Feng, X., Patel, D., Mohammad, A., Kozak, D., Choi, S., Ashraf, M., & Xu, X. (2020). Factors Affecting the Particle Size Distribution and Rheology of Brinzolamide Ophthalmic Suspensions. International Journal of Pharmaceutics, 586(April), 119495. https://doi.org/10.1016/j.ijpharm.2020.119495
Wolska, E., & Szymańska, M. (2023). Comparison of the In Vitro Drug Release Methods for the Selection of Test Conditions to Characterize Solid Lipid Microparticles. Pharmaceutics, 15(2). https://doi.org/10.3390/pharmaceutics15020511
Yoo, J., & Won, Y. Y. (2020). Phenomenology of the Initial Burst Release of Drugs from PLGA Microparticles. ACS Biomaterials Science and Engineering, 6(11), 6053–6062. https://doi.org/10.1021/acsbiomaterials.0c01228
Zoubari, G., Ali, R., & Dashevskiy, A. (2019). Water-insoluble polymers as binders for pellet drug layering: Effect on drug release and performance upon compression. International Journal of Pharmaceutics, 569(May), 118520. https://doi.org/10.1016/j.ijpharm.2019.118520
Zuo, J., Gao, Y., Bou-Chacra, N., & Löbenberg, R. (2014). Evaluation of the DDSolver software applications. BioMed Research International, 2014. https://doi.org/10.1155/2014/204925
Published
2025-04-08
How to Cite
Choiri, S., Fursanah, H., Ramadhani, J. S., Isnaini, I. R. M., Afidah, Z. A. N., & Amanah, J. C. (2025). METFORMIN HCl CONTROLLED RELEASE MICROPARTICLES: DoE- BASED FORMULATION DEVELOPMENT AND IN-VIVO PROOF OF CONCEPT STUDY. Indonesian Journal of Pharmacy. https://doi.org/10.22146/ijp.10287
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Research Article
