Oral pioglitazone HCl-loaded solid lipid microparticles: Formulation design and bioactivity studies

Mona Hassan Rafiee Bazigha K. Abdul Rasool Mohamed Haider Hanan S. Anbar   

Open Access   

Published:  Nov 16, 2022

DOI: 10.7324/JAPS.2023.130218

Pioglitazone hydrochloride (PGZ) is a hypoglycemic drug used to treat type 2 diabetes with a short biological half-life and poor oral absorption. The current study was conducted to prepare oral PGZ-loaded lipid microparticles (PGZ-LMPs) for improving PGZ’s solubility and oral bioavailability and maintaining its sustained release. The Design-Expert program was employed to design and analyze various PGZ-LMP formulations. The microparticles were prepared by the solvent injection technique using cetyl alcohol and surfactants. The developed formulations were characterized in vitro for particle size, loading efficiency, and PGZ release. The DDSolver software was employed to investigate the mechanism of the drug release and the appropriate kinetic model for describing PGZ release from LMPs. The optimized formulation was characterized using FT-IR spectroscopy, scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) and was subjected to an in vivo preclinical study to evaluate and confirm its antidiabetic activity. The optimized formula had a mean particle size of 4.73 ± 0.06 nm and a smooth, spherical structure. PGZ-LMPs exhibited excellent homogeneity with a PDI of 0.27 ± 0.06 and showed a high EE% of 71.3% ± 1.293. The FT-IR and DSC analyses confirmed that PGZ was encapsulated in the LMPs and there was no interaction between the excipients and PGZ. PGZ was perceived to be released from the optimized formulation after 8 hours (Q8 = 70.53 ± 0.503). By comparing the Makoid–Banakar equation to other models (R2 = 0.9666) by DDSolver, it proved to be the best model for fitting and describing PGZ release from LMPs (p < 0.05). Finally, the in vivo study on diabetic albino Wistar rats confirmed that the optimized PGZ-LMP formulation resulted in higher therapeutic effectiveness and a prolonged duration of action than the marketed product and control groups.

Keyword:     Bioavailability cetyl alcohol DDSolver Design-Expert diabetes in vitro release microparticles pioglitazone solid lipid


Rafiee MH, Abdul Rasool BK, Haider M, Anbar HS. Oral pioglitazone HCl-loaded solid lipid microparticles: Formulation design and bioactivity studies. J Appl Pharm Sci, 2022. https://doi.org/10.7324/JAPS.2023.130218

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

HTML Full Text


Abdul Rasool BK, Azeez O S, Lootah HA, Abusharbain IM, Abu-Alhaj HA, Nessa, F. Extended-release niosomal hydrogel for ocular targeting of piroxicam: in vitro and ex vivo evaluation. J Pharm Res Int, 2014; 4(21):2494-510; doi.org/10.9734/BJPR/2014/13723 https://doi.org/10.9734/BJPR/2014/13723

Abdul Rasool BK, Khalifa A, Abu-Gharbieh E, Khan R. Employment of alginate gastroretentive floating in situ gel for controlled delivery of celecoxib: solubilization and formulation studies. Biomed Res Int, 2020; 2020. doi: 10.1155/2020/1879125 https://doi.org/10.1155/2020/1879125

Abdul Rasool BK, Mohammed AA, Salem YY. The optimization of a dimenhydrinate transdermal patch formulation is based on the quantitative analysis of in vitro release data by DDSolver through skin penetration studies. Sci Pharm, 2021; 89:33; doi.org/10.3390/ scipharm89030033 https://doi.org/10.3390/scipharm89030033

Al Shuwaili AH, Abdul Rasool BK, Abdulrasool AA. Optimization of elastic transfersomes formulations for transdermal delivery of pentoxifylline. Eur J Pharm Biopharm, 2016; 102:101-14. doi: 10.1016/j. ejpb.2016.02.013 https://doi.org/10.1016/j.ejpb.2016.02.013

Bartos C, Varga P, Szabó-Révész P, Ambrus R. Physico-chemical and in vitro characterization of chitosan-based microspheres intended for nasal administration. Pharmaceutics. 2021;13(5):608; doi: 10.3390/ pharmaceutics13050608 https://doi.org/10.3390/pharmaceutics13050608

Behbahani ES, Ghaedi M, Abbaspour M, Rostamizadeh K. Optimization and characterization of ultrasound assisted preparation of curcumin-loaded solid lipid nanoparticles: application of central composite design, thermal analysis and X-ray diffraction techniques. Ultrason Sonochem, 2017; 38:271-80; doi: 10.1016/j.ultsonch.2017.03.013 https://doi.org/10.1016/j.ultsonch.2017.03.013

Bhosale UM, Galgatte UC, Chaudhari PD. Development of pioglitazone hydrochloride lipospheres by melt dispersion technique: optimization and evaluation. J App Pharm Sci, 2016; 6(1):107-17; doi: 10.7324/JAPS.2016.600118 https://doi.org/10.7324/JAPS.2016.600118

Boni FI, Cury BSF, Ferreira NN, Gremião MPD. Ionic cross-linking as a strategy to modulate the properties of oral mucoadhesive microparticles based on polysaccharide blends. Pharmaceutics, 2021; 13(3):407; doi: 10.3390/pharmaceutics13030407 https://doi.org/10.3390/pharmaceutics13030407

Chaudhury A, Duvoor C, Reddy Dendi VS, Kraleti S, Chada A, Ravilla R, Marco A, Shekhawat NS, Montales MT, Kuriakose K, Sasapu A, Beebe A, Patil N, Musham CK, Lohani GP, Mirza W. Clinical review of antidiabetic drugs: implications for type 2 diabetes mellitus management. Front Endocrinol (Lausanne), 2017; 8:6; doi: 10.3389/fendo.2017.00006 https://doi.org/10.3389/fendo.2017.00006

Chen W, Palazzo A, Hennink WE, Kok RJ. Effect of particle size on drug loading and release kinetics of gefitinib-loaded PLGA microspheres. Mol Pharm, 2017; 14:459-67; doi.org/10.1021/acs.molpharmaceut.6b00896 https://doi.org/10.1021/acs.molpharmaceut.6b00896

Elbary AA, Kassem MA, Abou Samra MM, Khalil RM. Formulation and hypoglycemic activity of pioglitazone-cyclodextrin inclusion complexes. Drug Discov Ther, 2008; 2(2):94-107.

Gupta NV, Gowda DV, Balamuralidhara V, Khan MS. Preparation and comparative bioavailability studies of indomethacin-loaded cetyl alcohol microspheres. J Pharm (Cairo), 2013; 2013:109837; doi: 10.1155/2013/109837 https://doi.org/10.1155/2013/109837

Haider M, Abdin SM, Kamal L, Orive G. Nanostructured lipid carriers for delivery of chemotherapeutics: a review. Pharmaceutics, 2020a; 12(3):288; doi: 10.3390/pharmaceutics12030288 https://doi.org/10.3390/pharmaceutics12030288

Haider M, Elsayed I, Ahmed IS, Fares AR. In situ-forming microparticles for controlled release of rivastigmine: in vitro optimization and in vivo evaluation. Pharmaceuticals (Basel), 2021; 14(1):66; doi: 10.3390/ph14010066 https://doi.org/10.3390/ph14010066

Haider M, Elsherbeny A, Jagal J, Hubatová-Vacková A, Saad Ahmed I. Optimization and evaluation of poly(lactide-co-glycolide) nanoparticles for enhanced cellular uptake and efficacy of paclitaxel in the treatment of head and neck cancer. Pharmaceutics, 2020b; 12(9):828; doi: 10.3390/pharmaceutics12090828 https://doi.org/10.3390/pharmaceutics12090828

Housaindokht MR, Nakhaei PA. Study the effect of HLB of surfactant on the particle size distribution of hematite nanoparticles prepared via the reverse microemulsion. Solid State Sci, 2012; 14(5):622-5; doi: 10.1016/j.solidstatesciences.2012.01.016 https://doi.org/10.1016/j.solidstatesciences.2012.01.016

Hyma P, Abbulu K. Formulation and characterization of self-microemulsifying drug delivery system of pioglitazone. Biomed Prev Nutr, 2013; 3(4):345-50; doi: 10.1016/j.bionut.2013.09.005 https://doi.org/10.1016/j.bionut.2013.09.005

Kamel R, El-batanony R, Salama A. Pioglitazone-loaded three-dimensional composite polymeric scaffolds: a proof of concept study in wounded diabetic rats. Int J Pharm, 2019; 570:118667; doi: 10.1016/j. ijpharm.2019.118667 https://doi.org/10.1016/j.ijpharm.2019.118667

Kapoor G, Pathak DP, Bhutani R, Husain A, Jain S, Iqbal MA. Synthesis, ADME, docking studies and in vivo anti-hyperglycaemic potential estimation of novel Schiff base derivatives from octadec-9-enoic acid. Bioorg Chem, 2019; 84:478-92. doi: 10.1016/j.bioorg.2018.12.004 https://doi.org/10.1016/j.bioorg.2018.12.004

Khalifa AM, Abdul Rasool BK. Optimized mucoadhesive coated niosomes as a sustained oral delivery system of famotidine. AAPS PharmSciTech, 2017; 18(8):3064-75; doi: 10.1208/s12249-017-0780-7 https://doi.org/10.1208/s12249-017-0780-7

Khamanga SM, Walker RB. In vitro dissolution kinetics of captopril from microspheres manufactured by solvent evaporation. Dissolution Technol, 2012; 19:42-51. https://doi.org/10.14227/DT190112P42

Li W, Zhang L, Ge X, Xu B, Zhang W, Qu L, Choi CH, Xu J, Zhang A, Lee H, Weitz DA. Microfluidic fabrication of microparticles for biomedical applications. Chem Soc Rev, 2018; 47(15):5646-83; doi: 10.1039/c7cs00263g https://doi.org/10.1039/C7CS00263G

Oliveira PM, Matos BN, Pereira PAT, Gratieri T, Faccioli LH, Cunha-Filho MSS, Gelfuso GM. Microparticles prepared with 50-190kDa chitosan as promising non-toxic carriers for pulmonary delivery of isoniazid. Carbohydr Polym, 2017; 174:421-31; doi: 10.1016/j.carbpol.2017.06.090 https://doi.org/10.1016/j.carbpol.2017.06.090

Prasad PS, Imam SS, Aqil M, Sultana Y, Ali A. QbD-based carbopol transgel formulation: characterization, pharmacokinetic assessment and therapeutic efficacy in diabetes. Drug Deliv, 2016; 23(3):1057-66; doi: 10.3109/10717544.2014.936536 https://doi.org/10.3109/10717544.2014.936536

Qian C, McClements DJ. Formation of nanoemulsions stabilized by model food-grade emulsifiers using high-pressure homogenization: factors affecting particle size. Food Hydrocoll, 2011; 25:1000-8; doi: 10.1016/j.foodhyd.2010.09.017 https://doi.org/10.1016/j.foodhyd.2010.09.017

Rafiee MH, Abdul Rasool BK. An overview of microparticulate drug delivery system and its extensive therapeutic applications in diabetes. Adv Pharm Bull, 202212(4):730-46; doi: 10.34172/apb.2022.075 https://doi.org/10.34172/apb.2022.075

Rahman Z, Zidan AS, Habib MJ, Khan MA. Understanding the quality of protein-loaded PLGA nanoparticles variability by Plackett- Burman design. Int J Pharm, 2010; 389(1-2):186-94; doi: 10.1016/j. ijpharm.2009.12.040 https://doi.org/10.1016/j.ijpharm.2009.12.040

Scalia S, Young PM, Traini D. Solid lipid microparticles as an approach to drug delivery. Expert Opin Drug Deliv, 2015; 12(4):583-99; doi: 10.1517/17425247.2015.980812 https://doi.org/10.1517/17425247.2015.980812

Schubert MA, Müller-Goymann CC. Solvent injection as a new approach for manufacturing lipid nanoparticles--evaluation of the method and process parameters. Eur J Pharm Biopharm, 2003; 55(1):125-31; doi: 10.1016/s0939-6411(02)00130-3 https://doi.org/10.1016/S0939-6411(02)00130-3

Schwartz SS. Optimizing glycemic control and minimizing the risk of hypoglycemia in patients with type 2 diabetes. Drugs Context. 2013; 2013:212255; doi: 10.7573/dic.212255 https://doi.org/10.7573/dic.212255

Shaveta S, Singh J, Afzal M, Kaur R, Imam SS, Alruwaili NK, Alharbi KS, Alotaibi NH, Alshammari MS, Kazmi I, Yasir M, Goyel A, Ameeduzzafar. Development of solid lipid nanoparticle as carrier of pioglitazone for amplification of oral efficacy: formulation design optimization, in-vitro characterization and in-vivo biological evaluation. J Drug Deliv Sci Technol, 2020; 57:101674; doi: 10.1016/j.jddst.2020.101674 https://doi.org/10.1016/j.jddst.2020.101674

Silva-Abreu M, Gonzalez-Pizarro R, Espinoza LC, Rodríguez- Lagunas MJ, Espina M, García ML, Calpena AC. Thiazolidinedione as an alternative to facilitate oral administration in geriatric patients with alzheimer's disease. Eur J Pharm Sci, 2019; 129:173-80; doi: 10.1016/j. ejps.2019.01.008 https://doi.org/10.1016/j.ejps.2019.01.008

Song R, Murphy M, Li C, Ting K, Soo C, Zheng Z. Current development of biodegradable polymeric materials for biomedical applications. Drug Des Devel Ther, 2018 Sep 24; 12:3117-3145; doi: 10.2147/DDDT.S165440 https://doi.org/10.2147/DDDT.S165440

Suke SG, Negi H, Mediratta PK, Banerjee BD, Sharma KK. Anti-arthritic and anti-inflammatory activity of combined pioglitazone and prednisolone on adjuvant-induced arthritis. Eur J Pharmacol, 2013; 718 (1-3):57-62; doi: 10.1016/j.ejphar.2013.09.019 https://doi.org/10.1016/j.ejphar.2013.09.019

Tabish SA. Is diabetes becoming the biggest epidemic of the twenty-first century? Int J Health Sci (Qassim), 2007; 1(2):V-VIII.

Thakkar H, Sharma RK, Mishra AK, Chuttani K, Murthy RR. Albumin microspheres as carriers for the antiarthritic drug celecoxib. AAPS PharmSciTech, 2005; 6(1):E65-73. doi: 10.1208/pt060112 https://doi.org/10.1208/pt060112

Wang Y, Sun T, Zhang Y, Chaurasiya B, Huang L, Liu X, Tu J, Xiong Y, Sun C. Exenatide loaded PLGA microspheres for long-acting antidiabetic therapy: Preparation, characterization, pharmacokinetics and pharmacodynamics. RSC Adv, 2016; 6:37452-62; doi: 10.1039/c6ra02994a https://doi.org/10.1039/C6RA02994A

Wu C, Luo X, Baldursdottir SG, Yang M, Sun X, Mu H. In vivo evaluation of solid lipid microparticles and hybrid polymer-lipid microparticles for sustained delivery of leuprolide. Eur J Pharm Biopharm. 2019; 142:315-21; doi: 10.1016/j.ejpb.2019.07.010 https://doi.org/10.1016/j.ejpb.2019.07.010

Wu S, Gong Y, Liu S, Pei Y, Luo X. Functionalized phosphorylated cellulose microspheres: design, characterization and ciprofloxacin loading and releasing properties. Carbohydr Polym, 2021; 254:117421; doi: 10.1016/j.carbpol.2020.117421 https://doi.org/10.1016/j.carbpol.2020.117421

Zhang W, Liu C, Chen S, Liu M, Zhang L, Lin S, Shu G, Yuan Z, Lin J, Peng G, Zhong Z, Yin L, Zhao L, Fu H. Poloxamer modified florfenicol instant microparticles for improved oral bioavailability. Colloids Surfaces B Biointerfaces, 2020; 193:111078; doi: 10.1016/j.colsurfb.2020.111078 https://doi.org/10.1016/j.colsurfb.2020.111078

Zirak MB, Pezeshki A. Effect of surfactant concentration on the particle size, stability and potential zeta of beta carotene nano lipid carrier. Int J Curr Microbiol App Sci, 2015; 4:924-32.

Article Metrics

0 Absract views 1 PDF Downloads 1 Total views

   Abstract      Pdf Download

Related Search

By author names

Citiaion Alert By Google Scholar

Name Required
Email Required Invalid Email Address

Comment required