IMPLICATION OF CENTRAL COMPOSITE DESIGN IN THE DEVELOPMENT OF SIMVASTATIN- LOADED NANOSPONGES Original Article SADHANA NOOTHI 1,2 , NARENDER MALOTHU 1* , ANKARA ARETI 1 , PRASANNA KUMAR DESU 1 , SARVAN KUMAR 3 1 KL College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram, AP, India. 2 Department of Pharmaceutical engineering, B V Raju institute of technology, Narsapur, Medak, Telangana, India. 3 Department of Pharmacology, G Pulla Reddy College of Pharmacy, Hyderabad, Telangana, India * Corresponding author: Narender Malothu; * Email: narendermalothu@gmail.com Received: 28 May 2023, Revised and Accepted: 03 Jul 2023 ABSTRACT Objective: The present study’s objective was to apply a central composite design to develop the simvastatin-loaded nanosponge formulation to improve its oral bioavailability. Methods: With the help of a design expert (State-Ease version 13.0.1), a central composite design was selected for the formulation of simvastatin- loaded nanosponges by using a defined concentration of Eudragit L-100 (X1) and PVA (X2) as independent variables and particle size (Y1), percent (%) entrapment efficiency (EE) (Y2), in vitro drug release (Y3) as dependent variables. Fourteen (SF1-SF14) formulations were prepared using the emulsion solvent evaporation and evaluated for surface morphology, particle size, drug-excipient compatibility, %EE, and % drug release. The optimized model (SF14) obtained from a design expert was evaluated for in vivo pharmacokinetics in animal models. Results: SF14 was formulated and evaluated for morphology (shape and size) of the particle, % EE, in vitro % drug release, and its kinetics. The formulation showed particle size of 163±0.45 nm, 80.54 %±0.57 of EE, and 97.13%±0.38 of drug release at 8h. The release kinetics followed the zero-order and Higuchi mechanisms with non-fiction diffusion. In vivo results showed Cmax, Tmax, AUC0-t, AUC0-α, and MRT0-α for nanosponges were 0.175 µg/ml, 6 h, 1.561 µg/mlh, 1.755 µg/mlh, 11.77 h, respectively. Conclusion: The results indicated a significant increase in the bioavailability of the drug in nanosponges compared with standard drugs. The experimentally designed nanosponge formulations have been successfully developed, and evaluated parameters show that the nanosponge formulation of Simvastatin is a promising delivery through the oral route. Keywords: Nanosponges, Eudragit L-100, Surface response method, Particle size, Central composite design © 2023 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) DOI: https://dx.doi.org/10.22159/ijap.2023v15i5.48453. Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION Due to its ease of administration and patient compliance, the conventional drug delivery method is a frequently utilized strategy for various medications. However, it has a few drawbacks, like dose frequency, narrow therapeutic index, and fluctuations [1]. Different advanced drug delivery systems, like controlled, sustained, and targeted delivery, including nanotechnology, was focused on enhancing the solubility and improving the release characteristics of drug molecules [2]. Novel drug delivery systems are being used to improve or enhance the bioavailability of the drug and deliver the drug released at a specific site. Nanosponge technology is a novel emerging approach to improving the solubility and bioavailability of poorly water-soluble drugs [3, 4]. Nanosponges are one of the novel formulations in recent trends of nano-drug delivery. Nanosponges can be able to entrap both water- soluble and insoluble drugs. These are non-toxic, porous, stable at high temperatures, and insoluble in water and organic solvents [5- 7]. These nanosponges circulate throughout the body, approach the desired location, and release the medication in a planned and controlled manner during parenteral administration. Hyperlipidaemia is an acquired disorder defined as elevated lipid levels in the body, including HDL, LDL, and VLDL, caused due to diet and genetics [8, 9]. Simvastatin (SIM) is a lipid-lowering drug belonging to the statins class used to lower abnormal lipid levels and reduce the risk of cardiovascular disease by inhibiting cholesterol production in the liver. SIM has less bioavailability (5%) due to low solubility, short half-life (1.9 h), and protein binding is 95% [10, 11]. Due to low solubility and less half-life, and high protein binding (>95%), conventional release formulations may cause adverse events of HMG-CoA reductase inhibitor activity [12]. Novel formulations like liposomes, niosome, liquid crystals, and nanoparticles are formulated [13] to improve solubility and hepatic availability. Nanosponge is also one of the novel formulations. As per recent reports, a few studies achieved the nanosponge formulations by employing ethyl cellulose, Eudragit S-100 [14] as rate retardant polymers with cyclodextrin [15] and polyvinyl alcohol (PVA) as copolymer. In our earlier studies, we tried to develop a nanosponge of SIM with ethyl cellulose by claiming this technology [16]. However, we have noticed low entrapment efficiency (%EE) with the use of ethyl cellulose combination with PVA. To produce a superior nanosponge formulation, an experimental design approach was adapted by considering two independent variables i.e., Eudragit L-100 as a rate retardant polymer and PVA as a copolymer for the formulation of nanosponges. The formulated nanosponges were evaluated for size, %EE, in vitro, in vivo drug release, and release kinetics [17, 18]. MATERIALS AND METHODS Materials Hetero Drugs, Hyderabad, provided a complimentary sample of SIM and Eudragit-L100. Polymers like PVA, solvents, and other chemicals were procured from SD Fine Chemicals, Mumbai. All chemicals used were analytical grade. Implication of quality by design (QbD) concept QbD is a systematic approach to drug development that emphasizes understanding the critical process and product parameters that affect product quality and designing a formulation and manufacturing process that ensures consistent quality [19, 20]. When applied to the formulation of SIM nanosponges, QbD can have several implications. QbD can help to select the appropriate raw materials for the nanosponge formulation. By understanding the impact of each raw material on the final product quality, one can choose the most suitable materials to ensure consistent product quality. The steps involved in this procedure include i. identification of Critical Quality Attributes (CQAs) for SIM nanosponges ii. Defining International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 15, Issue 5, 2023