Cellulose ether and carbopol 971 based gastroretentive controlled release formulation design, optimization and physiologically based pharmacokinetic modeling of ondansetron hydrochloride minitablets

This study aims to design and optimize ondansetron (OND) gastro-retentive floating minitablets for better and prolonged control of postoperative nausea and vomiting (PONV) with improved patient compliance. Minitablets were directly compressed and encapsulated in a size 2 capsule shell with an overall dose of 24 mg. Central composite design (CCD) was applied keeping one cellulose ether derivative HPMC K15M and Carbopol 971 as variable and used as swelling and rate retarding agents. The other cellulose derivative i.e. sodium carboxymethyl cellulose, along with mannitol, sodium bicarbonate, and talc, were used in fixed quantities. The floating lag time, total floating time, swelling index, in-vitro drug release, and zero-order (RSQ value), were critical quality parameters.

Highlights

• Ondansetron CR floating minitablets were prepared using HPMC K15M and Carbopol 971

• Numerical and graphical optimization technique to get the optimized formulation

• Physical characterization of minitablets using DSC, SEM and FTIR
• Compressibility, compactibility, invitro release and invivo imaging studies.
• In-vivo PBPK modeling of the optimized gastroretentive floating minitablets

The optimized formulation (F_pred) was evaluated for all critical parameters, along with surface morphology, thermal stability, chemical interaction, and accelerated stability. The in silico PBPK modeling was applied to compare the bioavailability of F_pred with reference OND immediate-release tablets. The numerical optimization model predicted >90 % drug release with zero-order at 12 h. In silico PBPK modeling revealed comparable relative bioavailability of F_pred with the reference formulation. The gastroretentive floating minitablets of OND were successfully designed for prolonged emesis control in patients receiving chemotherapeutic agents.

Chemical and reagents

Ondansetron HCl (OND) was gifted by Pharmadic Laboratories (Pvt) Ltd., Pakistan. Hydroxypropyl methylcellulose (Methocel K15M) (Colorcon, Dartford, Kent, UK) and Carbopol 971 (Lubrizol Inc. USA). Mannitol, sodium bicarbonate, and sodium carboxymethyl cellulose (SCMC) (Sigma-Aldrich, USA). Talc (lubricant), potassium dihydrogen phosphate, hydrochloric acid, and sodium hydroxide were obtained from Merck, Germany.

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Tahmina Maqbool, Rabia Ismail Yousuf, Farrukh Rafiq Ahmed, Muhammad Harris Shoaib, Asma Irshad, Muhammad Talha Saleem, Faaiza Qazi, Sana Sarfaraz, Syed Adnan Rizvi, Zafar Alam Mahmood, Cellulose ether and carbopol 971 based gastroretentive controlled release formulation design, optimization and physiologically based pharmacokinetic modeling of ondansetron hydrochloride minitablets, International Journal of Biological Macromolecules, 2024, 133841, ISSN 0141-8130,
https://doi.org/10.1016/j.ijbiomac.2024.133841.