Design and evaluation of oseltamivir phosphate dual-phase extended-release tablets for the treatment of influenza
Abstract
In this study, once-daily extended-release tablets with dual-phase release of oseltamivir phosphate were developed for the treatment of influenza. The goal was to improve patient adherence and offer more therapeutic choices. The tablets were manufactured using wet granulation, bilayer tablet compression, and enteric membrane-controlled coating processes. Various polymers, such as hydroxypropyl methylcellulose (HPMC K100MCR, K15MCR, K4MCR, K100LV), enteric polymers (HPMC AS-LF, Eudragit L100-55) and membrane-controlled polymers (OPADRY® CA), were used either individually or in combination with other common excipients.
The formulations include enteric-coated extended-release tablet (F1), hydrophilic matrix extended-release tablet (F2), semipermeable membrane-controlled release tablet (F3) and a combination extended-release tablet containing both enteric and hydrophilic matrix (F4). The in vitro drug release profile of each formulation was fitted to the first-order model, and the Ritger-Peppas model suggested that Fickian diffusion was the primary mechanism for drug release.
Comparative bioequivalence studies with Tamiflu® (oseltamivir phosphate) capsules revealed that formulations F1, F2, and F3 did not achieve bioequivalence. However, under fed conditions, formulation F4 achieved bioequivalence with a relative bioavailability of 95.30% (90% CI, 88.83%-102.15%). This suggests that the formulation F4 tablet could potentially be a new treatment option for patients with influenza.
Introduction
Oseltamivir is an ethyl ester prodrug of oseltamivir carboxylate, an inhibitor of the neuraminidase enzyme of the influenza virus (Gubareva et al., 2000). Initiate treatment with oseltamivir within 48 h of the onset of influenza symptom. The recommended oral dosage of oseltamivir for treating influenza in adults and adolescents aged 13 and older is 75 mg twice daily for 5 days. After oral administration of oseltamivir phosphate, oseltamivir is absorbed from the gastrointestinal tract and extensively converted, primarily by hepatic esterases, to oseltamivir carboxylate. At least 75 % of an oral dose is absorbed into the systemic circulation as oseltamivir carboxylate, while less than 5 % of the oral dose reaches the systemic circulation as oseltamivir. The main side effects of oseltamivir phosphate are gastrointestinal reactions, followed by neurological and psychiatric abnormalities (Dutkowski et al., 2003). Regarding administration, it can be taken with or without food. For some patients, taking the drug with food can improve tolerability.
In our fast-paced society, patients may unintentionally miss doses due to factors such as demanding work or study schedules, or reduced appetite following an illness, which can affect treatment effectiveness. Introducing an extended-release dosage form that reduces the frequency of administration has the potential to provide patients with improved drug experiences and additional treatment options. This can enhance patient compliance and convenience (Altreuter et al., 2018). Conventional extended-release formulations are characterized by gradual and consistent drug release, with a limited initial release rate and quantity. In contrast to immediate-release formulations, conventional extended-release formulations take longer to reach the minimum effective concentration after oral administration. For diseases that require rapid symptom relief, such as influenza, extended-release formulations are unable to achieve the same prompt attainment of effective drug concentrations in the blood as immediate-release formulations. To overcome these challenges, a dual-phase tablet with immediate and extended-release characteristics has been formulated to be taken once daily. This aims to reduce dosing frequency and improve patient compliance.
Multiple factors influence drug release in dual-release tablets, including the physical and chemical properties of the ingredients, the coating film material, interactions between the ingredients, tablet porosity, swelling, and erosion. These factors collectively influence the ultimate release behavior of the drug (Jin et al., 2022). Moreover, the degree to which these factors influence drug release may vary among various formulations, ultimately affecting the drug’s in vivo pharmacokinetic behavior. The variations in the internal pH environment of the body have a significant impact on the dissolution and erosion of excipients, thereby influencing the drug release process. Polymer materials commonly utilized in extended-release formulations encompass hydrophilic gel matrices (e.g., HPMC, PVP, Carbopol, PEO), enteric polymers (e.g., Eudragit, HPMCP, HPMCAS), and insoluble polymers (e.g., EC). The utilization, either individually or in combination, of these materials enables diverse drug release mechanisms to cater to varying release rate requirements. This research explored dual-phase extended-release formulations encompassing combinations of enteric coatings and hydrophilic gel matrices, individual hydrophilic gel matrices, insoluble polymers coatings, and enteric and hydrophilic gel matrices combination compression. Notably, a preliminary achievement of the desired drug release was observed with a combination compression of Eudragit enteric material and HPMC hydrophilic gel matrix. HPMC, commonly utilized in pharmaceutical extended-release formulations, is a synthetic extended-release material (Sinha et al., 2007), while Eudragit (Patra et al., 2017), belonging to the poly(meth)acrylate ester class, demonstrates pH-dependent and non-pH-dependent properties due to different linking groups. Specifically, Eudragit L100-55 dissolves above pH 5.5 and, in combination with hydrophilic gel matrices, can delay drug release in the stomach, preserving drug release upon intestinal dissolution (Terao et al., 2001). The combination of Eudragit L100-55 and HPMC in compressing tablets streamlines the preparation process, reduces variables, and cuts costs, combine with hydrophilic matrices and pH-sensitive drug release mechanisms, rendering it an optimal choice. Instances of such technological applications include flurbiprofen compression coated tablets (Veerareddy and Vemula, 2012), flurbiprofen-sodium alginate compression coated tablets (Makhlof et al., 2009), and diclofenac sodium compressed coated tablets (Chickpetty et al., 2010).
A 505(b)(2) application is a type of US New Drug Application (NDA) that includes comprehensive reports of safety and efficacy investigations. However, it differs from a standard NDA in that it relies on data from studies not conducted by or for the applicant, and for which the applicant has not obtained a right of reference (Freije et al., 2020). Many 505(b)(2) applications rely on a bioavailability/bioequivalence (BA/BE) study for approval, where the proposed product must demonstrate bioequivalence to the reference listed drug. Typically, in addition to BA/BE studies, extended-release formulations of drugs often require additional clinical trials in patients to confirm efficacy and ensure equivalent therapeutic effects compared to immediate-release formulations. Nonetheless, variations in formulation or dosage form can significantly affect the speed and amount of drug absorption.
This highlights the necessity for further clinical trials, which are expensive and time-consuming, making it a critical factor for pharmaceutical companies to consider. Furthermore, the main goal of this study on dosage form design is to comprehensively analyze the pharmacokinetic parameters through human pharmacokinetic research for the extended-release formulation of oseltamivir phosphate and oseltamivir phosphate capsules. By evaluating the bioequivalence and efficacy, the goal is to determine whether the extended-release tablet has achieved similar clinical efficacy to the commercial capsule, potentially eliminating the need for clinical trials to verify efficacy in patients.
In this study, a series of extended-release tablet formulations of oseltamivir phosphate were developed, and their drug release mechanisms were investigated. In vitro-in vivo correlations of the tablet were examined, and steady-state plasma drug concentrations were predicted through non-parametric superposition using Phoenix® WinNonlin® Version 6.4 (Certara L.P). Our objective was to develop a tablet that is not only fast-acting, but also provides extended release, while being bioequivalent and equally effective compared to the capsule.
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Materials
Oseltamivir phosphate was generously provided by YiChang HEC ChangJiang Pharmaceutical Co., Ltd. in China. D-Mannitol (PEARLITOL® 100SD) was purchased from Roquette in France. Croscarmellose Sodium was supplied by Guangzhou Standard Pharma Co., Ltd. in China. Sodium stearyl fumarate and sodium starch glycolate were purchased from JRS Pharma GmbH & Co. KG in Germany. Methacrylic Acid and Ethyl Acrylate Copolymer (Eudragit L100-55) was purchased from Evonik Nutrition & Care GmbH.
Liping Yu, Xin Huang, Manhua Jiang, Wentao Guo, Xue Li, Fangfang Huang, Jinsong You, Design and evaluation of oseltamivir phosphate dual-phase extended-release tablets for the treatment of influenza, International Journal of Pharmaceutics, Volume 661, 2024, 124364, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124364.
Read also our introduction article on “Sodium Stearyl Fumarate“ here:
