Optimization of bilayer tablet manufacturing process for fixed dose combination of sustained release high-dose drug and immediate release low-dose drug based on quality by design (QbD)

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Abstract

A fixed dose combination (FDC) bilayer tablet, consisting of high-dose metformin HCl in a sustained release layer and low-dose evogliptin tartrate in an immediate release layer, was developed based on a quality by design (QbD) approach. To implement QbD approach, the bilayer tableting process parameters judged as high risk through risk analysis were optimized by a central composite face-centered design as a design of experiment (DOE) methodology. Using DOE, the optimized conditions of the tableting process for drug products that satisfy the established quality target product profiles were obtained. The content uniformity of low-dose evogliptin tartrate in the optimized bilayer tablet prepared on a large scale was confirmed by at-line transmittance Raman spectroscopy as a process analytical technology. In addition, the in vitro drug release and in vivo pharmacokinetic studies showed that metformin HCl and evogliptin tartrate in the bilayer tablet is bioequivalent to those of the respective reference drugs. Furthermore, the physicochemical stability of the optimized bilayer tablet during storage under long-term and accelerated conditions was also confirmed. Therefore, it can be concluded that the QbD approach is an effective way to develop a new FDC bilayer tablet that is easy to scale up for successful commercialization.

Introduction

Therapeutic dosage administration to take two or more medications are frequently required for patients with metabolic syndrome. To benefit from this combination therapy, the sequential administration of drugs following a prescribed time schedule is essential for the certain desired pharmacological therapies. The dosing complexity of multiple medications may negatively affect patient compliance (Oh et al., 2016). It has been reported that patient compliance is reduced as the dosage regimes become more complex with the administration of a large number of medicines prescribed. Two or more drugs are formulated in a single dosing form with a fixed ratio, and it is termed as fixed-dose combinations (FDC). This FDC has become an effective way to increase patient compliance by inducing convenient administration of medicines (Bangalore et al., 2007, Pan et al., 2008, Park et al., 2020a).

The formulation design of FDCs should be developed considering the physical properties, compatibility, loading dose, and dissolution characteristics of the two drugs. Bilayer tablets are one of the best options for developing FDC formulations, with different drug dissolution behaviors for each drug in a single dosage form (e.g., drugs with a sustained release (SR) and immediate release (IR) profiles). In addition, circumvention of the physicochemical incompatibilities of active pharmaceutical ingredients (APIs) can also be achieved. These promising advantages of the bilayer tablet have been reported in several literatures (Abebe et al., 2014, Efentakis and Peponaki, 2008). In addition, the bilayer tablet technology can provide the chance of extension of a drug product life cycle (Devtalu et al., 2013).

Several FDC bilayer tablets containing two dosages have been developed to have an IR dosage combined with an SR dosage in a single dosage unit. This efficient pharmaceutical formulation can reduce the dosing complexity and risk of inappropriate administration (Mandal and Pal, 2008). Most patients with type 2 diabetes mellitus (T2DM) generally take more than two oral dosage forms to control blood glucose level (Blonde et al., 2014, Han et al., 2019). Switching from one drug to another in a patient with poorly controlled glycemia or maximizing the dosage of an existing drug rarely achieves the desired outcomes. Adding another antidiabetic drug to the regimen already being administered often achieves more effective glycemic control in a T2DM patient with poor glycemic control. The several combination therapies have shown improvement in glycemic control in comparison with monotherapy (Phung et al., 2014).

Metformin HCl is an antihyperglycemic drug, and it is commercially developed to oral solid dosage form to treat patients with T2DM (Chen et al., 2020, Madsen et al., 2019). It improves hyperglycemia in T2DM mainly through the suppression of glucose production in the liver. In addition, it also results in increased insulin sensitivity, increased oxidation of fatty acid, enhanced peripheral glucose uptake, and decreased glucose absorption (Bailey and Turner, 1996, Nathan et al., 2009). For these prominent pharmacological effects, metformin HCl has become the first option for T2DM treatment (Maruthur et al., 2016). Nevertheless, metformin HCl has some problems, such as adverse gastrointestinal symptoms including diarrhea, nausea, and vomiting or low oral bioavailability and short half-life (Fowler, 2007, Pentikäinen et al., 1979). To improve compliance and gastrointestinal tolerability, a SR formulation of metformin HCl has been successfully marketed for once-daily dosing (Blonde et al., 2004, Coleman et al., 2012, Oh et al., 2016).

Evogliptin tartrate is a dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of T2DM (Dong-A ST, Seoul, Republic of Korea) (Ahren, 2007, Gu et al., 2014). Recently, a once-daily dose tablet dosage form containing 5 mg of evogliptin tartrate was approved by the Ministry of Food and Drug Safety (MFDS) (Kim et al., 2012b, Kim et al., 2016). It is recommended that DPP-4 inhibitors can be prescribed in combination with metformin HCl for patients who do not achieve the desired glycemic control with metformin HCl monotherapy (American Diabetes Association, 2013). It has been reported that the co-administration of a metformin HCl and DPP-4 inhibitor is an effective strategy for the T2DM treatment because of the complementary action mechanisms of the two drugs (Ahren, 2008, Mishriky et al., 2015, Yokoh et al., 2015). Based on these previous reports, evogliptin tartrate can be used as a combination therapy with metformin HCl for the enhanced treatment of T2DM (Rhee et al., 2016).

There has been various publications and guidelines that include scope, definition, and high-level guidance of QbD in the pharmaceutical area (Ahmed et al., 2018, Guideline, 2009). The main goal of commercial drug products is the successful development of robust quality products with the desired target product profile (QTPP) (Beg et al., 2019, Kuk et al., 2019). To carry out QbD, the QTPP and critical quality attributes (CQAs) should be defined first based on prior knowledge. Then, the identification of critical material attributes and critical process parameters (CPPs) that can affect CQAs, is required based on risk assessments (RAs) (Mishra et al., 2018, Shah et al., 2019). In addition, design space should be confirmed after the design of experiment (DOE) and RAs (Lawrence et al., 2014, Nadpara et al., 2012). The final drug products developed based on the QbD can have various advantageous such as improved stability, lower costs, enhanced therapeutic efficacy, and reduced side effects (Choi et al., 2019, Kuk et al., 2019).

At the present time, the QbD based research and development of FDC bilayer tablets are still in early stage, and it must be useful and necessary to apply QbD to FDC dosage unit development (Lee et al., 2017). Especially, in the development of a bilayer tablet containing two different drugs with a large difference in the dose of API, the negative effects on CQA (e.g., drug content uniformity) that can occur due to such a large difference in dose, and researches based on the QbD approach to solve this issue, are very scarce. Thus, this study was aimed to develop an optimized FDC bilayer tablet, containing low-dose evogliptin tartrate and high-dose metformin HCl, based on the QbD approach to treat T2DM patients with a single daily dose. The FDC bilayer tablet consisted of SR metformin HCl layer (1000 mg) and IR evogliptin tartrate layer (6.87 mg) (Oh et al., 2016). Immediate action of evogliptin tartrate will help in controlling excess sugar, which will then be maintained by the prolonged action of metformin HCl through sustained absorption at upper gastrointestinal tract (Mandal and Pal, 2008).

The QTPPs was defined early in the development of the FDC bilayer tablet, based on the analysis of each reference marketed drug, Diabex XR® (Daewoong, Seoul, Korea; containing metformin HCl) and Suganon® (Donga ST, Seoul, Korea; containing evogliptin tartrate), and is presented in Table 1.

A DOE based on the QbD approach was used to optimize the tableting process of the bilayer tablet. In particular, we focused on the content uniformity of relatively much smaller dose drugs in the development of a bilayer tablet containing two different drugs with a large difference in the dose of API. Thus, the content uniformity of evogliptin tartrate in the optimized bilayer tablet prepared on a large scale was evaluated using transmittance Raman spectroscopy (TRS) as a process analytical technology, with a priority compared to metformin HCl. Furthermore, the optimized formulation was characterized by comparing its dissolution properties with each marketed reference drug and in vivo beagle dog pharmacokinetic parameters of the two drug combination therapies.

Section snippets

Materials

Metformin HCl was obtained from Granules India Limited (Madhapur, Hyderabad, India). Evogliptin tartrate was supplied by Dong-A ST (Seoul, Korea). Polyvinylpyrrolidone (PVP K30) and crospovidone were purchased from BASF (Ludwigshafen, Land Rheinland Pfalz, Germany). Hypromellose (hydroxymethyl cellulose, HPMC2208) and methyl polymethacrylate (Eudragit S100) were purchased from Dow Chemical (Montgomeryville, PA, USA) and Evonik (Essen, NRW, Germany), respectively. Carbomer 934P was supplied by

Definition of critical quality attributes (CQA) for bilayer tablet

The CQAs for drug product were identified from the analysis of QTPP to use in the initial RA (Table 4) under the premise that the CQAs must fulfill the predefined requirements to ensure the desired quality of drug product (Kuk et al., 2019, Lee et al., 2017). The identified subset of CQAs were appearance, friability, hardness, assay, content uniformity, dissolution, degradation products, residual solvents, and microbial limits through the initial RA. These CQAs have the potential to be altered

Conclusions

In this study, a new FDC bilayer tablet consisting of 1000 mg metformin HCl in a SR layer and 6.87 mg evogliptin tartrate in an IR layer was developed based on the QbD approach. As a reference marketed drug, Diabex XR® and Suganon® were selected. The formulation and granulation process of each layer was applied by taking the pre-established formulation and granulation process of a marketed tablet dosage form containing each component as it is. It would be the most efficient way that a bilayer

CRediT authorship contribution statement

Dong Han Won: Conceptualization, Methodology, Investigation, Formal analysis, Writing - original draft. Heejun Park: Methodology, Investigation, Writing - original draft, Writing - review & editing. Eun-Sol Ha: Methodology, Investigation, Formal analysis, Writing - original draft. Hwan-Ho Kim: Methodology, Formal analysis. Sun Woo Jang: Conceptualization, Writing - review & editing. Min-Soo Kim: Conceptualization, Investigation, Writing - review & editing, Supervision, Funding acquisition.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2020R1A2C4002166).

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