Category: Formulation and Quality
Purpose: Metformin is a first-line medication for treating type 2 diabetes, and in recent years, also used for fixed-dose combination with dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium-glucose cotransporter-2 (SGLT-2) inhibitors in tablet form. However, these tablets are very large in size, due to the high-dose regimen of metformin (1,000 mg per day for sustained release) and the need of additional excipients for sustained release of a highly soluble drug, metformin. This is even worse when metformin is included in the fixed-dose combination. Evogliptin (SuganonTM and SugametTM) is an orally bioavailable DPP-4 inhibitor developed by Dong-A ST (Seoul, Korea). As with any other fixed-dose combination of DPP-4 inhibitor and metformin, evogliptin/metformin bi-layer tablet, SugametTM, also has a problem of the large size. There have been some efforts to reduce the size of this bi-layer tablet in our research group. In this study, active coating system and aqueous ethylcellulose coating dispersion (SureleaseTM) were introduced for the removal of evogliptin layer in bi-layer tablets and the reduction of the amount of sustained-release agent in the metformin layer, respectively. The aims of this study were to prepare fixed-dose combination tablet composed of evogliptin coating layer and metformin core tablet, and to optimize the formulation, especially considering the dissolution behavior of drugs and the chemical stability of evogliptin.
Methods: Metformin core tablets were prepared using the wet granulation method. First, metformin granules were composed of metformin hydrochloride, binders, and methacrylic acid-methyl methacrylate copolymer (1:2), a sustained-release agent. Second, carbomer and hydroxypropyl methylcellulose (HPMC) 100,000SR were additionally mixed with the metformin hydrochloride granules. The powder mix was compressed into core tablets with a total weight of 1,270 mg. To generate an effective coating film, the aqueous ethylcellulose coating dispersion and polyvinyl alcohol-based coating agent (OpadryTM) were incorporated and a lab-size pan coater was used. The ratio of the aqueous ethylcellulose coating dispersion was investigated for sustaining the release of metformin and the three kinds of polyvinyl alcohol-based coating agents were screened for increasing the chemical stability of evogliptin in the coating layer. The crystallinity of the evogliptin in the coating layer was analyzed using X-ray powder diffraction (XRD). For the heat-stress stability study, evogliptin-coated tablets were exposed to 60oC, ambient humidity for 4 weeks. The in vitro dissolution test was conducted for 8 h using paddle method in pH 1.2 buffer solution.
Results: As shown in Fig 1, there were characteristic Bragg peaks of metformin core tablets and coating agent, except for those of evogliptin, in the diffractogram of evogliptin coating layer (Green line). It demonstrated that crystalline evogliptin was transformed to the amorphous state, when dissolved evogliptin in coating solution was coated onto core tablets. Recent studies have demonstrated that increased molecular mobility resulting from the formation of amorphous state can affect the chemical stability of pharmaceuticals. Especially, there is a high possibility of degradation of amorphous state drugs, which has a lower glass transition temperature (Tg), under ambient or heat stress conditions. Therefore, SureleaseTM was incorporated into the evogliptin coating layer to overcome the degradation problem. As shown in Fig 2, it was observed that the total amount of related substances was decreased in this coating layer. It was attributed to the decrease of molecular mobility caused by the incorporation of ethylcellulose, which has high Tg (about 130oC) and comprises approximately 75% of the SureleaseTM solid content. However, coating layer containing only the SureleaseTM excessively inhibited the dissolution of metformin from the core tablets. Therefore, three different kinds of coating agent (OpadryTM A~C), which functioned as a pore-forming agent in coating-layer, were screened. Due to relatively lower Tg of polyvinyl alcohol (PVA) and polyethylene glycol (PEG) in OpadryTM, the total amount of related substances was relatively increased under heat stress (60oC) condition (Fig 2). But, it was less than an acceptable limit when OpadryTM C, with the minimum amount of PVA and PEG, is incorporated. The dissolution behavior of metformin was also equivalent to that of SugametTM.
Conclusion: The prepared evogliptin active coating tablets showed a significantly smaller size than any other fixed-dose combination of DPP-4 inhibitor and metformin with chemical stability and equivalent dissolution profile. The chemical stability of amorphous evogliptin was improved by including SureleaseTM and the equivalent dissolution profile was obtained by using OpadryTM C in the coating layer. Taken together, the modification of coating agent composition enables fixed-dose combination, such as a combination of DPP-4 inhibitor and metformin, to be more efficient by increasing patient compliance and quality of pharmaceutical products.
Yong Min Kim– Research Fellow, Dong-A ST Pharmaceuticals, Co., LTD., Yongin-si, Kyonggi-do, Republic of Korea
Jeong Woong Seo– Yongin-si, Kyonggi-do, Republic of Korea
Yong Hwan Park– Yongin-si, Kyonggi-do, Republic of Korea
Yu young Kim– Yongin-si, Kangwon-do, Republic of Korea
Hyung don Hwang– Yongin-si, Kyonggi-do, Republic of Korea
Hwan Ho Kim– Yongin-si, Kyonggi-do, Republic of Korea
Dong Han Won– Yongin-si, Kyonggi-do, Republic of Korea
Sun-woo Jang– Yongin-si, Kyonggi-do, Republic of Korea
Jeong-Woong Seo– Senior Scientist, n/a, Yongin-si, Gyeonggi-do, Korea, Republic Of