Abstract
Maximization of drug-loading can significantly reduce the size of dosage form and consequently decrease the cost of manufacture. In this research, two challenges were addressed: poor flow and tableting problems of high-drug loading (>70%) formulation of canagliflozin (CNG), by adopting the moisture-activated dry granulation (MADG) process. In this method, heating and drying steps were omitted so, called green granulation process. A 32 full-factorial design was performed for optimization of key process variables, namely the granulation fluid level (X1) and the wet massing time (X2). Granulation of CNG was carried out in the presence of polyvinylpyrrolidone, and the prepared granules were compressed into tablets. Regression analysis demonstrated the significant (p ≤ 0.05) effect of X1 and X2 on properties of granules and corresponding tablets, with pronounced impact of X1. Additionally, marked improvement of granules’ properties and tableting of CNG were observed. Furthermore, the optimized process conditions that produced good flow properties of granules and acceptable tablets were high level of granulation fluid (3.41% w/w) and short wet massing time (1.0 min). Finally, the MADG process gives the opportunity to ameliorate the poor flow and tableting problems of CNG with lower amounts of excipients, which are important for successful development of uniform dosage unit.
Highlights
In 2013, the U.S Food and Drug Administration had approved Canagliflozin (CNG) for the management of adult patients with type-II diabetes mellitus [1]
The CNG is recommended as the first add-on agent for those hyperglycemic patients for whom monotherapy of metformin is unable to efficiently control plasma glucose levels [3]
Diagnostic plots were generated for granules and tablet responses to evaluate the goodness of fit of the applied model and confirm its significance
Summary
In 2013, the U.S Food and Drug Administration had approved Canagliflozin (CNG) for the management of adult patients with type-II diabetes mellitus [1]. The CNG is one of the orally acting sodium-glucose co-transporter-2 inhibitors that reduces the renal tubular reabsorption of glucose into the systemic circulation, decreasing plasma glucose levels in hyperglycemic patients [2]. It is possibly prescribed as a monotherapy or in combination with any of the existing antidiabetic agents, like metformin [3]. Following single oral administration of 50, 100 and 300 mg, CNG was rapidly absorbed with peak plasma concentration attained within 1–2 h. After single oral dose administration, the terminal half-life of CNG was 10.6–13.1 h, with a large volume of distribution of 119 L. The renal clearance of CNG was in the range of 1.3–1.55 mL/min for doses of 100 and 300 mg, respectively [4]
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