Development of Clinically Optimized Sitagliptin and Dapagliflozin Complex Tablets: Pre-Formulation, Formulation, and Human Bioequivalence Studies

Abstract

The purpose of this study is to derive an optimal drug release formulation with human clinical bioequivalence in developing a sitagliptin phosphate monohydrate-dapagliflozin propanediol hydrate fixed-dose combination (FDC) tablet as a treatment for type 2 diabetes mellitus. As a treatment for type 2 diabetes mellitus, the combined prescription of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors is common. Therefore, this study simplified the number of individual drugs taken and improved drug compliance by developing FDC tablets containing sitagliptin phosphate monohydrate as a DPP-4 inhibitor and dapagliflozin propanediol hydrate as an SGLT-2 inhibitor. To derive the optimal dosage form, we prepared single-layer tablets, double-layer tablets, and dry-coated tablets and evaluated the drug control release ability, tableting manufacturability, quality, and stability. Single-layer tablets caused problems with stability and drug dissolution patterns. When the dissolution test was performed on the dry-coated tablets, a corning effect occurred, and the core tablet did not completely disintegrate. However, in the quality evaluation of the double-layer tablets, the hardness was 12–14 kilopond, the friability was 0.2%, and the disintegration was within 3 min. In addition, the stability test revealed that the double-layer tablet was stable for 9 months under room temperature storage conditions and 6 months under accelerated storage conditions. In the drug release test, only the FDC double-layer tablet showed the optimal drug release pattern that satisfied each drug release rate. In addition, the FDC double-layer tablet showed a high dissolution rate of over 80% in the form of immediate-release tablets within 30 min in a pH 6.8 dissolution solution. In the human clinical trial, we co-administered a single dose of a sitagliptin phosphate monohydrate-dapagliflozin propanediol hydrate FDC double-layered tablet and the reference drug (Forxiga®, Januvia®) in healthy adult volunteers. This study showed clinically equivalent results in the stability and pharmacodynamic characteristics between the two groups.

Efficacy of Fixed-dose Combination of Dapagliflozin and Sitagliptin in Type 2 Diabetes Mellitus Using Continuous Glucose Monitoring: A Real-world Study in India

“…Dapagliflozin, a SGLT2 inhibitor, decreases glucose reabsorption by increasing excretion via urine, thus lowering the blood glucose level. ( 5)Another oral antidiabetic, Sitagliptin, an orally active DPP-4 inhibitor, promotes insulin secretion in hyperglycaemic patients by elevating the levels of glucagon-like peptide-1(GLP-1) and incretin hormone, thereby inhibiting glucagon secretion, reducing HbA1c and fasting as well as postprandial glucose levels [11]. Prior preclinical and clinical studies have validated the synergistic efficacy of dapagliflozin and sitagliptin on insulin resistance [7,12] Since most of these clinical studies were conducted in Chinese, Japanese and European populations, the benefits of FDC of dapagliflozin and sitagliptin in the Indian population are indistinct [12,13].…”