Abstract
Introduction.
Combination products of linagliptin and empagliflozin are widely used for the treatment of type 2 diabetes mellitus. Both active substances belong to class III of the Biopharmaceutical Classification System (BCS), characterized by high solubility and low permeability. In the development of generic medicinal products, demonstration of therapeutic equivalence is critical; for this purpose, a comparative in vitro dissolution kinetics test is conducted within the framework of a biowaiver. However, for class III drugs, permeability is the rate-limiting step of absorption, necessitating the use of additional methodologies for its assessment.
Aim.
Comparative study of dissolution and permeability profiles of linagliptin and empagliflozin from film-coated tablets of a test combination product and a reference product using the Dissoflux™ methodology to substantiate the applicability of this approach in the assessment of biopharmaceutical equivalence.
Materials and methods.
The study objects were film-coated tablets of the test product (combination of linagliptin 2.5 mg and empagliflozin 10 mg) and a reference product of identical dosage. The comparative dissolution kinetics test (CDKT) was performed using a paddle apparatus (TrustE-8 basic, Electrolab, India) at 50 rpm in media with pH 1.2, 4.5 and 6.8 (volume 500 mL). Permeability studies were conducted using the Dissoflux™ system (Electrolab, India) in pH 6.8 medium (donor) and buffer solution with 0.05 % Tween 20 (acceptor, pH 7.4). Quantitative determination of the active substances was performed by HPLC-UV with gradient elution on a Symmetry® C18 column (Waters Corporation, USA).
Results and discussion.
The developed HPLC-UV method demonstrated high reproducibility and accuracy. In media with pH 1.2, 4.5 and 6.8, the release of active substances from both dosage forms exceeded 85 % by 15 minutes, indicating equivalence of dissolution profiles. The permeability test results using the Dissoflux™ methodology demonstrated comparable accumulation profiles of both active substances in the acceptor chamber. The Flux ratio for linagliptin was 92.13 %, and for empagliflozin 100.31 %.
Conclusion.
The comparability of dissolution profiles of linagliptin and empagliflozin from the test and reference products in all three media was demonstrated. Pilot data from the permeability test in vitro using the Dissoflux™ system demonstrated the potential of this methodology as an ancillary tool for biopharmaceutical evaluation during drug development, although final conclusions require statistical confirmation based on no fewer than three independent replicates.