TY - JOUR

T1 - Improved Biopharmaceutical Properties of Oral Formulations of 1,2,4-Thiadiazole Derivative with Cyclodextrins

T2 - In Vitro and in Vivo Evaluation

AU - Promzeleva, Maria

AU - Volkova, Tatyana

AU - Proshin, Alexey

AU - Siluykov, Oleg

AU - Mazur, Anton

AU - Tolstoy, Peter

AU - Ivanov, Sergey

AU - Kamilov, Felix

AU - Terekhova, Irina

N1 - Funding Information: This work was supported by Russian Science Foundation (project no. 15-13-10017). The authors thank the Center for collective use “Chemistry” (Ufa Institute of Chemistry of RAS) for HPLC analysis. Solid-state NMR measurements were conducted at the Center for Magnetic Resonance, St. Petersburg State University Research Park. Publisher Copyright: © 2017 American Chemical Society. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

PY - 2018/2/12

Y1 - 2018/2/12

N2 - The synthesized 1,2,4-thiadiazole derivative displaying biological activity has low aqueous solubility and dissolution rate. Novel oral formulations of thiadiazole with β- and hydroxypropyl-β-cyclodextrins were obtained by grinding and freeze-drying methods with the purpose to improve the aqueous solubility. Complex formation of 1,2,4-thiadiazole derivative with cyclodextrins was confirmed by means of solid-state 13C MAS CP/TOSS NMR. Solubility, dissolution rate and permeability of the solid inclusion complexes were evaluated in different biorelevant media (SGF, FaSSGF, FaSSIF) simulating the conditions in the gastrointestinal tract. It was demonstrated that the content of biorelevant media affects the properties of the inclusion complexes. In particular, solubilizing effect of cyclodextrins became less pronounced when the micelles of taurocholic acid and lecithin are formed in the dissolution media. The inclusion of thiadiazole into cyclodextrin cavity is in competition with its partitioning into the micelles and this should be taken into account when the in vivo behavior is predicted. The results of in vitro and in vivo experiments were found to be in agreement and showed the highest solubility, dissolution rate and bioavailability of the freeze-dried complexes of thiadiazole with hydroxypropyl-β-cyclodextrin. These complexes can be proposed as more effective dosage forms for oral administration.

AB - The synthesized 1,2,4-thiadiazole derivative displaying biological activity has low aqueous solubility and dissolution rate. Novel oral formulations of thiadiazole with β- and hydroxypropyl-β-cyclodextrins were obtained by grinding and freeze-drying methods with the purpose to improve the aqueous solubility. Complex formation of 1,2,4-thiadiazole derivative with cyclodextrins was confirmed by means of solid-state 13C MAS CP/TOSS NMR. Solubility, dissolution rate and permeability of the solid inclusion complexes were evaluated in different biorelevant media (SGF, FaSSGF, FaSSIF) simulating the conditions in the gastrointestinal tract. It was demonstrated that the content of biorelevant media affects the properties of the inclusion complexes. In particular, solubilizing effect of cyclodextrins became less pronounced when the micelles of taurocholic acid and lecithin are formed in the dissolution media. The inclusion of thiadiazole into cyclodextrin cavity is in competition with its partitioning into the micelles and this should be taken into account when the in vivo behavior is predicted. The results of in vitro and in vivo experiments were found to be in agreement and showed the highest solubility, dissolution rate and bioavailability of the freeze-dried complexes of thiadiazole with hydroxypropyl-β-cyclodextrin. These complexes can be proposed as more effective dosage forms for oral administration.

KW - bioavailability

KW - biorelevant media

KW - cyclodextrins

KW - inclusion complexes

KW - thiadiazole

UR - http://www.scopus.com/inward/record.url?scp=85041899417&partnerID=8YFLogxK

UR - http://www.mendeley.com/research/improved-biopharmaceutical-properties-oral-formulations-124thiadiazole-derivative-cyclodextrins-vitr

U2 - 10.1021/acsbiomaterials.7b00887

DO - 10.1021/acsbiomaterials.7b00887

M3 - Article

AN - SCOPUS:85041899417

VL - 4

SP - 491

EP - 501

JO - ACS Biomaterials Science and Engineering

JF - ACS Biomaterials Science and Engineering

SN - 2373-9878

IS - 2

ER -