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Formulation of self-microemulsifying drug delivery system (SMEDDS) by D-optimal mixture design to enhance the oral bioavailability of a new cathepsin K inhibitor (HL235).
Int J Pharm. 2020 Jan 05; 573:118772.IJ

Abstract

HL235 is a new cathepsin K inhibitor designed and synthesized to treat osteoporosis. Since HL235 has poor aqueous solubility, a self-microemulsifying drug delivery system (SMEDDS) was formulated to enhance its oral bioavailability. A solubility study of HL235 was performed to select a suitable oil, surfactant and cosurfactant. Pseudoternary phase diagrams were plotted to identify the microemulsion region and to determine the range of components in the isotropic mixture. D-optimal mixture design and a desirability function were introduced to optimize the SMEDDS formulation for the desired physicochemical characteristics, i.e., high drug concentration at 15 min after dilution with simulated gastric fluid (SGF) and high solubilization capacity. The optimized HL235-loaded SMEDDS formulation consisted of 5.0% Capmul MCM EP (oil), 75.0% Tween 20 (surfactant) and 20.0% Carbitol (cosurfactant). The droplet size of the microemulsion formed by the optimized formulation was 10.7 ± 1.6 nm, and the droplets were spherical in shape. Pharmacokinetic studies in rats showed that the relative oral bioavailability of the SMEDDS formulation increased up to 3.22-fold compared to its solution in DMSO:PEG400 (8:92, v/v). Thus, the formulation of SMEDDS optimized by D-optimal mixture design could be a promising approach to improve the oral bioavailability of HL235.

Authors+Show Affiliations

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea.R&D Center, Hanlim Pharm. Co., Ltd, Seoul 06634, Republic of Korea.College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: ddkim@snu.ac.kr.

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

31765770

Citation

Visetvichaporn, Voradanu, et al. "Formulation of Self-microemulsifying Drug Delivery System (SMEDDS) By D-optimal Mixture Design to Enhance the Oral Bioavailability of a New Cathepsin K Inhibitor (HL235)." International Journal of Pharmaceutics, vol. 573, 2020, p. 118772.
Visetvichaporn V, Kim KH, Jung K, et al. Formulation of self-microemulsifying drug delivery system (SMEDDS) by D-optimal mixture design to enhance the oral bioavailability of a new cathepsin K inhibitor (HL235). Int J Pharm. 2020;573:118772.
Visetvichaporn, V., Kim, K. H., Jung, K., Cho, Y. S., & Kim, D. D. (2020). Formulation of self-microemulsifying drug delivery system (SMEDDS) by D-optimal mixture design to enhance the oral bioavailability of a new cathepsin K inhibitor (HL235). International Journal of Pharmaceutics, 573, 118772. https://doi.org/10.1016/j.ijpharm.2019.118772
Visetvichaporn V, et al. Formulation of Self-microemulsifying Drug Delivery System (SMEDDS) By D-optimal Mixture Design to Enhance the Oral Bioavailability of a New Cathepsin K Inhibitor (HL235). Int J Pharm. 2020 Jan 5;573:118772. PubMed PMID: 31765770.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Formulation of self-microemulsifying drug delivery system (SMEDDS) by D-optimal mixture design to enhance the oral bioavailability of a new cathepsin K inhibitor (HL235). AU - Visetvichaporn,Voradanu, AU - Kim,Kyung-Hee, AU - Jung,Kyungjin, AU - Cho,Yun-Seok, AU - Kim,Dae-Duk, Y1 - 2019/11/23/ PY - 2019/06/11/received PY - 2019/10/04/revised PY - 2019/10/06/accepted PY - 2019/11/26/pubmed PY - 2020/10/24/medline PY - 2019/11/26/entrez KW - Cathepsin K inhibitor KW - D-optimal mixture design KW - Formulation KW - SMEDDS SP - 118772 EP - 118772 JF - International journal of pharmaceutics JO - Int J Pharm VL - 573 N2 - HL235 is a new cathepsin K inhibitor designed and synthesized to treat osteoporosis. Since HL235 has poor aqueous solubility, a self-microemulsifying drug delivery system (SMEDDS) was formulated to enhance its oral bioavailability. A solubility study of HL235 was performed to select a suitable oil, surfactant and cosurfactant. Pseudoternary phase diagrams were plotted to identify the microemulsion region and to determine the range of components in the isotropic mixture. D-optimal mixture design and a desirability function were introduced to optimize the SMEDDS formulation for the desired physicochemical characteristics, i.e., high drug concentration at 15 min after dilution with simulated gastric fluid (SGF) and high solubilization capacity. The optimized HL235-loaded SMEDDS formulation consisted of 5.0% Capmul MCM EP (oil), 75.0% Tween 20 (surfactant) and 20.0% Carbitol (cosurfactant). The droplet size of the microemulsion formed by the optimized formulation was 10.7 ± 1.6 nm, and the droplets were spherical in shape. Pharmacokinetic studies in rats showed that the relative oral bioavailability of the SMEDDS formulation increased up to 3.22-fold compared to its solution in DMSO:PEG400 (8:92, v/v). Thus, the formulation of SMEDDS optimized by D-optimal mixture design could be a promising approach to improve the oral bioavailability of HL235. SN - 1873-3476 UR - https://www.unboundmedicine.com/medline/citation/31765770/Formulation_of_self_microemulsifying_drug_delivery_system__SMEDDS__by_D_optimal_mixture_design_to_enhance_the_oral_bioavailability_of_a_new_cathepsin_K_inhibitor__HL235__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-5173(19)30817-8 DB - PRIME DP - Unbound Medicine ER -