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Int J Pharm. 2017 Jun 15;525(1):60-70. doi: 10.1016/j.ijpharm.2017.04.028. Epub 2017 Apr 13.

Novel dabigatran etexilate hemisuccinate-loaded polycap: Physicochemical characterisation and in vivo evaluation in beagle dogs.

Author information

1
College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea; Pharmaceutical Research Centre, Hanmi Pharm. Co., Paltan-myeon, 893-5 Hwaseong, Gyeonggi-Do 445-913, Republic of Korea.
2
College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea.
3
Pharmaceutical Research Centre, Hanmi Pharm. Co., Paltan-myeon, 893-5 Hwaseong, Gyeonggi-Do 445-913, Republic of Korea; College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, Republic of Korea.
4
College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, Republic of Korea.
5
School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, Republic of Korea.
6
College of Pharmacy, Chung-Ang University, 221 Heuksuk-dong Dongjak-gu, Seoul 156-756, Republic of Korea.
7
Pharmaceutical Research Centre, Hanmi Pharm. Co., Paltan-myeon, 893-5 Hwaseong, Gyeonggi-Do 445-913, Republic of Korea. Electronic address: jswoo@hanmi.co.kr.
8
College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea. Electronic address: hangon@hanyang.ac.kr.

Abstract

The purpose of this study was to develop a novel dabigatran etexilate hemisuccinate (DEH) salt-loaded polycap with bioequivalence to the dabigatran etexilate mesylate (DEM)-loaded commercial product. DEH prepared with dabigatran etexilate base (DE) and succinic acid was less hygroscopic but less soluble than DEM. Numerous micronized DEHs and DEH-loaded solid dispersions were prepared employing the spiral jet-milling and spray-drying techniques, respectively. Among the formulations prepared, a micronized DEH prepared with the injection air at 1.5bar and the grinding air at 2bar, and a DEH-loaded solid dispersion prepared with 6g HPMC most improved the drug solubility, respectively. Moreover, the micronized DEH provided more increased drug solubility and dissolution compared with the solid dispersion, even though its drug solubility was still lower than that of DEM. Unlike the situation in other studies, the enhanced solubility and dissolution of DEH was more due to particle size reduction than to a change to the amorphous form. The micronized DEH prepared with Myrj 52S had greater drug solubility than preparations with other surfactants. Among the organic acids investigated, only fumaric acid (128.8mg) showed a similar pattern in pH changes to the DEM-loaded commercial product. Furthermore, in order to make the environment acidic while preventing the direct contact of the drug with fumaric acid, the polycap was composed of a tablet containing the micronized DEH, Myrj 52S and other ingredients, and separate fumaric acid. This micronized DEH-loaded polycap was dissolution- and bio-equivalent to the DEM-loaded commercial product in beagle dogs. Thus, the novel micronized DEH-loaded polycap would be a promising alternative to the DEM-loaded commercial product.

KEYWORDS:

Bioequivalence; Dabigatran etexilate; Dabigatran etexilate hemisuccinate; Jet milling; Pulverisation; Solubility

PMID:
28414137
DOI:
10.1016/j.ijpharm.2017.04.028
[Indexed for MEDLINE]

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