Effect of HM30181 mesylate salt-loaded microcapsules on the oral absorption of paclitaxel as a novel P-glycoprotein inhibitor.
The purpose of this study was to develop HM30181 mesylate salt (HM30181M)-loaded microcapsules as a novel P-glycoprotein inhibitor for enhancing the oral absorption of paclitaxel. The effect of various carriers including hydrophilic polymers and solvents on the solubility of HM30181M were evaluated. Among the hydrophilic polymers and solvents tested, HPMC and methylene chloride (and ethanol) provided the highest HM30181M solubility. Numerous HM30181M-loaded microcapsules were prepared with HPMC, silicon dioxide and acidifying agents using a spray-drying technique, and their solubility, dissolution and physicochemical properties were evaluated. Furthermore, a pharmacokinetic study was performed after oral administration of paclitaxel alone, simultaneously with HM30181M powder or HM30181M-loaded microcapsules to rats. Among the acidifying agents investigated, phosphoric acid provided the best improvement in the solubility and dissolution of HM30181M. Moreover, the microcapsule composed of HM30181M, HPMC, silicon dioxide and phosphoric acid at a weight ratio of 3:6:3:2 remarkably enhanced the solubility and dissolution of HM30181M compared with the HM30181M powder alone. The microcapsules were spherical in shape, had a reduced particle size of about 7μm, and contained HM30181M in an amorphous state. Furthermore, this microcapsule significantly enhanced HM30181M absorption, making it about 1.7-fold faster and 1.6-fold greater after simultaneous administration, leading to about 70- and 2-fold improved oral bioavailability of paclitaxel compared with paclitaxel alone and the simultaneous administration with HM30181M powder, respectively. Thus, this novel microcapsule could be a potential candidate for effective P-glycoprotein inhibition during oral administration of paclitaxel.
College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea; Pharmaceutical Research Centre, Hanmi Pharm. Co., Paltan-myeon, 893-5 Hwaseong, Gyeonggi-Do 445-913, South Korea.
Jin Cheul
JC
Kim
College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea; Pharmaceutical Research Centre, Hanmi Pharm. Co., Paltan-myeon, 893-5 Hwaseong, Gyeonggi-Do 445-913, South Korea.
Kyeong Soo
KS
Kim
College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea.
Dong Shik
DS
Kim
College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea.
Sung Giu
SG
Jin
College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea.
Dong Wuk
DW
Kim
Pharmaceutical Research Centre, Hanmi Pharm. Co., Paltan-myeon, 893-5 Hwaseong, Gyeonggi-Do 445-913, South Korea.
Yong Il
YI
Kim
Pharmaceutical Research Centre, Hanmi Pharm. Co., Paltan-myeon, 893-5 Hwaseong, Gyeonggi-Do 445-913, South Korea.
Jae-Hyun
JH
Park
College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, South Korea.
Jong Oh
JO
Kim
College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, South Korea.
Chul Soon
CS
Yong
School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, South Korea.
Yu Seok
YS
Youn
Pharmaceutical Research Centre, Hanmi Pharm. Co., Paltan-myeon, 893-5 Hwaseong, Gyeonggi-Do 445-913, South Korea. Electronic address: jswoo@hanmi.co.kr.
Jong Soo
JS
Woo
College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea. Electronic address: hangon@hanyang.ac.kr.
Han-Gon
HG
Choi
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000737:chemistry*; D001682:Biological Availability; D002214:Capsules / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry; D007546:Isoquinolines / Q000737:chemistry*; D007785:Lactose / Q000031:analogs & derivatives / Q000737:chemistry; D008297:Male; D008698:Mesylates / Q000737:chemistry*; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010756:Phosphoric Acids / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011208:Powders / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012822:Silicon Dioxide / Q000737:chemistry; D012995:Solubility; D013777:Tetrazoles / Q000737:chemistry*
C521083:4-oxo-4H-chromene-2-carboxylic acid (2-(2-(4-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl)-phenyl)-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl)amide; D018435:ATP Binding Cassette Transporter, Subfamily B; D001578:Benzopyrans; D002214:Capsules; D004337:Drug Carriers; D007546:Isoquinolines; D008698:Mesylates; D010756:Phosphoric Acids; D011108:Polymers; D011208:Powders; D013777:Tetrazoles; C509290:hydroxypropylmethylcellulose-lactose matrix; D012822:Silicon Dioxide; D008747:Methylcellulose; C030242:phosphoric acid; D007785:Lactose; D017239:Paclitaxel
Bioavailability; HM30181 mesylate salt; Microcapsule; P-glycoprotein inhibitor; Paclitaxel; Solubility