Development of novel sibutramine base-loaded solid dispersion with gelatin and HPMC: physicochemical characterization and pharmacokinetics in beagle dogs.
To develop a novel sibutramine base-loaded solid dispersion with enhanced solubility and bioavailability, various solid dispersions were prepared using a spray drying technique with hydrophilic polymers such as gelatin, HPMC and citric acid. Their solubility, thermal characteristics and crystallinity were investigated. The dissolution and pharmacokinetics of the sibutramine base-loaded solid dispersion were then compared with a sibutramine hydrochloride monohydrate-loaded commercial product (Reductil). The solid dispersions prepared with gelatin gave higher drug solubility than those prepared without gelatin, irrespective of the amount of polymer. The sibutramine base-loaded solid dispersions containing hydrophilic polymer and citric acid showed higher drug solubility compared to sibutramine base and sibutramine hydrochloride monohydrate. Among the formulations tested, the solid dispersion composed of sibutramine base/gelatin/HPMC/citric acid at the weight ratio of 1/0.8/0.2/0.5 gave the highest solubility of 5.03+/-0.24 mg/ml. Our DSC and powder X-ray diffraction results showed that the drug was present in an altered amorphous form in this solid dispersion. The difference factor (f(1)) values between solid dispersion and commercial product were 2.82, 6.65 and 6.31 at pH 1.2, 4.0 and 6.8, respectively. Furthermore, they had the similarity factor (f(2)) value of 65.68, 53.43 and 58.97 at pH 1.2, 4.0 and 6.8, respectively. Our results suggested that the solid dispersion and commercial product produced a similar correlation of dissolution profiles at all pH ranges. The AUC, C(max) and T(max) of the parent drug and metabolite I and II from the solid dispersion were not significantly different from those of the commercial product, suggesting that the solid dispersion might be bioequivalent to the commercial product in beagle dogs. Thus, the sibutramine base-loaded solid dispersion prepared with gelatin, HPMC and citric acid is a promising candidate for improving the solubility and bioavailability of the poorly water-soluble sibutramine base.
Lim
Hyun-Tae
HT
College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, South Korea.
Balakrishnan
Prabagar
P
Oh
Dong Hoon
DH
Joe
Kwan Hyung
KH
Kim
Young Ran
YR
Hwang
Doo Hyung
DH
Lee
Yong-Bok
YB
Yong
Chul Soon
CS
Choi
Han-Gon
HG
D000818:Animals; D019440:Anti-Obesity Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D055598:Chemical Phenomena; D003503:Cyclobutanes / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D003890:Desiccation; D004285:Dogs; D004337:Drug Carriers; D005780:Gelatin; D065347:Hypromellose Derivatives; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives; D011108:Polymers / Q000737:chemistry; D011208:Powders; D012995:Solubility
D019440:Anti-Obesity Agents; D003503:Cyclobutanes; D004337:Drug Carriers; D011108:Polymers; D011208:Powders; D065347:Hypromellose Derivatives; D005780:Gelatin; D008747:Methylcellulose; C058254:sibutramine