Enhanced solubility and bioavailability of sibutramine base by solid dispersion system with aqueous medium.
To develop a novel sibutramine base-loaded solid dispersion with improved solubility bioavailability, various solid dispersions were prepared with water, hydroxypropylmethyl cellulose (HPMC), poloxamer and citric acid using spray-drying technique. The effect of HPMC, poloxamer and citric acid on the aqueous solubility of sibutramine was investigated. The physicochemical properties of solid dispersion were investigated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction. The dissolution and pharmacokinetics in rats of solid dispersion were evaluated compared to the sibutramine hydrochloride monohydrate-loaded commercial product (Reductil). The sibutramine base-loaded solid dispersion gave two type forms. Like conventional solid dispersion system, one type appeared as a spherical shape with smooth surface, as the carriers and drug with relatively low melting point were soluble in water and formed it. The other appeared as an irregular form with relatively rough surface. Unlike conventional solid dispersion system, this type changed no crystalline form of drug. Our results suggested that this type was formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting from changing the hydrophobic drug to hydrophilic form. The sibutramine-loaded solid dispersion at the weight ratio of sibutramine base/HPMC/poloxamer/citric acid of 5/3/3/0.2 gave the maximum drug solubility of about 3 mg/ml. Furthermore, it showed the similar plasma concentration, area under the curve (AUC) and C(max) of parent drug, metabolite I and II to the commercial product, indicating that it might give the similar drug efficacy compared to the sibutramine hydrochloride monohydrate-loaded commercial product in rats. Thus, this solid dispersion system would be useful to deliver poorly water-soluble sibutramine base with enhanced bioavailability.
Li
Dong Xun
DX
College of Pharmacy, Yeungnam University, 214-1 Dae-dong, Gyongsan 712-749, South Korea.
Jang
Ki-Young
KY
Kang
Wonku
W
Bae
Kyoungjin
K
Lee
Mann Hyung
MH
Oh
Yu-Kyoung
YK
Jee
Jun-Pil
JP
Park
Young-Joon
YJ
Oh
Dong Hoon
DH
Seo
Youn Gee
YG
Kim
Young Ran
YR
Kim
Jong Oh
JO
Woo
Jong Soo
JS
Yong
Chul Soon
CS
Choi
Han-Gon
HG
D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003503:Cyclobutanes / Q000737:chemistry* / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014867:Water / Q000737:chemistry*
D003503:Cyclobutanes; D014867:Water; C058254:sibutramine