Pharmaceutical Nanotechnology
Development of novel sibutramine base-loaded solid dispersion with gelatin and HPMC: Physicochemical characterization and pharmacokinetics in beagle dogs

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Abstract

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 (f1) 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 (f2) 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, Cmax and Tmax 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.

Introduction

Obesity is a chronic, multifactorial disorder that has reached epidemic proportions in most industrialized countries and is threatening to become a global epidemic (Popkin, 1998). The risks of morbidity and mortality increase with increasing body weight and waist circumference (an index of the visceral localization of fat). Obese patients have higher risks for coronary artery disease, hypertension, hyperlipidemia, diabetes mellitus, certain cancers, cerebrovascular accident, osteoarthritis, obstructive pulmonary disease, and sleep apnea (Rippe et al., 1998). Efforts to develop innovative anti-obesity drugs have intensified, and there have been calls for medically based outcome measures for obesity treatments that are more appropriate than those currently used (Clapham et al., 2001, Halpern and Mancini, 2003).

Sibutramine, an anti-obesity drug, is a potent inhibitor of the reuptake of noradrenaline and serotonin (Carek and Dickerson, 1999), and may stimulate thermogenesis by its activation of β3-adrenoceptors in brown adipose tissue (Connoley et al., 1999, McNeely and Goa, 1998). Sibutramine base has not been used in commercial products due to its poor water-solubility and instability. It has a solubility of about 0.01 mg/ml and a melting point of about 55 °C (Li et al., 2010). However, sibutramine hydrochloride monohydrate, a salt form, has been used in a commercial product (Reductil®) because of its improved solubility and stability (McNeely and Goa, 1998). It has a solubility of about 3 mg/ml at pH 5.2 and a melting point of about 190 °C (Fang et al., 1999). Recently, considerable attention has been focused on the improvement of drug solubility by synthesizing different salt forms. Sibutramine mesylate (Kim et al., 2005) and sibutramine tartrate (HPC, 2006) have been synthesized, and showed an increase in solubility to 2500 and 500 mg/ml at pH 5.2, respectively. However, in order to use these new synthesized materials as commercial products, clinical tests must be carried out. Another oral formulation of sibutramine base, a solid dispersion prepared with poloxamer, was developed but showed little improvement in solubility (Li et al., 2010, Sheen et al., 1995).

Thus, in this study, in order to develop a novel sibutramine base-loaded solid dispersion with enhanced solubility and bioavailability, various solid dispersion systems 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 compared with a sibutramine hydrochloride monohydrate-loaded commercial product.

Section snippets

Materials

Sibutramine base, HPMC 2910 (hydroxypropylmethylcellulose 2910) and gelatin were obtained from Cipla Co. (India), Shin-Etsu Co. (Tokyo, Japan) and Sammi Co. (Anyang, South Korea), respectively. Citric acid was provided by Yung-Jin Pharm. Co. (Anyang, South Korea) and was of USP grade. The commercial product (Reductil®; in capsule form) was purchased from Abbott Korea Co. (Seoul, South Korea). All other chemicals were of reagent grade and were used without further purification.

Animals

All animal care

Results and discussion

In this study, the solid dispersion system was prepared using a spray drying technique with hydrophilic polymers in order to improve the solubility of the poorly water-soluble sibutramine base. Hydrophilic polymers such as gelatin and HPMC were dissolved in 30% ethanol and the poorly water-soluble drug was suspended or dissolved in these solutions. The resulting solutions were spray-dried so that the sibutramine base formed a solid dispersion together with the hydrophilic polymers (Joe et al.,

Conclusion

In conclusion, the sibutramine base-loaded solid dispersion composed of sibutramine base/gelatin/HPMC/citric acid at the weight ratio of 1/0.8/0.2/0.5 gave a solubility of 5.03 ± 0.24 mg/ml. Furthermore, it showed similar dissolution to the sibutramine hydrochloride monohydrate-loaded commercial product and was 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

Acknowledgements

This work was supported by Mid-career Researcher Program through NRF grant funded by the MEST (No. 2010-0000363) and financially supported by the Ministry of Science and Technology (M10414030001-05N1403-00140) in South Korea.

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