Enhanced Solubility and Bioavailability of Sibutramine Base by Solid Dispersion System with Aqueous Medium

Abstract

Sibutramine [1-(4-chlorophynyl)-N,N-dimethyl-a-(2-methylpropyl)cyclobutane methane amine] is a newer antiobesity drug with a novel mechanism of action.1) It contains a potent inhibitor of the reuptake of noradrenaline (NA), serotonin (5-HT) and may stimulate thermogenesis by its activation of b 3 -adrenoceptors in brown adipose tissue. [2][3][4] In human subjects, sibutramine is rapidly metabolized to an Nmono-desmethyl metabolite (desmethylsibutramine [Metabolite I]) and an N,N-didesmethyl metabolite (didesmethylsibutramine [Metabolite II]). The in vivo effects of sibutramine are predominantly the results of the action of the above 2 metabolites. 4-7)Sibutramine hydrochloride monohydrate is the commercially available formulation of sibutramine with the relatively high solubility of 2.9 mg/ml at pH 5.2 and melting point of 190°C. 4,8) However, sibutramine base with low solubility has not been used in commercial formulation. Various oral formulations of sibutramine such as another salt form such as sibutramine mesylate 9,10) and sibutramine tartrate, 11) solid dispersions with poloxamer [12][13][14] and inclusion complex. 15)One of the well established method for increasing the solubility and bioavailability of poorly water-soluble drugs is solid dispersion.16) Several conventional methods such as melting, solvent evaporation and solvent wetting were reported to prepare solid dispersions. 17,18) However, the solid dispersion prepared by melting method with high temperature might chemically decompose the drugs. 19,20) In the case of solvent evaporation and solvent wetting method, the drug in the solid dispersions changed to amorphous form, resulting that the drug might be unstable. 18) Furthermore, a large amount of hydrophilic carriers against drug in these conventional solid dispersions must be needed to improve the solubility of poorly water-soluble drugs. 21,22) In this study, to improve the bioavailability of poorly water-soluble sibutramine base, various sibutramine baseloaded 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 then investigated. The physicochemical properties of solid dispersion were investigated using scanning electron microscope (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 ® ). This commercial product is a conventional capsule which contains 100 mg sibutramine hydrochloride monohydrate and is usually taken multiple times a day. Poloxamer has been employed to enhance the solubility and bioavailability of poorly water-soluble drugs. 19,23) HPMC is frequently used in the preparation of conventional pharmaceutical oral dosage form due to its hydrophilic and soft property. 24,25) To develop a novel sibutramine base-...

Effect of the solid-dispersion method on the solubility and crystalline property of tacrolimus

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“…Several solid-dispersion methods such as the melting method, the solvent-evaporation method and the solvent-wetting method were previously reported to prepare the solid dispersions (Miller et al, 2007;Leuner and Dressman, 2000;Yamashita et al, 2003). Moreover, a novel solid-dispersion system termed 'surface-attached solid dispersion' has been developed (Li et al, 2010;Park et al, 2009). Unlike other solid dispersions, surface-attached solid dispersion is prepared with water and carriers without an organic solvent for enhancing the solubility and stability of poorly watersoluble drugs.…”

“…This solid-dispersion method has several advantages over other methods on an industrial scale, such as there being no necessity to remove an organic solvent, less potential toxicity and no danger of explosion of organic solvents. Furthermore, this solid dispersion could enhance the solubility and bioavailability of poorly water-soluble drugs without changing their crystalline state (Li et al, 2010;Park et al, 2009).…”

Clopidogrel Napadisilate Monohydrate Loaded Surface-Modified Solid Dispersion: Physicochemical Characterization and <i>in Vivo</i> Evaluation

“…HPMC (4567.6±666.5 µg/mL) and Tween 80 (5628.4±55.8 µg/mL) increased drug solubility to the greatest degree among the tested hydrophilic polymers and surfactants (data not shown). 9) In addition, these carriers have been widely used as additives in the pharmaceutical industry, 13,14) and are regarded as non-toxic and non-irritant ingredients.…”

Preparation and characterization of emulsified solid dispersions containing docetaxel

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