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

Lim, Hyun Tae; Balakrishnan, Pachamuthu; Oh, Dong Hoon; Joe, Kwan Hyung; Kim, Young Ran; Hwang, Doo Hyung; Lee, Yong-Bok; Yong, Chul Soon; Choi, Han Gon

doi:10.1016/j.ijpharm.2010.07.013

Cited by 38 publications

(18 citation statements)

References 24 publications

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“…Moreover, the oral solution gave a similar dissolution rate to the commercial granules. The dissolution profiles of the oral solution and the commercial granules were compared using the following equation of difference factor (f 1 ) and similarity factor (f 2 ); commercial granules, respectively [21,24]. In these equations, 0 \ f 1 \ 15 and 50 \ f 2 \ 100 are a similar correlation between the dissolution patterns of the two products.…”

Section: Resultsmentioning

confidence: 99%

“…For determining the drug solubility in the montelukast sodium-loaded oral solutions, these solutions were filtered through a Whatman nylon filter (0.45 lm) and diluted with the mobile phase [21,22]. The concentrations of drug in these diluted solutions were determined using an HPLC system (Hitachi L-2000 series; Hitachi, Tokyo, Japan) consisting of an octylsilane analytical column (Inertsil Ò C8, 4.6 mm 9 15 cm, 5 lm).…”

Section: Drug Solubilitymentioning

confidence: 99%

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Novel montelukast sodium-loaded clear oral solution prepared with hydroxypropyl-β-cyclodextrin as a solubilizer and stabilizer: enhanced stability and bioequivalence to commercial granules in rats

Kim

Kwon

et al. 2015

J Incl Phenom Macrocycl Chem

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To develop a montelukast sodium-loaded clear oral solution with enhanced stability that was bioequivalent to commercial granules in rats for the treatment of asthma, various montelukast sodium-loaded solutions were prepared with various amounts of solubilizers and stabilizer, and their solubility and stability were investigated. Furthermore, the dissolution and pharmacokinetic studies were carried out in rats with the optimised formulation and the commercial montelukast sodium-loaded granules. Among the solubilizers tested in this study, hydroxypropyl-b-cyclodextrin (HP-b-CD) was selected because it greatly improved the drug solubility and stability. Furthermore, EDTA sodium was used as a stabilizer because it gave excellent stability. In particular, the montelukast-loaded oral solution, an aqueous clear solution containing montelukast sodium, HP-b-CD, methylparaben sodium, propylparaben sodium and EDTA sodium at w/v percentages of 1.04/156/1.8/0.2/1, gave similar dissolution to the commercial granules in 0.5 % (w/v) sodium lauryl sulphate in water, FDA-regulated dissolution medium. This oral solution gave similar plasma concentrations and pharmacokinetic parameters to the commercial granules, suggesting that it was bioequivalent to the commercial granules in rats. Moreover, it was physically and chemically stable at 25°C/60 % RH and 40°C/75 % RH for at least 12 months. Thus, this oral solution is strongly recommended as an alternative to the oral montelukast-loaded product for the treatment of asthma.

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Section: Resultsmentioning

confidence: 99%

Section: Drug Solubilitymentioning

confidence: 99%

Novel montelukast sodium-loaded clear oral solution prepared with hydroxypropyl-β-cyclodextrin as a solubilizer and stabilizer: enhanced stability and bioequivalence to commercial granules in rats

Kim

Kwon

et al. 2015

J Incl Phenom Macrocycl Chem

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“…Thus, the high plasma concentration and bioavailability of the drug from this solid dispersion compared to that of CNM might be related to the enhanced drug solubility and dissolution. 19,23,24) The pharmacokinetic study revealed that this solid dispersion significantly improved the oral bioavailability of the drug compared to that of CB and CNM.…”

Section: Stability Of Cb Cnm and Cnm-loaded Solid Dispersionmentioning

confidence: 99%

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

Kim

Kwon

et al. 2015

Biological & Pharmaceutical Bulletin

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To develop a novel solid dispersion of clopidogrel napadisilate monohydrate (CNM) with improved stability and oral bioavailability, surface-modified solid dispersions were prepared by spray-drying using water as a solvent, Tween 80 as a surfactant, and hydroxypropylmethyl cellulose (HPMC) as a hydrophilic polymer, and optimized according to drug solubility. Its solid-state characterization was evaluated by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The stability study was performed at 50°C/75% RH over a period of 6 weeks. Its dissolution profiles and oral bioavailability in rats were also compared with that of CNM and clopidogrel bisulfate (CB). The solid dispersion, composed of CNM/HPMC/Tween80 at a weight ratio of 10/2.5/2.5, in which CNM was in the crystalline state, increased the drug solubility approximately 4.6-fold. It showed a significantly better dissolution profile than that of CNM in all the dissolution media, and gave either similar or higher dissolution compared to that of CB. This solubility and dissolution enhancement was attributed to improved wetting and solubilization of CNM crystals due to hydrophilic carriers attached on the drug surface. It had excellent stability, thereby addressing the stability problem of CB powder. Furthermore, it increased the area under curve (AUC) values by about 4-fold and 1.6-fold compared to CNM and CB, respectively, suggesting that it improved the oral bioavailability of the drug in rats. Thus, this solid dispersion system prepared with water, HPMC and Tween 80 can be used to enhance the bioavailability of CNM as well as to solve the stability problem of CB.Key words clopidogrel napadisilate monohydrate; surface-modified solid dispersion; water; stability; bioavailability Clopidogrel, a non-competitive inhibitor of adenosine diphosphate in platelets is an orally administered antiplatelet agent prescribed for cerebral and peripheral vascular diseases and for the early and long term secondary prevention of atherothrombotic events in patients with acute coronary syndromes.1) This drug is practically insoluble in water; hence, its commercial salt form, clopidogrel bisulfate (CB) has been widely used in the pharmaceutical industry. CB is highly soluble in water and rapidly absorbed in vivo; however, this salt form is slightly hygroscopic and has been reported not stable under accelerated heat and moisture conditions, producing severe amounts of degradants.2) Thus, to increase the stability of the drug, a new salt form, clopidogrel napadisilate monohydrate (CNM), has been prepared with improved stability.3) Even though CNM demonstrated increased stability, this salt showed poor aqueous solubility compared to the CB salt.3) Therefore, a novel formulation strategy is needed to resolve the solubility issue of stable CNM.Drug solubility remains one of the most challenging aspects of formulation development because it results in poor bioavailability of the drug. Among the various approaches to improve the ...

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“…Quantification was performed by multiple reaction-monitoring (MRM) of the protonated precursor ions and the related product ions, using the ratio of the area under the peak for each solution and a weighting factor of 1/y 2 . The analytical data were processed with Analyst software (MassLynx, version 4.0) (Cho et al, 2010;Lim et al, 2010). The calibration curve was constructed over a range of 1-500 (R 2 = 0.9993) and 10-2500 ng/ml (R 2 = 0.9992) in plasma and with a lower limit of quantification (LLOQ) of 1 and 10 ng/ml for clopidogrel and SR26334, respectively.…”

Section: Hplc-ms-ms Conditionsmentioning

confidence: 99%

“…6). The more HPMC were added to 3 g (against 11.069 g clopidogrel napadisilate), the more increased the drug solubility in the solid dispersions (Lim et al, 2010;Okimoto et al, 1997). However, the solid dispersion prepared with HPMC 4 g (formulation V) hardly improved drug solubility in all solutions compared to those with HPMC 3 g (formulation IV).…”

Section: Clopidogrel Napadisilate-loaded Solid Dispersionmentioning

confidence: 99%

New clopidogrel napadisilate salt and its solid dispersion with improved stability and bioequivalence to the commercial clopidogrel bisulphate salt in beagle dogs

Kim

Suh

et al. 2011

International Journal of Pharmaceutics

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

Cited by 38 publications

References 24 publications

Novel montelukast sodium-loaded clear oral solution prepared with hydroxypropyl-β-cyclodextrin as a solubilizer and stabilizer: enhanced stability and bioequivalence to commercial granules in rats

Novel montelukast sodium-loaded clear oral solution prepared with hydroxypropyl-β-cyclodextrin as a solubilizer and stabilizer: enhanced stability and bioequivalence to commercial granules in rats

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

New clopidogrel napadisilate salt and its solid dispersion with improved stability and bioequivalence to the commercial clopidogrel bisulphate salt in beagle dogs

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