• Bulletin of the Korean Chemical Society
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• 제29권4호
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• pp.749-754
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• 2008

To increase the solubility of sibutramine freebase, the solid dispersion was prepared using a fluid-bed granulator. The solid dispersion containing sibutramine freebase was characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). After filling the sibutramine solid dispersion in the gelatin hard capsule, we performed in vitro dissolution test, the stability test under accelerated conditions and pharmacokinetic study in beagle dogs. The DSC and XRD data showed that sibutramine solid dispersion would be amorphous state. The dissolution rate of sibutramine solid dispersion was significantly increased about 70% than sibutramine freebase. The stability of sibutramine solid dispersion capsules was equivalent or above to commercial product of sibutramine. In beagle dogs, the sibutramine solid dispersion showed equivalent pharmacokinetic behavior with commercial product of sibutramine hydrochloride. In conclusion, the solid dispersion system provided a possible way to overcome the low solubility of sibutramine freebase, and the sibutramine solid dispersion can be a bioequivalent with the commercial product in humans.

• Journal of Pharmaceutical Investigation
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• 제40권1호
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• pp.33-38
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• 2010

Sibutramine is a serotonin-norepinephrine reuptake inhibitor indicated for the management of obesity in conjunction with a reduced calorie diet. The oral administration of sibutramine is followed by its dose-related side effects. In this study, sibutramine was formulated into drug in adhesive (DIA) patches in an attempt to overcome these problems. The effects of different formulation variables including pressure-sensitive adhesive (PSA), loading amount of drug, thickness of matrix and enhancer on the skin permeation of the drug were evaluated using excised hairless mouse skin. In the acrylic adhesive with carboxyl functional group, low release of sibutramine was observed due to the strong interaction between carboxyl group of adhesive and amine group of sibutramine. The acrylic adhesive without functional group provided good adhesion force and allowed high drug loading. Changing drug load as well as thickness of the matrix was found to alter permeation rate. $Crovol^{(R)}$ PK40 and $Crovol^{(R)}$ A40, were found to be effective enhancers for sibutramine. The optimized patch contained 20% sibutramine, and 5% $Crovol^{(R)}$ A40 as permeation enhancer, in $80\;{\mu}m$ thick Duro-$Tak^{(R)}$ 87-9301 matrix.

• Journal of Pharmaceutical Investigation
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• 제40권1호
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• pp.15-21
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• 2010

Sibutramine is an orally administered centrally-acting antiobesity agent and inhibits both noradrenaline(norephinephirine) and serotonin(5-HT) reuptake. These effects are contributed by its active metabolites, M1 and M2. However, as the free base form of sibutramine is an oil form in room temperature, it had the problem of handling and stability. Thus, this drug should be used in the form of acid salt form in the pharmaceutical application. Unfortunately, anhydrous sibutramine hydrochloride is highly hygroscopic and unstable. In order to solve the hygroscopicity of the anhydrous salt form, another sibutramine acid salt form must be developed as a hydrate form. In this study. to overcome these problems, various of sibutramine acid salt forms were prepared with the pharmaceutically available salts such as maleate, esylate, mandelate, camsylate, besylate, salicylate, tartrate, isethionate and malate forms, and their physicochemical properties were investigated. Sibutramine malate was selected for excellent solubility and stability among the listed salt forms above. Its pharmacokinetic parameters were evaluated in rats comparing with sibutramine HCl, resulting in similar parameters. In vitro dissolution study of sibutramine malate-loaded capsule was performed comparison with commercial product ($Reductil^{(R)}$) in pH 1.2, pH 4.0, pH 6.8 and water medium. Our results indicated that there were no significant differences in their dissolution profiles were similar in all tested medium. Thus, sibutramine malate-loaded capsule should be a potential candiate due to its excellent solubility, good stability and biosimilar absorption.

• Bulletin of the Korean Chemical Society
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• 제31권6호
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• pp.1496-1500
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• 2010

Sibutramine enantiomers were separated successfully by capillary zone electrophoresis using substituted cyclodextrins as chiral selectors. The effects of cyclodextrin concentration, pH, voltage, buffer type, and electrolyte concentration on the migration time and resolution of enantiomers were examined. Separation of sibutramine enantiomers on an unmodified fused silica capillary (total length, 54 cm; effective length, 45 cm) was achieved using a mixed buffer of 20 mM phosphate/10 mM citrate containing either 5 mM methyl-${\beta}$-cyclodextrin (pH 4.3) or 5 mM carboxymethyl-${\beta}$-cyclodextrin (pH 6.5). Samples were injected with a pressure of 50 mbar for 5 s and were detected at a wavelength of 223 nm. The established method showed good precision and accuracy, with intra- and inter-day variations of less than 2.9 and 4.7%, respectively, and recoveries of 95.7 - 103.8%. The stability constants of (R)- and (S)-sibutramine demonstrated that the resolution of sibutramine enantiomers was attributable primarily to the difference in stability constants. When this optimized method was applied to the determination of sibutramine enantiomers in commercial drug formulations, it proved to be economical and convenient, affording sufficient accuracy, precision, and reproducibility as well as sensitivity and selectivity.

• 폴리머
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• 제32권3호
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• pp.193-198
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• 2008

시부트라민은 비만을 치료하기 위한 식욕억제제로서 높은 결정성을 갖는 난용성 약물이다. 이러한 난용성 약물의 용해도를 증가시키기 위하여 고체분산법을 바탕으로 한 분무건조기를 이용하여 미립구를 제조할 수 있었다. 제조된 미립구는 주사전자현미경을 이용하여 제조시 사용한 용매에 따른 미립구 형태차이를 확인할 수 있었으며 용매증발 속도가 빠를수록 구형을 이루는 것을 확인할 수 있었다. X선 회절기를 이용하여 제조된 미립구에서 시부트라민의 결정성이 10%이하로 감소되었음을 확인하였다. 제조된 미립구는 pH 1.2와 pH 6.8에서 방출을 실시하였으며 시부트라민이 pH에 따라서 용해도 차이가 크다는 것을 확인하였다. 또한, 경필 캡슐을 이용한 것이 정제형태보다 방출이 약 4배 정도 빠르다는 것을 확인할 수 있었다. 이러한 결과를 바탕으로 제형의 형태에 따라 방출거동이 조절될 수 있음을 확인하였다.

• Biomolecules & Therapeutics
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• 제23권4호
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• pp.386-389
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• 2015

Sibutramine is an anorectic that has been banned since 2010 due to cardiovascular safety issues. However, counterfeit drugs or slimming products that include sibutramine are still available in the market. It has been reported that illegal sibutramine-contained pharmaceutical products induce cardiovascular crisis. However, the mechanism underlying sibutramine-induced cardiovascular adverse effect has not been fully evaluated yet. In this study, we performed cardiovascular safety pharmacology studies of sibutramine systemically using by hERG channel inhibition, action potential duration, and telemetry assays. Sibutramine inhibited hERG channel current of HEK293 cells with an $IC_{50}$ of $3.92{\mu}M$ in patch clamp assay and increased the heart rate and blood pressure ($76{\Delta}bpm$ in heart rate and $51{\Delta}mmHg$ in blood pressure) in beagle dogs at a dose of 30 mg/kg (per oral), while it shortened action potential duration (at $10{\mu}M$ and $30{\mu}M$, resulted in 15% and 29% decreases in $APD_{50}$, and 9% and 17% decreases in $APD_{90}$, respectively) in the Purkinje fibers of rabbits and had no effects on the QTc interval in beagle dogs. These results suggest that sibutramine has a considerable adverse effect on the cardiovascular system and may contribute to accurate drug safety regulation.

• 대한임상독성학회지
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• 제7권2호
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• pp.176-179
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• 2009

A 38-year-old woman was admitted to our hospital due to agitation, nausea, chest discomfort, tachycardia and hypertension 6h after ingesting approximately 60 capsules of sibutramine. The woman developed the clinical features of acute psychosis, including auditory hallucination, agitation and paranoid ideation, on day 2. No relevant changes were detected on the laboratory examinations or on the electrocardiogram throughout the period of hospitalization. She was treated with risperidone and benzodiazepine. The symptoms subsequently resolved completely with cessation of the provoking agent. The patient was discharged on day 7 and the follow-up revealed no sequelae for 5 months.

• Genomics & Informatics
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• 제6권3호
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• pp.117-125
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• 2008

Recently, obesity has become a worldwide public health concern and the use of anorectic drugs has drastically increased. In this study, sibutramine and phendimetrazine, representative marketed anorectics, were repeatedly administered per os on a daily basis into C57BL/6 mice and the effects of these drugs on food intakes, body weight changes and gene expression profiles were monitored for up to following 7 days. Methamphetamine, which has a potent anorectic effect, was used as a positive control. Anorectic effects were sustained only for two days by phendimetrazine or methamphetamine, but for six days by sibutramine. The modulations of gene expressions in the hypothalamus and the striatum were investigated using microarrays on day 2 and day 7 post-administration, which corresponded to the anorectic period and a return of appetite respectively, for all three drugs tested. Differences in overall gene expression profiles in the stratum on day 2 for sibutramine and phendimetrazine seems to reflect difference between the two in terms of the onsets of drug tolerance. According to microarray findings, the Ankrd26 gene appears to have an important anorectic role, whereas the up-regulation of the olfaction system appeared to be involved in the drug tolerance of anorectics. The microarray data presented in this study demonstrates the usefulness of gene expression analysis for gathering information on the efficacy and safety of anorectic drugs.

• 동의생리병리학회지
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• 제19권5호
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• pp.1267-1271
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• 2005

To investigate the effect of the frequently used anti-obese medicine GyeongshinhaeGihwan 1 (GGT1), in food intake, body weight and food efficiency ratio for high fat diet induced obese male rats. Also, to value the diffences between GyeogshinhaeGihwan 1 and FDA approved Sibutramine in anti-obesity effect. High fat diet induced obese male rats were classified into four groups - positive control group, negative control group, GyeongshinhaeGihwan 1 group and Sibutramine group - and their food intake and body weight were observed for eight weeks. Anti-obesity effect was estimated with food efficiency ratio which is calculated by weight inclose divided by food intake. The result shown in Fig. 2 suggests that the GyeongshinhaeGihwan 1 group is more effective on food intake control than the Sibutramine group. Average weight variation shows an increase in both positive/negative control group and medication group. Also, the result in Fig. 3 indicates that average food efficiency ratio decreases contrary to the average weight variation. In addition, repeatedly estimated variance analysis on average food efficiency ratio of the GyeonushinhaeGihwan 1 group shows (1) the result corollary to the time of observation of food efficiency ratio was effective under 0.05 variance (P-value 0.000). The differences between each groups were not shown under 0.05 variance. Compared to the control group, medication groups were visually more effective on food intake control. Although both groups had a tendency of weight increasing, food efficiency ratio considering food intake and weight variation rate showed a decrease. Especially, the medication group variated less than the control group corollary to the point of time, proving the individuals react less sensitive to the medicine. Moreover, there were no differences in the anti-obesity effect between GyeongshinhaeGihwan 1 group and Sibutramine group studied by repeatedly estimating variance analysis(P-value: 0.610). When considering Sibutramine as an anti-obesity medicine approved by FDA, the point of being classifed in the same group proves the effect of GyeongshinhaeGihwan 1 as an anti-obesity medicine.

• Journal of Pharmaceutical Investigation
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• 제41권1호
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• pp.45-50
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• 2011

Nonclassical pathway of crystallization has been utilized to modify the properties and morphologies of inorganic and organic/inorganic materials. In here, the polymer-directed crystallization method has been applied to the pharmaceutical active ingredient to assess the applicability for as a particle engineering tool. The polymer-directed crystallization was successful to modifying the crystal size, habit and morphology, but it was not effective to discover the novel polymorphs of Sibutramine (SB). SB was selected as a model drug and polyacrylic acid (PAA), polyethylene imine (PEI) and chitosan (CHI) were added as a crystallization pathway modifier. SB was crystallized via drowning crystallization using methanol or ethanol as a solvent and water as a non-solvent. The significant interactions between polymer and the drug were confirmed by measuring the solubility of the drug in presence of polymer during the crystallization. The crystal forms of SB are characterized by X-ray diffraction (XRD), scanning electron microscope (SEM) and optical microscope (OM). The polymer-directed crystallization seems to be able to modify the crystal properties of pharmaceutical active ingredient, which is critical in determining the bioavailability, processability, and stability.