• Title/Summary/Keyword: Sibutramine

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Biopharmaceutical Evaluation of a Solid Dispersion System Containing Sibutramine Freebase

  • Lee, Min-Suk;Chang, Hee-Chul;Kim, Taewan;Park, Jung-Hwa;Lee, Bong-Sang;Kim, Sung-Hee;Kim, Do-Hwan;Kim, Bo-Gyun;Oh, Seong-Tae;Kang, Myung-Joo;Park, Jong-Hyeok;Lee, Jaehwi;Choi, Young-Wook
    • Bulletin of the Korean Chemical Society
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    • v.29 no.4
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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.

Formulation and Evaluation of Transdermal Patch Containing Sibutramine

  • Subedi, Robhash Kusam;Jang, Jun-Ho;Kim, Jae-Il;Park, Young-Joon;Choi, Hoo-Kyun
    • Journal of Pharmaceutical Investigation
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    • v.40 no.1
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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.

Development of Pharmaceutical Dosage Form with New Sibutramine Salt (시부트라민 신규염을 이용한 새로운 시부트라민 제제의 개발)

  • Moon, Jin-Wook;Shin, Teak-Hwan;Lee, Dong-Wook;Cho, Jun-Young;Chang, Sung-Ju;Hwang, Sung-Joo
    • Journal of Pharmaceutical Investigation
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    • v.40 no.1
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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.

Enantioseparation and Determination of Sibutramine in Pharmaceutical Formulations by Capillary Electrophoresis

  • Zhu, Hongmei;Wu, Enqi;Chen, Jianbo;Men, Chuvan;Jang, Yu-Seon;Kang, Won-Ku;Choi, Jung-Kap;Lee, Won-Jae;Kang, Jong-Seong
    • Bulletin of the Korean Chemical Society
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    • v.31 no.6
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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.

Sibutramine Release Behavior from Microspheres Prepared by Spray-Dry Method (분무건조 방법으로 제조된 미립구에서 Sibutramine의 방출거동)

  • Park, Jung-Soo;Oh, Jung-Soo;Oh, Jae-Min;Kim, Yun-Tae;Lee, Jun-Hee;Mo, Jong-Hyun;Lee, Hai-Bang;Khang, Gil-Son
    • Polymer(Korea)
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    • v.32 no.3
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    • pp.193-198
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    • 2008
  • Sibutramine is a highly crystalline and poorly water soluble drug as the appetite depressant for obesity treatment. In order to increase water solubility of sibutramine, microspheres including sibutramine were prepared by solid dispersion method using a spray dryer. The crystallinity and morphology of the prepared microspheres were confirmed by SEM and XRD. The morphology of micro spheres has gradually changed into spherical shape as increasing evaporation rate of solvent. According to XRD analysis, crystallinity of sibutramine in micro spheres was decreased by below 10%. Release behavior of microspheres was investiaged at pH 1.2, pH 6.8, and solubility of the sibutramine was significantly different depending on pH. The hard capsule showed fast release of sibutramine comparing with the tablet. These results demonstrated that the pharmaceutical preparation is able to control the release behaviors.

Cardiovascular Safety Pharmacology of Sibutramine

  • Yun, Jaesuk;Chung, Eunyong;Choi, Ki Hwan;Cho, Dae Hyun;Song, Yun Jeong;Han, Kyoung Moon;Cha, Hey Jin;Shin, Ji Soon;Seong, Won-Keun;Kim, Young-Hoon;Kim, Hyung Soo
    • Biomolecules & Therapeutics
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    • v.23 no.4
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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.

A Case of Acute Psychosis after Sibutramine Ingestion (시부트라민(sibutramine) 음독 후 발생된 급성 정신병증 1례)

  • Kim, Hyung-Min;Woo, Seon-Hee;Choi, Se-Min;So, Byung-Hak
    • Journal of The Korean Society of Clinical Toxicology
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    • v.7 no.2
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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.

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Gene Expression Profiling in C57BL/6 Mice Treated with the Anorectic Drugs Sibutramine and Phendimetrazine and Their Mechanistic Implications

  • Ko, Moon-Jeong;Choi, Hyo-Sung;Ahn, Joon-Ik;Kim, So-Young;Jeong, Ho-Sang;Chung, Hye-Joo
    • Genomics & Informatics
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    • v.6 no.3
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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.

Study on Effect of GyeongshinhaeGihwan 1 in Body Weight and Food Intake for High fat Diet Induced Obese Male Rats (고지방식이 수컷 비만백서에서 경신해지환(輕身解脂丸)이 체중 및 사료섭취량에 미치는 영향)

  • Jung Yang-Sam;Yoon Ki-Hyeon;Choi Seung-Bae;Shin Soon-Shik
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.19 no.5
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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.

Polymer-directed Crystallization of Sibutramine using Cellulose Derivatives

  • Bae, Ha-Rim;Lee, Hye-Seung;Lee, Min-Kyung;Lee, Jong-Hwi
    • Journal of Pharmaceutical Investigation
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    • v.41 no.1
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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.