ABSTRACT
Sibutramine hydrochloride monohydrate, chemically 1-(4-chlorophenyl)-N,N-dimethyl-alpha-(2-methylpropyl) hydrochloride monohydrate (SB.HCI.H20), was approved by the U.S. Food and Drug Administration for the treatment of obesity. The objective of this study was to develop, validate, and compare methods using UV-derivative spectrophotometry (UVDS) and reversed-phase high-performance liquid chromatography (HPLC) for the determination of SB.HCI.H20 in pharmaceutical drug products. The UVDS and HPLC methods were found to be rapid, precise, and accurate. Statistically, there was no significant difference between the proposed UVDS and HPLC methods. The enantiomeric separation of SB was obtained on an alpha-1-acid glycoprotein column. The R- and S-sibutramine were eluted in < 5 min with baseline separation of the chromatographic peaks (alpha = 1.9 and resolution = 1.9).
Subject(s)
Cyclobutanes/analysis , Appetite Depressants/analysis , Appetite Depressants/chemistry , Appetite Depressants/standards , Chromatography, High Pressure Liquid/methods , Chromatography, High Pressure Liquid/standards , Chromatography, High Pressure Liquid/statistics & numerical data , Cyclobutanes/chemistry , Cyclobutanes/standards , Humans , Quality Control , Reference Standards , Reproducibility of Results , Sensitivity and Specificity , Solid Phase Extraction/methods , Spectrophotometry, Ultraviolet/methods , Spectrophotometry, Ultraviolet/standards , Spectrophotometry, Ultraviolet/statistics & numerical data , StereoisomerismABSTRACT
Controlled studies have shown that sibutramine produces dose-related weight loss when given in the range 5-30 mg per day, with optimal doses of 10 and 15 mg per day. Weight loss with sibutramine is 3-5 kg better than placebo at 24 weeks, and weight loss is maintained to 52 weeks at doses of 10 and 15 mg. By six months, 69% of patients treated with sibutramine 15 mg achieve a 5% or greater reduction in their baseline weight. The weight loss achieved with sibutramine was similar to that achieved with dexfenfluramine over 12 weeks (4.5 kg compared with 3.2 kg). Sibutramine-induced weight loss has been found to be accompanied by a significant reduction in waist/hip ratio, and decreases in plasma triglycerides, total cholesterol and low density lipoprotein (LDL) cholesterol. There were also increases in high density lipoprotein (HDL) cholesterol. In patients with type II diabetes, sibutramine-induced weight loss was accompanied by a shift towards improved glycaemic control. In controlled studies, 84% of sibutramine-treated patients reported adverse events, compared with 71% of patients receiving placebo. The most frequently reported adverse events are related to pharmacological actions of sibutramine, and include dry mouth, decreased appetite, constipation and insomnia.