ABSTRACT
To overcome the problems associated with bioavailability and systemic side effects of the drug by oral administration, monolithic matrix type transdermal patches containing cinnarizine (CNZ) were developed. For this purpose, films based on hydroxypropyl methylcellulose and polyvinylpyrrolidone as matrix-forming polymers were designed. Physical characteristics of transdermal films and drug-excipient compatibility were investigated. Factors affecting in vitro drug release and ex vivo skin penetration and permeation of the drug were studied. It was confirmed that films displayed sufficient flexibility and mechanical strength for application onto the skin for a long time period. Ex vivo penetration experiments gave satisfactory results for transdermal drug delivery through rat skin. The parameters determining good skin penetration were also evaluated. The highest drug permeation rate was obtained with incorporation of Transcutol® (0.102 mg/cm2/h) into the base CNZ formulation, followed by propylene glycol (0.063 mg/cm2/h), menthol (0.045 mg/cm2/h), and glycerin (0.021 mg/cm2/h) as penetration enhancers (p < 0.05). As a result, the developed transdermal patches of CNZ may introduce an alternative treatment for various conditions and diseases such as idiopathic urticarial vasculitis, Ménière's disease, motion sickness, nausea, and vertigo. Thus, the risk of systemic side effects caused by the drug can be reduced or eliminated
Subject(s)
Administration, Oral , Cinnarizine , Histamine Agonists/adverse effects , Cholinergic Antagonists , Anesthetics/classification , Skin , In Vitro Techniques/methods , Pharmaceutical Preparations/analysis , Hypromellose Derivatives/adverse effects , Drug LiberationABSTRACT
OBJECTIVE: To develop a gradient supercritical fluid chromatography method for the separation of cinnarizine and its four related substances. METHODS: Cinnarizine and its four related substances were separated on a Torus DIOL column (3.0 mm×100 mm,1.7 μm) maintained at 40 ℃ with the mobile phase consisting of CO2 and methanol with 0.1% TFA-0.1% TEA at 1.5 mL•min-1, the detection wavelength was set at 230 nm and the back pressure was set at 1.38×107 Pa. RESULTS: Cinnarizine and its four related substances were separated in 4.5 min with satisfying resolutions. Good linear relationships were established between the peak response and the concentration in the range of 2-20 μg•mL-1 for each related substance (r>0.999 9) and the detection limits were 0.7-1.3 ng(S/N≥3). Good linear relationships were established between the peak response and the concentration in the range of 0.05-1.0 μg•mL-1 for cinnarizine (r=1.000 0). The spiked recovery of four related substances of cinnarizine was 98.0%-106.7%, and the RSD was 2.57%-4.44%(n=9). CONCLUSION: The established method can be applied in the simultaneous determination of the related substances of cinnarizine and provide reference for the quality control.
ABSTRACT
ABSTRACT Formulators face great challenges in adopting systematic approaches for designing self-nanoemulsifying formulations (SNEFs) for different drug categories. In this study, we aimed to build-up an advanced SNEF development framework for weakly basic lipophilic drugs, such as cinnarizine (CN). First, the influence of formulation acidification on CN solubility was investigated. Second, formulation self-emulsification in media with different pH was assessed. Experimentally designed phase diagrams were also utilized for advanced optimization of CN-SNEF. Finally, the optimized formulation was examined using cross polarizing light microscopy for the presence of liquid crystals. CN solubility was significantly enhanced upon external and internal acidification. Among the various fatty acids, oleic acid-based formulations showed superior self-emulsification in all the tested media. Surprisingly, formulation turbidity and droplet size significantly decreased upon equilibration with CN. The design was validated using oleic acid/Imwitor308/Cremophor El (25/25/50), which showed excellent self-nanoemulsification, 43-nm droplet size (for CN-equilibrated formulations), and 88 mg/g CN solubility. In contrast to CN-free formulations, CN-loaded SNEF presented lamellar liquid crystals upon 50% aqueous dilution. These findings confirmed that CN-SNEF efficiency was greatly enhanced upon drug incorporation. The adopted strategy offers fast and accurate development of SNEFs and could be extrapolated for other weakly basic lipophilic drugs.
Subject(s)
Solubility/drug effects , Process Optimization/classification , Cinnarizine/analysis , Drug Compounding/statistics & numerical data , Acidification/analysisABSTRACT
Objective: To develop a HPLC method for the determination of tissue distribution of cinnarizine in rats. Methods: Cinnarizine (2 mg/Kg) was injected into the tail vein of rats. Tissue sample was alkalized with sodium hydroxide solution and extracted with methyl tert-butyl ether. The separation was performed on a Hypersil C18 column using methanol-water-glacial acetic acidacid-triethylamine (70:30:0.6:0.4) as the mobile phase at UV 254 nm. The distribution of cinnarizine in the heart, liver, spleen, lung, kidney, stomach, small intestine, brain, fat and testes was determined. Results: The limit of detection of cinnarizine in the hepatic tissue was 0.02 μg/ml and the linear range was 0.05-1 0 μg/ml. The limit of detection in the intestine tissue was 0.02 μg/ml and the linear range was 0.05-1 μg/ml, which meets the requirement for the analysis of biological samples. Cinnarizine was extensively distributed in rat body, with highest concentration found in the lung. Conclusion: Our method is easy to perform, accurate and sensitive, which makes it suitable for preclinical pharmacokinetic research of cinnarizine.
ABSTRACT
OBJECTIVE:To develop an HPLC-FLU method for the determination of cinnarizine in rat plasma and to study its pharmacokinetics. METHODS:6 rats were given cinnarizine injection(3 mg?kg-1)by venous cannula and after 5 min,10 min, 20 min,40 min,60 min,120 min and 240 min,blood samples were collected. HPLC-FLU was established to determine the plasma concentration of cinnarizine and the pharmacokinetic evaluation was carried out. RESULTS:The linear range of cinnarizine was 10～1 000 ng?mL-1(r=0.999 6)and the limit of detection of cinnarizine was 0.2 ng?mL-1,the average recovery being 95.9%～98.6% with RSD
ABSTRACT
Objective To investigate the effects of divitamins notonginseng and cinnarizine capsule(DNCC) on acute cerebral ischemia.Methods ICR mice were administered three doses of DNCC(420,210,and 105mg/kg;ig.) for ten days,then the gasping time after decapitation was recorded.After three doses of DNCC(292,146,and 73mg/kg;ig.) were given respectively for ten days in rats,the effects of DNCC on the infarct size,histological changes and neurological function scores caused by focal cerebral ischemia which was induced by middle cerebral artery occlusion were investigated.Results DNCC prolonged the gasping time of mice after decapitation and improved the neurological function scores,cerebral ischemia injury and decreased the infarct size in rats.Conclusion DNCC has a protective effect against acute cerebral ischemia.