| Troxerutin(TX, vitamin P4), a semi-synthetic derivative of the natural flavonoid rutin, is the main component of venoruton. It has aroused considerable interesting due to its broad pharmacological and biological properties such as anti-oxidative, anti-inflammatory, anti-fibrinolytic, anti-thrombotic effects. Troxerutin is clinically used for the management of cardiovascular and cerebrovascular diseases, including chronic venous insufficiency(CVI), hematomas and blood flow disorders. Although troxerutin has been commonly used for many years, some pharmacokinetic studies of troxerutin showed that troxerutin was less efficiently absorbed and the oral bioavailability is very low. Microemulsions have been intensively utilized as drug delivery systems because of its prominent advantages including better drug solubilization, ease of preparation and protection against enzymatic hydrolysis, as well as the potential for enhanced absorption due to main ingredients acting as permeation enhancers. Thus, we thought it may be plausible to improve the bioavailability of troxerutin by the use of a microemulsion to improve the oral absorption of troxerutin. The main contents are summarized as follows:1. Preparation and quality assessment of troxerutin microemulsionThe pseudo-ternary phase diagrams were constructed to confirm the formula oftroxerutin microemulsion by investigating some influencing factors, such as, Surfactants, cosurfactants, oils, Km values, temperature, et al. A stable W/O microemulsion formulation consists of lecithin, ethanol, isopropyl myristate and water(23.30/11.67/52.45/12.59 w/w) was successfully developed. Different physico-chemical parameters of the microemulsions were characterized. Troxerutin microemulsion was yellow, good mobility and transparent. The morphology of microemulsion observed by TEM was a spherical appearance and uniform size. The conductivity and p H value of troxerutin microemulsion was(2.08±0.08) μs/cm and 4.37±0.08. The mean droplet size of microemulsions measured by the particle detector was(50.20±4.05) nm and the polydispersity index values(PDI) were 0.187±0.025. After storage for 6 months, the optimized troxerutin microemulsion exhibited transparency, clarity and no drug precipitation or color change. Contents of troxerutin were(5.51±0.14) mg/ml by HPLC.2. Pharmacokinetic studies in ratsThe pharmacokinetic prameters of troxerutin microemulsion was compared with that of suspension after single-dose administration(56.7 mg/kg) in male Wistar rats. The results were as follows: Cmax values of suspension was 61.66±10.46 ng/m L and that of the microemulsion was 107.78±21.28 ng/m L. AUC0→∞values of suspension was 375.65±43.75 h ng/m L and that of the microemulsion was 772.16±113.63 h ng/m L, yielding a relative bioavailability of 205.55%. Thus microemulsion could improve the extent of troxerutin absorption.3. Transport study of troxerutin in MDCK cell monolayerIn vitro MDCK cell permeability studies were carried out to evaluate thepermeability enhancement effect of microemulsion. HPLC method was used to analyse the concentration of troxerutin. Then the permeability coefficient(Papp) and excretion ratio(ER) were calculated. The result shows that the Papp of troxerutin in solution was 1.27±0.07×10-7cm/s(permeability from A to B direction) and 1.44±0.06×10-7cm/s(permeability from B to A direction), and that of troxerutin loaded in microemulsion increased up to 3.64±0.31±0.36×10-7cm/s(permeability from A to B direction) and 3.93±0.49×10-7cm/s(permeability from B to A direction). |
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