Simvastatin Solid Dispersions Of Research

Simvastatin,a Hydroxymethylglutaryl coenzyme A reductase inhibitor,has been used as a kind of effective therapeutic agent for hypercholestreolaemia,which inhibit the synthesis of hydroxymethylglutaryl and endogenous cholesterol.Simvastatin,a patented product of Merck corporation, was first marketed in in Sweden in1988,granted FDA approval in1911, and allowed Merck Sharo&Dohme pharmacy corporation to import at Hangzhou in1997.Now,the related products in the domestic market include tablets,capsules and dripping pills.Due to its poor water solubility, resuleted in oral dosage forms of simvastatin are poorly absorbed in body, and they have low absolute bioavailability. Solid dispersion technique is often used to improve the solubility of poorly soluble drugs.In this study, simvastatin solid dispersion was prepared to improve its solubility and bioavailability, and carried on its quality evaluation and pharmacokinetics study in Beagle.The first part,The preformulation study of simvastatin solid dispersion. We studied the thermal stability of simvastatin based on the basic physicochemical properties of simvastatin and preparation process of solid dispersion.The results showed that simvastatin keeps relatively stable at80℃below.Three HPLC analysis methods was proposed to determine the content of simvastatin and study the dissolution rate of simvastatin solid dispersion and capsules.The methodological evaluation showed that these methods had good repeatability, sensitivity and accuracy.The second part,The preparation study of simvastatin solid dispersion. Simvastatin solid dispersions were prepared using solvent method,melting method and solvent-melting method with water soluble carrier materials PEG4000,PEG6000,F68and PVPk30as carrier.Use dissolution rate as the indicator, we studied the impact factors,including the types of carrier materials,Preparation method,temperature,the amount of solvent and ratio of drug and carrier,of solid dispersions on preparing technology.The optimization of prescriptionpreparation of simvastatin solid dispersion was definited:dissolve simvastatin1g and PVPk307g in alcohol40mL to keep continuous stirring fot1h at60℃, then the mixtures were concentrated under vacuum until the alcohol removed completely,products dried in a vaccum desiccator at room temperature,grind to finepowder,crushed,screened through mesh size of80,dry place protected from light to store. The third part, The quality standard study of simvastatin solid dispersion.the dispersion state of simvastatin insolid dispersion and physical mixtur were studied with methods of differential scanning calorimetry (DSC), X-ray diffraction (X-RD), Fourier Transform infrared spectroscopy (FTIR) and scanning electron microscopic (SEM) analysis techniques.The results showed that the simvastatin presented tiny crystal state in physical mixtur, amorphous state or molecular state in solid dispersion.The character, equilibrium solubility, partition coefficient, powder moisture absorption,release in vitro and content of simvastatin solid dispersion were researched.The results showed that the equilibrium solubility and partition coefficient of simvastatin solid dispersion increased.The solid dispersion power,strong moisture absorption,must be stored in dry and hermetic condition.The release in vitro of the three batches of simvastatin solid dispersion complied with the relevant requirements.The release of simvastatin was complete within20minutes both from solid dispersion capsule and commercial capsule.The fourth part.The pharmacokinetic study of simvastatin solid dispersion in Beagle dogs.The pharmacokinetic characteristics in Beagle dogs of simvastatin solid dispersion were studied with the simvastatin commercial capsule as the reference preparation.The data of drug concentration in blood was analyzed by DAS2.1.1pharmacokinetics intelligent analysis software.the pharmacokinetics parameter and relative bioavailability were calculated,The result showed that the AUC0～tof test and reference preparation were225.23±22.29ng/mL*h and132.98±28.29ng/mL*h, Cmax were81.55±14.34ng-mL-1and37.05±8.11, Tmax were1.625±0.63h and1.00±0.41h, the relative bioavailability of simvastatin solid dispersion was135.63%calculated with AUC0～t.Solid dispersion is able to increase the bioavailability of simvastatin.