| ObjectiveValsartan and hydrochlorothiazide are both the poorly solube drugs, which have better clinical therapeutic effect in hypertension, especially the mild to moderate hypertemnsion. There are some advantages like less side effects and effective in treatment, when these two drugs are combined. These two drugs have the lower bioavailability, due to the poorly dissolubilition in water. In this rearch, valsartan and hydrochlorothiazide nanocrystals will be prepared. Aim to increasing the in vitro dissolution and then enhanced the oral bioavailability by the nanosized crystalline drugs. And it will provide a reference for the preparation of nanocrystal and the development of the two drugs preparation in the future.Methods and rasults:1 The preparation and lyophilization of the valsartan nanosuspensionsIn this study, valsartan nanosuspensions will be prepared by precipditationultrasonication. Paticle size and polydispersity will be the indicators to choose the optimum formulation and the stability will be the auxiliary index. By the single factor test, effects of different solvents, drugs concentration,organic phase and inorganic phase volume ratio, kinds and concentrations of stabilizer, ultrasonic intensity and times, freezing dry protective agent and concentration, will be shown in particle size and PDI. The optimum process parameters were as follow: the concentration of valsartan in ethanol as organic solvent is 0.01g/ml, tween-80 in water as inorganic is 0.0025g/ml, the volume ratio between organic and inorganic was 1:10 and the preparation temperature is mixture ice and water(under 6℃), the ultrasonic powder input 570 w and time lengths 10 min. Freeze drying agent is mannitol, the concentraction is 5%(w/v). The nanosuspension will be put into freeze dryer when its room temperature, the prefreezing time is 9h, all the freeze drying process lasted 48 h. The particle size of nanosuspension is 110.4±12.3nm, the redisperse freeze drying prower is 120.2±10.4nm nm. In addition, the experiment also eatablish the method for the determination the concentration of valsartan. The result show that, the method is specific, accurately and sensitivity. Valsartan was linear over the concentraction range of 2.0μg/ml~25μg/ml. And the nanosuspension with a good stability.2 The preparation and lyophilization of the hydrochlorothiazide nanosuspensionsIn this study, hydrochlorothiazide nanosuspension will be prepared by preci PDItation and the process of crystallization will happened in 4 degree temperature. Paticle size and polydispersity will be the indicators to choose the optimum formulation and the stability will be the auxiliary index. By the single factor test, effects of different solvents, concentration and organic phase and inorganic phase volume ratio, kinds and concentrations of stabilizer, freezing dry protective agent and concentration, will be shown in particle size and PDI. Then using the orthogonal L9(33)test to optimized the perfect prescription, the three factors are organic and inorganic phases ratio, the concentration of drug and stabilizer. The optimum process parameters were as follow: the concentration of hydrochlorothiazide in acetone as organic solvent is 0.0475g/ml, PVP-K30 in water as inorganic is 0.0025g/ml, the volume ratio between organic and inorganic was 1:10, then put it in 4 degrees for 48 h. This prescription has a good stability. The freeze dried formulation is, put the 20%(w/v) mannitol solution into the nanosuspension liquid, the volume ratio is 1:1. When the freeze dried cooling to-50 degree, put the nanosuspension in and freezing dried for 39 h. The particle size of nanosuspension is 323.5±26.9nm, PDI=0.294±0.032, the redisperse freeze drying prower is 596.7±33.2nm, PDI=0.389±0.021. In addition, the experiment also eatablish the method for the determination the concentration of hydrochlorothiazide. The result show that, the method is specific, accurately and sensitivity. Hydrochlorothiazide was linear over the concentraction range of 0.5μg/ml~12μg/ml. And the nanosuspension with a good stability.3 Investigation of the characterization and physical properties of valsartan and hydrochlorothiazide nanocrystalsThe result show that valsantan and hydrochlorothiazide nanocrystals are significantly increased both in solubility and in vitro dissolution, compared the raw materials and physical mixture. The difference scanning calorimetry(DSC) may confirmed that the valsantan nanocrystal has been change to another type which is differdent from the raw material and the hydrochlorothiazide nanocrystals change to amorphous. The transmission electron microscope scanning showed the appearance of valsartan nanocrystals is the spherical crystal and unchanging befor and after the preparation, so was the hydrochlorothiazide nanocrystals. The appearance of the hydrochlorothiazide nanocrystals is a tablet. Both the x-ray and DSC results show that crystals from of hydrochlorothiazide nanocrystals is amorphous forms. The x-ray result of valsartan nanocrystals found it different from DSC, and it could’t character what’s the crystal from is.4 The study on pharmacokinetics about the compound valsantan and hydrochlorothiazideHPLC method was established for determination of plasma concentration of valsantan and hydrochlorothiazide. The result were valsantan linear range was 20~4000μg/ml, the lower limit of quantification was 20ng/ml, the detection limit was 20ng/ml, the extraction recoveries of valsantan is greater than 85%. The hydrochlorothiazide linear range was 50~1000μg/ml, the lower limit of quantification was 50ng/ml, the detection limit was 50ng/ml, the extraction recoveries of valsantan is greater than 85%. There is no any endogenous impurities to disturb the samples’ determing. The stability of both two drugs in plasma sample was good. The dosage of drug administration were valsantan 14.4mg/kg, hydrochlorothiazide 2.25mg/kg. The result as follow: the self-samples and the tablets sells in the market, valsantan: Tmax were 46.56 min and 71.38min; Cmax were 1786.8ng/ml and 603.3ng/ml; AUC were 227045.4(ng/ml*min) and 120829.1(ng/ml*min), the self-samples and the tablets sells in the market, hydrochlorothiazide: Tmax were 81.11 min and 84.31min; Cmax were 408.1ng/ml and 218.1ng/ml; AUC were 128814.4(ng/ml*min) and 65979.6(ng/ml*min). In vivo bioavailability demonstrated that the valsartan was 1.89 fold and the hydrochlorothiazide was 1.76 fold than the marketed drugs. |
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