| Objectives: Hypertension,a worldwide common disease of cardiovascular system, is also a public health problem in global. Epidemiologic study showed that the sickness rate of hypertension in the world is about 10% and in China the number is 11.08%. Especially in Shanghai and Guangzhou,the incidence is about 14%. Since 1990s sickness rate has upgraded 32% in the town and 36% in village. So hypertension's prevention and therapy has become pressing event. Numerous anti-hypertension drugs could be divided into seven groups according to mechanism, and their efficacies were 40%～60% when being used alone. They were used as combination frequently in order to control hypertension and elevate therapeutic effect. Enalapril Maleate is ACEI and Felodipine is CCB. Their comp- application were reasonable, efficient, convenient, less adverse reaction and organ protective.Prepared compound Dropping pills can control release of drug, increase solubility and absorption.Methods: On the basis of scientific literatures and pretesting, PEG 6000 ,stearic acid, glyceryl monostearate and poloxamer F188 were adopted as matrix to make up dropping pills.At first, on the basis of pretesting, we analyzed the factors that influenced shape of dropping pills. Then through the orthogonal experiment of three influencing factors and three levels, we analyzed the effects of dropping distance, temperature of drug liquid and dropping rate to select the optimal technology. In the course of that, the spherical degree and relative standard deviation of pills weight difference were selected as evaluation indexes.Then based on the analysis of the factors that influenced the drug release behavior ,the orthogonal experiment L9(34) was used to prepare dropping pills.we used to similar factor to evaluate similarity of release curve. According to accumulative release percentage at 2h,6h,10h to select optimize prescription.Three batches of dropping pills were prepared and studied by dissolution test and detecting release reproducibity. The release data were analyzed with three models.A series of rated experiments were carried out including description, identification, test, assay, dissolution and so on.The chemical and physical stability of optimal formula was investigated under following circumstances: high temperature, high humidity, strong light and long natural store condition. Dissolution test and content assay were taken to examine the stability of dropping pills.Pharmacokinetics study in vivo of rabbits: We select the rabbits as laboratory animal, which were divided into 2 groups in random. One group was given dropping pills and the other was given market tablets . Crossover experiment was taken after two weeks. Plasma sample were obtained at different time. High-performance Liquid Chromatograph with Ultraviolet detector was adopted in examining concentration of plasma. Pharmacokinetics parameters were caculated with 3p97.Results: The optimal technology and formula were defined through simple factor test and orthogonal experiments.Dropping pills made from the optimal formula was round and whole with good spherical degree and suitable rigidity. The accumulative release percentage of three batchs dropping pills had good reproducibility.The friability of dropping pills was 0.64%. Uniformity of dosage units: The value A+1.80S of Enalapril Maleate is 4.24,The value A+1.80S of Felodipine is 3.88, they are both fewer than 15. The average content of Enalapril Maleate was 101.6%.The average content of Felodipine was 99.13%. HPLC was used to detect contents of two ingredients. The linearity range of Enalapril Maleate was 21.08μg·ml-1～105.4μg·ml-1, regression equation was Y=15463X+32439(r=0.9999).The RSD values of precision and reproducibility were 0.41% and 0.85% respectively. The average recovery was 100.5% and RSD was 0.52%. The linearity range of Felodipine was 22.30μg·ml-1～111.5μg·ml-1, regression equation was Y=82286X+ 40711(r=0.9999). The RSD values of precision and reproducibility were 0.28% and 1.03% respectively. The average recovery was 99.53% and RSD was 0.74%. Excipients had no interference with the results. Compound Enalapril Maleate/ Felodipine dropping pills had good reproducibility in vitro. The release percentage of Enalapril Maleate at 1h was less than 90%, the release percentage of Felodipine consistent with the regulation 2h(10%～30%),6h (42%～68%),10h(≥75%).Stability experiment: The result of high humidity test showed that 10 days after compound dropping pills being placed in humidity(RH 92.5%),the weight increased about 10%;its content decreased about 10% after 10 days. Two ingredients were stable in 40℃. The result of strong light test showed that two ingredients were both sensitive to light, dropping pills should be protected from light in production and storage. The result of long-term experiment showed that the data were not significantly different from before.Pharmacokinetic study: We take the experiment according to defined HPLC condition. Enalapril Maleate complied with two compartment model in vivo.The main pharmacokinetics parameters were respectively as following: test preparation reference preparation T1/2α(h) 0.262±0.12 0.748±0.14 T1/2β(h) 2.289±0.43 4.380±3.21 T1/2Ka(h) 0.570±0.18 0.459±0.15 Tmax(h) 2.17±0.41 1.04±0.25 Cmax(ng·ml-1) 65.54±4.37 84.57±6.79 AUC(ng·ml-1)*h 228.9±18.6 188.7±42.6 F(%) 121.3 100Compared with market conventional tablet, the ingredient Enalapril Maleate of compound Enalapril Maleate/Felodipine dropping pills extended peak time of drug and increased bioavailability obviously.Conclusions: Compound Enalapril Maleate/Felodipine dropping pills had good effect of release property and repetition in vitro. The drug release complied with Higuchi equation. The methods of identification , test,assay and dissolution for dropping pills were established, which provided a guideline with quality control. The experiment in vivo showed the ingredient Enalapril Maleate of dropping pills lengthened T(peak) and elevated relative bioavailability.
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