Study On Self-Microemulsifying Drug Delivery Systems (SMEDDS) And Solid-SMEDDS Of Nitrendipine

Nitrendipine (NTD) is a calcium channel blocker and widely used as an antihypertensive drug in clinical. It has a low solubility in gastrointestinal fluids and undergoes extensive first-pass metabolism in the liver, which leads to poor oral bioavailability (10-20%). It was found that Self-(micro)emulsifying drug delivery systems (S(M)EDDS) could efficiently improve oral absorption of the poorly soluble drugs by rapid self-emulsification and subsequently dispersion in the absorption sites. So the main objectives of our reseaches are to prepare SMEDDS for increasing the solubility and dissolution of NTD, and improving its bioavailability, and to establish a new in vitro evaluation method for this self-emulsifying systems, and to study the solidification techniques and solid self-emulsifying formulations. The results proved to be valuable for the investigation and development of such dosage forms.In order to prepare SMEDDS and to evaluate their in vitro properties, first of all, the UV analytic method was established to detect the content and dissolution of NTD. The physical and chemical properties of NTD were investigated in our study. The balance solubility and Log P of NTD in solution of water, PH6.8 PBS, 0.1mol·L-1 HCL were 3.20±0.41,2.82±0.32, 3.01±0.58 μg·mL-1, and 2.18,2.24,2.68 respectively. The results indicated NTD was a highly lipophilic and poorly water soluble drug, which would be fit to prepare SMEDDS.In the pre-formulation study, the saturated solubility of NTD in different oils, surfactants, and cosurfactants were examined. Pseudo-ternary phase diagrams were conducted. The SMEDDS were obtained by comparing the self-microemulsifying domain and by the evaluation of the resultant of emulsion’s appearance. According to the assays, the initially optical blank SMEDDS were composed of Labrafil M 1944CS, Cremophor RH40, and Transcutol P. The temperature, blending speed, Km value, kind and volume of media on the self-emulsifying efficiency were investigated in details, and finally, the conditions of 37℃, middle blending speed and diluting with 100-fold volume of the distilled water were utilized for evaluating the efficiency of self-microemulsifying. When the values of Km1 and Km2 were 6:1 and 7:3, NTD did not affect the self-microemulsifying region, self-microemulsifying time and the droplet size obviously, comparing with the blank SMEDDS. Based on the above work, the initially optical formulation of NTD and preparation technology were selected. The dissolution rate of NTD from this SMEDDS was faster than that of the market conventional tablet. The dissolution of SMEDDS at 60 min was about 90%, but less than 10% for the tablet.The lipolysis modle in vitro simulating environment of GIT and analytical method (HPLC) for lipolysis samples were established. The results indicated that after lipolysis the system of Miglyol 812-Cremophor RH40/Tween 80 (2:1)-Transcutol P had the higher solubility in theaqueous phase than that of Labrafil M 1944CS-Cremophor RH40-Transcutol P, which would be helpful for evaluation of SMEDDS characteristic in vivo after oral administration and be usful to select the optimal formulation.Additionally supersaturation state of different SMEDDS was studied. After one hour’s dilution with water, the system of Miglyol 812-Cremophor RH40/Tween 80 (2:1)-Transcutol P had the highest solubility in the six selected systems, which conformed to the results of lipolysis. So the optimal formulation of SMEDDS was determined.Some different hydrophilic high molecular polymers maintaining the supersaturation state of the optimal SMEDDS were investigated. The order of maintaining the supersaturation state was Kollidon VA64>HPMC E5>HPMC K100 LV>PVP K30>HPMC K4M. Especially for Kollidon VA64 and HPMC E5 which had fine effect, different concentration was selected. At low concentration (<0.5%), two polymers had a increasing effect with the concentration increased. However the increasing effect was not obvious when the concentration above 0.5%. The percentages of dissolved NTD was about 80% for Kollidon VA64 and 50% for HPMC E5, when the optimal SMEDDS was diluted for four hours with 0.5% solution of the two polymers.The liquid SMEDDS were solidified by three solidification techniques, using the optimized adsorbents of silicon dioxide and Kollidon VA64 (2:1). The powder prepared by spray drying and lyophilization had finer rarefaction and flowability than that mixed by hand, which had the highest yield. Although there were some difference in dissolution of the three powder, the degree was not significant. Considering the operation and cost, the preparation technique was chosen to that mixed by hand. The results of DSC showed that NTD was amorphous in that powder mixed by hand.The solid self-microemulsifying (SME) pellets of NTD were prepared via extrusion/spheronization technique, based on the selection of adsorbent and solidification method. The optimal formulation and preparation technology were determined through investigation of the influential factors of composition and technique. The percentages of SMEDDS, silicon dioxide, crospovidone, microcrystalline cellulose and lactose were 30%, 5%,15%,35% and 15%, respectively. The extrusion speed was 30 rpm, spheronization speed was 1600 rpm, and spheronization time was 5 min. The prepared pellets were then dried for 10 h at 40℃, and the objective pellets were selected through 16-24 screen meshes. The results of pellets properties investigation indicated that pellets had high yield, good appearance and large hardness. The in vitro release of SME-pellets was over 85% within 60 min, significantly higher than that of the conventional tablets. Through TEM graph, SMEDDS released from the pellets could form little globular milk drops (less than 100 nm), which belonged to micro-milk and had uniform distribution (mean diameter 72±16 nm). The results of DSC showed that NTD was amorphous in dosage form. The stability of SME-pellets was fine in low temperature, cold-hot cycling, and high humidity. The content of NTD decreased obviously in high temperature and strong light, and the SME-pellets were more stable than liquid SMEDDS under the same condition.The NTD SME-pellets were prepared. Then, three kinds of coated pellets were prepared by using HPMC, Eudragit L-30D-55 and Eudragit L100-Eudragit S100 combinations of 1:5 as coater, respectively. The three kinds of pellets coated with HPMC, Eudragit L-30D-55 and Eudragit L100-Eudragit S100 combinations of 1:5 could dissolve in any pH conditions water, at pH 5.5 or above and at pH 6.8 or higher, respectively. NTD sustained-release capsules were developed by encapsulating the above three kinds of coated pellets at certain ratio in hard gelatin capsules. The release profiles showed a characteristic of pH-dependent gradient-release in the simulated gastrointestinal pH conditions.A selective, rapid and sensitive UPLC-MS/MS method was developed for the quantification of NTD in dog plasma. The fully validated method was successfully applied to a pharmacokinetic study. The plasma profiles of NTD in beagle dogs following oral administration of liquid SMEDDS, SME-pellets, pH-dependent gradient-release SME-pellets and conventional tablets at a single dose were investigated. Compared with the conventional tablets, the Cmax and AUC0-t of the liquid SMEDDS, SME-pellets were increased significantly, and the relative bioavailability of liquid SMEDDS and SME-pellets were 227.9% and 255.1% respectively. Compared with SME-pellets, the pH-dependent gradient-release SME-pellets had lower Cmax and longer Tmax. However, bioavailability of the sustained-release formulation decreased significantly. On the one hand the result indicated pellets were an useful dosage form for the solid SE-formulations, and on the other hand it also indicated the drug with sparingly aqueous solubility and distinct first-pass effect would be relatively difficult to prepare the sustained or controlled- release formulation.