Formulation, Optimization, and In vivo Evaluation of Gastroretentive Drug Delivery System of Nifedipine for the Treatment of Preeclampsia.

The study aimed to develop gastroretentive drug delivery system of nifedipine, its optimization, and in vivo evaluation. Bilayered tablet of nifedipine was prepared using central composite design with 3 factors, 5 responses, and 15 experimental trials. Response surface methodology along with numerical and graphical optimization was used to select the best formulation. Scanning electron microscopy study of optimized tablet at different time interval was carried out which showed formation of porous structure on the tablet surface. In vivo studies for optimized formulation were carried out on 10 healthy human volunteers and obtained pharmacokinetic parameters were compared with the marketed formulation, "Nicardia XL." Optimized formulation containing 3.083 mg HPMC K15M, 29.859 mg HPMC E15LV, and 3.541 mg Carbopol 974P releases the drug in a desired manner and remain buoyant for more than 12 h in human stomach. Both the formulations were found to have similar in vitro release profile (f1 4.5089 and f2 55.8274) and also were found to be bioequivalent. Finally, the stability study of the optimized formulation proved the integrity of the optimized formulation. Hence, the data suggest gastroretention as a promising approach to enhance bioavailability of nifedipine.

Effect and underlying mechanism of Bu-Shen-An-Tai recipe on ovarian apoptosis in mice with controlled ovarian hyperstimulation implantation dysfunction.

The effect and underlying mechanism of Bu-Shen-An-Tai recipe on ovarian apoptosis in mice with controlled ovarian hyperstimulation (COH) implantation dysfunction were studied. The COH implantation dysfunction model in mice was established by intraperitoneal injection of 7.5 IU pregnant mare's serum gonadotrophin (PMSG), followed by 7.5 IU human chorionic gonadotrophin (HCG) 48 h later. Then the female mice were mated with male at a ratio of 2:1 in the same cage at 6:00 p.m. The female mice from normal group were injected intraperitoneally with normal saline and mated at the corresponding time. Day 1 of pregnancy was recorded by examining its vaginal smears at 8:00 a.m. of the next day. Fifty successfully pregnant mice were equally randomly divided into 5 groups: normal control pregnant group (NC), COH implantation dysfunction model group (COH), low dosage of Bu-Shen-An-Tai recipe group (LOW), middle dosage of Bu-Shen-An-Tai recipe group (MID) and high dosage of Bu-Shen-An-Tai recipe group (HIGH). Then from day 1, the mice in different groups were respectively intragastrically given corresponding treatments at 9:00 a.m. for 5 consecutive days. The concentrations of 17ß-estradiol (E2) and progesterone (P4) were determined by radioimmunoassay (RIA). The ultrastructural changes of ovarian tissues were observed by transmission electron microscope (TEM). The histopathological changes of ovarian tissues were observed by HE staining. The number of atretic follicles and pregnant corpus luteum were also recorded. TUNEL was applied to measure apoptotic cells of ovarian tissues. Western blotting was used to detect the protein expression of apoptosis- related factors like Bax, Bcl-2 and cleaved-caspase-3 in ovarian tissue of mice. The results showed that ovarian weight, the concentrations of E2 and P4, the number of atretic follicles and pregnant corpus luteum, as well as the apoptosis of granulosa cells were significantly increased in the COH group. The ultrastructures of ovarian tissues in the COH group showed that chromatin in granulosa cells was increased, agglutinated, aggregated or crescent-shaped. The focal cavitation and the typical apoptotic bodies could be seen in granulosa cells in the late stage of apoptosis. After the treatment with different doses of Bu-Shen-An-Tai recipe, the ultrastructural changes of ovarian granulosa cells apoptosis were dramatically improved and even disappeared under TEM. Visible mitochondria and mitochondrial cristae were increased and vacuoles were significantly reduced. The lipid dropltes were shown in a circluar or oval shape. The protein expression levels of Bax and cleaved-caspase-3 were decreased, and the expression of Bcl-2 protein was increased after treatment. It was concluded that Bu-Shen-An-Tai recipe can inhibit the apoptosis of ovarian granulosa cells, probably by up-regulating the protein expression of Bcl-2 and down-regulating Bax and cleaved-caspase-3, which contributes to the formation and maintenance of ovarian corpus luteum. It's helpful to promote the embryonic implantation, to reduce embryo loss and ultimately to improve the success rate of pregnancy.

Development of Novel High Density Gastroretentive Multiparticulate Pulsatile Tablet of Clopidogrel Bisulfate Using Quality by Design Approach.

Myocardial infarction, i.e., heart attack, is a fatal condition which is on the increase all over the world. It is reported that a large number of heart attack occur in morning hours which are attributable to platelet aggregation. Chronotherapy at this stage can be crucial. Clopidogrel bisulfate (CLB) is an antiplatelet agent and has become a drug of choice for prevention of heart attack. It is soluble in acidic pH and has a narrow absorption window. So, its long residence time in stomach is desirable. Therefore, a novel high density tablet was developed comprising multiparticulate pellets with pulsatile release necessary to maintain chronotherapy of heart attack. The pellets were prepared by extrusion-spheronization and coated in fluidized bed processor with different coating material to achieve pulsatile release. The size, shape of pellets, and drug release were evaluated. High density tablet containing coated pellets was formulated and evaluated for retention in stomach. Quality by design tools was used to design and optimize the processes. Timed release observed by dissolution study showed lag time of 6 h followed by burst release of drug up to 94% in 1 h. Density of tablets was found to be 2.2 g cm-3 which is more than gastric fluid. In vivo x-ray studies in rabbit revealed 8 h of gastric retention of tablet at the bottom of the stomach. Thus, CLB high density pulsatile system looks to open up a window of opportunity for developing formulations with drugs that are stable in gastric region and needed chronotheraupetic activity.