Preparation and characterization of metoprolol tartrate containing matrix type transdermal drug delivery system.

The present study aimed to develop matrix-type transdermal drug delivery system (TDDS) of metoprolol tartrate using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA). The transdermal films were evaluated for physical parameters, Fourier transform infrared spectroscopy analysis (FTIR), differential scanning calorimetry (DSC), in vitro drug release, in vitro skin permeability, skin irritation test and stability studies. The films were found to be tough, non-sticky, easily moldable and possess good tensile strength. As the concentration of PVA was increased, the tensile strength of the films was also increased. Results of FTIR spectroscopy and DSC revealed the absence of any drug-polymer interactions. In vitro release of metoprolol followed zero-order kinetics and the mechanism of release was found to be diffusion rate controlled. In vitro release studies of metoprolol using Keshary-Chein (vertical diffusion cell) indicated 65.5 % drug was released in 24 h. In vitro skin permeation of metoprolol transdermal films showed 58.13 % of the drug was released after 24 h. In vitro skin permeation of metoprolol followed zero-order kinetics in selected formulations. The mechanism of release was found to be diffusion rate controlled. In a 22-day skin irritation test, tested formulation of transdermal films did not exhibit any allergic reactions, inflammation, or contact dermatitis. The transdermal films showed good stability in the 180-day stability study. It can be concluded that the TDDS of MPT can help in bypassing the first-pass effect and will provide patient improved compliance, without sacrificing the therapeutic advantages of the drugs.

Dual crosslinked pectin-alginate network as sustained release hydrophilic matrix for repaglinide.

Repaglinide, an oral antidiabetic agent, has a rapid onset of action and short half-life of approximately 1h. Developing a controlled and prolonged release delivery system is required to maintain its therapeutic plasma concentration and to eliminate its adverse effects particularly hypoglycemia. The present study aimed to develop controlled release repaglinide loaded beads using sodium alginate and pectin with dual cross-linking for effective control of drug release. The prepared beads were characterized for size, percentage drug entrapment efficiency, in vitro drug release and the morphological examination using scanning electron microscope. For the comparative study, the release profile of a marketed conventional tablet of repaglinide (Prandin® tablets 2mg, Novo Nordisk) was determined by the same procedure as followed for beads. The particle size of beads was in the range of 698±2.34-769±1.43µm. The drug entrapment efficiency varied between 55.24±4.61 to 82.29±3.42%. The FTIR results suggest that there was no interaction between repaglinide and excipients. The XRD and DSC results suggest partial molecular dispersion and amorphization of the drug throughout the system. These results suggest that repaglinide did not dissolve completely in the polymer composition and seems not to be involved in the cross-linking reaction. The percent drug release was decreased with higher polymer concentrations. In conclusion, the developed beads could enhance drug entrapment efficiency, prolong the drug release and enhance bioavailability for better control of diabetes.

Involvement of the NF-кB/p50/Bcl-3 complex in response to antiangiogenic therapy in a mouse model of metastatic renal cell carcinoma.

Renal cell carcinoma (RCC) represents approximately 2-3% of human malignancies. Nuclear transcription factor кB (NF-кB) is composed of a family of transcription factors that have been associated with the development and progression of RCC. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we evaluated the expression of NF-кB in metastatic tumor cells from animals treated with ES. Balb/c-bearing Renca-EGFP cells were treated with NIH/3T3-LendSN or NIH/3T3-LXSN cells as a control. At the end of the in vivo experiment, plasma Renca-EGFP-sorted cells and tissue lung samples were collected. A real-time PCR array for NF-κB target genes revealed that ES therapy led to down regulation of Bcl-3 (P<0.031), NF-кB1 (P<0.001) and c-Rel (P<0.004) in the ES-treated group. Using an electrophoretic mobility shift assay (EMSA), we observed a reduction in NF-kB binding activity in ES-treated Renca-EGP cells. Furthermore, a supershift assay showed a clear shift of the NF-кB DNA band in samples incubated with a p50 antibody. By immunohistochemistry analysis, ES treatment resulted in a significant reduction in expression of p50. (ES vs. control P<0.05). The immunoprecipitation experiments confirmed the presence of a p50/Bcl-3 complex in nuclear extracts from cells of metastatic lung tissues. Our findings indicate that p50 and Bcl-3 plays a regulatory role in gene transcription in RCC.

Endostatin neoadjuvant gene therapy extends survival in an orthotopic metastatic mouse model of renal cell carcinoma.

Despite recent advances in targeted therapy, renal cell carcinoma (RCC) remains one of the most lethal urologic malignancies. Approximately 30% of patients with localised RCC will develop metastases after curative surgery. Presurgical therapy has been explored for treatment of localised RCC. Endostatin (ES) is a fragment of collagen XVIII that possesses antiangiogenic activity. In this study, we examined the potential use of an antiangiogenic agent as a neoadjuvant therapy in an orthotopic metastatic mouse model of RCC. BALB/c mice bearing Renca cells were treated before nephrectomy with NIH/3T3-LendSN cells. At the end of the experiment, ES serum levels were measured. Primary and metastatic tumour area and microvascular area were determined. In the survival studies, mice were monitored daily until they died. ES serum levels in treated mice were higher in the control group (P<0.05). The median primary tumour area and the mean microvascular area were significantly lower in the ES-treated group compared to control group (P<0.05). The proliferation of Renca cells in the ES-treated group was significantly reduced compared with the control group (P<0.01). ES therapy led to a significant reduction in the number of pulmonary metastatic nodules compared with the control group (P<0.01). Kaplan-Meier survival curves showed that the probability of survival was significantly higher in mice receiving ES therapy (P=0.0243, Log-Rank test). Our results indicated that neoadjuvant ES gene therapy has the potential to decrease tumour burden, extend survival, and may have clinical benefit in the management of RCC.