The present investigations demonstrate the application of solvent resistant stirred cell ultrafiltration technique for removal of toxic impurities of surfactant (PVA) from the polymeric drug nanoparticles (tamoxifen) prepared by emulsification solvent evaporation method. This technique offers added benefit of producing more concentrated nanoparticles dispersion without causing significant particle size growth which is observed in other purification techniques, e.g., centrifugation and ultracentrifugation.
Background: Tamoxifen is widely used for treatment of estrogen receptor positive breast cancer. It is, however, associated with severe side effects of cancerous proliferation on uterus endometrium. The tumor targeting formulation strategies can effectively overcome drug side effects of tamoxifen and provide safer drug treatment. Objective: Designing tumor targeted PLGA nanoparticles of tamoxifen by attaching hyaluronic acid (HA) as ligand to actively target the CD44 receptors present at breast cancer cells surface. Methods: PLGA-PEG-HA conjugate was synthesized in the laboratory and its tamoxifen loaded nanoparticles were fabricated and characterized by FTIR, NMR, DSC, and XRD analysis. Formulation optimization was done by Box- Behnken design using Design Expert software. The formulations were evaluated for in- vitro drug release and cytotoxic effect on MCF-7 cell lines. Results: The particle size, PDI, and drug encapsulation efficiency of optimized nanoparticles were 294.8, 0.626, and 65.16% respectively. Optimized formulation showed 9.56 % burst release and sustained drug release for 8 h. The drug release was effected by non-fickian diffusion process supplemented further by erosion of polymeric matrix and followed korsmeyer-Peppas model. MTT cell line assay shows 47.48 % cell mortality when treated with tamoxifen loaded PLGA-PEG-HA nanoparticles. Conclusion: Hyaluronic acid conjugated PLGA-PEG nanoparticles of tamoxifen were designed for active targeting to breast cancerous cells. The results of MTT assay showed that tamoxifen nanoparticles formulation was more cytotoxic than tamoxifen drug alone which is attributed to their preferential uptake by cell lines by affinity of CD44 receptors of cell lines to HA ligand present in nanoparticles.
The aim of the present study was to experimentally compare the attributes, drawbacks, and limitations of the most commonly employed in vitro drug release test methods for nanoparticle systems and to explore the possibility of one method being adopted as a standard for quality control of nanoparticle-based products. Three in vitro drug release test methods, i.e., direct addition, dialysis bag, and low-pressure ultrafiltration, were employed for evaluation of drug release from tamoxifen-loaded poly(lactic-co-glycolic acid) nanoparticles. Relevant operational characteristics of each test method were compared. Drug release data were fitted in different release kinetics models, i.e., zero order, first order, Higuchi, Hixson-Crowell, and Korsmeyer-Peppas. The coefficient of determination (R 2 ), release rate constant (k), and release exponent (n) values were calculated. The direct addition method showed rapid initial drug release, whereas a slow release rate was observed in the dialysis bag method. Results of the low-pressure ultrafiltration method were consistent with the direct addition method and various operational characteristics were more realistic than the other two methods. Overall, the findings support that low-pressure ultrafiltration can be considered as a standard regulatory test method for in vitro release of nanoparticle-based formulations.
Objective: The present research was aimed to develop ketoconazole (KT) loaded microemulsion-based gel formulation for effective topical delivery through enhanced drug solubility, improved skin permeation and reduced side effects overcoming drawbacks of conventional dosage forms. Methods: For the selection of oil, surfactant and co-surfactant mixture (Smix) ratio, the phase titration method was used and pseudo-ternary phase diagrams were prepared. D-optimal mixture design was employed to optimize the microemulsion system taking oil, Smix and water as independent variables and particle size, polydispersity index, zeta potential, % transmittance and cumulative % drug release as response variables. Finally, topical gel formulation of KT-loaded microemulsion was developed and evaluated for physico-chemical properties, rheological properties, in vitro drug release kinetics and ex-vivo drug permeation. Results: The optimized microemulsion was found to be a transparent formulation with 19.7 nm particle size, 0.268 polydispersity index,-0.2 mV zeta potential, 97.83% transmittance and 85.85% cumulative drug release at 24 h. The developed gel of optimized microemulsion possessed pH 6.20, viscosity 2178 cps, spreadability 18.634 g.cm2/sec, adhesiveness 45.989 N/mm2, and cohesiveness-85.583. The in vitro drug release was found to be 69.08 % (at 24 h), showing sustained release and Higuchi kinetic profile. The developed gel exhibited 1.84-fold higher drug permeation flux as compared to the marketed product. Conclusion: The developed gel formulation possessed all desired quality attributes and physico-chemical properties. The in vitro and ex-vivo study data proved it’s suitability as a better alternative to conventional products in the effective treatment of fungal skin infections.
Objective: Butorphanol is a commonly used medication for the management of postoperative pain and suffers low bioavailability and high first-pass metabolism. The objective of the current studies was to develop a butorphanol tartrate-loaded dissolving microneedle patch to overcome the limitation of first-pass metabolism without causing any discomfort to the patient. Methods: Butorphanol tartrate-loaded microneedle patch was prepared using Lapox resin micro-molds. The microneedle patch was optimized using the box-Behnken design and the quantity of PVA, HPMC K4M, and HPMC K15M was optimized and evaluated for fractured axial force, microscopic evaluation, in vitro drug permeation studies, and ex-vivo permeation experiments. Results: The developed microneedle patch meets all the evaluation parameters within the desired range. The height and tip diameter of the microneedles were found to be 700 µm to 800 µm and 60 µm to 61 µm. An axial fractured force of the optimized microneedle patch was found to be 189.67 N, suitable for penetrating the stratum corneum. The in vitro cumulative % drug permeated showed the permeation of the drug for 8 h with a total of 89.12 %, which shows the permeation of the drug occurred in a controlled manner. Conclusion: Butorphanol tartrate-loaded microneedle patch was successfully developed and the results concluded that the microneedles were hard enough to pass the stratum corneum and release the drug into the systemic circulation without reaching the pain receptors; further, the release study suggested that the drug was released for a prolonged period eliminating the problem of first-pass effect and frequent administration.
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