Zebunnissa Ramtoola

Influence of particle size and dissolution conditions on the degradation properties of polylactide-co-glycolide particles

Polymer degradation usually plays a crucial role in drug release from sustained release polyester systems, therefore in order to elucidate the mechanism governing release, it appears essential to analyse the in vitro degradation behaviour of these devices. In this study the influence of processing conditions, particle characteristics and release media temperature on the degradation of PLGA spherical particles were examined. It was found that a linear relationship between the degradation rate and particle size existed, with the larger particles degrading fastest. In smaller particles degradation products formed within the particle can diffuse easily to the surface while in larger particles degradation products have a longer path to the surface of the particle during which autocatalytic degradation of the remaining polymer material can occur. The influence of release media temperature on the degradation of PLGA particles was also examined. At lower incubation temperatures PLGA microparticles showed an induction period after which polymer degradation proceeded. The rate of polymer degradation was found to increase with increasing incubation temperature. The polymer erosion profile was fitted to the Prout-Tompkins equation and the rate constants were used to determine the activation energy of PLGA hydrolysis.

Application of face centred central composite design to optimise compression force and tablet diameter for the formulation of mechanically strong and fast disintegrating orodispersible tablets

A two factor, three level (3(2)) face centred, central composite design (CCD) was applied to investigate the main and interaction effects of tablet diameter and compression force (CF) on hardness, disintegration time (DT) and porosity of mannitol based orodispersible tablets (ODTs). Tablet diameters of 10, 13 and 15 mm, and CF of 10, 15 and 20 kN were studied. Results of multiple linear regression analysis show that both the tablet diameter and CF influence tablet characteristics. A negative value of regression coefficient for tablet diameter showed an inverse relationship with hardness and DT. A positive value of regression coefficient for CF indicated an increase in hardness and DT with increasing CF as a result of the decrease in tablet porosity. Interestingly, at the larger tablet diameter of 15 mm, while hardness increased and porosity decreased with an increase in CF, the DT was resistant to change. The optimised combination was a tablet of 15 mm diameter compressed at 15 kN showing a rapid DT of 37.7s and high hardness of 71.4N. Using these parameters, ODTs containing ibuprofen showed no significant change in DT (ANOVA; p>0.05) irrespective of the hydrophobicity of the ibuprofen.

Localised controlled release of simvastatin from porous chitosan-gelatin scaffolds engrafted with simvastatin loaded PLGA-microparticles for bone tissue engineering application.

Localised controlled release of simvastatin from porous freeze-dried chitosan-gelatin (CH-G) scaffolds was investigated by incorporating simvastatin loaded poly-(dl-lactide-co-glycolide) acid (PLGA) microparticles (MSIMs) into the scaffolds. MSIMs at 10% w/w simvastatin loading were prepared using a single emulsion-solvent evaporation method. The MSIM optimal amount to be incorporated into the scaffolds was selected by analysing the effect of embedding increasing amounts of blank PLGA microparticles (BL-MPs) on the scaffold physical properties and on the in vitro cell viability using a clonal human osteoblastic cell line (hFOB). Increasing the BL-MP content from 0% to 33.3% w/w showed a significant decrease in swelling degree (from 1245±56% to 570±35%). Scaffold pore size and distribution changed significantly as a function of BL-MP loading. Compressive modulus of scaffolds increased with increasing BL-MP amount up to 16.6% w/w (23.0±1.0kPa). No significant difference in cell viability was observed with increasing BL-MP loading. Based on these results, a content of 16.6% w/w MSIM particles was incorporated successfully in CH-G scaffolds, showing a controlled localised release of simvastatin able to influence the hFOB cell proliferation and the osteoblastic differentiation after 11 days.

Investigation of the interaction of biodegradable micro- and nanoparticulate drug delivery systems with platelets

Objectives  Biodegradable micro‐ and nanoparticles are being increasingly investigated for drug delivery and targeting of therapeutics. The size and surface properties of these particles are important factors influencing their interaction and uptake by various cells, tissues and organs. Optimising these properties, to enhance cellular uptake, may increase their potential for interaction with other physiological components such as platelets resulting in platelet activation and inappropriate thrombus formation. The aim of this study was to investigate the potential interaction of particulates with platelets.

Fluphenazine release from biodegradable microparticles: Characterization and modelling of release

Abstract The release of actives encapsulated in biodegradable poly-lactide-co-glycolide (PLGA)-based microparticles may be diffusion controlled, dependent on polymer degradation, or may occur by a combination of drug diffusion and polymer degradation. This report applies a model, describing combined diffusional and polymer degradation-assisted drug release, to quantify the release of fluphenazine HCl (F-HCl) from PLGA microspheres. Parameters for the release process showed that both the initial drug release phase and the polymer controlled drug release phase were dependent on the F-HCl loading of the microspheres. The percentage drug released in the burst phase and the length of the lag phase were dependent on F-HCl loading. In the degradation controlled release phase, drug release was faster the higher the loading, as shown by the decrease in tmax from 27 to 10 days, as F-HCl loadings increased from 4.2 to 16.6%w/w. The presence of F-HCl was found to catalyse the degradation of PLGA polymer during particle manufacture and during dissolution. When compared to drug free microspheres, F-HCl accelerated PLGA degradation as shown by the ∼5-fold increase in both PLGA degradation rate constant (k) and reduction in tmax.

Investigation of a novel 3-fluid nozzle spray drying technology for the engineering of multifunctional layered microparticles

Objective: To examine the potential of a novel 3-fluid nozzle spray drying technology to formulate differentiated layered microparticles (MPs) of diclofenac sodium (DFS)/ethyl cellulose (EC). Methods: DFS/EC MPs were formulated using the inner and/or outer nozzles of a novel 3-fluid nozzle and compared with MPs formed using conventional (2-fluid) spray drying. MPs were characterised for particle size and for morphology by TEM and SEM. Distribution of DFS and EC of MPs was analysed by FT-IR and DSC. A two-factor, three-level (32) factorial design was applied to investigate the effect and interaction of total feed solid content (TSC) and feed flow rate (FFR) on MP size, D50% and D90%, bulk density and MP yield. Results: Interestingly, TEM demonstrated that MPs formed by 3-fluid nozzle spray drying showed a heterogeneous internal morphology consisting of a core and coat, characteristic of a microcapsule. In comparison, MPs from conventional spray drying showed a homogeneous internal morphology, characteristics of a matrix system. This differential distribution of DFS/EC was supported by FT-IR and DSC. Results of multiple linear regression analysis showed a linear relationship for the effect of TSC and FFR on all responses except for D50% where a quadratric model was valid. The effect of TSC/FFR on MP size and yield was similar to conventional spray drying. Conclusion: The novel 3-fluid nozzle spray drying offers a new method of designing layered microparticles or microcapsules which can have wide applications from drug stabilisation to controlled drug delivery and targeting.

Effect of Microencapsulation Shear Stress on the Structural Integrity and Biological Activity of a Model Monoclonal Antibody, Trastuzumab

The aim of the present study was to investigate the influence of process shear stressors on the stability of a model monoclonal antibody, trastuzumab. Trastuzumab, at concentrations of 0.4–4.0 mg/mL, was subjected to sonication, freeze-thaw, lyophilisation, spray drying and was encapsulated into micro- and nanoparticles. The stressed samples were analysed for structural integrity by gel electrophoresis, SDS-PAGE, and size exclusion chromatography (SEC), while the conformational integrity was analysed by circular dichroism (CD). Biological activity of the stressed trastuzumab was investigated by measuring the inhibition of cell proliferation of HER-2 expressing cell lines. Results show that trastuzumab was resistant to the process shear stresses applied and to microencapsulation processes. At the lowest concentration of 0.4 mg/mL, a low percent (<9%) of soluble/reversible aggregates may have been formed. No loss of structural integrity, conformation was observed and no significant change in the biological activity of trastuzumab was observed (ANOVA; p > 0.05). The results of this study conclude that trastuzumab may be resistant to various processing stresses. These findings have important implications with respect to pharmaceutical processing of monoclonal antibodies.

Intranasal and intravenous administration of octa‐arginine modified poly(lactic‐co‐glycolic acid) nanoparticles facilitates central nervous system delivery of loperamide

The potential of poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles (NPs) surface modified with octa‐arginine (R8) for central nervous system (CNS) delivery was investigated.

Influence of Parathyroid Hormone-Loaded PLGA Nanoparticles in Porous Scaffolds for Bone Regeneration

Biodegradable poly(lactide-co-glycolide) (PLGA) nanoparticles, containing human parathyroid hormone (PTH (1–34)), prepared by a modified double emulsion-solvent diffusion-evaporation method, were incorporated in porous freeze-dried chitosan-gelatin (CH-G) scaffolds. The PTH-loaded nanoparticles (NPTH) were characterised in terms of morphology, size, protein loading, release kinetics and in vitro assessment of biological activity of released PTH and cytocompatibility studies against clonal human osteoblast (hFOB) cells. Structural integrity of incorporated and released PTH from nanoparticles was found to be intact by using Tris-tricine SDS-PAGE. In vitro PTH release kinetics from PLGA nanoparticles were characterised by a burst release followed by a slow release phase for 3–4 weeks. The released PTH was biologically active as evidenced by the stimulated release of cyclic AMP from hFOB cells as well as increased mineralisation studies. Both in vitro and cell studies demonstrated that the PTH bioactivity was maintained during the fabrication of PLGA nanoparticles and upon release. Finally, a content of 33.3% w/w NPTHs was incorporated in CH-G scaffolds, showing an intermittent release during the first 10 days and, followed by a controlled release over 28 days of observation time. The increased expression of Alkaline Phosphatase levels on hFOB cells further confirmed the activity of intermittently released PTH from scaffolds.

Comparative evaluation of the degree of pegylation of poly(lactic-co-glycolic acid) nanoparticles in enhancing central nervous system delivery of loperamide.

In this study, we examined the relative cellular uptake of nanoparticles (NPs) formulated using poly(lactic‐co‐glycolic acid) (PLGA) polymers with increasing degree of pegylation (PLGA‐PEG) and their potential to deliver loperamide to the brain of a mouse.