An overview of the production methods for core-shell microspheres for parenteral controlled drug delivery

Core-shell microspheres hold great promise as a drug delivery system because they offer several benefits over monolithic microspheres in terms of release kinetics, for instance a reduced initial burst release, the possibility of delayed (pulsatile) release, and the possibility of dual-drug release. Also, the encapsulation efficiency can significantly be improved. Various methods have proven to be successful in producing these core-shell microspheres, both the conventional bulk emulsion solvent evaporation method and methods in which the microspheres are produced drop by drop. The latter have become increasingly popular because they provide improved control over the particle characteristics. This review assesses various production methods for core-shell microspheres and summarizes the characteristics of formulations prepared by the different methods, with a focus on their release kinetics

Microfluidic Production of Polymeric Core-Shell Microspheres for the Delayed Pulsatile Release of Bovine Serum Albumin as a Model Antigen

For many vaccines, multiple injections are required to confer protective immunity against targeted pathogens. These injections often consist of a primer administration followed by a booster administration of the vaccine a few weeks or months later. A single-injection vaccine formulation that provides for both administrations could greatly improve the convenience and vaccinee’s compliance. In this study, we developed parenterally injectable core-shell microspheres with a delayed pulsatile release profile that could serve as the booster in such a vaccine formulation. These microspheres contained bovine serum albumin (BSA) as the model antigen and poly(DL-lactide-co-glycolide) (PLGA) with various DL-lactide:glycolide monomer ratios as the shell material. Highly monodisperse particles with different particle characteristics were obtained using a microfluidic setup. All formulations exhibited a pulsatile in vitro release of BSA after an adjustable lag time. This lag time increased with the increasing lactide content of the polymer and ranged from 3 to 7 weeks. Shell thickness and bovine serum albumin loading had no effect on the release behavior, which could be ascribed to the degradation mechanism of the polymer, with bulk degradation being the main pathway. Co-injection of the core-shell microspheres together with a solution of the antigen that serves as the primer would allow for the desired biphasic release profile. Altogether, these findings show that injectable core-shell microspheres combined with a primer are a promising alternative for the current multiple-injection vaccines

Microsphere-Based Rapamycin Delivery, Systemic Versus Local Administration in a Rat Model of Renal Ischemia/Reperfusion Injury

The increasing prevalence and treatment costs of kidney diseases call for innovative therapeutic strategies that prevent disease progression at an early stage. We studied a novel method of subcapsular injection of monodisperse microspheres, to use as a local delivery system of drugs to the kidney. We generated placebo- and rapamycin monodisperse microspheres to investigate subcapsular delivery of drugs. Using a rat model of acute kidney injury, subcapsular injection of placebo and rapamycin monodisperse microspheres (monospheres) was compared to subcutaneous injection, mimicking systemic administration. We did not find any adverse effects related to the delivery method. Irrespective of the injection site, a similar low dose of rapamycin was present in the circulation. However, only local intrarenal delivery of rapamycin from monospheres led to decreased macrophage infiltration and a significantly lower amount of myofibroblasts in the kidney, where systemic administration did not. Local delivery of rapamycin did cause a transient increase in the deposition of collagen I, but not of collagen III. We conclude that therapeutic effects can be increased when rapamycin is delivered subcapsularly by monospheres, which, combined with low systemic concentrations, may lead to an effective intrarenal delivery method

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Kidney injury triggers fibrosis, the final common pathway of chronic kidney disease (CKD). The increase of CKD prevalence worldwide urgently calls for new therapies. Available systemic treatment such as rapamycin are associated with serious side effects. To study the potential of local antifibrotic therapy, we administered rapamycin-loaded microspheres under the kidney capsule of ureter-obstructed rats and assessed the local antifibrotic effects and systemic side effects of rapamycin. After 7 days, microsphere depots were easily identifiable under the kidney capsule. Both systemic and local rapamycin treatment reduced intrarenal mTOR activity, myofibroblast accumulation, expression of fibrotic genes, and T-lymphocyte infiltration. Upon local treatment, inhibition of mTOR activity and reduction of myofibroblast accumulation were limited to the immediate vicinity of the subcapsular pocket, while reduction of T-cell infiltration was widespread. In contrast to systemically administered rapamycin, local treatment did not induce off target effects such as weight loss. Thus subcapsular delivery of rapamycin-loaded microspheres successfully inhibited local fibrotic response in UUO with less systemic effects. Therapeutic effect of released rapamycin was most prominent in close vicinity to the implanted microspheres. (C) 2014 Elsevier Ltd. All rights reserved

Amylodextrin and poly(DL-lactide) oral controlled release matrix tablets. Concepts for understanding their release mechanisms

Verreweg de meeste medicijnen dienen oraal te worden ingenomen in de vorm van een tabletje. Dit is niet alleen gebruiksvriendelijk, de tabletten zijn ook relatief eenvoudig te produceren. Een deel van de tabletten voor oraal gebruik geeft het farmacon (de werkzame stof) gedurende een langere periode (meestal 4 tot 16 uur) af. Deze tabletten bevatten speciale hulpstoffen die de afgifte van het farmacon reguleren. Bij de matrix-tablet bijvoorbeeld is het farmacon ingebed in een matrix van een polymere hulpstof. Promovendus Rob Steendam bestudeerde twee polymere hulpstoffen, het op zetmeel gebaseerde amylodextrine en het bio-afbreekbare polymelkzuur. Zijn onderzoek geeft meer inzicht in het mechanisme van medicijnafgifte van matrix-tabletten met deze hulpstoffen. Hierdoor is het in de toekomst mogelijk eenvoudiger om deze matrix-tabletten (op industriële schaal) te fabriceren.

Plasticisation of amylodextrin by moisture: Consequences for drug release from tablets

Moisture influences the consolidation behaviour of amylodextrin powders and the porosity and mechanical strength of compacts thereof. The aim of this study is to relate moisture content and compact properties to drug release characteristics of amylodextrin tablets. Therefore, amylodextrin tablets containing theophylline monohydrate were prepared and their release characteristics were studied as a function of moisture content and initial porosity. Drug release from amylodextrin tablets occurs through a leaching mechanism in which cracks are progressively formed in the hydrated part of the matrix leading to almost constant release rates. Small variations in moisture content resulted in large changes of the release rate. A unique relationship between porosity and release rate, which was independent on moisture content and compaction pressure, was observed. Above a critical porosity of 0.075 crack formation was followed by disintegration and fast release. Below this critical porosity, tablet:; stayed intact despite of the formation of cracks, and sustained release was observed. It is concluded that control over moisture content is essential for the production of amylodextrin tablets with reproducible release characteristics. Using amylodextrin containing 10-17% moisture, tablets with a constant release behaviour can be obtained if sufficient compaction pressure (> 300 MPa) is applied. Lubrication of amylodextrin powders reduces the effect of porosity significantly and improves the robustness of amylodextrin tablets as a release controlling excipient in tablets largely. (C) 2000 Elsevier Science B.V. All rights reserved

Tailored protein release from biodegradable poly(ε-caprolactone-PEG)- b-poly(ε-caprolactone) multiblock-copolymer implants

In this study, the in vitro release of proteins from novel, biodegradable phase-separated poly(ε-caprolactone-PEG)-block-poly(ε-caprolactone), [PCL-PEG]-b-[PCL]) multiblock copolymers with different block ratios and with a low melting temperature (49-55 °C) was studied. The effect of block ratio and PEG content of the polymers (i.e. 22.5, 37.5 and 52.5 wt%) as well as the effect of protein molecular weight (1.2, 5.8, 14, 29 and 66 kDa being goserelin, insulin, lysozyme, carbonic anhydrase and albumin, respectively) on protein release was investigated. Proteins were spray-dried with inulin as stabilizer to obtain a powder of uniform particle size. Spray-dried inulin-stabilized proteins were incorporated into polymeric implants by hot melt extrusion. All incorporated proteins fully preserved their structural integrity as determined after extraction of these proteins from the polymeric implants. In general, it was found that the release rate of the protein increased with decreasing molecular weight of the protein and with increasing the PEG content of the polymer. Swelling and degradation rate of the copolymer increased with increasing PEG content. Hence, release of proteins of various molecular weights from [PCL-PEG]-b-[PCL] multi-block copolymers can be tailored by varying the PEG content of the polymer. © 2014 Elsevier B.V. All rights reserved