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Yet, no standardized test method for drug release measurements from PLGA-based microparticles has been generally agreed on, or described by the regulatory authorities. Often, perfect sink conditions are provided in vitro to avoid artificial drug saturation effects. However, the maintenance of such conditions might strongly affect PLGA degradation. The involved physicochemical processes are complex and the potential impact of perfect sink conditions is not yet well understood. Differently sized, highly porous, carbamazepine- and ibuprofen-loaded PLGA microparticles were prepared by a W/O/W emulsion solvent extraction/evaporation technique. The initial drug loading was intentionally low (3-4%) so that the two drugs were molecularly dispersed within the polymeric matrices (monolithic solutions). This was important to be able to exclude potential limited drug solubility effects on the resulting release kinetics. Drug release into phosphate buffer pH 7.4 was measured under perfect sink conditions. SEC, DSC and SEM were used to characterize polymer degradation. The decrease in the average polymer molecular weight, glass transition temperature as well as changes in the inner and outer morphology of the PLGA microparticles were strongly affected by the bulk fluid's volume. In the case of the poorly water-soluble drug carbamazepine, much lower "microparticle mass:phosphate buffer volume" ratios were required to maintain perfect sink conditions, resulting in stable pH values within the bulk fluid, slower PLGA degradation and, thus, lower drug release rates. Thus, great care has to be taken when defining the conditions for in vitro drug release measurements from PLGA-based microparticles, avoiding potentially artificial conditions for polymer degradation., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The aim of this study was to better understand the importance of the "microparticle mass:bulk fluid volume" ratio during in vitro drug release measurements from PLGA microparticles. Initially porous/non-porous, ibuprofen/lidocaine/propranolol HCl-loaded systems were exposed to phosphate buffer pH 7.4 in agitated test tubes, varying the microparticle concentration from 5:1 to 20:1mg:mL. Interestingly, drug release was virtually unaffected by the "microparticle mass:bulk fluid volume" ratio in the case of initially porous, ibuprofen-loaded microparticles, exhibiting complete drug release within about 1 week. Optical microscopy, SEM, DSC and pH measurements of the bulk fluid revealed no major impact of the microparticle concentration on the systems' properties within the first couple of days. However, a more rapid and pronounced decrease in the pH of the release medium occurred after 10-14 d at elevated "microparticle mass:bulk fluid volume" ratios. This resulted in an accelerated: (i) decrease in the glass transition temperature, (ii) microparticle agglomeration, and (iii) increase in the internal and external microparticle porosity. Importantly, this phenomenon did not significantly affect drug release from initially porous, lidocaine-loaded microparticles, exhibiting complete release within about 18 d. In contrast, drug release became significantly faster at higher "microparticle mass:bulk fluid volume" ratios in the case of initially non-porous, lidocaine-loaded microparticles and initially porous, propranolol HCl-loaded systems, exhibiting complete release after 1 and 2 months, respectively. Thus, depending on the type of system, the "microparticle mass:bulk fluid volume" ratio may or may not affect the observed release kinetics in vitro. This should be carefully taken into account when defining the experimental conditions for drug release measurements from this type of advanced drug delivery systems.

Many drugs are not able to cross the Blood Brain Barrier (BBB) and, thus, cannot reach a target site within the Central Nervous System (CNS). Local controlled drug delivery can help to overcome this restriction. However, this is a highly challenging approach and only one product is yet available on the market: Gliadel, which is used to reduce the risk of local tumor recurrence upon resection of malignant glioma. The aim of this study was to evaluate the potential of local controlled drug delivery to the CNS to reduce the consequences of ischemic stroke. Fenofibrate as well as its active metabolite fenofibric acid were encapsulated within PLGA microparticles. Importantly, fenofibrate-loaded microparticles effectively reduced the consequences of ischemic stroke in Wistar rats: the total, cortical and striatal infarct volumes decreased from 257 to 197, 193 to 139, and 64 to 58 mm(3), respectively. Interestingly, fenofibric acid-loaded microparticles did not show significant in vivo efficacy, which might be attributable to a potentially limited distribution pattern within the brain and/or limited cell uptake. Thus, local controlled drug delivery to the CNS also has a significant potential for the treatment/prevention of other types of diseases than cancer. Furthermore, this approach can help to provide proof of concept in vivo in the early drug discovery phase, if the drug candidate cannot cross the BBB.

Purpose: To better understand the importance of the environmental conditions for drug release from biodegradable microparticles allowing for the development of more appropriate in vitro release measurement techniques., Methods: Propranolol HCl diffusion in various agarose gels was characterized by NMR and UV analysis. Fick's law was used to theoretically predict the mass transport kinetics. Drug release from PLGA-based microparticles in such agarose gels was compared to that measured in agitated bulk fluids ("standard" method)., Results: NMR analysis revealed that the drug diffusivity was almost independent of the hydrogel concentration, despite of the significant differences in the systems' mechanical properties. This is due to the small size of the drug molecules/ions with respect to the hydrogel mesh size. Interestingly, the theoretically predicted drug concentration-distance-profiles could be confirmed by independent experiments. Most important from a practical point of view, significant differences in the release rates from the same batch of PLGA-based microparticles into a well agitated bulk fluid versus a semi-solid agarose gel were observed., Conclusion: Great care must be taken when defining the in vitro conditions for drug release measurements from biodegradable microparticles. The obtained new insight can help facilitating the development of more appropriate in vitro release testing procedures.

Different types of ibuprofen- and lidocaine-loaded, poly(lactic-co-glycolic acid) (PLGA)-based microparticles and thin, free films of various dimensions were prepared and physico-chemically characterized in vitro. The obtained experimental results were analyzed using mathematical theories based on Fick's second law of diffusion. Importantly, the initial drug loadings were low in all cases (4%, w/w), simplifying the mathematical treatment and minimizing potential effects of the acidic/basic nature of the two model drugs on polymer degradation. Interestingly, the type of drug and device geometry strongly affected the resulting release kinetics and relative importance of the involved mass transport mechanisms. For instance, the relative release rate was almost unaffected by the system size in the case of spherical microparticles, but strongly depended on the thickness of thin, free films, irrespective of the type of drug. Ibuprofen and lidocaine release was found to be primarily diffusion controlled from the investigated PLGA-based microparticles for all system sizes, whereas diffusion was only dominant in the case of the thinnest free films. Interestingly, the type of drug did not significantly affect the resulting polymer degradation kinetics. However, ibuprofen release was always much faster than lidocaine release for all system geometries and sizes. This can probably be attributed to attractive ionic interactions between protonated, positively charged lidocaine ions and negatively charged, deprotonated carboxylic end groups of PLGA, hindering drug diffusion. The determined apparent diffusion coefficients of the drugs clearly point out that the mobility of an active agent in PLGA-based delivery systems does not only depend on its own physico-chemical properties and the type of PLGA used, but also to a large extent on the size and shape of the device. This has to be carefully taken into account when developing/optimizing this type of advanced drug delivery systems.

Porous, poly(lactic-co-glycolic acid) (PLGA)-based microparticles were prepared using a water-in-oil-in-water (W/O/W) solvent extraction/evaporation technique. Lidocaine was used as a model drug and different-sized particle fractions were obtained by sieving. The physicochemical properties of the devices and changes thereof upon exposure to phosphate buffer pH 7.4 were studied using optical and scanning electron microscopy, size exclusion chromatography (SEC), differential scanning calorimetry (DSC), gravimetric analysis and in vitro drug release measurements. In contrast to non-porous microparticles of identical composition, the relative drug release rate was found to decrease with increasing system size. SEC, DSC and gravimetric analysis showed that the degradation rate of the polymer increased with increasing microparticle dimension, indicating that autocatalytic effects play an important role even in small and highly porous PLGA-based microparticles. However, these effects were much less pronounced than in non-porous devices. Importantly, they were overcompensated by the effects of the increasing diffusion pathway lengths with increasing system dimension. Thus, high initial microparticle porosities do not only lead to increased drug mobilities, but can also fundamentally alter the underlying mass transport mechanisms.

The major aim of this study was to better understand the importance of autocatalysis in poly(lactic-co-glycolic acid) (PLGA)-based microparticles used as controlled drug delivery systems. Upon contact with biological fluids, PLGA is degraded into shorter chain alcohols and acids. An accumulation of the latter can lead to significant drops in micro-pH and subsequent accelerated polymer degradation. The system size, determining the diffusion path lengths, plays a crucial role for the occurrence/absence of autocatalytic effects. Using an oil-in-water solvent-extraction/evaporation process, different-sized drug-free and drug-loaded, PLGA-based microparticles were prepared and physicochemically characterized (SEM, DSC, SEC, optical microscopy, and UV-spectrophotometry) before and upon exposure to simulated biological fluids. Based on these experimental results, an adequate mathematical theory was developed describing the dominating mass transfer processes and chemical reactions. Importantly, a quantitative relationship could be established between the dimension of the device and the resulting drug release patterns, taking the effects of autocatalysis into account.