PLG Microspheres Research Articles

Carbol fuchsin stain enhances detection of poly‐(d, l‐lactide‐co‐glycolide) microspheres in exenatide extended‐release cutaneous injection‐site foreign body reaction

Injection of high-viscosity fluids into subcutaneous tissues may lead to a granulomatous reaction called sclerosing lipogranuloma (SL). Poly-(d,l-lactide-co-glycolide) (PLG or PLGA) microspheres are used as vehicles for extended-release drugs. Here we describe the histopathologic features of a case of SL induced by exenatide extended-release injections, and the staining pattern of PLG microspheres and microsphere remnants with carbol fuchsin.

Novel application of synchrotron x-ray computed tomography for ex-vivo imaging of subcutaneously injected polymeric microsphere suspension formulations

PurposeSubcutaneously or intramuscularly administered biodegradable microsphere formulations have been successfully exploited in the management of chronic conditions for over two decades, yet mechanistic understanding of the impact of formulation attributes on in vivo absorption rate from such systems is still in its infancy.MethodsSuspension formulation physicochemical attributes may impact particulate deposition in subcutaneous (s.c.) tissue. Hence, the utility of synchrotron X-ray micro-computed tomography (μCT) for assessment of spatial distribution of suspension formulation components (PLG microspheres and vehicle) was evaluated in a porcine s.c. tissue model. Optical imaging of dyed vehicle and subsequent microscopic assessment of microsphere deposition was performed in parallel to compare the two approaches.ResultsOur findings demonstrate that synchrotron μCT can be applied to the assessment of microsphere and vehicle distribution in s.c. tissue, and that microspheres can also be visualised in the absence of contrast agent using this approach. The technique was deemed superior to optical imaging of macrotomy for the characterisation of microsphere deposition owing to its non-invasive nature and relatively rapid data acquisition time.ConclusionsThe method outlined in this study provides a proof of concept feasibility for μCT application to determining the vehicle and suspended PLG microspheres fate following s.c. injection. A potential application for our findings is understanding the impact of injection, device and formulation variables on initial and temporal depot geometry in pre-clinical or ex-vivo models that can inform product design.Graphical abstract

Collagen-PEG composite microspheres for bone regeneration

Event Abstract Back to Event Collagen-PEG composite microspheres for bone regeneration Candice Sears1, Sarah Dang2, Colin Dodson1, Allison Rice-Ficht3, Carl Gregory3 and Roland Kaunas1 1 Texas A&M University, Biomedical Engineering, United States 2 Texas A&M University, Chemical Engineering, United States 3 Texas A&M Health Science Center, Molecular and Cellular Medicine, United States Introduction: Of the 5.6 million bone fractures that occur annually in the United States, about 10% fail to repair[1]. The canonical Wingless (cWnt) signaling pathway is critical for healing of bone fractures[2]. We have demonstrated that inhibiting peroxisome proliferator-activating receptor gamma with GW9662 (GW) reduces negative cross-talk on the cWnt pathway, resulting in a pro-osteogenic hMSC phenotype (OEhMSCs)[3]. OEhMSCs secrete an extracellular matrix (hMatrix) that mimics the composition of anabolic bone tissue and strongly enhances hMSC retention and subsequent bone repair in vivo[3]. We designed composite microspheres for co-administration of GW and hMatrix to facilitate cell retention and bone repair in vivo. Materials and Methods: GW was co-dissolved with poly(lactic-co-glycolic acid) (PLGA, 10%, w/v) in dichloromethane and PLGA solution was added to poly(vinyl alcohol) solution (8%, w/v). The solution was added to distilled water, and stirring was continued to obtain spheres that were then sieved to obtain a size of 20-32 µm. Poly(ethylene glycol) diacrylate (PEGDA) spheres containing the PLG microspheres were produced using a continuous-flow emulsion and photocrosslinking technique. The continuous phase consisted of mineral oil with 0.5% Span 80, while the dispersed phase was a solution of PLGA spheres, 30% PEGDA and 8% Lithium phenyl-2,4,6-trimethylbenzoylphosphinate in a functionalized collagen (Acrylate-PEG-Collagen) solution. ELISA and qRT-PCR for osteogenic markers were used to assess osteogenesis. Results and Discussion: An osteogenic microsphere was developed to coadminister hMatrix and GW to enhance hMSC retainment and promote osteorepair in vivo. Initial feasibility was demonstrated using collagen type I since this is the major component of hMatrix. We have functionalized collagen type I with photo-cross-linkable groups[4] to enable their incorporation into PEGDA microspheres. We also loaded GW into PLGA nanoparticles which were encapsulated in the PEGDA spheres and quantified the drug release profile. Specific gene and protein detection by qRT-PCR and osteoprotegerin assay of the adhered hMSCs revealed that GW induced osteogenesis. Conclusions: Conventional hMSC therapies have had limited success in bone regeneration. Autologous bone grafting is the gold standard to regenerate critical sized bone defects. Conversely, this procedure is associated with donor site morbidity and a limited volume of material available. The use of bone morphogenetic proteins have also been used, however, their use is associated with ectopic bone growth, paralysis, and inflammation[5]-[9]. Our composite microspheres incorporate biopolymers such as hMatrix to provide a favorable microenvironment and signal to cells to enhance their performance in vivo. We have developed a method to create microspheres for bone regeneration that provides both chemical and bioactive cues to promote new bone growth for critical sized bone defects.

Poly(lactide-co-glycolide) microspheres for MRI-monitored transcatheter delivery of sorafenib to liver tumors

The multi-kinase inhibitor (MKI) sorafenib can be an effective palliative therapy for patients with hepatocellular carcinoma (HCC). However, patient tolerance is often poor due to common systemic side effects following oral administration. Local transcatheter delivery of sorafenib to liver tumors has the potential to reduce systemic toxicities while increasing the dose delivered to targeted tumors. We developed sorafenib-eluting PLG microspheres for delivery by intra-hepatic transcatheter infusion in an orthotropic rodent HCC model. The particles also encapsulated iron-oxide nanoparticles permitting magnetic resonance imaging (MRI) of intra-hepatic biodistributions. The PLG microspheres (diameter≈1μm) were loaded with 18.6% (w/w) sorafenib and 0.54% (w/w) ferrofluid and 65.2% of the sorafenib was released within 72h of media exposure. In vitro studies demonstrated significant reductions in HCC cell proliferation with increasing doses of the sorafenib-eluting microspheres, where the estimated IC50 was a 29μg/mL dose of microspheres. During in vivo studies, MRI permitted intra-procedural visualization of intra-hepatic microsphere delivery. At 72h after microsphere infusion, microvessel density was significantly reduced in tumors treated with the sorafenib-eluting microspheres compared to both sham control tumors (by 35%) and controls (by 30%). These PLG microspheres offer the potential to increase the efficacy of molecularly targeted MKI therapies while reducing systemic exposures via selective catheter-directed delivery to HCC.

Preparation of hydroxyapatite-decorated poly(lactide-co-glycolide) microspheres for paclitaxel delivery

Paclitaxel (Tax) is an anticancer drug with extremely low water solubility, and development of the formulation without organic solvents is highly desirable. Hydroxyapatite (HA) is a biocompatible and porous inorganic material that can be used effectively in drug delivery systems, but poor dispersibility in water limits its application. In this study, HA-decorated poly(lactide-co-glycolide) (PLG) spheres with several micrometers were prepared and characterized. PLG microspheres adsorbed Tax, independent in the HA decorating, and their water dispersibility was retained after the HA decorating. Tax-loaded HA-decorated PLG microspheres (Tax/HA/PLG) could thus be highly dispersed in water, increasing their cellular uptake. Most Tax molecules were stably adsorbed to the HA and HA-decorated PLG (HA/PLG) particles. Although the cytotoxicity of Tax-loaded HA was much lower than that of free Tax, the drug activity of Tax/HA/PLG was markedly improved. Since the morphology of microtubules was changed after the Tax/HA/PLG treatment, the HA/PLG could work as a carrier for Tax.

Enhancing osteoconductivity of fibrin gels with apatite-coated polymer microspheres.

Fibrin gels are a promising material for use in promoting bone repair and regeneration due to their ease of implant formation, tailorability, biocompatibility, and degradation by natural processes. However, these materials lack necessary osteoconductivity to nucleate calcium, integrate with surrounding bone, and promote bone formation. Polymeric substrata formed from poly(lactide-co-glycolide) (PLG) are widely used in bone tissue engineering. A carbonated apatite layer of bone-like mineral can be successfully grown on the surface of PLG microspheres after a multiday incubation process in modified simulated body fluid. Such coatings improve the osteoconductivity of the polymer, provide nucleation sites for cell-secreted calcium, and enhance the potential osseointegration with host tissue. We examined the capacity of mineralized polymeric microspheres suspended within fibrin hydrogels to enhance the osteoconductivity of fibrin gels and increase the osteogenic potential of these materials. The inclusion of microparticles, both nonmineralized and mineralized, reduced the capacity of mesenchymal stem cells (MSCs) to contract the gel. When cultured in osteogenic media, we detected a near linear increase in both calcium and phosphate incorporation in gels containing mineralized microspheres and entrapped MSCs. The osteoconductivity of acellular fibrin gels with mineralized and nonmineralized microspheres was assessed in a rodent calvarial bone defect over 12 weeks. Compared to untreated rodent calvarial bone defects, we detected significant increases in early vascularization when treated with fibrin gels, with greater vascularization, on average, occurring with gels containing microspheres. We detected a trend for increased bone mineral density in gels containing mineralized microspheres after 12 weeks. These findings demonstrate that the osteoconductivity of fibrin gels can be increased by inclusion of mineralized microspheres, but additional signals may be required to rapidly accelerate bone repair.

Fabrication and characterisation of 2NDPA-loaded poly(lactide-co-glycolide) (PLG) microspheres for explosive safety

We demonstrate the microencapsulation of a double-base (DB) rocket propellant stabiliser, 2-nitrodiphenylamine (2-NDPA), that can potentially increase the shelf life of DB rocket propellants. Poly(lactide-co-glycolide) (PLG) microspheres loaded with 2-NDPA were prepared using the oil-in-water emulsion technique. The microsphere size was found to be inversely related to the mixing rate. It was also found that a higher theoretical loading of 2-NDPA resulted in larger microspheres. In addition, a Rosin Rammler distribution function gave an accurate representation of the microsphere size distribution, and the release rate 2-NDPA from PLG microspheres was found to be size dependent. We show that parameters such as the stirring speed and the percent loading of 2-NDPA can be varied to tailor the release of 2-NDPA from PLG microspheres. In addition, we have shown that temperature has a dramatic effect on the release of 2-NDPA from PLG microcapsules.

Reduction of structural perturbations in bovine serum albumin by non-aqueous microencapsulation.

Protein stability is a factor limiting the use of sustained-release devices in medical applications. The aim of this study was to reduce structural perturbations occurring in the frequently used model protein, bovine serum albumin (BSA), upon microencapsulation in poly(D,L-lactide-co-glycolide) (PLG) microspheres. Spray freeze-dried BSA was encapsulated into PLG microspheres by a completely non-aqueous oil-in-oil encapsulation procedure. FTIR spectroscopy was used as a non-invasive method to quantify procedure-induced structural perturbations in BSA. Spray-freeze drying of BSA caused significant structural perturbations that were minimized by co-spray freeze-drying BSA with trehalose. BSA-containing microspheres were produced by suspension of the powder by homogenization in methylene chloride containing PLG, followed by formation of coacervate droplets by the addition of silicon oil and hardening using the solvent heptane. Resulting microspheres had dimensions of approximately 100 microm and the encapsulation efficiency for BSA was > 90%. FTIR data showed that the structure of the BSA-trehalose formulation encapsulated into PLG microspheres was less perturbed than that of BSA obtained from buffer alone. The results demonstrate that the structure-guided encapsulation approach introduced for non-aqueous casting encapsulation procedures can be extended to the non-aqueous production of pharmaceutically relevant PLG microspheres involving a complex encapsulation procedure.

Prevention of structural perturbations and aggregation upon encapsulation of bovine serum albumin into poly(lactide-co-glycolide) micropheres using the solid-in-oil-in water technique.

Bovine serum albumin (BSA) was encapsulated into poly(lactide-co-glycolide) (PLG) microspheres by a solid-in-oil-in-water (s/o/w) technique. We tested whether perturbations in BSA secondary structure could be minimized during encapsulation by using trehalose and how this would influence BSA aggregation and release. BSA secondary structure was monitored noninvasively by Fourier-transform infrared spectroscopy. When BSA was co-lyophilized with trehalose, lyophilization-induced structural perturbations were significantly reduced. The formulation obtained (BSA-Tre) was encapsulated into PLG microspheres and, by optimizing critical encapsulation parameters, a loading efficiency of 85% was achieved. However, due to the loss of the excipient in the o/w emulsion step, the structure of BSA-Tre was more perturbed than before encapsulation. Excipient-loss and encapsulation-induced structural perturbations could be prevented by saturating the aqueous phase in the o/w step with trehalose and by using the organic solvent chloroform. This in turn reduced the formation of soluble BSA aggregates. BSA was released from PLG microspheres using the improved formulations with an initial release in 24 h of not more than 22%, followed by a sustained release over at least 2 weeks. In summary, optimization of the encapsulation conditions in the s/o/w procedure resulted in the encapsulation of BSA without procedure-induced structural perturbations and minimized the release of aggregated protein. This demonstrates that the s/o/w technique is an excellent alternative to the most common encapsulation procedure, namely the water-in-oil-in-water technique.

Encapsulation of bovine serum albumin in poly(lactide-co-glycolide) microspheres by the solid-in-oil-in-water technique.

Non-aqueous protocols to encapsulate pharmaceutical proteins into biocompatible polymers have gained much attention because they allow for the minimization of procedure-induced protein structural perturbations. The aim of this study was to determine if these advantages could be extended to a semi-aqueous encapsulation procedure, namely the solid-in-oil-in-water (s/o/w) technique. The model protein bovine serum albumin (BSA) was encapsulated into poly(lactide-co-glycolide) (PLG) microspheres by first suspending lyophilized BSA in methylene chloride containing PLG, followed by emulsification in a 1% aqueous solution of poly(vinyl alcohol). By variation of critical encapsulation parameters (homogenization intensity, BSA:PLG ratio, emulsifier concentration, ratio of organic to aqueous phase) an encapsulation efficiency of > 90% was achieved. The microspheres obtained showed an initial burst release of < 20%, a sustained release over a period of about 19 days, and a cumulative release of at least 90% of the encapsulated BSA. Different release profiles were observed when using different encapsulation protocols. These differences were related to differences in the microsphere erosion observed using scanning electron microscopy. Release of BSA was mainly due to simple diffusion or to both diffusion and microsphere erosion. Fourier-transform infrared studies were conducted to investigate the secondary structure of BSA during the encapsulation. Quantification of the alpha-helix and beta-sheet content as well as of overall structural changes showed that the secondary structure of encapsulated BSA was not more perturbed than in the lyophilized powder used initially. Thus, the encapsulation procedure did not cause detrimental structural perturbations in BSA. In summary, the results demonstrate that the s/o/w technique is an excellent alternative to the water-in-oil-in-water technique, which is still mainly used in the encapsulation of proteins in PLG microspheres.

Optimization of PLG microspheres for tailored drug release

Here we explore the opportunity to design and then produce tailored release of therapeutic drugs from microcapsules. By use of “building blocks,” formed from well characterized microcapsule populations, an inverse design algorithm has been developed that provides an optimal (in a least squares sense) combination of building blocks to achieve a desired release history. Previously we have reported experiments and a well validated mathematical model for computing drug release histories from PLG microcapsules, and these form the backbone of the present optimization algorithm. To expand our available basis for finding useful optimal solutions, we also report work to validate the mathematical model for two different molecular weights. Thus, our building blocks comprise populations that differ by microsphere mean diameter, polydispersity, and polymer molecular weight, giving three separate parameters that effect drug release rate, and from which we build a foundation for our tailored release. Here we have taken a basis of six different microcapsule release systems, from which we build a tailored release history using constrained optimization to fit a prescribed release profile. Comparison of predicted release with measurements from the tailored microcapsule populations was found to produce excellent results, with correlation coefficients greater than 0.98. By way of demonstration, a triple pulse design is described that illustrates the power of the method.

Growth of hydroxyapatite coatings on biodegradable polymer microspheres.

Mineral-coated microspheres were prepared via a bioinspired, heterogeneous nucleation process at physiological temperature. Poly(d,l-lactide-co-glycolide) (PLG) microspheres were fabricated via a water-in-oil-in-water emulsion method and were mineral-coated via incubation in a modified simulated body fluid (mSBF). X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy with associated energy-dispersive X-ray spectroscopy confirmed the presence of a continuous mineral coating on the microspheres. The mineral grown on the PLG microsphere surface has characteristics analogous to those of bone mineral (termed "bonelike" mineral), with a carbonate-containing hydroxyapatite phase and a porous structure of platelike crystals at the nanometer scale. The assembly of mineral-coated microspheres into aggregates was observed when microsphere concentrations above 0.50 mg/mL were incubated in mSBF for 7 days, and the size of the aggregates was dependent on the microsphere concentration in solution. In vitro mineral dissolution studies performed in Tris-buffered saline confirmed that the mineral formed was resorbable. A surfactant additive (Tween 20) was incorporated into mSBF to gain insight into the mineral growth process, and Tween 20 not only prevented aggregation but also significantly inhibited mineral formation and influenced the characteristics of the mineral formed on the surface of PLG microspheres. Taken together, these findings indicate that mineral-coated PLG microspheres or mineral-coated microsphere aggregates can be synthesized in a controllable manner using a bioinspired process. These materials may be useful in a range of applications, including controlled drug delivery and biomolecule purification.

Poly(ethylene glycol)-Modified Proteins: Implications for Poly(lactide-co-glycolide)-Based Microsphere Delivery

The reduced injection frequency and more nearly constant serum concentrations afforded by sustained release devices have been exploited for the chronic delivery of several therapeutic peptides via poly(lactide-co-glycolide) (PLG) microspheres. The clinical success of these formulations has motivated the exploration of similar depot systems for chronic protein delivery; however, this application has not been fully realized in practice. Problems with the delivery of unmodified proteins in PLG depot systems include high initial "burst" release and irreversible adsorption of protein to the biodegradable polymer. Further, protein activity may be lost due to the damaging effects of protein-interface and protein-surface interactions that occur during both microsphere formation and release. Several techniques are discussed in this review that may improve the performance of PLG depot delivery systems for proteins. One promising approach is the covalent attachment of poly(ethylene glycol) (PEG) to the protein prior to encapsulation in the PLG microspheres. The combination of the extended circulation time of PEGylated proteins and the shielding and potential stabilizing effects of the attached PEG may lead to improved release kinetics from PLG microsphere system and more complete release of the active conjugate.

Macromolecule Release from Monodisperse PLG Microspheres: Control of Release Rates and Investigation of Release Mechanism

Novel macromolecular therapeutics such as peptides, proteins, and DNA are advancing rapidly toward the clinic. Because of typically low oral bioavailability, macromolecule delivery requires invasive methods such as frequently repeated injections. Parenteral depots including biodegradable polymer microspheres offer the possibility of reduced dosing frequency but are limited by the inability to adequately control delivery rates. To control release and investigate release mechanisms, we have encapsulated model macromolecules in monodisperse poly(D,L-lactide-co-glycolide) (PLG) microspheres using a double-emulsion method in combination with the precision particle fabrication technique. We encapsulated fluorescein-dextran (F-Dex) and sulforhodamine B-labeled bovine serum albumin (R-BSA) into PLG microspheres of three different sizes: 31, 44, and 80 microm and 34, 47, and 85 microm diameter for F-Dex and R-BSA, respectively. The in vitro release profiles of both compounds showed negligible initial burst. During degradation and release, the microspheres hollowed and swelled at critical time points dependant upon microsphere size. The rate of these events increased with microsphere size resulting in the largest microspheres exhibiting the fastest overall release rate. Monodisperse microspheres may represent a new delivery system for therapeutic proteins and DNA and provide enhanced control of delivery rates using simple injectable depot formulations.

Modifying the Proliferative State of Target Cells to Control DNA Expression and Identifying Cell Types Transfected In Vivo

Although the majority of current gene transfer techniques have focused on increasing the ability of the DNA to enter the cell, it is possible that changing the proliferative and migratory state of cells will influence the cells ability to take up and express plasmid DNA. This study was designed to test the hypothesis that growth factors (basic fibroblast growth factor (bFGF) and hepatocyte growth factor/scatter factor (HGF/SF)) used to alter the proliferative and migratory state of cells can alter plasmid DNA uptake and expression. In vitro studies indicate that enhancing cell proliferation with growth factor exposure enhances plasmid DNA uptake and expression. Furthermore, dual localized delivery of bFGF and plasmid DNA in vivo increases the expression, 3-6 times over control, as compared to plasmid delivery alone. Dual delivery of a factor promoting cell proliferation and a plasmid led to a further increase in the expression of the plasmid encoding bone morphogenetic protein-2 in a rat cranial defect by specific cell populations. The results of these studies suggest that increasing the proliferative state of target cell populations can enhance non-viral gene transfer.

Effect of mean diameter and polydispersity of PLG microspheres on drug release: Experiment and theory

The need to tailor release rate profiles from polymeric microspheres is a significant problem. Microsphere size, which has a significant effect on drug release rate, can potentially be varied to design a controlled drug delivery system with desired release profile. In this work the effects of microspheres mean diameter, polydispersity, and polymer degradation on drug release rate from poly(lactide-co-glycolide) (PLG) microspheres are described. Piroxicam containing PLG microspheres were fabricated at 20% loading, and at three different impeller speeds. A portion of the microspheres was then sieved giving five different size distributions. In vitro release kinetics were determined for each preparation. Based on these experimental results, a suitable mathematical theory has been developed that incorporates the effect of microsphere size distribution and polymer degradation on drug release. We show from in vitro release experiments that microsphere size has a significant effect on drug release rate. The initial release rate decreased with an increase in microsphere size. In addition, the release profile changed from first order to concave-upward (sigmoidal) as the microsphere size was increased. The mathematical model gave a good fit to the experimental release data. For highly polydisperse populations (polydispersity parameter b < 3), incorporating the microsphere size distribution into the mathematical model gave a better fit to the experimental results than using the representative mean diameter. The validated mathematical model can be used to predict small-molecule drug release from PLG microsphere populations.

Temporally regulated delivery of VEGF in vitro and in vivo.

The exposure duration and tissue distribution will likely dictate the success of vascular endothelial growth factor (VEGF) in therapeutic angiogenesis. We hypothesized that these variables can be regulated via the manner in which the VEGF is incorporated into polymer constructs (formed with a gas foaming technique) used for its delivery. VEGF was incorporated directly into poly(lactide-co-glycolide) (PLG) scaffolds or pre-encapsulated in PLG microspheres used to fabricate scaffolds. Protein release kinetics and tissue distribution were determined using iodinated VEGF. VEGF was positioned predominantly adjacent to scaffold pores when incorporated directly and was released rapidly (40-60% in 5 days). Pre-encapsulation led to the VEGF being more deeply embedded and resulted in a delayed release. Alterations in polymer composition, scaffold size, and matrix composition generated minor variations in release kinetics. In vivo, the released VEGF generated local protein concentrations above 10 ng/mL at distances up to 2 cm from the implant site for the 21 days of the experiment, with negligible release into the systemic circulation, and significantly enhanced local angiogenesis. These data indicate that VEGF can be administered in a sustained and localized fashion in vivo, and the timing of VEGF delivery can be altered with the mechanism of incorporation into polymer scaffolds used for its delivery.

Biodegradation and biocompatibility of contraceptive-steroid-loaded poly ( dl-lactide-co-glycolide) injectable microspheres: in vitro and in vivo study

Purpose A controlled-release drug delivery of contraceptive steroids levonorgestrel (LNG) and ethinyl estradiol (EE) has been developed by successful encapsulation of LNG and EE in poly (lactide-co-glycolide) (PLG) microspheres. Materials and Methods Smooth, spherical, steroid-loaded PLG microspheres with a mean size of 10–25 μm were prepared by using the water/oil/water double-emulsion solvent evaporation method. Results In vitro release profiles showed an increased burst release of LNG/EE on Week 1; thereafter, the release was sustained. At the end of Week 7, the release of LNG/EE from 1:5 and 1:10 PLG microspheres was 75.64% and 62.55%. respectively. In vitro degradation studies showed that the PLG microspheres maintained surface integrity up to Week 8 and then eroded completely by Week 20. In an in vivo study, the serum concentration of LNG/EE in rats showed a triphasic release response, with an initial burst release of 8 ng/mL LNG and 14 pg/mL EE on Day 1; thereafter, a controlled release of the drugs to the systemic circulation was maintained until Week 15, maintaining constant drug levels of 2 ng/mL LNG and 3–4 pg/mL EE in the blood. Histological examination of steroid-loaded PLG microspheres injected intramuscularly into the thigh muscle of Wistar rats showed minimal inflammatory reaction, demonstrating that contraceptive-steroid-loaded microspheres were biocompatible. Conclusion This controlled-release and biocompatible nature of the PLG microspheres may have potential application in contraceptive therapy.

The effect of γ-irradiation and polymer composition on the stability of PLG polymer and microspheres

The effects of lactide:glycolide ratio and γ-irradiation on the stability characteristics of poly( d,l-lactide- co-glycolide) ( dl-PLG) co-polymer and microspheres were studied. Samples containing 50:50, 65:35, 75:25, 85:15 and 95:5 lactide:glycolide were studied as both the raw polymer and microspheres. The samples were characterised and degradation was monitored using a variety of spectroscopic, chromatographic, thermal and particle analysis techniques. The lactide:glycolide ratio was shown to be an important parameter in controlling the degradation of PLG co-polymer, especially in the microspheres, and the raw polymer samples were observed to be less stable than the microspheres. γ-Irradiation was shown to reduce the molecular weight of the PLG samples without significantly affecting the polydispersity, suggesting a random chain scission degradation mechanism. The detrimental effects of γ-irradiation were shown to continue on storage of the samples for 4 weeks in the solid state at ambient and accelerated conditions.

Small-Molecule Release from poly(D,L-Lactide)/Poly(D,L-Lactide-co-Glycolide) Composite Microparticles

Addition of biodegradable polymer shells surrounding polymeric, drug-loaded microparticles offers the opportunity to control drug release rates. A novel fabrication method was used to produce microparticles with precise control of particle diameter and the thickness of the polymer shell. The effect of shell thickness on release of a model drug, piroxicam, has been clearly shown for 2- to 15-microm thick shells of poly(D,L-lactide) (PDLL) surrounding a poly(D,L-lactide-co-glycolide) (PLG) core and compared to pure PLG microspheres loaded with piroxicam. Furthermore, the core-shell microparticles are compared to microspheres containing blended polymers in the same mass ratios to demonstrate the importance of the core-shell morphology. Combining PDLL(PLG) microcapsules of different shell thicknesses allows nearly constant release rates to be attained for a period of 6 weeks.