PLGA Matrices Research Articles

Donepezil accelerates the release of PLGA microparticles via catalyzing the polymer degradation regardless of the end groups and molecular weights

Poly (lactic-co-glycolic acid) (PLGA) is one of the most successful polymers for sustained parenteral drug products in the market. However, rational selection of PLGA in the formulations is still challenging due to the lack of fundamental studies. The present study aimed to investigate the influence of donepezil (DP) on the in-vitro and in-vivo performance of PLGA sustained microspheres. Three kinds of PLGAs with different end groups and molecular weights were selected. Then DP-loaded PLGA microspheres (DP-MSs) with similar particle size, drug loading, and encapsulation efficiency were prepared using an o/w emulsion-solvent evaporation method. Laser diffraction and scanning electron microscopy showed that the prepared DP-MSs were about 35 μm and spherical in shape. Differential scanning calorimetry and X-ray diffraction indicated that DP was in an amorphous state inside the microspheres. Unexpectedly, the molecular weight and end group of PLGAs did not significantly influence the in-vitro and in-vivo performance of the DP-MSs. The gel permeation chromatography indicated that the degradation rates of PLGAs were accelerated with the incorporation of DP into the microspheres, and the molecular weight of all three kinds of PLGAs sharply dropped to about 11,000 Da within the initial three days. The basic catalysis effect induced by DP might be responsible for the accelerated degradation of PLGAs, which led to similar in-vitro release profiles of DP from different PLGA matrices. A point-to-point level A correlation between the in-vitro release and the in-vivo absorption was observed, which confirmed the accelerated release of DP from the DP-MSs in-vivo. The results indicated that the influence of DP on the degradation of PLGA should be considered when developing DP-sustained microspheres.

Implications of changes in physical state of drugs in poly(lactide-co-glycolide) matrices upon exposure to moisture and release medium

The objective of this study was to investigate the influence of the drug physical state (dissolved or dispersed) in poly(lactide-co-glycolide) (PLGA) on drug release and potential changes in physical state upon contact with moisture or release medium. PLGA matrices containing risperidone, ibuprofen or dexamethasone were prepared as films by solvent casting or as implants by hot melt extrusion. The physical state of the drugs in the polymer was examined by DSC and polarized light microscopy and the in-vitro drug release was compared for different drug physical states.Incubation of drug-PLGA matrices at 40 °C/75% RH (relative humidity) resulted in a decrease in microclimate pH in the PLGA matrices upon moisture uptake, dissolving initially dispersed risperidone because of an increased drug solubility in the matrix. In contrast, initially dissolved ibuprofen precipitated in the matrix because of a decrease in drug solubility at lower pH values and a fast water uptake. Dexamethasone did not show any change of physical state under the same conditions; the drug is barely soluble in the dry matrix and its solubility is not pH dependent. Risperidone was released faster from PLGA matrices with dissolved versus dispersed drug, substantially reducing the lag time. The crystallization process of ibuprofen could be inhibited by the use of a higher molecular weight PLGA grade. The inhibition resulted in a faster release from solid solution than from the corresponding solid dispersion. However, ibuprofen, which was deliberately precipitated on the surface of a PLGA matrix by incubation at 40 °C/75% RH, was able to bridge the lag time and led to a linearization of a typical PLGA release profile.In conclusion, a change in the physical state of the drug in PLGA affects the drug release profile. A change can be induced by incubation at 40 °C/75% RH. Furthermore, moisture contact and storage conditions of PLGA drug delivery systems should be carefully considered during handling to avoid undesired drug release changes.

Biomimetic Engineering of a Scavenger-Free Nitric Oxide-Generating/Delivering System to Enhance Radiation Therapy.

Nitric oxide (NO) is a potent tumor-cell radiosensitizer but it can be readily scavenged by hemoglobin (Hb) in vivo. A biomimetic incubator that can generate and deliver NO in a scavenger (Hb)-free environment to enhance its radiosensitizing effect to maximize its efficacy in radiotherapy is proposed. This NO incubator comprises a poly(lactic-co-glycolic acid) (PLGA) hollow microsphere (HM) that contains an NO donor (NONOate) and a surfactant molecule (sodium caprate, SC) in its aqueous core. In acidic tumorous environments, the PLGA shell of the HM allows the penetration of protons from the outside, activating the hydrolytic cleavage of NONOate, spontaneously generating NO bubbles, which are immediately trapped/stabilized by SC. The SC-stabilized NO bubbles in the HM are then squeezed through the spaces of its PLGA matrices by the elevated internal pressure. Upon leaving the HM, the entrapped NO molecules may passively diffuse through their SC-stabilized/protected layer gradually to the tumor site, having a long-lasting radiosensitizing effect and inhibiting tumor growth. The entire process of NO generation and delivery is conducted in a scavenger (Hb)-free environment, mimicking the development of young ovoviviparous fish inside their mothers' bodies in the absence of predators before birth.

Spray-Formed Layered Polymer Microneedles for Controlled Biphasic Drug Delivery.

In this study we present polymeric microneedles composed of multiple layers to control drug release kinetics. Layered microneedles were fabricated by spraying poly(lactic-co-glycolic acid) (PLGA) and polyvinylpyrrolidone (PVP) in sequence, and were characterized by mechanical testing and ex vivo skin insertion tests. The compression test demonstrated that no noticeable layer separation occurred, indicating good adhesion between PLGA and PVP layers. Histological examination confirmed that the microneedles were successfully inserted into the skin and indicated biphasic release of dyes incorporated within microneedle matrices. Structural changes of a model protein drug, bovine serum albumin (BSA), in PLGA and PVP matrices were examined by circular dichroism (CD) and fluorescence spectroscopy. The results showed that the tertiary structure of BSA was well maintained in both PLGA and PVP layers while the secondary structures were slightly changed during microneedle fabrication. In vitro release studies showed that over 60% of BSA in the PLGA layer was released within 1 h, followed by continuous slow release over the course of the experiments (7 days), while BSA in the PVP layer was completely released within 0.5 h. The initial burst of BSA from PLGA was further controlled by depositing a blank PLGA layer prior to forming the PLGA layer containing BSA. The blank PLGA layer acted as a diffusion barrier, resulting in a reduced initial burst. The formation of the PLGA diffusion barrier was visualized using confocal microscopy. Our results suggest that the spray-formed multilayer microneedles could be an attractive transdermal drug delivery system that is capable of modulating a drug release profile.

PLGA‐based in situ‐forming system: degradation behavior in the presence of hydroxyapatite nanoparticles

The degradation behavior of poly(lactic‐co‐glycolic acid) (PLGA) is important for its application as a biomaterial. In this work, the influence of nano‐hydroxyapatite (nano‐HA) on the degradation behavior of PLGA matrix was studied. PLGA‐based in situ forming system containing nano‐HA was prepared using the immersion precipitation method and the polymer hydrolysis was investigated in a phosphate buffer (pH 7.4) at 37°C. The pH values in the testing medium were evaluated to quantify the degradation process. Gel permeation chromatography and scanning electron microscopy techniques were employed to monitor changing of the weight‐average molecular weight (MW) and the body structures of PLGA matrices, respectively. To model the MW changes, a first‐order degradation model was employed. The formed PLGA matrices had different porosities that effected water penetration into the matrices following the hydrolysis process. The obtained degradation rate constant using a mathematical model for PLGA matrices with different nano‐HA content was about from 2.5 to 4.5 times lower than neat PLGA matrix. POLYM. ENG. SCI., 59:1028–1035, 2019. © 2019 Society of Plastics Engineers

Leuprolide Acetate Release Study from γ-Irradiated PLGA-based In Situ Forming System.

It is well known that the properties of polymers can be altered by exposure to γ- ray. γ-irradiation has been used as a sterilization method for polymeric drug delivery devices, and its drug release profile must not be significantly changed. In this study, the effect of γ-irradiation on the release profile of leuprolide acetate from PLGA-based in situ forming system was investigated. Poly(lactide-co-glycolide) (PLGA) was dissolved in N-methylpyrrolidinone (NMP) and irradiated with a total dose of 8 kGy γ-ray emitted by a 60Co source. Then, leuprolide acetate was added to the polymer solution. PLGA-based in situ forming systems were prepared by injecting some specific amount of prepared solution into a buffer phosphate pH 7.4 at 37 °C. The effects of γ-ray on drug release profiles, morphology of matrices and thermal properties as well as stability of polymer were evaluated. The results showed that γ-irradiation causes a decrease in glass transition temperature (Tg) of PLGA from 43.4 to 38.1°C. A reduction in molecular weight of PLGA by about 17.8 % was found as consequence of radiolytic degradation. The morphological studies of PLGA matrices confirmed that the irradiated sample had higher porosity than the non-irradiated sample. It is found that the amount of released leuprolide acetate from irradiated matrix was increased by about 1.6 times after 33 days compared to the nonirradiated ones. In vitro drug release experimental data were fitted using the Gallagher- Corrigan model which indicated that diffusion and degradation were the predominant mechanisms of drug release. Accordingly, leuprolide acetate was released faster from the irradiated matrix compared to the non- irradiated matrix.

The Effect of Fluid Shear Stress on the In Vitro Release Kinetics of Sirolimus from PLGA Films.

Drug-carrying coatings of stents implanted in blood vessels are exposed to various blood flows. This study investigated the effect of fluid shear stress on the in vitro release kinetics of sirolimus from poly(lactic-co-glycolic acid) (PLGA) films. The homemade parallel plate flow chamber was used to exert quantitative shear stress on the sirolimus-carrying film. By adjusting the flow rate of the release media in the chamber, three levels of shear stress (3.6, 12.0, and 36.0 dyn/cm2) were respectively applied. For each level of shear stress employed, the release kinetics of sirolimus from the PLGA films exhibited a four-phase profile: an initial burst release phase (Phase I), a lag phase (Phase II), a second burst release phase (Phase III), and a terminal release phase (Phase IV). During Phases I and II, sirolimus was released slowly and in small amounts (<10%); however, during Phases III and IV, the drug release increased considerably. Comparisons of different shear stresses indicated that greater shear stress resulted in earlier and faster sirolimus release, with more cumulative drug release observed. PLGA film degradations (molecular weight reduction, mass loss, and surface topographical variations) were also investigated to better explain the observed drug release behavior. Consequently, fluid shear stress was found to significantly accelerate the release of sirolimus from the PLGA matrices. Therefore, this study could provide a practical method for evaluating the in vitro drug release from polymer matrices under uniform shear stress, and might help improve the design of biodegradable coatings on drug-eluting stents.

Glycolic acid-catalyzed deamidation of asparagine residues in degrading PLGA matrices: a computational study.

Poly(lactic-co-glycolic acid) (PLGA) is a strong candidate for being a drug carrier in drug delivery systems because of its biocompatibility and biodegradability. However, in degrading PLGA matrices, the encapsulated peptide and protein drugs can undergo various degradation reactions, including deamidation at asparagine (Asn) residues to give a succinimide species, which may affect their potency and/or safety. Here, we show computationally that glycolic acid (GA) in its undissociated form, which can exist in high concentration in degrading PLGA matrices, can catalyze the succinimide formation from Asn residues by acting as a proton-transfer mediator. A two-step mechanism was studied by quantum-chemical calculations using Ace-Asn-Nme (Ace = acetyl, Nme = NHCH3) as a model compound. The first step is cyclization (intramolecular addition) to form a tetrahedral intermediate, and the second step is elimination of ammonia from the intermediate. Both steps involve an extensive bond reorganization mediated by a GA molecule, and the first step was predicted to be rate-determining. The present findings are expected to be useful in the design of more effective and safe PLGA devices.

Poly(lactic-co-glycolic acid) matrix incorporated with nisin as a novel antimicrobial biomaterial.

The use of poly(lactic-co-glycolic acid) (PLGA) matrix as a biomolecule carrier has been receiving great attention due to its potential therapeutic application. In this context, we investigated the PLGA matrix capacity to incorporate nisin, an antimicrobial peptide capable of inhibiting the growth of Gram-positive bacteria and bacterial spores germination. Nisin-incorporated PLGA matrices were evaluated based on the inhibitory effect against the nisin-bioindicator Lactobacillus sakei. Additionally, the PLGA-nisin matrix stability over an 8-months period was investigated, as well as the nisin release profile. For the incorporation conditions, we observed that a 5 h incorporation time, at 30 °C, with 250 μg/mL nisin solution in PBS buffer pH 4.5, resulted in the highest inhibitory activity of 2.70 logAU/mL. The PLGA-nisin matrix was found to be relatively stable and showed sustained drug delivery, with continuous release of nisin for 2 weeks. Therefore, PLGA-nisin matrix is could be used as a novel antimicrobial delivery system and an alternative to antibiotics incorporated into PLGA matrices.

Simple measurements for prediction of drug release from polymer matrices – Solubility parameters and intrinsic viscosity

PurposeThis study describes how protein release from polymer matrices correlate with simple measurements on the intrinsic viscosity of the polymer solutions used for casting the matrices and calculations of the solubility parameters of polymers and solvents used. MethodMatrices of poly(dl-lactide-co-glycolide) (PLGA) were cast with bovine serum albumin (BSA) as a model drug using different solvents (acetone, dichloromethane, ethanol and water). The amount of released protein from the different matrices was correlated with the Hildebrand and Hansen solubility parameters of the solvents, and the intrinsic viscosity of the polymer solutions. Matrix microstructure was investigated by transmission and scanning electron microscopy (TEM and SEM). Polycaprolactone (PCL) matrices were used in a similar way to support the results for PLGA matrices. ResultsThe maximum amount of BSA released and the release profile from PLGA matrices varied depending on the solvent used for casting. The maximum amount of released BSA decreased with higher intrinsic viscosity, and increased with solubility parameter difference between the solvent and polymer used. The solvent used also had an effect on the matrix microstructure as determined by TEM and SEM. Similar results were obtained for the PCL polymer systems. ConclusionsThe smaller the difference in the solubility parameter between the polymer and the solvent used for casting a polymer matrix, the lower will be the maximum protein release. This is because of the presence of smaller pore sizes in the cast matrix if a solvent with a solubility parameter close to the one of the polymer is used. Likewise, the intrinsic viscosity of the polymer solution increases as solubility parameter differences decrease, thus, simple measurements of intrinsic viscosity and solubility parameter difference, allow the prediction of protein release profiles.

Positive Charge of "Sticky" Peptides and Proteins Impedes Release From Negatively Charged PLGA Matrices.

The influence of electrostatic interactions and/or acylation on release of charged ("sticky") agents from biodegradable polymer matrices was systematically characterized. We hypothesized that release of peptides with positive charge would be hindered from negatively charged poly(lactic-co-glycolic acid) (PLGA) microparticles. Thus, we investigated release of peptides with different degrees of positive charge from several PLGA microparticle formulations, with different molecular weights and/or end groups (acid- or ester-terminated). Indeed, release studies revealed distinct inverse correlations between the amount of positive charge on peptides and their release rates from each PLGA microparticle formulation. Furthermore, we examined the case of peptides with net charge that changes from negative to positive within the pH range observed in degrading microparticles. These charge changing peptides displayed counterintuitive release kinetics, initially releasing faster from slower degrading (less acidic) microparticles, and releasing slower from the faster degrading (more acidic) microparticles. Importantly, trends between agent charge and release rates for model peptides also translated to larger, therapeutically relevant proteins and oligonucleotides. The results of these studies may improve future design of controlled release systems for numerous therapeutic biomolecules exhibiting positive charge, ultimately reducing time-consuming and costly trial and error iterations of such formulations.

Injectable scaffold as minimally invasive technique for cartilage tissue engineering: in vitro and in vivo preliminary study.

Cartilage is a tissue with limited repair capacity and also sparse population of cells entrapped within a dense extracellular matrix, therefore, delivery of the cells to site of damaged cartilage can improve its healing potential. Synthetic biomaterials such as poly (d,l-lactide-co-glycolide) (PLGA) have been used as both preformed or injectable scaffolds in tissue engineering in order to carry and keep cells in the site of injury with minimal side effects. The injectable biocompatible polymeric scaffolds can reach to effected area via minimally invasive injection without need to open the joint, less painful approach and also having possibility to fill complicated shape defects. In this study, it was hypothesized that PLGA solved in n-methyl pyrrolidine (NMP) may act as a proper carrier for cell delivery to the site of the damage and also supports their growth. The results of in vitro assays including both live/dead (AO/PI) and MTT showed the majority of the cells were remained alive between 3 up to 21 days, respectively. The amount of resealed GAG from the mesenchymal stem cells (MSCs) which were in contact with both PLGA and alginate constructs (used as control) indicated that for day 7 MSCs in contact with alginate secreted more GAG (3.45 ± 0.453 µg/mL for alginate and 2.36 ± 0.422 µg/mL for PLGA matrices), but at longer times (21 days) cells in contact with PLGA elicited more GAG (6.26 ± 0.968 µg/mL for alginate and 8.47 ± 0.871 µg/mL for the PLGA matrices). Sol–gel systems comprising PLGA, NMP, and cells as well as alginate/cells were subcutaneously injected into four nude mice (each mouse had three injection sites). PLGA/NMP was solidify immediately and formed an interconnecting 3-D porous structure that allowed body fluid to penetrate through them. In vivo evaluation showed that PLGA/NMP scaffolds could support injected cells as a fibrocartilage tissue was formed after 6 months of injection. We found that PLGA/NMP system might be a proper minimally invasive therapeutics option for cartilage repair.

Development and characterization of GRGDSPC-modified poly(lactide-co-glycolide acid) porous microspheres incorporated with protein-loaded chitosan microspheres for bone tissue engineering

Scaffolds that can achieve cell adhesion and controlled release of protein drugs are very promising in bone tissue engineering. Due to their biocompatibility and injectablity, poly(lactide-co-glycolide acid) (PLGA) porous microspheres (PLGA-pMS) present potential scaffolds in bone tissue engineering. However, their application is hampered by the burst release of protein drugs and hydrophobicity that leads to poor cell adhesion. To overcome these drawbacks, we developed novel PLGA-pMS by incorporating bovine serum albumin (BSA) loaded chitosan microspheres (CS-MS) in Gly-Arg-Gly-Asp-Ser-Pro-Cys (GRGDSPC) modified PLGA-pMS (CS-MS/PLGA-pMS). GRGDSPC was used to enhance the hydrophilicity and cell affinity of the porous microspheres. Results showed that PLGA-pMS had a size of 446.77±19.46μm, with an average surface pore size of 21.56±3.02μm, whereas CS-MS had a size of 15.98±0.96μm and 16.35±0.38μm (5% and 10% TPP-prepared CS-MS, respectively). A scanning electron microscope (SEM) and a confocal laser scanning microscope (CLSM) revealed that CS-MS were partly embedded in the PLGA matrices and the integrity of CS-MS was retained. Thermogravimetry analyzer (TGA) also demonstrated that CS-MS were incorporated into PLGA-pMS. The CS-MS/PLGA-pMS had a size of 454.02±16.09μm, with a BSA encapsulation efficiency of 53.19±1.67% and 62.16±3.44% (5% and 10% TPP-prepared CS-MS, respectively). CS-MS/PLGA-pMS exhibited a sustained FITC-BSA release for 28 days. Modification of GRGDSPC significantly improved adhesion of MG-63 cells on the porous microspheres. In conclusion, CS-MS/PLGA-pMS may act as potential bifunctional scaffolds for bone tissue engineering.

One-Step Production of Protein-Loaded PLGA Microparticles via Spray Drying Using 3-Fluid Nozzle

The aim of this study was to investigate the potential of using a spray-dryer equipped with a 3-fluid nozzle to microencapsulate protein drugs into polymeric microparticles. Lysozyme and PLGA were used as a model protein and a model polymer, respectively. The effects of process and formulation variables, such as i) the type of organic solvent, ii) the feeding rate ratio of the outer PLGA-containing feed solution to inner lysozyme-containing feed solution, and iii) the mass ratio of PLGA to protein, on the properties (morphology, internal structure, protein surface enrichment and release profiles) of the spray dried microparticles were investigated to understand protein microencapsulation and particle formation mechanisms. The spherical, condensed microparticles were obtained with D50 of 1.07-1.60μm and Span in the range of 0.82-1.23. The lysozyme surface content decreased upon different organic solvents used as follows: acetonitrile > acetone > dichloromethane. Additionally, the lysozyme surface enrichment decreased slightly when increasing the feeding rate ratio of the outer feed solution to the inner feed solution from 4:1 to 10:1. Furthermore, it was observed that there was a correlation between the degree of burst release and the lysozyme surface enrichment, whereas the lysozyme loading content had no substantial impact on the release kinetics. The present work demonstrates the potential of spray dryer equipped with a 3-fluid nozzle in microencapsulation of proteins into PLGA matrices with different characteristics by varying process and formulation parameters.

Novel “Breath Figure”‐Based Synthetic PLGA Matrices for In Vitro Modeling of Mammary Morphogenesis and Assessing Chemotherapeutic Response

Biodegradable poly(lactic-co-glycolic acid) (PLGA) porous films are developed to support mammary cell growth and function. Such porous polymer matrices of PLGA are generated using the easily implemented water-templating "breath-figure" technique that allows water droplets to penetrate the nascent polymer films to create a rough porous polymer film. Such breath figure-based micropatterned porous films show higher epithelial differentiation and growth than the corresponding flat 2D films, and represent the first instance of using them for tissue culture. Specifically, the breath figure morphology supports robust acinar growth with almost double the number of lobular-alveolar units compared to the 2D cultures. Gene profile analysis indicates that the cells grown on porous polymer films show enhanced expressions of mammary differentiation genes (GATA3, EMA, and INTEGB4) but lower the expression of mesenchymal gene (CALLA). Hormonal stimulation of these cultures dramatically increases expression of progenitor marker gene Notch1. Importantly, cells grown on porous PLGA films exhibit an enhanced resistance to doxorubicin treatment in comparison to 2D cultures. Breath-figure PLGA films show promise in mimicking in vivo mammary functions and can potentially be used to screen chemotherapeutic drugs. The simplicity and ease of fabrication of these polymer films is especially appealing to the development of effective biomaterials to support cell culture and differentiation.

Poly(lactic-co-glycolic acid) Encapsulated Gadolinium Oxide Nanoparticles for MRI-Based Cell Tracking

Superparamagnetic iron oxide particles have proven useful for cell tracking applications by monitoring cell transplantation and migration in living organisms. However, one perceived drawback is that these particles cause dark contrast in MRI, sometimes yielding confusion with other biological phenomena, which also yield dark contrast. To that end, researchers have investigated the use of gadolinium oxide (Gd2O3) based contrast agents for MRI-based cell tracking, as Gd2O3 has favorable r1 molar relaxivity. We synthesized Gd2O3 nanocrystals and encapsulated them within PLGA matrices to form approximatley to 150 nm nanoparticles. r1 was 1.9 mM(-1) sec(-1) and r2 was 8.4 mM(-1) sec(-1). Cell labeling with particles was well tolerated by cells except at very high doses. MRI of labeled cells showed that labeled cells could achieve both R1 and R2 enhancements due to the internalized particles. R2 enhancements were approximately to twice that of R1 enhancements suggesting the use of very short echo times when using Gd2O3 based contrast agents for MRI-based cell tracking.

Local BMP-7 release from a PLGA scaffolding-matrix for the repair of osteochondral defects in rabbits

The use of tissue engineering to repair large osteochondral defects has been impeded by the limited regenerative capacity of cartilage. Herein, we describe the local release of bone morphogenetic protein 7 (BMP-7) to stimulate the bone marrow-derived progenitors to repair osteochondral defects. BMP-7-releasing poly(d,l-lactide-co-glycolide) (PLGA) matrix was specially designed to retain the dual-function of local BMP-7 release and progenitor-scaffolding with its defect-fitting architecture. To optimize the release kinetics during the repair period, BMP-7/PLGA film was cast on the surface of a cylindrical PLGA matrix. The matrix demonstrated a release profile of BMP-7 in a sustained manner over 28days, maintaining its biological activity. The cylindrical PLGA matrices loaded with BMP-7 were implanted into the osteochondral defects (2mm in diameter, 3mm in depth) in rabbit knees. Histological observations revealed that neo-cartilage generation was completed in a well-integrated morphology with its surrounding normal cartilage and subchondral bone at 12weeks post-implantation. Partial degradation of the PLGA matrix during the repair period guided neo-cartilage formation, which verified the effective scaffolding function of the matrix. Regenerated cartilage in BMP-7-treated defects stained positive for type II collagen and glycosaminoglycan (GAG). Adjacent BMP-7-untreated defects were also repaired with cartilage regeneration, suggesting the effect of local BMP-7 release in the synovial fluid. The BMP-7-unloaded PLGA matrix demonstrated guided cartilage regeneration to a certain extent, whereas the adjacent defects without the matrix revealed only fibrous tissue infiltration. These results indicated that a strategy employing the combined functions of local BMP-7 release and the cell scaffolding of a PLGA matrix might be a potential modality for osteochondral repair.

Entrapment of 5-fluorouracil into PLGA matrices using supercritical antisolvent processes

Two different supercritical antisolvent processes were performed to co-precipitate 5-fluorouracil (5-FU) and poly(lactide-co-glycolide) simultaneously. 5-FU is a hydrophilic antitumor agent, and is more effective when administered at a lower dose for a longer period of time. Controlled-release polymeric systems of 5-FU were produced, and morphology, thermal behavior, in-vitro release and cytotoxicity of microparticles were analysed. Dissolution studies showed that 33% of drug was released in 21 days, which represents a long-lasting profile. To evaluate the efficacy of the released drug on cancer cells, the MTT assay cytotoxicity test was performed using human lung carcinoma A549 cell lines. There was no significant difference between the cell inhibition rates of the released drug and unprocessed 5-FU at the same drug concentration level. IC50 values were 69.12 mg/ml for unprocessed 5-FU and 68.71 mg/ml for the released drug. Application of supercritical processing for co-precipitation of 5-FU and PLGA provided mild and non-aqueous conditions, so the hydrophilic drug incorporated in the polymer had good stability during the process.

PLGA Erosion: Solubility- or Diffusion-Controlled?

To calculate the degradation time-dependent formation of water-soluble PLGA oligomers and to evaluate the relation between calculated oligomer formation and actual erosion of a PLGA-based delivery system. A proper model of the erosion process would be expected to facilitate forecasting of drug release profiles from PLGA matrices due to the close relationship of erosional mass loss and drug release described in the literature. The molecular weight distribution (MWD), degradation and erosion behaviour of PLGA were characterized by gel permeation chromatography. PLGA was characterized by a lognormal distribution of mass fractions of individual molecular weights. Implementation of the pseudo-first-order reaction kinetics into the MWD function facilitated calculating the formation of water-soluble oligomers during degradation. The calculated soluble oligomer formation agreed excellently with measured erosional mass loss of a PLGA matrix in aqueous buffer, which suggested that the bulk erosion process was solely controlled by the kinetic of the formation of soluble oligomers and thus solubility-controlled and not diffusion-limited as conventionally assumed. The accurately calculated formation of soluble PLGA oligomers was in excellent agreement with the actual erosional mass loss of a PLGA matrix, suggesting that bulk erosion of PLGA represents a degradation-controlled dissolution process.

Mechanistic evaluation of alginate-HEC gelisphere compacts for controlled intrastriatal nicotine release in Parkinson's disease

This study focused on elucidating a mechanistic understanding in support of the multiple mechanisms which govern the formation of crosslinked alginate-hydroxyethylcellulose (Alg-HEC) gelispheres intended for the controlled intrastriatal release of nicotine as a neuroprotectant in Parkinson's Disease. HEC was incorporated as a reinforcing "protective" colloidal polymer to induce interactions between the free carboxyl groups of alginate with hydroxylated HEC monomers. Gelispheres were compressed within an external poly(lactic-co-glycolic acid) (PLGA) matrix to further prolong the release of nicotine. Sol-gel interconversion mechanisms, matrix deformability moduli, matrix fracture energies and chemometric models of the associated energy paradigms were analyzed for their influence on the mechanism and extent of nicotine release. Textural profiling demonstrated higher fracture energies (7.94-26.69 x 10(-4) J) and lower deformability moduli (12.24-58.36 N/mm) when gelispheres were cured in 2 M HCl as a postcuring step. Ba(2+) crosslinked gelispheres resulted in superiorly compact matrices with an increase in volume of 201-329% as compared to the Ca(2+) and Zn(2+) crosslinked matrices. The order of matrix compactness was as follows: Zn(2+) < Ca(2+) < Ba(2+). Molecular mechanisms of formation, interaction, conversion, and stability of sol-gel transitions depended on the type of crosslinker, crosslinking time, energy transactions, and interactions with molecules of the hydration medium. Ba(2+) crosslinked gelispheres released nicotine slower than Ca(2+) and Zn(2+) crosslinked gelispheres due to the higher energy requirement for interconversion to sol while the energy requirements for Ca(2+) and Zn(2+) was at a lower demand. Ba(2+) crosslinked gelispheres within PLGA matrices therefore retarded nicotine release in a pseudo-zero-order manner over 21 days.