Accelerated in vitro release testing of implantable PLGA microsphere/PVA hydrogel composite coatings

Dexamethasone loaded poly(lactic-co-glycolic acid) (PLGA) microsphere/PVA hydrogel composites have been investigated as an outer drug-eluting coating for implantable devices such as glucose sensors to counter negative tissue responses to implants. The objective of this study was to develop a discriminatory, accelerated in vitro release testing method for this drug-eluting coating using United States Pharmacopeia (USP) apparatus 4. Polymer degradation and drug release kinetics were investigated under "real-time" and accelerated conditions (i.e. extreme pH, hydro-alcoholic solutions and elevated temperatures). Compared to "real-time" conditions, the initial burst and lag phases were similar using hydro-alcoholic solutions and extreme pH conditions, while the secondary apparent zero-order release phase was slightly accelerated. Elevated temperatures resulted in a significant acceleration of dexamethasone release. The accelerated release data were able to predict "real-time" release when applying the Arrhenius equation. Microsphere batches with faster and slower release profiles were investigated under "real-time" and elevated temperature (60°C) conditions to determine the discriminatory ability of the method. The results demonstrated both the feasibility and the discriminatory ability of this USP apparatus 4 method for in vitro release testing of drug loaded PLGA microsphere/PVA hydrogel composites. This method may be appropriate for similar drug/device combination products and drug delivery systems.     

Preparation of a novel freeze thawed poly(vinyl alcohol) composite hydrogel for drug delivery applications.

We describe a drug delivery system based on a physically cross-linked poly(vinyl alcohol) (PVA) hydrogel for the release of Theophylline (TH). A composite was created by freezing an aqueous solution of PVA/NaOH onto a PVA/poly(acrylic acid) substrate. This formed a strong interface and demonstrated greater physical strength than the hydrogel alone. Such systems have potential for a variety of localised controlled drug delivery applications, for example, as coatings for implantable devices. Importantly, the results suggest that a versatile synthetic platform is possible that may provide different functional materials or combination of such. The resultant samples were characterised using optical microscopy, modulated differential scanning calorimetry (MDSC) and dissolution testing. The microstructure of the gels was examined using micro-thermal analysis (microTA) which is a combination of atomic force microscopy and thermal analysis. TH was found to have an effect on the crystalline structure and dissolution showed a Fickian release, suggesting that swelling and crystallinity were the controlling mechanisms.     

Drug Release From Irradiated PLGA and PLLA Multi-Layered Films

Poly(lactide-co-glycolic acid) (PLGA) and poly(L-lactide) (PLLA) films are widely studied for various biomedical applications. Because of their use for drug delivery, achieving controlled release from these biodegradable films has become an area of intense research. The objective of this study is therefore to investigate how PLGA and PLLA films fabricated through an irradiated-multi-layer approach can be a viable technique to achieve controlled drug delivery. In this study, lidocaine base (lido-base) and lidocaine salt (lido-salt) were used as model hydrophobic and hydrophilic drugs, respectively. Results show that multi-layer PLGA underwent pseudo surface degradation, while multi-layer PLLA degraded to a lesser extent over the same study period. Triphasic release was observed for lido-base, whereas lido-salt was released through a biphasic profile, from both polymer systems. The two dominating release phases for both drugs were diffusion and zero-order release, where the latter is characterized by the onset of mass loss. It was shown that PLGA had a shorter diffusion phase and a longer zero-order phase, while the contrary was true for PLLA. This difference was due to the faster degradation for PLGA. In conclusion, the hydrophilic gradient induced from an irradiated-multi-layer film system shows potential for controlled and sustained release of drugs.     

A novel approach to stabilization of protein drugs in poly(lactic-co-glycolic acid) microspheres using agarose hydrogel

A novel approach has been taken to stabilize protein drugs in poly(lactic-co-glycolic acid) (PLGA) microspheres. This approach creates a new protein drug delivery system, which is based on the combination of agarose hydrogel particles and PLGA microspheres. This combination produces a heterogeneously structured polymeric composite. The protein drug molecules are encapsulated in the agarose hydrogel particles and the drug-containing agarose hydrogel particles are further dispersed in the PLGA microspheres. One PLGA microsphere may contain many agarose hydrogel particles to form a PLGA–agarose composite microsphere. The PLGA–agarose composite microspheres have spherical shape and a smooth surface. They possess a normal or Gaussian size distribution and an average diameter of 150 μm. The PLGA–agarose composite microspheres have higher protein loading efficiency than that of the conventional PLGA microspheres. The hydration of the PLGA–agarose composite microsphere matrix is faster than that of the conventional PLGA microspheres. Protein drugs can be slowly released from the PLGA–agarose composite microspheres. The agarose hydrogel particles can stabilize protein drugs in the PLGA matrix, which is the major advantage of this novel protein drug delivery system over the conventional PLGA microspheres.     

Controlled release of dexamethasone from poly(vinyl alcohol) hydrogel

This study investigated a chemically crosslinked poly(vinyl alcohol) (PVA) hydrogel controlled drug delivery system to deliver the anti-inflammatory drug dexamethasone (DEX). The PVA hydrogels, with different crosslinking densities, were characterized by swelling studies, electron scanning microscopy, viscosity, Fourier transform infrared spectroscopy (FTIR) and in vitro release assessment. Increasing crosslinking density slowed and decreased swelling and water absorption. FTIR analysis suggested DEX has possible interactions with the crosslinker and the PVA polymer. In vitro release of DEX from PVA hydrogels was sustained for 33 days and appeared to fit the Higuchi and Korsmeyer–Peppas models. This work indicates the likelihood of PVA hydrogel as a controlled drug release system for DEX for anti-inflammatory uses.     

Extrusion printed polymer structures: a facile and versatile approach to tailored drug delivery platforms

A novel extrusion printing system was used to create drug delivery structures wherein dexamethasone-21-phosphate disodium salt (Dex21P) was encapsulated within a biodegradable polymer (PLGA) and water soluble poly(vinyl alcohol) (PVA) configurations. The ability to control the drug release profile through the spatial distribution of drug within the printed 3-dimensional structures is demonstrated. The fabricated configurations were characterised by optical microscopy and SEM to evaluate surface morphology. The results clearly demonstrate the successful encapsulation of dexamethasone within a laminated PLGA:PVA structure. The resulting drug release profiles from the structures show a two stage release profile with distinctly different release rates and minimal initial burst release observed. Dexamethasone release was monitored over a 4-month period. This approach clearly demonstrates that the extrusion printing technique provides a facile and versatile approach to fabrication of novel drug delivery platforms.     

Preparation and Characterization of a Composite PLGA and Poly(Acryloyl Hydroxyethyl Starch) Microsphere System for Protein Delivery

Purpose. To prepare and characterize a novel composite microsphere system based on poly(D,L-lactide-co-glycolide) (PLGA) and poly(acryloyl hydroxyethyl starch) (acHES) hydrogel for controlled protein delivery. Methods. Model proteins, bovine serum albumin, and horseradish peroxidase were encapsulated in the acHES hydrogel, and then the protein-containing acHES hydrogel particles were fabricated in the PLGA matrix by a solvent extraction or evaporation method. The protein-loaded PLGA-acHES composite microspheres were characterized for protein loading efficiency, particle size, and in vitro protein release. Protein stability was examined by size-exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and monitoring the enzymatic activity. Results. Scanning electron microscopy showed discrete PLGA microspheres containing many acHES particles. The composite microspheres were spherical and smooth in size range of 39-93 m. The drug loading efficiency ranged from 51 to 101%. The composite microspheres showed more favorable in vitro release than conventional PLGA microspheres. The composite microspheres showed 20% less initial with a gradual sustained release compared to high burst (60%) followed by a very slow release with the conventional PLGA microspheres. The composite microspheres also stabilized encapsulated proteins from the loss of activity during the microsphere preparation and release. Proteins extracted from the composite microspheres showed good stability without protein degradation products and structural integrity changes in the size-exclusion chromatography and SDS-PAGE analyses. Horseradish peroxidase extracted from microspheres retained more than 81% enzymatic activity. Conclusion. The PLGA-acHES composite microsphere system could be useful for the controlled delivery of protein drugs.     

Preparation and characterization of poly(D,L-lactic-co-glycolic Acid) microspheres containing flurbiprofen sodium

This study aimed to prepare biodegradable microspheres containing flurbiprofen sodium, a nonsteroidal anti-inflammatory drug (NSAID), as the drug delivery system to the periodontal pocket. Microspheres were prepared from biodegradable copolymers of poly (D,L-lactic-co-glycolic acid) (PLGA) using solvent evaporation method. The effects of the different copolymers and amounts of polyvinyl alcohol (PVA) as a dispersing agent on characteristics of the microspheres were evaluated. Although there was no correlation between microsphere size and amount of PVA, an optimum PVA concentration was essential to achieve narrower size distributions of microspheres. As the concentration of PVA increased, the drug loading of the microspheres increased. The effect of PVA on drug loading was found to be statistically significant for those microspheres prepared from PLGA 50:50 (p < 0.05). Regarding copolymer composition, PLGA 85:15 provided higher drug loading into the microspheres than PLGA 50:50 (p < 0.05). The recoveries of microspheres (60-80%) were affected neither by different PVA concentrations nor by copolymer compositions (p > 0.05). According to the first-order release rate constants of the microspheres, the microspheres of PLGA 50:50 released the drug at the highest rate consistently, with the highest hydrophilicity of this copolymer.     

A Heterogeneously Structured Composite Based on Poly(lactic-co-glycolic acid) Microspheres and Poly(vinyl alcohol) Hydrogel Nanoparticles for Long-Term Protein Drug Delivery

Purpose. To prepare a heterogeneously structured composite based on poly (lactic-co-glycolic acid) (PLGA) microspheres and poly(vinyl alcohol) (PVA) hydrogel nanoparticles for long-term protein drug delivery. Methods. A heterogeneously structured composite in the form of PLGA microspheres containing PVA nanoparticles was prepared and named as PLGA-PVA composite microspheres. A model protein drug, bovine serum albumin (BSA), was encapsulated in the PVA nanoparticles first. The BSA-containing PVA nanoparticles was then loaded in the PLGA microspheres by using a phase separation method. The protein-containing PLGA-PVA composite microspheres were characterized with regard to morphology, size and size distribution, BSA loading efficiency, in vitroBSA release, and BSA stability. Results. The protein-containing PLGA-PVA composite microspheres possessed spherical shape and nonporous surface. The PLGA-PVA composite microspheres had normal or Gaussian size distribution. The particle size ranged from 71.5 m to 282.7 m. The average diameter of the composite microspheres was 180 m. The PLGA-PVA composite microspheres could release the protein (BSA) for two months. The protein stability study showed that BSA was protected during the composite microsphere preparation and stabilized inside the PLGA-PVA composite microspheres. Conclusions. The protein-containing PLGA-PVA composite may be suitable for long-term protein drug delivery.     

Evaluation of an aliphatic polyurethane as a microsphere matrix for sustained theophylline delivery

Abstract

In spite of several biomedical applications of polyurethanes, very little attention has been focused on these polymers for controlled drug delivery. In this study, an aliphatic polyurethane, Tecoflex®, was evaluated as a microsphere matrix for the controlled release of theophylline. Polyurethane microspheres containing theophylline were prepared using a solvent evaporation technique from a dichloromethane solution of the polymer containing the drug. A dilute solution of poly(vinyl alcohol) served as the dispersion medium. Microspheres of good spherical geometry having theophylline content of 35% could be prepared by the technique. The release of the drug from the microspheres was examined in simulated gastric and intestinal fluids at 37°C. While a large burst effect was observed in gastric fluid, in the intestinal fluid a close to zero-order release was seen. Attempts were made to modulate the release by incorporating poly(ethylene glycol) in the matrix and also coating the spheres with paraffin wax. Preliminary data indicate that polyurethanes could be interesting matrices for controlled drug delivery.     

Combination of Hyaluronic Acid Hydrogel Scaffold and PLGA Microspheres for Supporting Survival of Neural Stem Cells

Purpose

To develop a biomaterial composite for promoting proliferation and migration of neural stem cells (NSCs), as well as angiogenesis on the materials, to rescue central nervous system (CNS) injuries.

Methods

A delivery system was constructed based on cross-linked hyaluronic acid (HA) hydrogels, containing embedded BDNF and VEGF-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres for controlled delivery and support for NSCs in the CNS. The surface morphologies were evaluated by SEM and AFM, mechanical property was investigated by rheological tests, and release kinetics were performed by ELISA. Bioactivity of released BDNF and VEGF was assessed by neuron and endothelial cell culture, respectively. Compatibility with NSCs was studied by immunofluorescent staining.

Results

Release kinetics showed the delivery of BDNF and VEGF from PLGA microspheres and HA hydrogel composite were sustainable and stable, releasing ~20–30% within 150 h. The bioactivities preserved well to promote survival and growth of the cells. Evaluation of structure and mechanical properties showed the hydrogel composite possessed an elastic scaffold structure. Biocompatibility assay showed NSCs adhered and proliferated well on the hydrogel.

Conclusions

Our created HA hydrogel/PLGA microsphere systems have a good potential for controlled delivery of varied biofactors and supporting NSCs for brain repair and implantation.

     

Biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microspheres for sustained release of risperidone: Zero-order release formulation

The preparation and investigation of sustained-release risperidone-encapsulated microspheres using erodible poly(D, L-lactide-co-glycolide) (PLGA) of lower molecular weight were performed and compared to that of commercial Risperdal Consta^? for the treatment of schizophrenia. The research included screening and optimizing of suitable commercial polymers of lower molecular weight PLGA50/50 or the blends of these PLGA polymers to prepare microspheres with zero-order release kinetics properties. Solvent evaporation method was applied here while studies of the risperidone loaded microsphere were carried out on its drug encapsulation capacity, morphology, particle size, as well as in vitro release profiles. Results showed that microspheres prepared using 50504A PLGA or blends of 5050-type PLGAs exerted spherical and smooth morphology, with a higher encapsulation efficiency and nearly zero-order release kinetics. These optimized microspheres showed great potential for a better depot preparation than the marketed Risperdal Consta^?, which could further improve the patient compliance.     

Effect of Polymer Blending on the Release of Ganciclovir from PLGA Microspheres

Purpose The aim of the study is to investigate the effect of polymer blending on entrapment and release of ganciclovir (GCV) from poly(d,l-lactide-co-glycolide) (PLGA) microspheres using a set of empirical equations. Methods Two grades of PLGA, PLGA 7525 [d,l-lactide:glycolide(75:25), MW 90,000–126,000 Da] and Resomer RG 502H [d,l-lactide:glycolide(50:50), MW 8000 Da], were employed in the preparation of PLGA microspheres. Five sets of microsphere batches were prepared with two pure polymers and their 1:3, 1:1, and 3:1 blends. Drug entrapment, surface morphology, particle size analysis, drug release, and differential scanning calorimetric studies were performed. In vitro drug-release data were fitted to a set of empirical sigmoidal equations by nonlinear regression analysis that could effectively predict various parameters that characterize both diffusion and degradation cum diffusion-controlled release phases of GCV. Results Entrapment efficiencies of GCV ranged from 47 to 73%. Higher amounts of GCV were entrapped in polymer blend microspheres relative to individual polymers. Triphasic GCV release profiles were observed, which consisted of both diffusion and degradation cum diffusion-controlled phases. In vitro GCV release was shortest for Resomer RG 502H microsphere (10 days) and longest for PLGA 7525 microspheres (90 days). Upon blending, the duration of release gradually decreased as the content of Resomer RG 502H in the matrix was raised. Equations effectively estimated the drug-release rate constants during both the phases with high R² values (>0.990). GCV release was slower from the blend microsphere during the initial diffusion phase. Majority of entrapped drug (70–95%) was released during the matrix degradation cum diffusion phase. Conclusions Drug entrapment and release parameters estimated by the equations indicate more efficient matrix packing between PLGA 7525 and Resomer RG 502H in polymer-blended microspheres. The overall duration of drug release diminishes with rising content of Resomer RG 502H in the matrix. Differential scanning calorimetry studies indicate stronger binding between the polymers in the PLGA 7525/Resomer RG 502H∷ 3:1 blend. Polymer blending can effectively alter drug-release rates of controlled delivery systems in the absence of any additives.     

In vitro study of lysozyme in poly(lactide-co-glycolide) microspheres with sucrose acetate isobutyrate

This study investigated the suitability of microsphere formulations for extended protein delivery and complete protein release. These microspheres were prepared by a multi-emulsion method and prepared using a mixture of poly(lactide-co-glycolide) (PLGA), RG 502H (lactide:glycolide=50:50, M(W) 9300) and sucrose acetate isobutyrate (SAIB). SAIB embedded into the microspheres and mixed with PLGA, improved the efficiency of enzyme encapsulation. The in vitro release rate of lysozyme (Lys) from the microspheres was reduced due to the high viscosity of the added SAIB and less degradation of PLGA by SAIB. These properties enabled prolonged release of Lys for up to 2 months, characterized by a minimal initial burst of Lys and nearly zero-order protein release kinetics result from co-administration of sorbitan monooleate 80. When it is considered that degradation products of SAIB are inactive for labile proteins, SAIB may be regarded as a promising candidate for long-acting protein delivery.     

白藜芦醇PLGA长效注射微球的制备及工艺考察

目的采用乳化溶剂挥发法制备白藜芦醇聚乳酸羟基乙酸[poly(lactic-co-glycolic acid),PL-GA]长效微球,评价各因素对微球性质的影响。方法以微球的包封率、载药量、突释和粒径作为微球的质量评价指标,研究分散相与连续相的体积比、PLGA浓度、聚乙烯醇(polyvinyl alcohol,PVA)浓度、搅拌速度对微球性质的影响,并优化白藜芦醇PLGA微球的制备工艺。结果分散相与连续相的体积比为1∶50时,包封率高,但4 h突释量达到76%,当分散相与连续相体积比由1∶50提升到1∶150时,突释降低了22%;随着聚合物浓度的增加粒径明显增大,突释显著降低;理论载药量对粒径影响不大,在高载药量时突释显著减少;搅拌速度的增加使粒径减小,突释增加;PVA浓度的增加对粒径没有明显的影响,但当PVA的质量浓度从1 g.L-1增加到5 g.L-1时,包封率从93.57%降低到80.31%。结论分散相与连续相的体积比、PLGA浓度、PVA浓度、搅拌速度对微球性质有很大的影响。优化条件下制备的微球形态完整,载药量为(27.86±1.00)%,包封率为(93.57±2.87)%,平均粒径约为21.12μm。白藜芦醇PLGA微球体外释放25 d的累积释药率达(94.04±4.94)%,有望研制成1个月给药1次的给药系统。     

Surface crosslinking for delayed release of proxyphylline from PHEMA hydrogels

Delayed release systems find applications in chronotherapeutics and colon-specific delivery. They have also been considered suitable carriers for the oral delivery of peptides and proteins. In prior work, our research group has reported surface crosslinking as an effective technique to modify drug release profiles for poly(vinyl alcohol) (PVA) hydrogels, reducing the early burst effect in particular. Here, we demonstrate the feasibility of delayed release of proxyphylline from poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels via surface crosslinking. Studies on in vitro drug release and the morphology changes of PHEMA hydrogels during swelling and drug release showed that the highly surface crosslinked layers and the ruptures occurring in these layers during swelling were likely responsible for the delayed release. In addition, the initial burst was significantly reduced or even eliminated from the drug release profile for PHEMA to achieve near zero-order release by judicious selection of two surface crosslinking parameters: crosslinking reagent concentration and exposure time used for the surface crosslinking treatment.     

5-Fluorouracil delivery from a novel three-dimensional micro-device: in vitro and in vivo evaluation

A novel three-dimensional biodegradable micro-device using microelectromechanical systems technology was developed for implantable controlled drug delivery. In order to evaluate the effect of monomer composition and molecular weight of poly(lactic-co-glycolic acid) (PLGA) on the drug release, three 5-Fluorouracil loaded micro-devices, made of 50/50, 27 kDa; 50/50, 40 kDa and 75/25 27 kDa PLGA, were prepared and characterized by in vitro and in vivo methods. The in vitro drug release from three micro-devices followed zero-order kinetics, and PLGA micro-device with the higher molecular weight and lactide/glycolide ratio tended to a longer sustained release period. The in vivo release results agreed with the in vitro results and drug release in vivo was faster than that in vitro for each of micro-devices. And three micro-devices showed different tumor inhibition effect in the tumor bearing mice. In addition, the SEM and weight loss experiments showed that PLGA micro-devices with lower molecular weight and lactide/glycolide ratio had faster degradation. These data provided the information for the optimization of the novel three-dimensional biodegradable micro-device to obtain more suitable systems for controlled release and to meet release requirements of different drugs.     

PLGA微球控释系统的突释及其控制

针对目前限制PLGA微球控释系统临床应用的突释问题，重点介绍了近年来国内外有关的研究进展，包括突释现象、突释原因、影响因素和控制突释的方法和技术。     

PLGA and PHBV Microsphere Formulations and Solid-State Characterization: Possible Implications for Local Delivery of Fusidic Acid for the Treatment and Prevention of Orthopaedic Infections

Purpose  To develop and characterize the solid-state properties of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(3-hydroxybutyric acid-co-3-hydroxyvaleric acid) (PHBV) microspheres for the localized and controlled release of fusidic acid (FA). Methods  The effects of FA loading and polymer composition on the mean diameter, encapsulation efficiency and FA released from the microspheres were determined. The solid-state and phase separation properties of the microspheres were characterized using DSC, XRPD, Raman spectroscopy, SEM, laser confocal and real time recording of single microspheres formation. Results  Above a loading of 1% (w/w) FA phase separated from PLGA polymer and formed distinct spherical FA-rich amorphous microdomains throughout the PLGA microsphere. For FA-loaded PLGA microspheres, encapsulation efficiency and cumulative release increased with initial drug loading. Similarly, cumulative release from FA-loaded PHBV microspheres was increased by FA loading. After the initial burst release, FA was released from PLGA microspheres much slower compared to PHBV microspheres. Conclusions  A unique phase separation phenomenon of FA in PLGA but not in PHBV polymers was observed, driven by coalescence of liquid microdroplets of a DCM-FA-rich phase in the forming microsphere. Electronic supplementary material   The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Development of multiple-layer polymeric particles for targeted and controlled drug delivery

The purpose of this work was to develop multilayered particles consisting of a magnetic core and two encompassing shells made up of poly(N-isopropylacrylamide) (PNIPAAm) and poly(d,l-lactide-co-glycolide) (PLGA) for targeted and controlled drug delivery. Transmission electron microscopy confirmed that multilayered particles were obtained with PNIPAAm magnetic nanoparticles embedded within the PLGA shell. Factorial analysis studies also showed that the particle size was inversely proportional to the surfactant concentration and sonication power and directly proportional to the PLGA concentration. Drug-release results demonstrated that these multilayer particles produced an initial burst release and a subsequent sustained release of both bovine serum albumin (BSA) and curcumin loaded into the core and shell of the particle, respectively. BSA release was also affected by changes in temperature. In conclusion, our results indicate that the multilayered magnetic particles could be synthesized and used for targeted and controlled delivery of multiple drugs with different release mechanisms.From the Clinical EditorAuthors demonstrate the synthesis of multilayered particles consisting of a magnetic core and two encompassing shells made up of poly (N-isopropylacrylamide) (PNIPAAm) and poly(D, L-lactide-co-glycolide) (PLGA) for targeted and controlled drug delivery. The presented results indicate successful synthesis and application for targeted and controlled delivery of multiple drugs with different release mechanisms.