Wei Li Lee

Altering the drug release profiles of double-layered ternary-phase microparticles.

Double-layered ternary-phase microparticles composed of a poly(D,L-lactide-co-glycolide) (50:50) (PLGA) core and a poly(L-lactide) (PLLA) shell impregnated with poly(caprolactone) (PCL) particulates were loaded with ibuprofen (IBU) and metoclopramide HCl (MCA) through a one-step fabrication process. MCA and IBU were localized in the PLGA core and in the shell, respectively. The aim of this study was to study the drug release profiles of these double-layered ternary-phase microparticles in comparison to binary-phase PLLA(shell)/PLGA(core) microparticles and neat microparticles. The particle morphologies, configurations and drug distributions were determined using scanning electron microscopy (SEM) and Raman mapping. The presence of PCL in the PLLA shell gave rise to an intermediate release rate of MCA between that of neat and binary-phase microparticles. The ternary-phase microparticles were also shown to have better controlled release of IBU than binary-phase microparticles. The drug release rates for MCA and IBU could be altered by changing the polymer mass ratios. Ternary-phase microparticles, therefore, provide more degrees of freedom in preparing microparticles with a variety of release profiles and kinetics.

Application of Raman microscopy to biodegradable double-walled microspheres.

Raman mapping measurements were performed on the cross section of the ternary-phase biodegradable double-walled microsphere (DWMS) of poly(D,L-lactide-co-glycolide) (50:50) (PLGA), poly(L-lactide) (PLLA), and poly(epsilon-caprolactone) (PCL), which was fabricated by a one-step solvent evaporation method. The collected Raman spectra were subjected to a band-target entropy minimization (BTEM) algorithm in order to reconstruct the pure component spectra of the species observed in this sample. Seven pure component spectral estimates were recovered, and their spatial distributions within DWMS were determined. The first three spectral estimates were identified as PLLA, PLGA 50:50, and PCL, which were the main components in DWMS. The last four spectral estimates were identified as semicrystalline polyglycolic acid (PGA), dichloromethane (DCM), copper-phthalocyanine blue, and calcite, which were the minor components in DWMS. PGA was the decomposition product of PLGA. DCM was the solvent used in DWMS fabrication. Copper-phthalocyanine blue and calcite were the unexpected contaminants. The current result showed that combined Raman microscopy and BTEM analysis can provide a sensitive characterization tool to DWMS, as it can give more specific information on the chemical species present as well as the spatial distributions. This novel analytical method for microsphere characterization can serve as a complementary tool to other more established analytical techniques, such as scanning electron microscopy and optical microscopy.

Early controlled release of peroxisome proliferator-activated receptor β/δ agonist GW501516 improves diabetic wound healing through redox modulation of wound microenvironment.

Diabetic wounds are imbued with an early excessive and protracted reactive oxygen species production. Despite the studies supporting PPARβ/δ as a valuable pharmacologic wound-healing target, the therapeutic potential of PPARβ/δ agonist GW501516 (GW) as a wound healing drug was never investigated. Using topical application of polymer-encapsulated GW, we revealed that different drug release profiles can significantly influence the therapeutic efficacy of GW and consequently diabetic wound closure. We showed that double-layer encapsulated GW microparticles (PLLA:PLGA:GW) provided an earlier and sustained dose of GW to the wound and reduced the oxidative wound microenvironment to accelerate healing, in contrast to single-layered PLLA:GW microparticles. The underlying mechanism involved an early GW-mediated activation of PPARβ/δ that stimulated GPx1 and catalase expression in fibroblasts. GPx1 and catalase scavenged excessive H2O2 accumulation in diabetic wound beds, prevented H2O2-induced ECM modification and facilitated keratinocyte migration. The microparticles with early and sustained rate of GW release had better therapeutic wound healing activity. The present study underscores the importance of drug release kinetics on the therapeutic efficacy of the drug and warrants investigations to better appreciate the full potential of controlled drug release.

Fabrication and Drug Release Study of Double-Layered Microparticles of Various Sizes

Double-layered microparticles, composed of poly(D,L-lactide-co-glycolide) (50:50) (PLGA) core and poly(L-lactide) (PLLA) shell, of controllable sizes ranging from several hundred microns to few microns were fabricated using a one-step solvent evaporation method. Metoclopramide monohydrochloride monohydrate (MCA), a hydrophilic drug, was selectively localized in the PLGA core. To achieve the double-layered particles of size approximately 2 µm, the process parameters were carefully manipulated to extend the phase separation time by increasing oil-to-water ratio and saturating the surrounding aqueous phase with solvent. Subsequently, the drug release profiles of the double-layered particles of various sizes were studied. Increased particle size resulted in faster degradation of polymers because of autocatalysis, accelerating the release rate of MCA. Interestingly, the effect of degradation rates, affected by particle sizes, on drug release was insignificant when the particle size was drastically reduced to 2-20 µm in the investigated double-layered particles. This understanding would provide critical insights into how the controllable formation and unique drug release profiles of double-layered particles of various sizes can be achieved.

Designing multilayered particulate systems for tunable drug release profiles.

Triple-layered microparticles comprising poly(D,L-lactide-co-glycolide, 50:50) (PLGA), poly(L-lactide) (PLLA) and poly(ethylene-co-vinyl acetate, 40 wt.% vinyl acetate) (EVA) were fabricated using a one-step solvent evaporation technique, with ibuprofen drug localized in the EVA core. The aim of this study was to investigate the drug release profiles of these triple-layered microparticles in comparison to double-layered (PLLA/EVA and PLGA/EVA) (shell/core) and single-layered EVA microparticles. Double- and triple-layered microparticles were shown to eliminate burst release otherwise observed for single-layered microparticles. For triple-layered microparticles, the migration of acidic PGA oligomers from the PLGA shell accelerated the degradation of the PLLA mid-layer and subsequently enhanced drug release in comparison to double-layered PLLA/EVA microparticles. Further studies showed that drug release rates can be altered by changing the layer thicknesses of the triple-layered microparticles, and through specific tailoring of layer thicknesses, a zero-order release can be achieved. This study therefore provides important mechanistic insights into how the distinctive structural attributes of triple-layered microparticles can be tuned to control the drug release profiles.

Formation and Degradation of Biodegradable Triple-Layered Microparticles

In this work, we report how biodegradable triple-layered microparticles can be fabricated through a simple, reliable, and economical one-step solvent evaporation technique. Characterization of triple-layered PLGA (shell)/PLLA (middle layer)/EVA (core) microparticles was conducted and their formation mechanism was described. Subsequently, in vitro hydrolytic degradation of these microparticles was investigated. It was found that the PLGA shell degraded rapidly leaving behind double-walled microparticles of PLLA/EVA after 40 days. The middle PLLA layer degraded more rapidly than expected because of the migration of PLGA oligomers that created a hydrophilic and acidic microenvironment in the PLLA layer. These degradation results therefore provide important insights into how triple-layered microparticles degrade, and how their degradation characteristics affect the drug releasing properties of these novel microparticles.

Manipulation of process parameters to achieve different ternary phase microparticle configurations.

Ternary phase microparticles of poly(D,L-lactide-co-glycolide) (50:50), poly(L-lactide) and poly(caprolactone) were fabricated through a one-step solvent evaporation technique. The purpose of this study was to examine the effects of various process parameters on the final configuration (i.e. polymer distribution and dimensions) of these composite microparticles and, subsequently, propose their mechanism of formation. Particle morphologies and configurations were determined using scanning electron microscopy, polymer dissolution tests and Raman mapping. It was found that a starting polymer solution prepared below the cloud point and an increased oil to water ratio will facilitate polymer configurations close to thermodynamic equilibrium, which is dictated by the interfacial energies of the components. By varying the polymer mass ratio or adjusting the precipitation rate, through stirring speed and oil to water ratio, a wide range of microparticles with different core-shell dimensions and embedded particulate sizes can also be fabricated. At the same time, lowering the polymer solution concentration and increasing the stirring speed may result in smaller microparticles. Correlation of these process parameters with the final composite particle morphology was thus established. This understanding should allow the controlled fabrication of ternary phase composite microparticles through a single step solvent evaporation technique.

Drug-eluting scaffolds for bone and cartilage regeneration

The advances in strategies for bone and cartilage regeneration have been centered on a concept that describes the close relationship between osteogenic cells, osteoconductive scaffolds, delivery growth factors and the mechanical environment. The dynamic nature of the tissue repair process involves intricate mimicry of signals expressed in the biological system in response to an injury. Recently, synergistic strategies involving hybrid delivery systems that provide sequential dual delivery of biomolecules and relevant topological cues received great attention. Future advances in tissue regeneration will therefore depend on multidisciplinary strategies that encompass the crux of tissue repair aimed at constructing the ideal functional regenerative scaffold. Here, functional scaffolds delivering therapeutics are reviewed in terms of their controlled release and healing capabilities.

Delivery of doxorubicin and paclitaxel from double-layered microparticles: The effects of layer thickness and dual-drug vs. single-drug loading.

UNLABELLED Double-layered microparticles composed of poly(d,l-lactic-co-glycolic acid, 50:50) (PLGA) and poly(l-lactic acid) (PLLA) were loaded with doxorubicin HCl (DOX) and paclitaxel (PCTX) through a solvent evaporation technique. DOX was localized in the PLGA shell, while PCTX was localized in the PLLA core. The aim of this study was to investigate how altering layer thickness of dual-drug, double-layered microparticles can influence drug release kinetics and their antitumor capabilities, and against single-drug microparticles. PCTX-loaded double-layered microparticles with denser shells retarded the initial release of PCTX, as compared with dual-drug-loaded microparticles. The DOX release from both DOX-loaded and dual-drug-loaded microparticles were observed to be similar with an initial burst. Through specific tailoring of layer thicknesses, a suppressed initial burst of DOX and a sustained co-delivery of two drugs can be achieved over 2months. Viability studies using spheroids of MCF-7 cells showed that controlled co-delivery of PCTX and DOX from dual-drug-loaded double-layered microparticles were better in reducing spheroid growth rate. This study provides mechanistic insights into how by tuning the layer thickness of double-layered microparticles the release kinetics of two drugs can be controlled, and how co-delivery can potentially achieve better anticancer effects. STATEMENT OF SIGNIFICANCE While the release of multiple drugs has been reported to achieve successful apoptosis and minimize drug resistance, most conventional particulate systems can only deliver a single drug at a time. Recently, although a number of formulations (e.g. micellar nanoparticles, liposomes) have been successful in delivering two or more anticancer agents, sustained co-delivery of these agents remains inadequate due to the complex agent loading processes and rapid release of hydrophilic agents. Therefore, the present work reports the multilayered particulate system that simultaneously hosts different drugs, while being able to tune their individual release over months. We believe that our findings would be of interest to the readers of Acta Biomaterialia because the proposed system could open a new avenue on how two drugs can be released, through rate-controlling carriers, for combination chemotherapy.

Gastric-floating microcapsules provide controlled and sustained release of multiple cardiovascular drugs

Floating polymeric microcapsules that simultaneously entrap multiple drugs were prepared using a solid/water/oil/water emulsion solvent evaporation method, based on harnessing interfacial phenomena and manipulation of the solvent removal process. The fabricated microcapsules exhibited excellent buoyancy in simulated gastric fluid and provided controlled and sustained release of multiple drugs for up to 24 h, thus revealing their potential as a rate-controlled oral drug delivery system.