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

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Abstract

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.

Introduction

Biocompatible polymeric microparticles of poly(lactic acid) (PLA) or poly(lactic acid-co-glycolic acid) (PLGA) have garnered much interest in the field of drug delivery in the past decade [1], [2]. These biodegradable particulate systems protect drugs from premature degradation, provide controlled and sustained drug release, and aid in improving therapeutic efficacy. However, as drug carriers, monolithic polymeric microparticles have several inherent problems, such as initial burst release [3], the inability to provide a variety of release profiles [4], [5], [6], [7], [8], [9], [10], and the inability to deliver multiple drugs from a single particle [11].

Double-layered particles composed of a polymeric shell surrounding a core of a second polymer have been shown to have better control drug release kinetics [11], [12], [13], [14]. The outer layer in this core-shell structure allows drugs localized in the core to be released by diffusion through this “membrane”. With the appropriate selection of the core and shell polymers, a variety of release profile and kinetics can be achieved, while eliminating some of the undesirable release characteristics of single-layered particles. Matsumoto et al. [15], [16] demonstrated that an outer non-drug-holding layer of poly(d,l-lactide) can eliminate the initial burst of cisplatin from that localized in the PLGA cores of multi-reservoir type microspheres. Shi et al. [11] have also reported that a near-complete and sustained release of hydrophilic bovine serum albumin and hydrophobic cyclosporin A was achieved using poly(ortho ester)-PLGA double-walled microspheres. Double-layered and even multi-layered and/or multi-phase particles can therefore provide an attractive and robust approach in drug delivery. Such particulate systems can offer greater versatility in controlling drug release through the manipulation of particle parameters, such as layer thicknesses, structural configurations, and polymer types.

Our group previously reported the fabrication of ternary-phase microparticles with a poly(d,l-lactide-co-glycolide) (PLGA) core and a poly(l-lactide) (PLLA) shell impregnated with poly(caprolactone) (PCL) particulates [17]. We also showed that the particle parameters (e.g., PCL particulate size, layer thickness, etc.) can be altered using this one-step fabrication process. For example, the physicochemical properties of the shell can be manipulated by changing the polymer content, whereby a higher PLLA content would yield a denser and thicker shell, while more PCL would result in a more rubbery shell impregnated with larger PCL particulates. Through such alterations, an assortment of “designer” microparticles can be fabricated.

While studies of drug release from double-layered microparticles have been reported, no such studies have been conducted using double-layered ternary-phase microparticles. Therefore, the aim of this study was to understand how the release profiles and kinetics of double-layered PLLA(shell)/PLGA(core) microparticles are altered when particles are transformed from being binary-phase to ternary-phase by adding PCL particulates to the shell. It is also of interest to know how different particle parameters and drugs can affect drug release. The model drugs used in this study were ibuprofen (IBU), which is hydrophobic, and metoclopramide monohydrochloride monohydrate (MCA), which is hydrophilic. In this study, MCA was localized in the core, while the IBU was localized in the shell of the microparticles.

Section snippets

Materials

PLLA (intrinsic viscosity (IV): 2.38, Bio Invigor), PLGA (50:50) (IV: 1.18, Bio Invigor), PCL (molecular weight (MW): 80 kDa, Aldrich), and poly(vinyl alcohol) (PVA) (MW: 30–70 kDa, Sigma-Aldrich) were used without further purification. Drugs were purchased from Sigma-Aldrich. Solvents such as dichloromethane (DCM), chloroform, and tetrahydrofuran (THF) were from Tedia Co., Inc. Phosphate-buffered saline (PBS) solution (pH 7.4) was purchased from OHME, Singapore. All drugs and solvents were used

Drug-loaded microparticles

A range of drug-loaded microparticles were fabricated. Fig. 1(a) shows the Raman mapping of IBU-MCA-loaded double-layered ternary-phase PLLA/PLGA/PCL (3:2:1) microparticles. PLGA and PLLA comprised the core and shell structures, respectively, with PCL uniformly dispersed as particulates within the PLLA shell. Hydrophilic MCA was encapsulated within the relatively more hydrophilic PLGA core, while hydrophobic IBU was localized in the relatively more hydrophobic shell, based on polymer-drug

Discussion

The drug release kinetics and profiles of binary- and ternary-phase microparticles are clearly distinct. The presence of PCL particulates within the PLLA shell (ternary-phase) played an important role in determining how hydrophilic drugs (present in the core) and hydrophobic drugs (present in the shell) are released. SEM, SEC and Raman mapping results show that two key factors are involved in differentiating the release kinetics of binary- and ternary-phase microparticles: morphological

Conclusions

Drug-loaded, double-layered ternary-phase PLLA/PLGA/PCL microparticles, with a PLGA core and a PLLA shell impregnated with PCL particulates, were fabricated using the water-in-oil-in-water double emulsion solvent evaporation technique. It was found that MCA and IBU were localized in the PLGA core and in the shell, respectively. The drug release properties of the ternary-phase microparticles were compared with those of binary-phase PLLA/PLGA and neat microparticles. The MCA-loaded ternary-phase

Acknowledgments

This work was supported by the research funding received from the Ministry of Education — AcRF Tier 1 (NTU).

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