Microfluidic conceived pH sensitive core–shell particles for dual drug delivery

Abstract

In current study, we report on the synthesis of core–shell microparticles for dual drug delivery by means of a two co-axial microfluidic device and online UV assisted free radical polymerization. Before developing pH-sensitive particles, ketoprofen loaded poly(methyl acrylate) core–ranitidine HCl loaded poly(acrylamide) shell particles were produced. Influence of inner and outer phases flow rates on particle size, shape, core diameter, shell thickness, and drug release properties was studied. All the particles were monodispersed with coefficient of variation below 5%. Furthermore, their diameter ranged from 100 to 151 μm by increasing continuous (Q_c) to middle (Q_m) phase flow rate ratio (Q_c/Q_m). Core diameter varied from 58 to 115 μm by decreasing middle (Q_m) to inner (Q_i) phase flow rate ratio (Q_m/Q_i) at constant continuous phase flow rate as confirmed by SEM images. It was observed that an optimum concentration of acrylamide (30 wt%) and an appropriate combination of surfactants were necessary to get core–shell particles otherwise Janus structure was obtained. FTIR confirmed the complete polymerization of core and shell phases. MTT assay showed variation in viability of cells under non-contact and contact conditions with less cytotoxicity for the former. Under non-contact conditions LD50 was 3.1 mg/mL. Release studies in USP phosphate buffer solution showed simultaneously release of ketoprofen and ranitidine HCl for non pH-sensitive particles. However, release rates of ranitidine HCl and ketoprofen were higher at low and high pH respectively. To develop pH-sensitive particles for colon targeting, the previous shell phase was admixed with few weight percentage of pH sensitive carboxyethyl acrylate monomer. Core and shell contained the same hydrophobic and hydrophilic model drugs as in previous case. The pH-sensitive shell prevented the release of the two entrapped molecules at low pH while increasing significantly their release rate at higher pH with a maximum discharge at colonic pH of 7.4.

Introduction

For many centuries man tried to treat diseases with different chemical entities but last century has seen a tremendous increase in the development of new active ingredients. These agents are delivered by suitable carriers called drug delivery systems. Emergence of new and more potent molecules necessitates the development of new controlled release drug delivery systems to counteract the problem raised with conventional systems. Controlled drug delivery systems in contrast offer several advantages like improved efficacy, reduced side effects, and improved patient compliance. Currently polymeric micro- and nano-particles and liposomes are widely used as controlled drug delivery systems (Wu et al., 2013).

Still these drug delivery vehicles as simple as microparticles have numerous inherent issues, like burst effect, difficulty in achieving zero-order release, and inability to incorporate and deliver two drugs in sequential or concurrent manner (Wang et al., 2010). Moreover, these systems also suffer from large particle size distribution and uncontrolled drug release kinetics. Recently it was found that shape and size of particles can play an important role in initial burst effect and release kinetics (Wu et al., 2013).

Core–shell particles can provide an effective control on the drug release kinetics and initial burst effect. Indeed the drug is usually localized in the core compartment while the shell increases the diffusion path of water toward the core and that of drug to the surroundings which ultimately limit the initial burst release (Kong et al., 2013, Tran et al., 2011). On the other hand, the release kinetics is faster in case of small particles (Khan et al., 2013) and thus an effective control over the drug release rate requires monodisperse particles. However, conventional core–shell particles are usually polydisperse in size (Lee et al., 2002, Tran et al., 2011) because of their synthesis methods which involve time consuming multistep procedures. Therefore, new methods are required for precise control of core and shell dimensions.

Microfluidics refers to the manipulation of fluid segments in devices for which at least one of the characteristic dimensions lies in the micron range. Microfluidic techniques allow the synthesis of microparticles from single phase flow or multiphase flow and offer several advantages over their counterpart macroscale techniques such as uniform particle size with coefficient of variation (CV) less than 5%, minimum amount of reagents, short mixing time, laminar flow, and high heat and mass transfers (Khan et al., 2013).

Core–shell particles have great promise in biomedical and pharmaceutical applications but their fabrication by conventional methods have limited their use. Conventional methods have several drawbacks, like the necessity to rely on high energy to obtain double emulsions, the production of polydisperse particles, the poor encapsulation efficiency, the lack of reproducibility, and control over other characteristics, such as core diameter and shell thickness (Kong et al., 2013). Moreover, in certain cases, the core is developed at first and then a shell layer is applied by dipping in a suitable solution (Babu et al., 2006). On the other hand, microfluidics has provided a facile approach to develop double emulsions that could serve as template for core–shell particles besides providing an efficient control over size and thickness of core and shell parts. So far many authors have tried to encapsulate a single molecule in the core and controlled its release kinetics by approaches, like magnetism, network density tuning, and thermal triggering (Gong et al., 2009, Kong et al., 2013, Rondeau, 2012, Yu et al., 2012). All these approaches used preformed polymers dissolved in a suitable solvent to form multiple emulsions which are later transformed into core–shell particles.

In current paper we started with two different monomers admixed with active pharmaceutical ingredients of different hydrophilicities. Double droplets were obtained in a two co-axial capillaries-based microfluidic device. These droplets were then polymerized by UV initiated free radical polymerization to produce core–shell particles containing a hydrophobic model drug in the core and a hydrophilic model drug in the shell. Obtained microparticles were characterized in terms of FTIR, SEM, encapsulation efficiency, cytotoxicity testing, and dual drug release as a function of their composition, size as well as pH of release medium.