Encapsulation of water-soluble drugs in Poly (vinyl alcohol) (PVA)- microparticles via membrane emulsification: Influence of process and formulation parameters on structural and functional properties

Highlights

• Uniform PVA microparticles production by membrane emulsification/cross-linking.

• Polymer concentration and cross-linking degree influence the particles structure.

• Physico-chemical properties of drug and polymer matrix control drug encapsulation.

• Tuned drug release is achieved by changing the cross-linking density.

• Cytocompatibility studies suggest PVA particles suitability for biomedical applications.

Abstract

Drug-loaded poly (vinyl alcohol) (PVA)-based microparticles have been synthetized by using membrane emulsification and chemical cross-linking. The encapsulation of two water-soluble molecules, catechol (CA) and diclofenac sodium (DS), has been considered as case studies. PVA hydrogels have been recognized as promising biomaterials and suitable candidates for drug delivery. However, the encapsulation of hydrophilic, low molecular weight drugs in particulate materials is currently an ambitious goal. The purpose of this work was to develop high-drug loading systems for hydrophilic molecule delivery based on uniformly distributed particulate carriers. Membrane emulsification has been used as advanced manufacturing method to design drug-loaded PVA microparticles with target properties in terms of particle size, particle size distribution, structure and functional activity. A special emphasis is laid on the important factors that contribute to tune the structured properties of microparticles, encapsulation efficiency/drug loading and drug delivery. In particular, the influence of emulsification method (membrane and homogenizing approaches), phase compositions (PVA concentration, drug concentration, physicochemical properties of drug), cross-linking reaction conditions (cross-linking agent concentration, acidic media) has been studied. Finally, the potential of PVA-based microparticles as drug delivery carriers as well as their in vitro cytotoxicity have been evaluated.

Introduction

Several types of polymeric particulate systems have been attempted as potential drug delivery systems to achieve site-specific and/or time-controlled delivery of small or large molecular weight drugs and other bioactive agents. As a family of particulate materials, hydrogel particles have gained considerable attention in recent years for their unique physicochemical properties resembling that of the living tissues such as high-water content, soft and rubbery consistency, low interfacial tension with water or biological fluids [1]. Hydrogels require control over the polymeric network structure for appropriate design, providing proper mechanical performances, tuning the degradation behavior of hydrogels and promoting the diffusion of bioactive agents. The choice of polymer, cross-linking reaction and cross-linking agent, as well as the fabrication techniques are key parameters that are receiving great attention to develop bespoke drug delivery system-based hydrogels for targeted applications. Microparticles, exhibiting particle sizes ranging from a few to several hundred microns, have stimulated great interest in academia and industry due to their simplicity and versatility, many products have been commercialized [2].

Poly (vinyl alcohol) (PVA) hydrogels have been recognized as promising biomaterials and suitable candidates for drug delivery systems [3] in oral, transdermal, buccal, intramuscular, rectal routes of administration [4]. PVA-based dosage forms can have different designs and shapes depending on the route of drug administration. The production of membranes and fibers based on PVA has been extensively reported [[5], [6], [7], [8], [9], [10], [11]], on the contrary, only few examples are available for the production of PVA particles [[12], [13], [14]]. The potential application of a drug delivery system depends on the choice of the drug carrier [15]. Membranes find broad application in pills, implants and patches for oral and transdermal/ocular delivery, respectively. Particulate drug delivery systems have attracted much attention due to the large surface to volume ratio associated with the small size. This has many effects on functioning of the particles and their properties. Size has a marked effect on ability of drug-delivery carriers to cross cell membranes, on bioavailability and blood circulation time. However, the selection of the appropriate production approach can tweak the functionality of the carriers. For instance, during particle formation, drugs contained in the dispersed phase of nascent particles formed by an emulsion system can partition into the surrounding external continuous phase, leading to substantial loss of payload. This uncontrolled reagent manipulation can ensue in the production of carriers with a low encapsulation efficiency and drug loading. Consequently, there is a need of developing efficient approaches to promote a high and efficient loading of cargos, as well as to ensure a high reproducibility and scalability to translate the production from laboratory to mass scale.

Through rational design, particulate drug-delivery systems can be manufactured to combine desirable structural properties (size, size distribution, morphology, surface properties) with their functionality (payload amount, drug delivery). Membrane emulsification (ME) is recognized as a powerful emulsification approach to assist particle formation at micro and nanoscale levels. Membrane emulsification exerts the advantages of governing and fine-tuning both structural and functional properties [16]. The template emulsions can be transformed into structured particles using a variety of solidification processes [17]. Membrane emulsification has been demonstrated to be one of the most efficient drug-encapsulation methods [18,19]. It is rationalized because droplets generation occurs by a drop-by-drop mechanism instead of drop disruption, evading the loss of payload by surrounding external continuous phase. In addition, the emulsification mechanism and the solidification conditions achieved in solid-lipid particles produced by membrane emulsification have been well-correlated with the improved encapsulation efficiency of amphiphilic and hydrophilic drugs [[20], [21], [22]]. Several marketed drugs suffer from poor water solubility, low permeability, rapid metabolism and elimination from the body along with poor safety and tolerability. For that reason, the encapsulation of lipophilic drugs by membrane emulsification has stimulated great interest in a myriad of scientific and biomedical fields [23]. However, considering that the majority of drugs are hydrophilic, and of these, many are low-molecular-weight molecules (less than 500 Da), there are several drawbacks to consider in order to improve their bioavailability [24]: 1) Hydrophilic drugs are often subject to low intracellular absorption, enzymatic degradation at the digestive tract and rapid renal clearance; 2) Low bioavailability can lead to lower than expected drug concentration, resulting in sub-optimal drug distribution and compromising pharmacokinetics/pharmacodynamics targets. Consequently, the controlled production of particulate delivery systems with a high loading of hydrophilic, low molecular weight drugs is currently an ambitious goal. To the best of our knowledge, the impact of membrane emulsification on hydrophilic drug encapsulation for continuous production of particulate materials based on hydrogels has never been evaluated. The work is expected to afford new insights in nano- and micro-scale design associated with PVA hydrogels for biomedical applications from their manufacturing to the design of functional material properties. Then, the aim of this work was to develop high-drug loading systems in continuous flow for a controlled delivery of hydrophilic bioactive molecules based on uniformly distributed PVA-based hydrogel microparticles by membrane emulsification approach. Conventional homogenization process was selected to benchmark the production of PVA microparticles and their physical and chemical properties. Two water-soluble bioactive molecules have been used as model drugs: Catechol and Diclofenac Sodium. Catechol is a benzene derivative molecule with two neighboring (ortho-) hydroxyl groups and plays a variety of important roles in biological processes [11]. Diclofenac sodium is the salt form of a phenylacetic acid and it is used in rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and allied conditions, as well as in the treatment of pain resulting from minor surgery, trauma and dysmenorrhea for its anti-inflammatory and analgesic properties [25]. As a novelty, this work has attempted the study of catechol and diclofenac sodium loading in PVA hydrogel microparticles produced by membrane emulsification and homogenization processes, coupled with chemical cross-linking reaction. Drug physicochemical properties, as well as the drug release profiles were studied on PVA hydrogel microparticles. Finally, as the main target of herein produced PVA microparticles is mainly focused on a biomedical application as drug delivery systems, it was evaluated their in-vitro toxicity in order to consider them as potential vectors for biomedicine drug delivery uses. This study is expected to give more insight for the micro-scale design associated with PVA hydrogels for the potential development of drug delivery devices.