PLGA/mesoporous silica hybrid structure for controlled drug release

Abstract

In this paper, we report a poly(d,l-lactide-co-glycolide) (PLGA)/mesoporous silica hybrid structure (PS hybrid structure), which was synthesized via a novel sol-gel route assisted by single emulsion solvent evaporation. The in intro drug release properties of both the mesoporous silica and the PS hybrid structure were investigated. It was observed that gentamicin-loaded mesoporous silica showed a sharp initial burst during the first day followed by a rather constant and low release over the subsequent period of 3 weeks. In comparison with the mesoporous silica without biodegradable polymer encapsulation, the PS hybrid structure could realize a reduced initial burst, with a plateau stage for nearly 3 weeks of slow release, followed by a sustained release stage lasting for nearly 2 weeks. The whole release period could last as long as 5 weeks. These distinct behaviors make the hybrid structure material promising as a new drug release material for bone filling applications.

Introduction

Search for a suitable biomaterial for bone filling is one of the ongoing research areas in orthopedic surgery. Several candidate materials have been considered for this application, including biopolymeric cements [1], apatite bioceramics [2], and more recently SiO₂-based bioactive glass [3]. While these bioactive materials can replace and regenerate the dead spaces caused by surgical intervention over traumatized or damaged bone, a typical scenario in association with the use of some of these biomaterials for bone filling is the osteomyelitis incidence, which is the inflammation of bone caused by a pyogenic organism. The main treatment technique for osteomyelitis is the systematic drug administration. In conventional drug delivery modes, such as spray or an injection of a dose or taking of a pill by the patient, the drug concentration in blood rises dramatically when the drug is taken, then peaks and finally declines. Since many drugs exhibit a plasma level above which they are toxic and below which they are ineffective, the plasma drug concentration in the patient at a particular time is largely dependent on the compliance with the prescribed routine. This is particularly problematic if the toxic and minimum effective levels are close to each other.

Local drug release in the implanted site appears to be a much more interesting alternative, where the goals of drug releasing system are to maintain the drug in the desired therapeutic range with just a single dose, localize delivery of the drug to a particular body compartment (which lowers the systemic drug level), reduce the need for follow-up care, preserve medications that are rapidly destroyed by the body, and to increase patient comfort and/or improve compliance.

The introduction of an appropriate drug release system into the bone implant site has been attempted and practiced. For example, an antibiotic loaded polymethylmethacrylate (PMMA) is currently in use clinically as a combination of bone filler and drug release system for fixing nonbioactive prostheses to the surrounding bone [4]. However, such material has several clinical disadvantages for long-term applications, one of the most serious issues of which is its nonadhesiveness with bone surface. Attempts have thus been made to utilize bioactive ceramics with a metastable calcium phosphate that has the same elementary chemical composition as the natural bones. In particular, polymer-ceramic composites have recently been studied as drug release materials for bone filling due to their excellent biocompatibility and integration with the osseous tissue [5], [6], [7], [8], [9]. Nevertheless, there is one major problem for the polymer-ceramic composites as far as drug release is concerned. Being utilized as a “macrophase”, the problem is that the drug species can only be loaded into the composites by mechanical mixing or being adsorbed directly into the matrices of polymer-ceramic composites, which, however, did not allow for a sustained release at the site over more than a few days. The drug release pattern was characterized by a sharp initial burst followed by little release in later stage, exhibiting a great disadvantage for long-term sustained delivery of antibiotics.

Mesoporous silica derived by using triblock copolymers has been addressed to have potential to act as a convenient reservoir for controlled drug delivery systems [10], [11]. The drug molecules can be hosted within the mesopores by immersion techniques and released via a diffusion-based mechanism if no drug-silica interaction considered [12]. The adjustable pore size and well-defined pore structure are expected to facilitate the free administration of drug release pattern. In this paper, poly(d,l-lactide-co-glycolide) (PLGA)/mesoporous silica (PS) hybrid microspheres were prepared. The antibiotic, gentamicin, was entrapped in the mesopores of the mesoporous silica instead of being adsorbed in the matrices of the composites. The purpose of this research is aimed at developing a hybrid structure for potential application as controlled drug delivery in the bone. PLGA may not be a very suitable encapsulation material, due to its degradation product is acidic and could initiate inflammatory. In the future work, we would consider application of collagen instead of PLGA.