Elsevier

Biomaterials

Volume 30, Issue 5, February 2009, Pages 850-858
Biomaterials

The controlled release of drugs from emulsified, sol gel processed silica microspheres

https://doi.org/10.1016/j.biomaterials.2008.09.066Get rights and content

Abstract

Controlled release silica sol gels are room temperature processed, porous, resorbable materials with generally good compatibility. Many molecules including drugs, proteins and growth factors can be released from sol gels and the quantity and duration of the release can vary widely. Processing parameters render these release properties exquisitely versatile. The synthesis of controlled release sol gels typically includes acid catalyzed hydrolysis to form a sol with the molecules included. This is then followed by casting, aging and drying. Additional steps such as grinding and sieving are required to produce sol gel granules of a desirable size. In this study, we focus on the synthesis of sol gel microspheres by using a novel process with only two steps. The novelty is related to acid–base catalysis of the sol prior to emulsification. Sol gel microspheres containing either vancomycin (antibiotic) or bupivacaine (analgesic) were successfully synthesized using this method. Both drugs showed controlled, load dependent and time dependent release from the microspheres. The in vitro release properties of sol gel microspheres were remarkably different from those of sol gel granules produced by grinding and sieving. In contrast to a fast, short-term release from granules, the release from microspheres was slower and of longer duration. In addition, the degradation rate of microspheres was significantly slower than that of the granules. Using various mathematical models, the data reveal that the release from sol gel powder is governed by two distinct phases of release. In addition, the release from emulsified microspheres is delayed, a finding that can be attributed to differences in surface properties of the particles produced by emulsification and those produced by casting and grinding. The presented results represent an excellent data set for designing and implementing preclinical studies.

Introduction

Controlled release focuses on delivering biologically active agents locally over extended periods of time [1], [2], [3]. The site specificity of the delivery reduces the potential side effects that can be associated with general administration of drugs through oral or parenteral therapy [1]. Prevalent mechanisms for the delivery of biological agents by controlled release devices are resorption of the drug carrier material and diffusion. The resorption of these devices may, however, cause an inflammatory tissue response, which interferes with the treatment sought for with the molecules [4], [5]. Thus, excellent controlled release materials are ideally biodegradable materials with generally good biocompatibility.

Room temperature processed, silica based sol gels are resorbable materials with a favorable tissue response [2], [9]. They have been studied for biomedical applications that include tissue, cell and enzyme encapsulation and controlled release of drugs [2], [3], [6], [7], [8], [9], [10], [11], [12], [13]. Derived from a metal alkoxide precursor, the sol is produced through a hydrolysis and polycondensation reaction [14]. Due to the mild processing conditions, high concentrations of many types of biologically active agents can be incorporated in the liquid sol. The agents are embedded in the matrix of the gel, which after condensation and drying becomes a porous, glassy solid [2], [3], [9], [10], [11], [12], [13]. Data show that controlled release of antibiotics, proteins, and growth factors is possible from this porous material [2], [9], [10], [11], [12], [13]. These studies also demonstrate that the release is dependent on synthesis parameters such as the molar ratio of silica precursor to water, type of precursor and the concentration of bioactive drugs [2], [10], [11].

Controlled release sol gels are usually manufactured through an acid catalyzed process followed by casting, aging and drying. This leads to the synthesis of pellets, which can then be ground and sieved to arrive at granules or powders [2], [3], [10], [11], [12].

Sol gel granules made by grinding down cast discs possess an angular geometry. The sharp edges of this geometry may elicit more of an inflammatory response than that expected from microspheres. So far microspheres have mostly been made with biodegradable polymers such as polylactic acid, polyglycolic acids and polylactic-co-glycolic acid [15], [16]. These microspheres, however, are not ideal as their degradation products have been observed to cause an inflammatory response [4], [5]. This probably would not be the case for sol gel microspheres, since it has been shown previously that silica sol gel granules demonstrate a favorable tissue response and enhanced bone healing [2], [9].

Sol gel microparticles have been synthesized using spray drying [17] or emulsification [6], [18]. The spray dried microspheres have been used in controlled release studies, however, these particles do not have excellent release properties as the spray drying caused a major reduction of the surface area and resulted in transforming highly porous sol gels into a dense material [17].

In this study, we focus on obtaining porous, controlled release sol gel microspheres using emulsification as the synthesis route. These microspheres were made both with and without biological agents incorporated. Specifically, we incorporated the antibiotic vancomycin and the analgesic bupivacaine. The selection of these molecules was related to our parallel programs that focus on osteomyelitis treatment [19] and surgical pain control [20]. Herein, we report on the synthesis parameters of emulsified acid – base catalyzed microspheres that affect optimal controlled release, with optimization being related to achieving release kinetics of vancomycin and bupivacaine with a desirable therapeutic profile. A novel acid–base catalysis was selected in order to shorten the time to gelation of the sol. A shorter time to gelation is essential to produce sol gel microspheres by emulsification. Synthesis parameters of interest were: pH and time to gelation of the acid–base catalyzed sol, water to alkoxide ratio in the sol, drug concentration added to the sol and rotational speed of emulsification.

Section snippets

Materials and methods

Sol gel derived silica microspheres were synthesized using an acid–base catalyzed hydrolysis of tetraethoxysilane (TEOS, Strem Chemicals, Newburyport, MA) followed by emulsification.

Morphology and size distribution

Using the acid–base catalyzed synthesis and emulsification process, silica sol gel microspheres with and without drugs were successfully produced. As illustrated in Fig. 1a and b, the particles appear as smooth microspheres. The appearance of vancomycin containing microspheres is illustrated in Fig. 1a and b. Images of microspheres in the range from 200 to 500 μm and of particles below 100 μm are shown in the optical (Fig. 1a) and SEM (Fig. 1b) micrographs, respectively.

The size distribution as a

Dissolution

When dissolution of silica in aqueous solutions is at a steady state of silica dissolution–deposition, the dissolution is given by a first order reaction (Eq. (1)) [21]. This equation indicates that the dissolution is dependent on diffusion of the solute away from the solid–liquid solution interface.Ct=kS(CeC),where, C: concentration of silicon in solution, Ce: equilibrum concentration or “solubility” of silicon, S: surface area of solid phase, k: rate constant, t: time.

In solutions with a

Discussion

Controlled release sol gel derived silica microspheres were successfully synthesized using a new acid–base catalyzed sol gel process followed by emulsification. By using base, the gelation is short and, upon emulsification, small powder is obtained in an efficient manner. The process involves only two steps: hydrolysis and emulsification. The size of emulsified microspheres depends on the speed of stirring during emulsification and can easily be varied over a large range (from 10 to 500 μm) by

Conclusions

Controlled release sol gel microspheres were successfully synthesized by using a simple and expedient two-step process: acid–base catalyzed hydrolysis followed by emulsification. In contrast to rapid, short-term release from ground granules, the drugs incorporated in the microspheres (the antibiotic vancomycin and the analgesic bupivacaine) showed a slower, long-term release. In addition, the microspheres were characterized by longer in vitro dissolution durations than those of the granules.

Acknowledgements

We gratefully acknowledge support from the Nanotechnology Institute of Pennsylvania and participation of Jonathan Wang and Ameya Phadke in some of the experiments and the data analysis.

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