Preparation of microspheres by the solvent evaporation technique

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Abstract

The microencapsulation process in which the removal of the hydrophobic polymer solvent is achieved by evaporation has been widely reported in recent years for the preparation of microspheres and microcapsules based on biodegradable polymers and copolymers of hydroxy acids. The properties of biodegradable microspheres of poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) have been extensively investigated. The encapsulation of highly water soluble compounds including proteins and peptides presents formidable challenges to the researcher. The successful encapsulation of such entities requires high drug loading in the microspheres, prevention of protein degradation by the encapsulation method, and predictable release of the drug compound from the microspheres. To achieve these goals, multiple emulsion techniques and other innovative modifications have been made to the conventional solvent evaporation process.

Introduction

The solvent evaporation method to produce microspheres of poly(lactic acid) (PLA), and its co-polymer poly(lactic-co-glycolic acid) (PLGA) has been studied extensively due to the biocompatibility of these polymers 1, 2, 3, 4. In the solvent evaporation process, the polymer is dissolved in a suitable water immiscible solvent, and the medicament is dispersed or dissolved in this polymeric solution. The resultant solution or dispersion is then emulsified in an aqueous continuous phase to form discrete droplets. In order for the microspheres to form, the organic solvent must first diffuse into the aqueous phase and then evaporate at the water/air interface. As solvent evaporation occurs, the microspheres harden and free flowing microspheres can be obtained after suitable filtration and drying.

The solvent evaporation method has been used extensively to prepare PLA and PLGA microspheres containing many different drugs 5, 6, 7. Several variables have been identified which can influence the properties of the microspheres, including drug solubility, internal morphology, solvent type, diffusion rate, temperature, polymer composition and viscosity, and drug loading 8, 9, 10, 11, 12. The effectiveness of the solvent evaporation method to produce microspheres depends on the successful entrapment of the active agent within the particles, and thus, this process is most successful with drugs which are either insoluble or poorly soluble in the aqueous medium which comprises the continuous phase [13]. Many types of drugs with different physical and chemical properties have been formulated into polymeric systems, including anti-cancer drugs 14, 15, narcotic agents 16, 17, local anesthetics [18], steroids 19, 20, and fertility control agents 21, 22.

Protein release from a bioerodible polymeric matrix can occur by diffusion through a tortuous water filled path through the polymeric matrix or through matrix erosion 23, 24. Recent advances in the solvent evaporation technique have allowed successful entrapment of highly water soluble drugs 25, 26, reactive compounds such as amine based drugs [27], proteins 28, 29, peptides 30, 31, and vaccines 32, 33. This review will summarize the advances in the solvent evaporation technique and the characteristics and related properties of biodegradable microspheres produced by this method.

Section snippets

Conventional O/W encapsulation

The microencapsulation of pharmaceutical compounds with PLA or PLGA by the solvent evaporation method has been investigated extensively during the past 25 years. The premise for this method is the emulsification of a polymeric solution in an aqueous continuous phase. A schematic diagram of the method is shown in Fig. 1. The O/W emulsion is produced by the agitation of two immiscible liquids. The drug substance is either dispersed or in solution in the polymer/solvent system or is captured in

Anhydrous systems

The encapsulation of water soluble drugs by the conventional O/W solvent evaporation method will generally result in rapid partitioning of the drug from the organic phase and into the aqueous phase, resulting in microspheres with little or no drug loading. Innovative modifications to the conventional O/W solvent evaporation method have been reported to circumvent this problem.

Anhydrous systems, which are comprised of an organic polymer phase emulsified in an immiscible oil, have been used to

Polymeric degradation induced by proteins, reactive compounds, or processing conditions

The influence of plasma proteins on the degradation of poly(L-lactide) microcapsules in relation to the potential distribution across a microcapsule/adsorbed protein layer interface, and the increased solubility of PLA caused by the presence of proteins, was reported by Makino et al. [65]. The degradation rate of PLA microcapsules in an aqueous medium was accelerated by the addition of albumin, γ-globulins, and fibrinogen. As previously reported by these researchers, PLA molecules of

Conclusions

In conclusion, the emulsion solvent evaporation method for production of PLA and PLGA microspheres has been used extensively for the encapsulation of a variety of pharmaceutical compounds. The efficacy of this microencapsulation process is dependant on many factors, including drug solubility, partition coefficient, polymer composition and molecular weight, and method of manufacture. These variables must be considered in order to develop a successful controlled release PLGA microsphere

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