ReviewMicroencapsulation by solvent extraction/evaporation: reviewing the state of the art of microsphere preparation process technology
Introduction
Biodegradable microspheres are widely investigated delivery systems for bioactive compounds such as low molecular weight and macromolecular therapeutics, antigens or DNA. As such they may add substantially to the value of therapies and vaccinations. Considered for parenteral, pulmonary, oral or nasal administration, they are capable of providing sustained and controlled release of the encapsulated bioactive compound, while the nonreleased bioactive material may be protected from degradation and physiological clearance. For vaccines, microspheres may provide additional adjuvancy [1], [2] and allow for direct targeting to professional antigen-presenting cells [3]. Furthermore, they may be surface-modified to target specific cells [4] and tissues [5].
Owing to their excellent biocompatibility, the biodegradable polyesters poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) are the most frequently used biomaterials for the microencapsulation of therapeutics and antigens [6], [7]. Other materials like proteins [5], polymer blends [8], polysaccharides such as chitosan [9], and lipids [10] have also been studied, although at a lower frequency. A large variety of bioactive compounds have been formulated into microspheres, among them are antineoplastic drugs [11], [12], narcotics [13], anaesthetic agents [14] as well as therapeutic peptides [15], [16] and proteins [17], [18], DNA [19], [20], viruses [21] and bacteria-derived compounds [22], [23]. Preparation technologies capable of producing larger amounts of microspheres in a safe, economic, robust and well-controlled manner are therefore required.
Microspheres have been prepared by various techniques, which feature partly competing, partly complementary characteristics. Many microencapsulation processes are modifications of the three basic techniques: solvent extraction/evaporation, phase separation (coacervation) and spray-drying [24]. Spray-drying is relatively simple and of high throughput but must not be used for highly temperature-sensitive compounds. Moreover, control of the particle size is difficult, and yields for small batches are moderate [25]. Coacervation is frequently impaired by residual solvents and coacervating agents found in the microspheres [26]. Furthermore, it is not well suited for producing microspheres in the low micrometer size range. The use of supercritical gases as phase separating agents was intensively studied to minimise the amount of potentially harmful residues in the microspheres, resulting in processes named, e.g., Precipitation with Compressed Antisolvent (PCA) [27], Gas or Supercritical fluid Anti-Solvent (GAS or SAS) and Aerosol Solvent Extraction System (ASES) [28]. Solvent extraction/evaporation neither requires elevated temperatures nor phase separation-inducing agents. Controlled particle sizes in the nano- to micrometer range can be achieved, but careful selection of encapsulation conditions and materials is needed to yield high encapsulation efficiencies and a low residual solvent content.
Microsphere preparation by solvent extraction/evaporation basically consists of four major steps: (i) dissolution or dispersion of the bioactive compound often in an organic solvent containing the matrix forming material; (ii) emulsification of this organic phase in a second continuous (frequently aqueous) phase immiscible with the first one; (iii) extraction of the solvent from the dispersed phase by the continuous phase, which is optionally accompanied by solvent evaporation, either one transforming the droplets into solid microspheres; (iv) harvesting and drying of the microspheres (Fig. 1).
This article reviews the current state of the art in solvent extraction/evaporation-based microencapsulation technology, with a focus on process-related aspects. Issues like materials, microsphere formulation, choice of appropriate solvents or surfactants are not central aspects of this review, although technology and starting materials are interconnected and can by no means be segregated completely. Both well-established and more advanced technologies will be reviewed.
Section snippets
Incorporation of bioactive compounds
Bioactive compounds may be added to the solution of the matrix material by either codissolution in a common solvent, dispersion of finely pulverised solid material or emulsification of an aqueous solution of the bioactive compound immiscible with the matrix material solution [29]. Codissolution may require a cosolvent to fully dissolve the drug in the matrix-containing solvent. Dispersion of the solid or dissolved bioactive material in the matrix-containing solution may be achieved by
Droplet formation
The droplet formation step determines the size and size distribution of the resulting microspheres. Microsphere size may affect the rate of drug release, drug encapsulation efficiency, product syringeability, in vivo fate in terms of uptake by phagocytic cells and biodistribution of the particles after subcutaneous injection of intranasal administration. In the following, the main procedures used for droplet formation in microsphere production are described. Henceforth, the different types of
Solvent removal
In both solvent extraction and evaporation, the solvent of the disperse phase, i.e., the drug/matrix dispersion, must be slightly soluble in the continuous phase so that partitioning into the continuous phase can occur leading to precipitation of the matrix material. In solvent evaporation, the capacity of the continuous phase is insufficient to dissolve the entire volume of the disperse phase solvent. Therefore, the solvent must evaporate from the surface of the dispersion to yield
Microsphere harvest and drying
Separation of the solidified microspheres from the continuous phase is usually done either by filtration or centrifugation. The particles may then be rinsed with appropriate liquids to remove adhering substances such as dispersion stabilisers or nonencapsulated drugs. Rinsing may involve elevated temperatures or the use of extraction agents to reduce the amount of residual solvent in the microspheres [109]. Finally, the microspheres are dried either at ambient conditions or under reduced
Conclusions
The widespread interest in microencapsulated drugs brought forth the need to prepare such particles in larger quantities and in sufficient quality suitable for clinical trials and commercialisation. The most frequently described solvent extraction/evaporation-based technology using simple beaker/stirrer setup is inappropriate for producing larger amounts of microspheres in an economic, robust and well-controlled manner. Static mixers warrant continuous production and simple scale-up, while the
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