Microencapsulation Methods for Delivery of Protein Drugs

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214 Biotechnol. Bioprocess Eng. 2001, Vol. 6, No. 4 Table 1. Examples of microencapsulation methods Chemical processes 1. evaporation and extraction Solvent solvent extraction Crygenic separation (Coacervation) Phase addition Non-solvent change Temperature polymer or salt addition Incompatible interaction (complex coacervation) Polymer-polymer complexation Polyelectrolyte polymerization Interfacial Mechanical processes 2. drying Spray chilling Spray desolvation Spray Supercritical fluid precipitation Single Emulsion Double Emulsion suspension/solution Protein polymer solution (oil) in Emulsion (o/o or o/w) solution Protein water in oil or water oil removal Solvent drying & Hardened microsphere Primary emulsion (w/o) water Secondary emulsion (w/o/w) removal Solvent drying & Hardened microsphere 1. Single emulsion (left) and double emulsion (right) sol- Fig. evaporation methods for microencapsulation of proteins. vent in a dispersed phase, which is a polymer solution in sent solvent such as dichloromethane or ethyl ace- organic Polylactic acid (PLA) and poly(lactide-co-glycolide) tate. are the most widely used biodegradable syn- (PLGA) polymers for sustained-release preparations. The thetic kinetics of active components can be controlled release changing molecular weight and/or copolymer ratio by those polymers. Drugs can be dispersed as solid parti- of or dissolved in polymer solution. The drug solution cles suspension is added into a continuous phase, which or be mineral oil (o/o) or aqueous solution (o/w) con- can emulsifiers. Emulsification is carried out by agitaining homogenization, or sonication. Emulsifiers in tation, continuous phase stabilize o/o or o/w emulsions the produced. Emulsifiers such as Span 85 [2], sorbi- being sesquioleate [3], aluminium tristearate [4] have tan used for o/o interface, and Carbopol been ® [2], 951 cellulose [5], polyvinyl alcohol (PVA) [6] have methyl used for o/w interface. been solvent in dispersed phase is removed by sol- Organic evaporation or by solvent extraction. In solvent vent process, hardening of emulsion occurs evaporation volatile organic solvent in dispersed phase leaches when continuous phase and evaporates from continuous into at atmospheric pressure. Using vacuum or a mod- phase increase in temperature can accelerate the evapoerate of organic solvent. In solvent extraction process, ration emulsion is transferred to a large amount of water the other quenching medium, and the extraction of or- or solvent occurs faster than in solvent evaporation ganic Thus, microspheres produced by solvent ex- process. process are more porous than the ones protraction by solvent evaporation. The porous structure duced results in faster release of peptide/protein drugs. usually long-term sustained release, solvent evaporation is For The prepared microspheres are collected by preferred. centrifugation or filtration, and freeze-dried. Emulsion (w/o/w) Methods Double double emulsion methods, an aqueous drug solu- In is first emulsified in a polymer-dissolved organic tion The w/o emulsion is then added into an aque- solvent. phase that contains emulsifier, thereby forming w/ ous emulsion. Then, the organic solvent is removed by o/w extracting into external aqueous phase and evaporation. Applications Emulsion Single emulsion solvent evaporation method has been Single to prepare microspheres/nanospheres containing used peptide and protein drugs. Insulin solution in various solvent was used in emulsification to prepare organic [7]. Other researchers used solid particles nanospheres bovine serum albumin (BSA) [2] or ovalbumin (OVA) of instead of protein solution, in a hope that protein [4], can be preserved in organic solvent. High en- activity efficiency was obtained using protein particapsulation The prepared microparticles tend to show initial cles. release profiles. Table 2 lists some examples of burst preparation using protein particles. A microparticle approach of protein particle preparation was used novel the encapsulation of bovine superoxide dismutase for into PLGA/PLA microspheres [5]. Protein (bSOD) particles were prepared by lyophilization of spherical glycol (PEG) aqueous mixture. protein-polyethylene approach resulted in high encapsulation efficiency This and high activity of the loaded enzyme (95%). In (88%)
Biotechnol. Bioprocess Eng. 2001, Vol. 6, No. 4 215 2. Encapsulation of protein particles by single emul- Table evaporation methods sion/solvent Protein particles Spray-dried BSA Micronized OVA Lyophilized bSOD/PEG ) (% 75 S O D o f b e 50 le a s e re u la tiv Q u m 100 25 Polymer Type PLGA o/o o/w Encapsulation efficiency >90% 20-50% Initial in release 1 day
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Microencapsulation Methods for Delivery of Protein Drugs

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