Microencapsulation Methods for Delivery of Protein Drugs

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222 Biotechnol. Bioprocess Eng. 2001, Vol. 6, No. 4 (A) (B) HO HO -OOC OHO 9. Monomer units (A) found in alginate and the alginate Fig. structure (B). From reference [69]. polymer Divalent and trivalent cations induce gelation residues. binding mainly to the guluronic blocks (Fig. 9). The by and macro-spheres are produced by dropping a microor drug-loaded alginate solution into aqueous cal- cell- chloride solution. Calcium ions diffuse into the cium drops, forming a three dimensional lattice of alginate crosslinked alginate. Polyelectrolyte complexa- ionically (PEC) with oppositely charged polyelectrolytes tion be added to increase the mechanical strength of may hydrogel and/or to provide a permeability barrier. the instance, addition of polycation (usually poly-L- For allows a membrane of polyelectrolyte complex lysine) form on the surface of alginate beads [69]. A number to natural and synthetic polyelectrolytes have been in- of Examples are listed in Table 5. vestigated. most of the droplets have been made with sy- Since needles, the particle sizes have been relatively ringe Smaller droplets can be formed using a vibration large. or air atomization method to extrude the algi- system solution (Fig. 10) [30]. The latter involves a Turbonate air-atomizer. Pressurized air is fed to mix with the tak alginate solution, forcing tiny liquid droplets sodium through the orifice of a nozzle. The calcium ions out the droplets of sodium alginate on contact to crosslink microgel droplets, which were further crosslinked form poly-L-lysine to form a membrane on the droplets. by obtained using this method were within Microparticles size range 5-15 µm [91]. the Applications OH Mannuronate (M) OH O -OOC O OH -OOC OHO O HO O HO -OOC OHO -OOC has been widely used in microcapsule sys- IG/PEC for cell encapsulation [82,87-89,92-94] and drug tems systems [76,77,83,85,86,95,96]. Due to mild delivery conditions, IG/PEC has recently attracted a new process for an application to protein delivery [71,78- attention Calcium alginate hydrogels have been 81,84,90,97,98]. for delivery of vascular endothelial growth factor used [71]. The alginate beads demonstrated the abil- (VEGF) to incorporate VEGF with efficiency between 30% ity 67% and constant release (5%/day) of VEGF for up and O OH O OH OH OH (G) Guluronate -OOC OH OH O OH O -OOC G M M G G O OH O 5. Examples of ionotropic gelation (IG) and polyelec- Table complexation (PEC) trolyte Polyelectrolytes IG with PEC with References Alginate (-) Calcium (+) - [70-72] Alginate (-) Calcium (+) Poly-L-Lysine (+) [73] Alginate (-) Calcium (+) Chitosan (+) [74, 75] Chitosan (+) Carboxymethyl cellulose (-) Tripolyphosphate (TPP)(-) - [76-81] Aluminium (+) Chitosan (+) [82] κ-carrageenan (-) Potassium (+) Chitosan (+) [83] ι-carrageenan (-) Amines (+) - [84] Pectin (-) Calcium (+) - [85] Gelan gum (-) Calcium (+) - [86] Alginate and cellulose sulfate (-) Calcium (+) Poly (methylene- co-guanidine) (+) [87, 88] Polyphosphazene (-) Calcium (+) Poly-L-Lysine (+) [89, 90] Sodium alginate 10. Schematic diagram of the preparation of alginate- Fig. microcapsules. polylysine 14 days. The ionic interaction between VEGF and to contributed to maintaining the biological activ- alginate ity of VEGF. Advantages main advantage of IG/PEC is the mild formula- The conditions for maintaining cell viability and protion integrity. All of the polyelectrolytes are watertein and thus proteins can be encapsulated without soluble, of organic solvents or elevated temperatures, both use which may damage protein integrity. Also, this sys- of tem is simple, fast and cost-effective. Limitations Turbotak atomizer chloride Calcium solution Polylysine added Pressurized gas Microcapsule biggest problem in applications of IG/PEC for The protein delivery, in spite of the great advan- controlled of mild conditions, is that the matrix and memtage formed by IG/PEC is not capable of controlling brane release rate for a long period of time. It does not the in cell encapsulation, where the membrane matter should provide sufficient permeability for the cell prod-
Biotechnol. Bioprocess Eng. 2001, Vol. 6, No. 4 223 i.e., a therapeutic protein. However, for IG/PEC to uct, used for controlled delivery of protein entities, a cer- be type of dense membrane (e.g., biodegradable polytain preferably capable of controlling the release rate, mers), be incorporated or alternative combinations of should should be explored to control the polyelectrolytes of the membrane, so that the release rate permeability be controlled over the desired span. Thus far, the may rate of the protein is likely to depend on the release properties of the model protein or the physicochemical medium in which the microparticles are placed release In case of alginate-poly-L-lysine system, all para- [71]. are tied to a single chemical complex, therefore meters is not easy to optimize the capsule condition. For this it new combinations of polyelectrolytes were reason, to allow independent modification of capsule proposed including size, wall thickness, mechanical parameters permeability, and surface characteristics [99]. strength, issue in IG/PEC is that some polyelectrolytes Another have biocompatibility problem. There have been might arguments concerning the biocompatibil- contradictory of alginates [100-102]. A host foreign-body reaction ity occurred on account of the implanted algi- (fibrosis) particles and mannuronic acid block was nate-based to be responsible for the fibrotic response, as a found stimulator of IL-1 and TNF-α production. Use of potent of high guluronic acid content was suggested alginates minimize the cytokine response. On the other hand, to study indicated that alginate particles with another guluronic acid contents provoked stronger re- high than the high mannuronic acid alginate particles sponse In general, polyionic hydrogels obtained by [102]. have rather low mechanical strength. A few IG/PEC have suggested ways to overcome this problem papers exploring alternative combinations of polyanions by polycations [87,99], introducing a different process and [103], or applying additional coating [82,98]. INTERFACIAL POLYMERIZATION polymerization features in situ polymeri- Interfacial of reactive monomers on the surface of a droplet zation or particles. Method reactive monomers (typically dichloride and Two are respectively dissolved in immiscible sol- diamine) and mixed to form o/w emulsion (dichloride in oil vents and diamine in water phase). The monomers dif- phase to the o/w interface where they react to form a fuse membrane (Fig. 11). A typical example of this polymeric is making nylon microcapsules [104]. Nona- method phase (chloroform/cyclohexane) containing surqueous (e.g., sorbitan trioleate) and aqueous buffer confactant drugs to be incorporated (enzymes or proteins), taining protein (e.g., BSA or hemoglobin) and dia- protective are prepared respectively. Two phases are mixed mine and stirred to make an w/o emulsion in an ice bath un- 11. Microencapsulation by interfacial polymerization Fig. From reference [104]. method. the desired droplet size is reached. Another nonaque- til phase containing acid chloride is added to the emulous for interfacial polymerization. Polymerization is sion by addition of excess nonaqueous phase. quenched are allowed to sediment and collected Microcapsules then washed in saline several times to remove or- and solvents and byproducts. ganic combinations of monomers can be used to Various a range of polymer membranes [104]. Sebacoyl obtain and 1,6-hexane diamine can be used to form chloride polyamide nylon 6, 10. The microcapsules using the system, however, tend to be fragile and difficult to this Terephthaloyl chloride and 1,6-hexane diamine handle. yield polyester membrane. Alternatively tere- can chloride can be used in combination with Lphthaloyl to yield poly(terephthaloyl L-lysine). Typically lysine chlorides and diamines are reactive monomers; acid isocyanates can be used instead of or as a par- however, substitute for acid chloride [105]. Alternatively, the tial composed of only one type of monomer can be polymer on the interface (Interfaicial addition polymeri- formed [104]. Polyalkylcyanoacrylate belongs to this zation) Aqueous drug solution and oil phase containing type. monomer are mixed to form an w/o cyanoacrylate The polymerization is initiated by water in emulsion. aqeous phase with cyanoacrylate dissolved in the oil the phase. Application Monomer B Monomer A Polymer membrane insulin nanoparticles were prepared using Recently addition polymerization techniques [106]. interfacial were prepared by addition of ethyl 2- Nanoparticles to a stirred w/o microemulsion consistcyanoacrylate of aqueous insulin solution, oil and surfactant. To ing exhaustive washing steps after polymerization avoid biocompatible oils (caprylic/capric triglyc- reaction, and mono-/diglycerides) and surfactants (polyerides 80 and sorbitan monooleate) were used to forsorbate the microemulsions. The obtained poly(ethyl 2mulate is known to be biodegradable. Since incyanoacrylate) was confined to the aqueous phase in w/o emulsulin sions, a high encapsulation efficiency (86%) could be
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Microencapsulation Methods for Delivery of Protein Drugs

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