Microencapsulation Methods for Delivery of Protein Drugs

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220 Biotechnol. Bioprocess Eng. 2001, Vol. 6, No. 4 Limitations many successful phase separation systems Although been demonstrated, each method has several limi- have The microspheres tend to aggregate and the tations. for mass production is difficult [48]. Agglom- scale-up occurs when the coacervate droplets are sticky eration adhere to each other before the solvent is com- and removed or before the droplets are hardened [31]. pletely produce well-defined microspheres, wide ‘stability To is required. The stability window is defined as window’ step where addition of non-solvent does not induce a but forms stable coacervates [34]. The agglomeration window is affected by the physicochemical stability of polymers used and/or the viscosity of the nature added. The presence of residual solvents is non-solvent concern in the non-solvent addition method. The a includes at least three different solvents, i.e., method polymer solvent and two polymer non-solvents. In the the polymer solvents are toxic compounds, general, as halogenated hydrocarbons (e.g., dichloro- such for which the exposure limits are regulated methane), the authority. For example, the concentration limit by dichloromethane is 600 ppm [49]. In addition to the for solvent, two non-solvents are generally known polymer remain in a substantial quantity. A study showed to depending on the type of solvent and polymer used, that residual solvents could be minimized by appropriate the methods [38]. The solvents, however, were in drying hard to remove. High levels of residues may al- general the microsphere morphology due to their plasticizter effect. Moreover, it may cause a toxicity problem ing influence crucial properties such as release profiles and drug stability. Undoubtedly, the search for toxico- and and technologically acceptable solvents and logically should continue for the non-solvent addi- non-solvents method to be more useful. tion a polymer-polymer interaction (complex coacerva- In the limited pH range and the use of cross-linking tion), can be potential problems. Since the technique is agent on electrostatic interactions between two polye- based pH of the medium is an important factor. lectrolytes, example, in a gelatin-acacia system, the pH should For below the isoelectric point of gelatin (pH 8.9) to be it positively charged. The pH range suitable for make gelatin-acacia system is between 2.6 and 5.5 [30]. the condition, however, is not appropriate for encapsu- This of acid-labile drug entities. The pH range could lation extended by the addition of water-soluble nonionic be such as polyethylene glycol [50,51]. Glutaral- polymers, and formaldehyde are commonly used as crossdehyde agents to harden the microcapsules in this techlinking A condensation reaction occurs between the nique. groups of the protein (e.g., gelatin) and the alde- amino The cross-linking agents may diffuse into the hydes. and also react with drug entities, therefore this core may not be appropriate for the protein drugs. method toxicity problems arise as well [30]. Potential SPRAY DRYING drying has been widely used in the pharmaceu- Spray food, and biochemical industries. The main applitical, in the pharmaceutical field include drying proccations granulation, preparation of solid dispersions, alteraess, of polymorphism of a drug, preparation of dry tion for aerosols, and encapsulation of drugs for powders masking and protection from oxidation [52]. Since taste late 1970s, the spray drying technique has been the for making microparticulate systems for controlled used delivery. drug Methods hydrophilic or hydrophobic polymer is dis- Either in a suitable solvent. Drug can be dissolved or solved in the solvent. Alternatively, drug solution suspended be emulsified in the polymer solution. The mixture can then sprayed through a nozzle of a spray dryer, is in solid microspheres that precipitated into resulting bottom collector [53]. Sometimes, the process the the use of plasticizers to form microcapsules of include spherical shape and smooth-surface by reducing regular rigidity of polymer chain [54]. the Alternative Technique (congealing): Spray congealing includes Spray-chilling dissolution or dispersion of the drug in a melted the without using solvent. This mixture fluid is then carrier into a cold air stream to make small droplets sprayed solidified by cooling at the temperature lower than and melting point of the carrier. This method was used the encapsulate bovine somatotropin (bST) in fat or wax to bST was dispersed in molten fat or wax and [55]. through an air/liquid spray nozzle. The micro- sprayed were formed as the molten droplets and were spheres on sieves in the desired size range (45-180 µm). collected was demonstrated that the microspheres were effec- It in maintaining increased level of bST in the blood tive treated animals for 4 weeks, increasing weight gains of and milk production. Applications spray-drying is relatively simple, fast and easy Since scale-up, it has been tried as an attractive alternative to the conventional methods, such as coacervation and to method to encapsulate protein drugs [48,56- emulsion The spray drying technique was applied to produce 65]. microparticles containing thyrotropin releasing PLGA (TRH) [48]. TRH in water and PLGA in ace- hormone were mixed to form a clear solution and then tonitrile Since the microparticles produced by conven- sprayed. spray dryer tended to agglomerate and adhere to tional surface of the chamber, they designed a double noz- the system such that additional nozzle might spray a zle solution as an anti-adherent simultaneously mannitol 8). Microparticles with mean particle size of 20 µm (Fig.
Biotechnol. Bioprocess Eng. 2001, Vol. 6, No. 4 221 Raw materials 8. Schematic diagram of a spray dryer used for prepara- Fig. of PLGA microparticles containing TRH. From reference tion [48]. obtained, from which zero order release of TRH were for one month with a minimal initial burst. continued 4 lists some examples of microspheres prepared by Table drying. spray Advantages of the major advantages of spray drying is its One applicability. Both hydrophilic and hydrophobic general can be used with proper selection of the sol- polymer [52]. Spray drying is useful for encapsulating even vent drugs, such as proteins or peptides, be- heat-sensitive it involves mild temperatures [52]. Although cause drying includes hot air stream, the temperature of spray droplets may be maintained below the drying air the due to rapid evaporation of the solvent. temperature effective temperature applied to the drug itself is The enough to be used for proteins. Moreover, spray mild is time effective. Spray drying can yield results drying to those of conventional methods in terms equivalent size distribution, particle morphology, and release of yet with the advantage of high encapsulation kinetics, and the short duration of the preparation efficiency [53]. The spray drying equipment is easily procedure at the manufacturing site. Also, as a one-stage available process, spray drying is ideal for production of closed materials and good manufacturing practice sterile (GMP) [30]. Limitations TRH-PLGA solution Air filter Pump air Double nozzle Heater Drying chamber Mannitol solution Spray nozzle Blower Cyclone Receiver During spray drying, considerable amounts of the 4. Examples of microencapsulation of proteins by spray Table drying Polymer Solvent Protein Particle size β-glucuronidase Bovine somatotropin Human erythropoietin Albumin/ with Acacia as PVP coacervate stabilizer anhy- Poly dride PLGA Distilled water 5 µm Dichloro- 1-5 µm methane Dichloro- 10 µm methane Release kinetics Ref. initial burst Biphasic: within 6h followed (31%) zero order release for 2 by weeks release for 6 h due to 90% fast degradation of the and small parti- polymer size cle burst during 24 h Initial no further release for and months, likely due to 2 interac- protein-polymer and insoluble protein tion aggregates can be lost during the process due to sticking material the microparticles to the wall of the drying chamber. of drying process can often lead to change of poly- Spray of the spray dried drugs [66,67]. For exammorphism progesterone crystal in its original alpha form (m.p. ples, turned into beta form (m.p. 395K) when it was 402K) dried in combination with PLA. Fiber formation spray be another major problem in spray drying PLA [67]. can are formed due to insufficient forces present to Fibers up the liquid filament into droplets. It depends on break the type of polymer and, to a lesser extent, the both of the spray solution. For example, ethyl cellu- viscosity solutions made spherical droplets at relatively high lose however PLA solutions of considerably concentrations, concentration and viscosity resulted in fibers. low are a number of process variables that should be There for drug encapsulation. They include feed optimized properties, such as viscosity, uniformity, and material of drug and polymer mixtures, feed rate, concentration of atomization, and the inlet and outlet tem- method [32]. The dependence on so many variables peratures become a problem in terms of reproducibility and a may process. In addition, the amount of polymer scale-up drugs for encapsulation may be limited, since and/or fluid of high viscosity cannot be sprayed. GELATION / IONOTROPIC COMPLEXATION POLYELECTROLYTE gelation (IG) is based on the ability of Ionotropic to crosslink in the presence of counter polyelectrolytes to form hydrogels. Since the use of alginate for cell ions [68], ionotropic gelation has been widely encapsulation used for both cell and drug encapsulation. Method is one of the most widely used polyanion for Alginate Alginate is composed of 1,4-linked microencapsulation. beta-D-mannuronic acid and alpha-D-guluronic acid [60] [56] [62]
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