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Protein Release From Gelatin Matrices REVIEW

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Text of Protein Release From Gelatin Matrices REVIEW

Advanced Drug Delivery Reviews 31 (1998) 287301

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Protein release from gelatin matricesYasuhiko Tabata, Yoshito Ikada*Research Center for Biomedical Engineering, Kyoto University, 53 Kawahara-cho Shogoin, Sakyo-ku, Kyoto 606, Japan

Abstract Gelatin is a denatured, biodegradable protein obtained by acid and alkaline processing of collagen. This processing affects the electrical nature of collagen, yielding gelatin with different isoelectric points (IEPs). When mixed with positively or negatively charged gelatin, an oppositely charged protein will ionically interact to form a polyion complex. This review article describes protein release from charged gelatin matrices on the basis of this polyion complexation. The biodegradable hydrogel matrices are prepared by chemical crosslinking of acidic or basic gelatin and are enzymatically degraded in the body with time. The degradation is controllable by changing the extent of crosslinking, which, in turn, produces hydrogels with different water contents. The time course of protein release is in good accordance with the rate of hydrogel degradation. It is very likely that the protein drug complexed with gelatin hydrogel is released as a result of its biodegradation. This gelatin hydrogel system releases the protein drug under maintenance of biological activity. This article will focus on experimental data that sustained release of growth factor from the gelatin hydrogels is very effective in exerting the biological functions of the growth factor. 1998 Elsevier Science B.V. Keywords: Gelatin; Growth factor; Sustained release; Degradation; Polyion complexation; Neovascularization; Bone formation

Contents 1. Introduction ............................................................................................................................................................................ 2. Preparation of gelatin hydrogels ............................................................................................................................................... 2.1. Block matrices ................................................................................................................................................................. 2.2. Injectable matrices ........................................................................................................................................................... 3. Complexation of protein with gelatin ........................................................................................................................................ 3.1. Polyion complexation in aqueous solution.......................................................................................................................... 3.2. Interaction of protein with gelatin hydrogels ...................................................................................................................... 4. Degradation of gelatin hydrogels .............................................................................................................................................. 5. bFGF release from gelatin hydrogels ........................................................................................................................................ 5.1. In vitro release ................................................................................................................................................................. 5.2. In vivo release ................................................................................................................................................................. 6. Biological activity ................................................................................................................................................................... 6.1. Neovasuclarization ........................................................................................................................................................... 6.2. Bone formation ................................................................................................................................................................ 7. Conclusions ............................................................................................................................................................................ References .................................................................................................................................................................................. *Corresponding author. Tel.: 075-751-4115; fax: 075-751-4144; e-mail: [email protected] 288 290 290 290 291 291 292 293 293 293 294 295 295 296 297 298

0169-409X / 98 / $19.00 1998 Elsevier Science B.V. All rights reserved. PII S0169-409X( 97 )00125-7

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Y. Tabata, Y. Ikada / Advanced Drug Delivery Reviews 31 (1998) 287 301

1. Introduction Recent advances in biotechnology has made it possible to produce various clinically useful peptides and proteins. While this technology has brought about the discovery and mass production of these bioactive macromolecules, several challenges need to be addressed with regard to their sustained delivery in a convenient, controlled manner, and targeting formulations. In contrast to conventional synthetic pharmaceuticals, proteins are susceptible to proteolysis, chemical change and denaturation during storage and administration in the body [1,2]. Signicant efforts have been made to improve formulations for better stabilization of proteins over a sufciently long storage time. Additional research has focused on the development of dosage forms that either prolong the biological activity of protein in the body or assist in targeting the protein to a specic tissue. One possible way to prolong activity is to incorporate a protein drug into an appropriate matrix for achieving sustained release of the drug at the site of action over a long period of time. It is highly possible that protein is protected against proteolysis and antibody neutralization, as far as it is, at least, incorporated in a release matrix for prolonged retention of the protein activity in vivo. There have been a number of research reports on protein release from polymer matrices: poly( L-lactic acid) (PLLA) and its copolymers with glycolic acid (PLGA) [3 31], PLGA polymer blends [18,32,33], PLLApolyethylene glycol (PEG) copolymers [34,35], poly(cyanoacrylates) [36,37], poly(anhydrides) [3840], poly(ortho esters) [41,42], polyphosphazene [43], poly(vinyl alcohol) [44], poly(vinyl pyrrolidone) [45], poly(acrylic acid) [46], poly(ethyleneco-vinyl acetate) [47,48], cellulose derivatives [4951], hyaluronic acid derivatives [52,53], alginate [5458], collagen [5961], gelatin [6067], starch [68,69], dextran [70] and brin [71]. As is stated in other chapters of this special issue, the largest problem of protein release technology is the loss of biological activity of the protein released from a proteinpolymer formulation. Thus, unless this problem is solved by a breakthrough, it seems difcult to expect a further research development in the area of protein release. It has been demonstrated that this activity loss results from denaturation and deactivation of

protein during the formulation process with a polymer matrix. When exposed to harsh environmental changes, such as heating and exposure to sonication and organic solutions, protein is generally denatured, losing its biological activity [9,14,20]. Therefore, it is important to exploit a new formulation method of protein carrier with polymers under mild conditions to minimize protein denaturation. From this viewpoint, polymer hydrogel may be a preferable candidate as a protein release matrix because of its biosafety and its high inertness towards protein drugs [72]. However, sustained release of protein over a long time period will not be expected from hydrogels, since the release rate of protein from hydrogels is generally diffusion-controlled through aqueous channels in the hydrogels. Thus, for achieving effective protein release, it will be a key strategy to immobilize the protein drug to polymer carrier molecules constituting the hydrogel through some molecular interactions. For one trial, we have been attempting to take advantage of electrostatic interactions between protein and polymer molecules for the sustained release of protein from the polymer hydrogel. It has been well recognized in polymer science that a positively or negatively charged polyelectrolyte electrostatically interacts with an oppositely charged partner to form a polyion complex [73,74]. It seems unlikely that all of the ionic interactions between the two polyelectrolytes with many charged groups are dissociated at the same time. As a result, in contrast to low-molecular-weight electrolytes, stable bonding will occur between the oppositely charged polyelectrolytes, which will not be dissociated easily. In the research eld of pharmaceutical science, this polyion complexation is not a new technology but has been extensively explored for drug coating and encapsulation. The application of this polyion complexation, which we will describe here, is Drug complexation with polymer carriers. This is a new trial that will allow us to pharmaceutically modify a charged polymeric drug to increase its stability, targeting and sustained release, leading to enhanced therapeutic efcacy. Charged drugs available for this trial include proteins and oligo- and polynucleotides, while biodegradable polymers, such as proteins, polysaccharides and poly(amino acid)s, are applicable as the polymer

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carriers. Another representative research eld of Drug complexation with polymer carriers that has been reported is gene therapy. It has been demonstrated that complexati