The influence of γ-sterilization on the physicochemical properties of a controlled release formulation for the insulin-like growth factor-I (IGF-I) was investigated in this study. Recombinant human insulin-like growth factor-I (rhIGF-I) was efficiently entrapped in poly (D,L-lactide-co-glycolide) (PLGA) microspheres by water-in-oil-in-water (W/O/W) solvent evaporation technique. Microspheres were irradiated at a dose of 25 kGy and evaluated by means of scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The stability of the released protein was investigated by circular dichroism (CD) and sodium dodecyl sulfate polyacrilamide gel electrophoresis (SDS-PAGE). No difference was noticed in microsphere size and morphology before and after irradiation. Drug loading remains essentially the same after the sterilization process. However, rhIGF-I aggregation was detected by electrophoresis. In addition, subtle changes in DSC pattern were noticed for irradiated microspheres. In vitro drug release from irradiated microspheres was also affected, showing an increased burst effect. From this results it can be concluded that γ-sterilization process causes changes in the properties of rhIGF-I loaded microspheres.
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References
1.
1. Cohen, S., Yoshioka, T., Lucarelli, M., Hwang, L.H., and Langer, R. (1991). Controlled Delivery Systems for Proteins Based on Poly(lactic/glycolic acid) Microspheres , Pharm. Res, 8: 713-720 .
2.
2. Baldwin, S.P. and Saltzman, W.M. (1998). Materials for Protein Delivery in Tissue Engineering , Adv. Drug Deliv. Rev., 33: 71-86 .
3.
3. Cleland, J.L., Duenas, E., Daugherty, A., Marian, M., Yang, J., Wilson, M., Celniker, A.C., Shahzamani, A., Quarmby, V., Chu, H.Mukku, V., Mac, A., Roussakis, M., Gillette, N., Boyd, B., Yeung, D., Brooks, D., Maa, Y-F., Hsu, C. and Jones, J.S. (1997). Recombinant Human Growth Hormone Poly(lactic-co-glycolic Acid) (PLGA) Microspheres Provide a Long Lasting Effect , J. Control Release, 49: 193-205 .
4.
4. Okada, H. (1997). One- and Three-Month Release Injectable Microspheres of the LH-RH Superagonist Leuprorelin Acetate , Adv. Drug Deliv. Rev., 28: 43-70 .
5.
5. Menei, P., Daniel, V., Montero-Menei, C., Brouillard, M., Pouplard-Barthelaix, A. and Benoit, J.P. (1993). Biodegradation and Brain Tissue Reaction to Poly(D,L-Lactide-co-glicolide) Microspheres , Biomaterials, 14: 470-478 .
6.
6. Zapf, J. and Froesch, E.R. (1986). Insulin-like Growth Factors Somatomedins; Structure, Secretion, Biological Action and Physiological Role , Horm. Res., 24: 121-130 .
7.
7. Torres-Aleman, I., Barrios, V. and Berciano, J. (1998). The Peripheral Insulin-like Growth Factor System in Amyotrophic Lateral Sclerosis and in Multiple Sclerosis , Neurology, 50: 772-776 .
8.
8. Torres-Aleman, I. (1999). Insulin-like Growth Factors as Mediators of Functional Plasticity in the Adult Brain , Horm. Metab. Res., 31: 114-119 .
9.
9. Fernández, A.M., Gonzalez de la Vega, A.G., Planas, B. and Torres-Aleman, I. (1999). Neuroprotective Actions of Peripherally Administered Insulin-like Growth Factor I in the Injured Olivo-Cerebellar Pathway , Eur. J. Neurosci., 11: 2019-2030 .
10.
10. Doré, S., Kar, S., Zheng, W-H. and Quirion, R. (2000). Rediscovering Good Old Friend IGF-I in the New Millennium: Possible Usefulness in Alzheimer's Disease and Stroke , Pharm. Acta. Helv., 74: 273-280 .
11.
11. Torres-Aleman, I., Barrios, V., Lledo, A. and Berciano, J. (1996). The Insulin-like Growth Factor I System in Cerebellar Degeneration , Ann. Neurol., 39: 335-342 .
12.
12. Fernandez, A.M., De La Vega, A.G. and Torres-Aleman, I. (1998). Insulin-like Growth Factor I Restores Motor Coordination in a Rat Model of Cerebellar Ataxia , In: Proc. Natl. Acad. Sci., USA., 95: 1253-1258 .
13.
13. Guler, H.P.Zapf, J. and Froesch, E.R. (1989). Short Term Metabolic Effects of Recombinant Insulin-like Growth Factor in Healthy Adults , N. Engl. J. Med., 317: 137-140 .
14.
14. Lam, X.M., Duenas, E.T.Daugherty, A.L., Levin, N. and Cleland, J.L. (2000). Sustained Release of Recombinant Human Insulin-like Growth Factor-I for Treatment of Diabetes , J. Control Release, 67: 281-292 .
15.
15. Singh, M., Shirley, B., Bajwa, K., Samara, E., Hora, M. and O'Hagan, D. (2001). Controlled Release of Recombinant Insulin-like Growth Factor from a Novel Formulation of Polylactide-co-glycolide Microparticles , J. Control Release, 70: 21-28 .
16.
16. Mohr, D., Wolff, M. and Kissel, T. (1999). Gamma Irradiation for Terminal Sterilization of 17-β-Estradiol Loaded Poly-(D,L-lactide-co-glycolide) Microspheres , J. Control Release, 61: 203-217 .
17.
17. Bruck, S.D. and Mueller, E.P. (1988). Radiation Sterilization of Polymeric Implant Materials , J. Biomed. Mater Res., 22: 133-144 .
18.
18. DeLuca, P.P., Kenley, R.A. and Hausberger, A.G. (1995). Gamma Irradiation Effects on Molecular Weight and in vitro Degradation of Poly (D,L-lactide-co-glycolide) Microparticles , Pharm. Res., 12: 233-242 .
19.
19. Volland, C., Wolff, M. and Kissel, T. (1994). The Influence of Terminal Gamma-sterilization on Captopril Containing Poly(D,L-lactide-co-glycolide) Microspheres , J. Control Release, 31: 293-305 .
20.
20. Montanari, L., Cilurzo, F., Valvo, L., Faucitano, A., Buttafava, A., Groppo, A., Genta, I. and Conti, B. (2001). Gamma Irradiation Effects on Stability of Poly(lactide-co-glycolide) Microspheres Containing Clonazepam , J. Control Release, 75: 317-330 .
21.
21. European Guideline 3AQ4a. (July 1992). The Use of Ionizing Radiation in the Manufacture of Medicinal Products, Official Publications of the European Communities, London .
22.
22. Smith, P.K., Krohn, R.I., Hermanson, G.T., Mallia, A.K., Gartner, F.H., Provenzano, M.D., Fujimoto, E.K., Goeke, N.M., Olson, B.J. and Klenk, D.C. (1985). Measurement of Protein using Bicinchoninic Acid , Anal. Biochem., 150: 76-85 .
23.
23. Hausberger, A.G., Kenley, R.A. and DeLuca, P. (1995). Gamma Irradiation Effects on Molecular Weight and in vitro Degradation of Poly(D,L-lactide-co-glicolide) Microparticles , Pharm. Res., 12: 851-856 .
24.
24. Bittner, B., Mäder, K., Kroll, C., Borchert, H-H. and Kissel, T. (1999). Tetracycline-HCl-loaded poly (D,L-lactide-co-glycolide) Microspheres Prepared by a Spray Drying Technique, Influence of γ-Irradiation on Radical Formation and Polymer Degradation , J. Control Release, 59: 23-32 .
25.
25. Fransson, J.R. (1997). Oxidation of Human Insulin-like Growth Factor I in Formulation Studies. 3. Factorial Experiments of the Effects of Ferric Ions, EDTA, and Visible Light on Methionine Oxidation and Covalent Aggregation in Aqueous Solution , J. Pharm. Sci., 86: 1046-1050 .
26.
26. Rothen-Weinhold, A., Besseghir, K., Vuaridel, E., Sublet, E. and Oudry, N. (1999). Stability Studies of a Somatostatin Analogue in Biodegradable Implants , Int. J. Pharm., 178: 213-221 .
27.
27. Fransson, J., Hallén, D. and Florin-Robertsson, E. (1997). Solvent Effects on the Solubility of Human Insulin-like Growth Factor I , Pharm. Res., 14: 606-612 .
28.
28. Souillac, P.O., Middaugh, C.R. and Rytting, J.H. (2002) Investigation of Protein-carbohydrate Interactions in the Dried State. 2. Diffuse Reflectance FTIR Studies , Int. J. Pharm., 235: 207-218 .
29.
29. Tracy, M.A., Ward, D.L., Firouzabadian, L., Wang, Y., Cong, N., Quian, R. and Zhang Y. (1999). Factors Affecting the Degradation Rate of Poly(lactide-co-glycolide) Microspheres in vivo and in vitro , Biomaterials, 20: 1057-1062 .
30.
30. Cleland, J.L., Lim, A., Barron, L., Duenas, E.T. and Powell, M.F. (1997). Development of a Single Shot Subunit Vaccine for HIV-1: Part 4. Optimizing Microencapsulation and Pulsatile Release of MN rgp 120 from Biodegradable Microspheres , J. Control Release, 47: 135-150 .
31.
31. Wang, J., Wang, B.M. and Schwendeman, S.P. (2000). Characterization of the Initial Burst Drug Release from Poly(D,L-lactide-co-glycolide) Microspheres II. Alterations in Surface Permeability Implicating in Cessation of Burst Release , In: Proceedings AAPS Annual Meeting, Indianapolis, USA.
32.
32. Faisant, N.Siepmann, J. and Benoit, J.P. (2002). PLGA-based Microparticles: Elucidation of Mechanisms and a New, Simple Mathematical Model Quantifying Drug Release , Eur. J. Pharm. Sci., 15: 355-366 .
33.
33. Crotts, G., Sah, H. and Park, TG. (1997). Adsorption Determines In-vitro Protein Release Rate from Biodegradable Microspheres: Quantitative Analysis of Surface Area during Degradation , J. Control Release, 47: 101-111 .
34.
34. Carrascosa, C., Torres-Aleman, I., Lopez-Lopez, C., Carro, E., Espejo, L., Torrado, S. and Torrado, J.J. (2003) Microspheres Containing Insulin-like Growth Factor for Treatment of Chronic Neurodegeneration, Biomaterials , in press.
