Abstract
The purpose of this study was to fabricate insulin-loaded double-walled and single-polymer poly(lactide-co-glycolide) (PLGA) microspheres using a fast degrading glucose core, hydroxyl-terminated poly(lactide-co-glycolide) (Glu-PLGA), and a moderate degrading carboxyl-terminated PLGA polymers. A modified water-in-oil-in-oil-in-water (w/o/o/w) emulsion solvent evaporation technique was employed to prepare double-walled microspheres, whereas single-polymer microspheres were fabricated by a conventional water-in-oil-in-water (w/o/w) emulsion solvent evaporation method. The effect of fabrication techniques and polymer characteristics on microspheres size, morphology, encapsulation efficiency, in vitro release, and insulin stability was evaluated. The prepared double-walled microspheres were essentially non-porous, smooth surfaced, and spherical in shape, whereas single-polymer microspheres were highly porous. Double-walled microspheres exhibited a significantly reduced initial burst followed by sustained and almost complete release of insulin compared to single-polymer microspheres. Initial burst release was further suppressed from double-walled microspheres when the mass ratio of the component polymers was increased. In conclusion, double-walled microspheres made of Glu-PLGA and PLGA can be a potential delivery system of therapeutic insulin.
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References
Carino GP, Jacob JS, Mathiowitz E. Nanosphere based oral insulin delivery. J Control Release. 2000;65(1):261–9.
Damgé C, Maincent P, Ubrich N. Oral delivery of insulin associated to polymeric nanoparticles in diabetic rats. J Control Release. 2007;117(2):163–70.
Wu ZM, Zhou L, Guo XD, Jiang W, Ling L, Qian Y, et al. HP55-coated capsule containing PLGA/RS nanoparticles for oral delivery of insulin. Int J Pharm. 2012;425(1):1–8.
Wu Z, Ling L, Zhou L, Guo X, Jiang W, Qian Y, et al. Novel preparation of PLGA/HP55 nanoparticles for oral insulin delivery. Nanoscale Res Lett. 2012;7(1):299.
Zhao X, Shan C, Zu Y, Zhang Y, Wang W, Wang K, et al. Preparation, characterization, and evaluation in vivo of Ins-SiO 2-HP55 (insulin-loaded silica coating HP55) for oral delivery of insulin. Int J Pharm. 2013;454(1):278–84.
Nyambura BK, Kellaway IW, Taylor KM. Insulin nanoparticles: stability and aerosolization from pressurized metered dose inhalers. Int J Pharm. 2009;375(1):114–22.
Al-Qadi S, Grenha A, Carrión-Recio D, Seijo B, Remuñán-López C. Microencapsulated chitosan nanoparticles for pulmonary protein delivery: in vivo evaluation of insulin-loaded formulations. J Control Release. 2012;157(3):383–90.
Ito Y, Hagiwara E, Saeki A, Sugioka N, Takada K. Feasibility of microneedles for percutaneous absorption of insulin. Eur J Pharm Sci. 2006;29(1):82–8.
Sahni J, Raj S, Ahmad FJ, Khar RK. Design and in vitro characterization of buccoadhesive drug delivery system of insulin. Indian J Pharm Sci. 2008;70(1):61.
Sintov AC, Levy HV, Botner S. Systemic delivery of insulin via the nasal route using a new microemulsion system: in vitro and in vivo studies. J Control Release. 2010;148(2):168–76.
Presmanes C, De Miguel L, Espada R, Alvarez C, Morales E, Torrado JJ. Effect of PLGA hydrophilia on the drug release and the hypoglucemic activity of different insulin-loaded PLGA microspheres. J Microencapsul. 2011;28(8):791–8.
Takenaga M, Yamaguchi Y, Ogawa Y, Kitagawa A, Kawai S, Mizushima Y, et al. Administration of optimum sustained-insulin release PLGA microcapsules to spontaneous diabetes-prone BB/WorTky rats. Drug Deliv. 2006;13(2):149–57.
Han Y, Tian H, He P, Chen X, Jing X. Insulin nanoparticle preparation and encapsulation into poly (lactic-co-glycolic acid) microspheres by using an anhydrous system. Int J Pharm. 2009;378(1):159–66.
Sharma G, Van Der Walle CF, Kumar MR. Antacid co-encapsulated polyester nanoparticles for peroral delivery of insulin: development, pharmacokinetics, biodistribution and pharmacodynamics. Int J Pharm. 2013;440(1):99–110.
Huang X, Brazel CS. On the importance and mechanisms of burst release in matrix-controlled drug delivery systems. J Control Release. 2001;73(2):121–36.
van de Weert M, Hennink WE, Jiskoot W. Protein instability in poly (lactic-co-glycolic acid) microparticles. Pharm Res. 2000;17(10):1159–67.
Lee TH, Wang J, Wang CH. Double-walled microspheres for the sustained release of a highly water soluble drug: characterization and irradiation studies. J Control Release. 2002;83(3):437–52.
Lee WL, Seh YC, Widjaja E, Chong HC, Tan NS, Loo J, et al. Fabrication and drug release study of double-layered microparticles of various sizes. J Pharm Sci. 2012;101(8):2787–97.
Rahman NA, Mathiowitz E. Localization of bovine serum albumin in double-walled microspheres. J Control Release. 2004;94(1):163–75.
Tan EC, Lin R, Wang CH. Fabrication of double-walled microspheres for the sustained release of doxorubicin. J Colloid Interface Sci. 2005;291(1):135–43.
Navaei A, Rasoolian M, Momeni A, Emami S, Rafienia M. Double-walled microspheres loaded with meglumine antimoniate: preparation, characterization and in vitro release study. Drug Dev Ind Pharm. 2014;40(6):701–10.
Zheng W. A water-in-oil-in-oil-in-water (W/O/O/W) method for producing drug-releasing, double-walled microspheres. Int J Pharm. 2009;374(1):90–5.
Devrim B, Bozkir A. Preparation and evaluation of double-walled microparticles prepared with a modified water-in-oil-in-oil-in-water (w1/o/o/w3) method. J Microencapsul. 2013;30(8):741–54.
Sah H. A new strategy to determine the actual protein content of poly (lactide-co-glycolide) microspheres. J Pharm Sci. 1997;86(11):1315–8.
Sah H. Protein instability toward organic solvent/water emulsification: implications for protein microencapsulation into microspheres. PDA J Pharm Sci Technol. 1999;53(1):3–10.
Sturesson C, Carlfors J. Incorporation of protein in PLG-microspheres with retention of bioactivity. J Control Release. 2000;67(2):171–8.
Sah H. Microencapsulation techniques using ethyl acetate as a dispersed solvent: effects of its extraction rate on the characteristics of PLGA microspheres. J Control Release. 1997;47(3):233–45.
Leach K. Effect of manufacturing conditions on the formation of double-walled polymer microspheres. J Microencapsul. 1999;16(2):153–67.
Yan C, Resau JH, Hewetson J, West M, Rill WL, Kende M. Characterization and morphological analysis of protein-loaded poly (lactide-co-glycolide) microparticles prepared by water-in-oil-in-water emulsion technique. J Control Release. 1994;32(3):231–41.
Ghaderi R, Sturesson C, Carlfors J. Effect of preparative parameters on the characteristics of poly (d, l-lactide-co-glycolide) microspheres made by the double emulsion method. Int J Pharm. 1996;141(1):205–16.
Xiao CD, Shen XC, Tao L. Modified emulsion solvent evaporation method for fabricating core–shell microspheres. Int J Pharm. 2013;452(1):227–32.
Mitranić I, Stevanović M, Nedeljković B, Ignjatović N, Uskoković D. Controllable synthesis of horseradish peroxidase loaded poly (D, L-lactide) nanospheres. J Bionanosci. 2009;3(1):22–32.
Ghassemi AH, Van Steenbergen MJ, Talsma H, Van Nostrum CF, Jiskoot W, Crommelin DJA, et al. Preparation and characterization of protein loaded microspheres based on a hydroxylated aliphatic polyester, poly (lactic-co-hydroxymethyl glycolic acid). J Control Release. 2009;138(1):57–63.
Panyam J, Dali MM, Sahoo SK, Ma W, Chakravarthi SS, Amidon GL, et al. Polymer degradation and in vitro release of a model protein from poly (D, L-lactide-co-glycolide) nano-and microparticles. J Control Release. 2003;92(1):173–87.
Igartua M, Hernandez RM, Esquisabel A, Gascon AR, Calvo MB, Pedraz JL. Influence of formulation variables on the in-vitro release of albumin from biodegradable microparticulate systems. J Microencapsul. 1997;14(3):349–56.
Batycky RP, Hanes J, Langer R, Edwards DA. A theoretical model of erosion and macromolecular drug release from biodegrading microspheres. J Pharm Sci. 1997;86(12):1464–77.
Hrynyk M, Martins-Green M, Barron AE, Neufeld RJ. Sustained prolonged topical delivery of bioactive human insulin for potential treatment of cutaneous wounds. Int J Pharm. 2010;398(1):146–54.
Doolaanea AA, Ismail AF, Nor NH, Mohamed F. Effect of surfactants on plasmid DNA stability and release from poly (D, L-lactide-co-glycolide) microspheres. Trop J Pharm Res. 2015;14(10):1769–78.
Ubaidulla U, Khar RK, Ahmad FJ, Sultana Y, Panda AK. Development and characterization of chitosan succinate microspheres for the improved oral bioavailability of insulin. J Pharm Sci. 2007;96(11):3010–23.
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The authors would like to thank International Islamic University Malaysia for providing financial assistance during this work through the project No. EDW B 14-217-1102.
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Ansary, R.H., Rahman, M.M., Awang, M.B. et al. Preparation, characterization, and in vitro release studies of insulin-loaded double-walled poly(lactide-co-glycolide) microspheres. Drug Deliv. and Transl. Res. 6, 308–318 (2016). https://doi.org/10.1007/s13346-016-0278-y
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DOI: https://doi.org/10.1007/s13346-016-0278-y