{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:30:02Z","timestamp":1792099802746,"version":"4.4.0"},"reference-count":66,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,11,24]],"date-time":"2019-11-24T00:00:00Z","timestamp":1574553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF- 2017R1C1B1006483"],"award-info":[{"award-number":["NRF- 2017R1C1B1006483"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2019R1F1A1056350"],"award-info":[{"award-number":["NRF-2019R1F1A1056350"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The aim of this study was to investigate the effects of various stabilizers on the encapsulation efficiency and release of exenatide-loaded PLGA (poly(lactic-co-glycolic acid)) microspheres prepared by the water-in-oil-in-water (W\/O\/W) solvent evaporation (SE) method. It was shown that the stabilizers affected exenatide stability in aqueous solutions, at water\/dichloromethane interfaces, on PLGA surfaces, or during freeze-thawing and freeze-drying procedures. Sucrose predominantly reduces instability generated during freeze-thawing and freeze-drying. Phenylalanine prevents the destabilization at the water\u2013dichloromethane (DCM) interface through decreased adsorption. Poloxamer 188 enhances stability in aqueous solutions and prevents adsorption to PLGA. Proline and lysine decrease adsorption on PLGA surfaces. Fourier transform infra-red spectroscopy (FT-IR) was used to find the molecular interaction of additives with exenatide or PLGA. Additives used in stability assessments were then added stepwise into the inner or outer water phase of the W\/O\/W double emulsion, and exenatide-loaded microspheres were prepared using the solvent evaporation method. The effect of each stabilizer on the encapsulation efficiency and release behavior of microspheres correlated well with the stability assessment results, except for the negative effect of poloxamer 188. Particle size analysis using laser diffractometry, scanning electron microscopy (SEM), water vapor sorption analysis, differential scanning calorimetry (DSC), and circular dichroism (CD) spectroscopy were also employed to characterize the prepared exenatide-loaded PLGA microsphere. This study demonstrated that an adequate formulation can be obtained by the study about the effect of stabilizers on peptide stability at the preformulation step. In addition, it can help to overcome various problems that can cause the destabilization of a peptide during the microsphere-manufacturing process and sustained drug release.<\/jats:p>","DOI":"10.3390\/pharmaceutics11120627","type":"journal-article","created":{"date-parts":[[2019,11,25]],"date-time":"2019-11-25T03:10:00Z","timestamp":1574651400000},"page":"627","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Effect of Stabilizers on Encapsulation Efficiency and Release Behavior of Exenatide-Loaded PLGA Microsphere Prepared by the W\/O\/W Solvent Evaporation Method"],"prefix":"10.3390","volume":"11","author":[{"given":"Heejun","family":"Park","sequence":"first","affiliation":[{"name":"College of Pharmacy, Pusan National University, 63 Busandaehak-ro, Geumjeong-gu, Busan 46241, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Hyun","family":"Ha","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, 63 Busandaehak-ro, Geumjeong-gu, Busan 46241, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Sol","family":"Ha","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, 63 Busandaehak-ro, Geumjeong-gu, Busan 46241, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"Dong-A ST Co., Ltd., Giheung-gu, Yongin, Gyeonggi 446-905, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Soo","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Pusan National University, 63 Busandaehak-ro, Geumjeong-gu, Busan 46241, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6521-3822","authenticated-orcid":false,"given":"Sung-Joo","family":"Hwang","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.jconrel.2010.05.011","article-title":"Issues in long-term protein delivery using biodegradable microparticles","volume":"146","author":"Ye","year":"2010","journal-title":"J. Control. Release"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Emami, F., Vatanara, A., Park, E.J., and Na, D.H. (2018). Drying technologies for the stability and bioavailability of biopharmaceuticals. Pharmaceutics, 10.","DOI":"10.3390\/pharmaceutics10030131"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0378-5173(99)00152-0","article-title":"Instability, stabilization, and formulation of liquid protein pharmaceuticals","volume":"185","author":"Wang","year":"1999","journal-title":"Int. J. Pharm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0169-409X(97)00049-5","article-title":"Preparation of microspheres by the solvent evaporation technique","volume":"28","author":"McGinity","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1023\/A:1026498209874","article-title":"Protein instability in poly (lactic-co-glycolic acid) microparticles","volume":"17","author":"Hennink","year":"2000","journal-title":"Pharm. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ijpharm.2007.11.012","article-title":"How to achieve sustained and complete protein release from PLGA-based microparticles?","volume":"350","author":"Giteau","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijpharm.2004.11.014","article-title":"Protein aggregation and its inhibition in biopharmaceutics","volume":"289","author":"Wang","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0169-409X(00)00144-7","article-title":"Factors affecting short-term and long-term stabilities of proteins","volume":"46","author":"Arakawa","year":"2001","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0168-3659(03)00194-9","article-title":"Biodegradable microspheres for protein delivery","volume":"90","author":"Sinha","year":"2003","journal-title":"J. Control. Release"},{"key":"ref_10","first-page":"963","article-title":"Long-acting preparations of exenatide","volume":"7","author":"Cai","year":"2013","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1517\/13543784.2012.638282","article-title":"Novel GLP-1 receptor agonists for diabetes","volume":"21","author":"Garber","year":"2012","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/S0968-0896(01)00263-2","article-title":"Medium-dependence of the secondary structure of exendin-4 and glucagon-like-peptide-1","volume":"10","author":"Andersen","year":"2002","journal-title":"Bioorg. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.colsurfa.2009.03.015","article-title":"Biocompatible microspheres based on acetylated polysaccharide prepared from water-in-oil-in-water (W1\/O\/W2) double-emulsion method for delivery of type II diabetic drug (exenatide)","volume":"340","author":"Yang","year":"2009","journal-title":"Colloids Surf. A Physicochem. Eng. Asp."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2504","DOI":"10.1007\/s11095-009-9966-3","article-title":"Pharmacokinetics and efficacy of a biweekly dosage formulation of exenatide in Zucker diabetic fatty (ZDF) rats","volume":"26","author":"Kwak","year":"2009","journal-title":"Pharm. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.ejps.2010.03.006","article-title":"Efficacy of a new sustained-release microsphere formulation of exenatide, DA-3091, in Zucker diabetic fatty (ZDF) rats","volume":"40","author":"Kwak","year":"2010","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1248\/cpb.58.1474","article-title":"Preparation, characterization, and pharmacodynamics of exenatide-loaded poly (DL-lactic-co-glycolic acid) microspheres","volume":"58","author":"Liu","year":"2010","journal-title":"Chem. Pharm. Bull."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1089\/dia.2011.0050","article-title":"Encapsulation of exenatide in poly-(D, L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes","volume":"13","author":"DeYoung","year":"2011","journal-title":"Diabetes Technol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.colsurfb.2013.08.048","article-title":"Preparation of uniform-sized exenatide-loaded PLGA microspheres as long-effective release system with high encapsulation efficiency and bio-stability","volume":"112","author":"Qi","year":"2013","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.ejps.2013.08.014","article-title":"Stability of exenatide in poly (d, l-lactide-co-glycolide) solutions: A simplified investigation on the peptide degradation by the polymer","volume":"50","author":"Liang","year":"2013","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.ijpharm.2013.07.012","article-title":"Effect of water on exenatide acylation in poly (lactide-co-glycolide) microspheres","volume":"454","author":"Liang","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1007\/s11095-013-1262-6","article-title":"Comparative studies on the influences of primary emulsion preparation on properties of uniform-sized exenatide-loaded PLGA microspheres","volume":"31","author":"Qi","year":"2014","journal-title":"Pharm. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4247","DOI":"10.1016\/j.actbio.2014.06.018","article-title":"Mechanistic studies for monodisperse exenatide-loaded PLGA microspheres prepared by different methods based on SPG membrane emulsification","volume":"10","author":"Qi","year":"2014","journal-title":"Acta Biomater."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1007\/s13233-014-2147-1","article-title":"\u03b2-cyclodextrin-bearing glycol chitosan for long-acting formulation of an exenatide derivative","volume":"22","author":"Jang","year":"2014","journal-title":"Macromol. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1007\/s11095-014-1298-2","article-title":"Acylation of exenatide by glycolic acid and its anti-diabetic activities in db\/db mice","volume":"31","author":"Liang","year":"2014","journal-title":"Pharm. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3109\/10717544.2013.871760","article-title":"Pharmacokinetics, in vitro and in vivo correlation, and efficacy of exenatide microspheres in diabetic rats","volume":"22","author":"Li","year":"2015","journal-title":"Drug Deliv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.3109\/03639045.2015.1107090","article-title":"In vitro and in vivo sustained release of exenatide from vesicular phospholipid gels for type II diabetes","volume":"42","author":"Zhang","year":"2016","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1248\/bpb.b15-00442","article-title":"An investigation into the gastrointestinal stability of exenatide in the presence of pure enzymes, everted intestinal rings and intestinal homogenates","volume":"39","author":"Sun","year":"2016","journal-title":"Biol. Pharm. Bull."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"37452","DOI":"10.1039\/C6RA02994A","article-title":"Exenatide loaded PLGA microspheres for long-acting antidiabetic therapy: Preparation, characterization, pharmacokinetics and pharmacodynamics","volume":"6","author":"Wang","year":"2016","journal-title":"RSC Adv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.jddst.2018.03.024","article-title":"Effect of size on the in vitro\/in vivo drug release and degradation of exenatide-loaded PLGA microspheres","volume":"45","author":"Lin","year":"2018","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2857","DOI":"10.1021\/acs.molpharmaceut.8b00344","article-title":"Long-acting release microspheres containing novel GLP-1 analog as an antidiabetic system","volume":"15","author":"Ruan","year":"2018","journal-title":"Mol. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Dong, N., Zhu, C., Jiang, J., Huang, D., Li, X., Quan, G., Liu, Y., Tan, W., Pan, X., and Wu, C. (2019). Development of composite PLGA microspheres containing exenatide-encapsulated lecithin nanoparticles for sustained drug release. Asian J. Pharm. Sci.","DOI":"10.1016\/j.ajps.2019.01.002"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1080\/15216549800204032","article-title":"The role of proline in the prevention of aggregation during protein folding in vitro","volume":"46","author":"Kumat","year":"1998","journal-title":"IUBMB Life"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0168-3659(98)00148-5","article-title":"Stabilization of proteins against methylene chloride\/water interface-induced denaturation and aggregation","volume":"58","author":"Sah","year":"1999","journal-title":"J. Control. Release"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.ejpb.2010.03.005","article-title":"Effect of various additives and polymers on lysozyme release from PLGA microspheres prepared by an s\/o\/w emulsion technique","volume":"75","author":"Tran","year":"2010","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4351","DOI":"10.1016\/j.biomaterials.2004.11.017","article-title":"Lysozyme and bovine serum albumin adsorption on uncoated silica and AlOOH-coated silica particles: The influence of positively and negatively charged oxide surface coatings","volume":"26","author":"Rezwan","year":"2005","journal-title":"Biomaterials"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.colsurfb.2014.07.025","article-title":"Surface modification of HSA containing magnetic PLGA nanoparticles by poloxamer to decrease plasma protein adsorption","volume":"122","author":"Shubhra","year":"2014","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2174\/156720107780362339","article-title":"Recent advances in protein and peptide drug delivery systems","volume":"4","author":"Baboota","year":"2007","journal-title":"Curr. Drug Deliv."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/S0006-3495(85)83932-1","article-title":"The stabilization of proteins by osmolytes","volume":"47","author":"Arakawa","year":"1985","journal-title":"Biophys. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1177\/0091270004274432","article-title":"Pharmacokinetics of an oral drug (acetaminophen) administered at various times in relation to subcutaneous injection of exenatide (exendin-4) in healthy subjects","volume":"45","author":"Blase","year":"2005","journal-title":"J. Clin. Pharmacol."},{"key":"ref_40","unstructured":"Steiner, S.S. (2008). Amylin Formulations. (Number WO2008124522A2), Patent."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1023\/A:1015354028908","article-title":"Lysozyme stability in primary emulsion for PLGA microsphere preparation: Effect of recovery methods and stabilizing excipients","volume":"19","author":"Kang","year":"2002","journal-title":"Pharm. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0168-3659(03)00074-9","article-title":"Stabilization of \u03b1-chymotrypsin at the CH2Cl2\/water interface and upon water-in-oil-in-water encapsulation in PLGA microspheres","volume":"89","author":"Montano","year":"2003","journal-title":"J. Control. Release"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/71875","article-title":"Protein stability in controlled-release systems","volume":"18","author":"Fu","year":"2000","journal-title":"Nat. Biotechnol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/j.addr.2011.06.015","article-title":"Molecular origins of surfactant-mediated stabilization of protein drugs","volume":"63","author":"Lee","year":"2011","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1021\/js9900654","article-title":"Protein behavior at the water\/methylene chloride interface","volume":"88","author":"Sah","year":"1999","journal-title":"J. Pharm. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0168-3659(00)00277-7","article-title":"The effect of a water\/organic solvent interface on the structural stability of lysozyme","volume":"68","author":"Hoechstetter","year":"2000","journal-title":"J. Control. Release"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1023\/A:1016063109373","article-title":"Stable formulations of recombinant human growth hormone and interferon-\u03b3 for microencapsulation in biodegradable mircospheres","volume":"13","author":"Cleland","year":"1996","journal-title":"Pharm. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3916","DOI":"10.1021\/bi00435a044","article-title":"An infrared spectroscopic study of the interactions of carbohydrates with dried proteins","volume":"28","author":"Carpenter","year":"1989","journal-title":"Biochemistry"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1016\/j.addr.2011.06.011","article-title":"Interactions of formulation excipients with proteins in solution and in the dried state","volume":"63","author":"Ohtake","year":"2011","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.jmb.2006.08.066","article-title":"Using Evolutionary Information and Ancestral Sequences to Understand the Sequence\u2013Function Relationship in GLP-1 Agonists","volume":"363","author":"Skovgaard","year":"2006","journal-title":"J. Mol. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1023\/A:1016278902839","article-title":"Adsorption of Salmon Calcitonin to PLGA Microspheres","volume":"12","author":"Calis","year":"1995","journal-title":"Pharm. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cis.2010.12.007","article-title":"Understanding protein adsorption phenomena at solid surfaces","volume":"162","author":"Rabe","year":"2011","journal-title":"Adv. Colloid Interface Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"11205","DOI":"10.1073\/pnas.1000346107","article-title":"Polymer particles that switch shape in response to a stimulus","volume":"107","author":"Yoo","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4723","DOI":"10.1039\/C5TB00515A","article-title":"Positive charge of \u201csticky\u201d peptides and proteins impedes release from negatively charged PLGA matrices","volume":"3","author":"Balmert","year":"2015","journal-title":"J. Mater. Chem. B Mater. Biol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.3390\/polym3031377","article-title":"Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier","volume":"3","author":"Makadia","year":"2011","journal-title":"Polymers"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.jconrel.2012.04.022","article-title":"Minimizing acylation of peptides in PLGA microspheres","volume":"162","author":"Zhang","year":"2012","journal-title":"J. Control. Release"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.jconrel.2009.03.006","article-title":"A new class of inhibitors of peptide sorption and acylation in PLGA","volume":"137","author":"Sophocleous","year":"2009","journal-title":"J. Control. Release"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1023\/A:1007582911958","article-title":"Visual Evidence of Acidic Environment Within Degrading Poly(lactic-co-glycolic acid) (PLGA) Microspheres","volume":"17","author":"Fu","year":"2000","journal-title":"Pharm. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/0003-2697(89)90136-X","article-title":"Isoelectric points of proteins: Theoretical determination","volume":"179","author":"Sillero","year":"1989","journal-title":"Anal. Biochem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.jconrel.2006.11.023","article-title":"Effect of excipients on PLGA film degradation and the stability of an incorporated peptide","volume":"117","author":"Houchin","year":"2007","journal-title":"J. Control. Release"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0168-3659(02)00414-5","article-title":"Feeding liquid, non-ionic surfactant and cyclodextrin affect the properties of insulin-loaded poly(lactide-co-glycolide) microspheres prepared by spray-drying","volume":"86","author":"Quaglia","year":"2003","journal-title":"J. Control. Release"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S0939-6411(97)00056-8","article-title":"Development and characterization of protein-loaded poly(lactide-co-glycolide) nanospheres","volume":"43","author":"Blanco","year":"1997","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S0939-6411(98)00011-3","article-title":"Protein encapsulation and release from poly(lactide-co-glycolide) microspheres: Effect of the protein and polymer properties and of the co-encapsulation of surfactants","volume":"45","author":"Blanco","year":"1998","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/S0168-3659(00)00315-1","article-title":"Influence of the co-encapsulation of different non-ionic surfactants on the properties of PLGA insulin-loaded microspheres","volume":"69","author":"Rosa","year":"2000","journal-title":"J. Control. Release"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1023\/A:1018822002353","article-title":"pH and Osmotic Pressure Inside Biodegradable Microspheres during Erosion","volume":"16","author":"Brunner","year":"1999","journal-title":"Pharm. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1007\/s11095-006-0180-2","article-title":"The Influence of Surfactant on PLGA Microsphere Glass Transition and Water Sorption: Remodeling the Surface Morphology to Attenuate the Burst Release","volume":"23","author":"Bouissou","year":"2006","journal-title":"Pharm. Res."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/12\/627\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:37:04Z","timestamp":1760189824000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/11\/12\/627"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,24]]},"references-count":66,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["pharmaceutics11120627"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics11120627","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,24]]}}}