Journal of Materials Science

, Volume 53, Issue 8, pp 5942–5957 | Cite as

Unveiling the slow release behavior of hollow particles with prolonged antibacterial activity

  • Agni Kumar Biswal
  • Mohd. Usmani
  • Shaikh Ziauddin Ahammad
  • Sampa Saha


The aim of this work was to fabricate polylactide-based hollow microspheres to act as slow-release antimicrobial carriers with prolonged antibacterial activity for controlled release applications and also to sharpen our understanding behind its slow release. Hollow particles were fabricated via water/oil/water (w/o/w) double-emulsion method by using hot water to accelerate solvent evaporation rate in order to make hollow core whereas non-hollow (solid) microspheres were formed via simple oil/water (o/w) emulsion method. Interestingly, in vitro release of hydrophilic antibacterial from solid microspheres (hydrophobic) were extremely slow due to strong association between antibacterial and polymer (polylactide) matrix via H-bonding, investigated by Raman microscopy and DSC study. The release rate increases significantly (> 4 times) in the case of hollow particles. The release kinetics study revealed that both hollow and solid particles predominantly followed diffusion-controlled process rather than a degradation pathway. These hollow microspheres demonstrate great promise as antibacterial agents against both gram-negative and gram-positive bacteria over a period of 30 days at 37 °C. The antibacterial effect of these particles was also evaluated on a food model (watermelon juice) and a significant reduction in bacterial growth was observed especially in the case of hollow microparticles. Hence, PLA-based hollow microspheres can be proposed as slow-release antimicrobial carriers for drug delivery or active packaging applications due to its ease of preparation and simplicity.


Compliance with ethical standards

Conflict of interest

Authors have no conflict of interest to declare.

Supplementary material

10853_2018_1991_MOESM1_ESM.docx (2 mb)
Supplementary material 1 (DOCX 2066 kb)


  1. 1.
    Kannan A, Hettiarachchy N, Johnson MG, Nannapaneni R (2008) Human colon and liver cancer cell proliferation inhibition by peptide hydrolysates derived from heat-stabilized defatted rice bran. J Agric Food Chem 56:11643–11647CrossRefGoogle Scholar
  2. 2.
    Economic Research Service (ERS)/USDA (2009) Economic Research Service, Washington DC. Accessed 10 Dec 2009
  3. 3.
    Nychas GJE (1995) Natural antimicrobials from animals. In: Gould GW (ed) New methods of food preservation. Springer, Boston, pp 58–83CrossRefGoogle Scholar
  4. 4.
    Heinonen M (2007) Antioxidant activity and antimicrobial effect of berry phenolics a Finnish perspective. Mol Nutr Food Res 51:684–691CrossRefGoogle Scholar
  5. 5.
    Sivarooban T, Hettiarachchy NS, Johnson MG (2008) Transmission electron microscopy study of Listeria monocytogenes treated with nisin in combination with either grape seed or green tea extract. J Food Prot 71:2105–2109CrossRefGoogle Scholar
  6. 6.
    Sivarooban T, Hettiarachchy NS, Johnson MG (2008) Physical and antimicrobial properties of grape seed extract, nisin, and EDTA incorporated soy protein edible films. Food Res Int 41:781–785CrossRefGoogle Scholar
  7. 7.
    Devlieghere F, Vermeulen A, Debevere J (2004) Chitosan: antimicrobial activity, interactions with food components and applicability as a coating on fruit and vegetables. Food Microbiol 21:703–714CrossRefGoogle Scholar
  8. 8.
    Baranauskienė R, Bylaitė E, Žukauskaitė J, Venskutonis RP (2007) Flavor retention of peppermint (Mentha piperita L.) essential oil spray-dried in modified starches during encapsulation and storage. J Agric Food Chem 55:3027–3036CrossRefGoogle Scholar
  9. 9.
    PeñaB Panisello C, Aresté G, Garcia-Valls R, Gumí T (2012) Preparation and characterization of polysulfone microcapsules for perfume release. Chem Eng J 179:394–403CrossRefGoogle Scholar
  10. 10.
    Gumí T, Gascón S, Torras C, Garcia-Valls R (2009) Vanillin release from macrocapsules. Desalination 245:769–775CrossRefGoogle Scholar
  11. 11.
    Romero-Cano MS, Vincent B (2002) Controlled release of 4-nitroanisole from poly(lactic acid) nanoparticles. J Control Release 82:127–135CrossRefGoogle Scholar
  12. 12.
    Heya T, Mikura Y, Nagai A, Miura Y, Futo T, Tomida Y, Shimizu H, Toguchi H (1994) Controlled release of thyrotropin releasing hormone from microspheres: evaluation of release profiles and pharmacokinetics after subcutaneous administration. J Pharm Sci 83:798–801CrossRefGoogle Scholar
  13. 13.
    Lancranjan I, Bruns C, Grass P, Jaquet P, Jervell J, Kendall-Taylor P, Lamberts SWJ, Marbach P, Ørskov H, Pagani G, Sheppard M, Simionescu L (1995) New development in the treatment and diagnosis of AcromegalySandostatin LAR®: pharmacokinetics, pharmaco-dynamics, efficacy, and tolerability in acromegalic patients. Metabolism 44:18–26CrossRefGoogle Scholar
  14. 14.
    Huang YY, Chung TW, Tzeng TW (1997) Drug release from PLA/PEG microparticulates. Int J Pharm 156:9–15CrossRefGoogle Scholar
  15. 15.
    U.S.F.D.A. (Food and Drug Administration of the United States) (1973, updated on 2017) GRAS substances (SCOGS). Report No 7. http://www.fda.goc/Food/IngredientsPackagingLabeling/GRAS/SCOGS/default.htm
  16. 16.
    Long MC, Nagegowda DA, Kaminaga Y, Ho KK, Kish CM, Schnepp J, Sherman D, Weiner H, Rhodes D, Dudareva N (2009) Involvement of snapdragon benzaldehyde dehydrogenase in benzoic acid biosynthesis. Plant J 59:256–265CrossRefGoogle Scholar
  17. 17.
    SCCNFP (Scientific Committee on Cosmetic Products an Non-food Products. Cosmetic Ingredients) (2011) Amended final safety assessment: benzyl alcohal, and benzoic acid and its salts and benzyl ester. European Commission, Brussels, pp 1–38Google Scholar
  18. 18.
    del Olmo A, Calzada J, Nunez M (2017) Benzoic acid and its derivatives as naturally occurring compounds in foods and as additives: uses, exposure, and controversy. Crit Rev Food Sci Nutr 57(14):3084–3103CrossRefGoogle Scholar
  19. 19.
    Campbell HE, Escudier MP, Patel P, Challacombe SJ, Sanderson JD, Lomer MCE (2011) Review article: cinnamon- and benzo-ate-free diet as a primary treatment for orofacial granulomatosis. Aliment Pharmacol Ther 34:687–701CrossRefGoogle Scholar
  20. 20.
    Lammarino M, Taranto AD, PalermoC Muscarella M (2011) Survey of benzoic acid in cheeses: contribution to the estimation of an admissible maximum limit. Food Addit Contam B4:231–237CrossRefGoogle Scholar
  21. 21.
    McCann D, Barrett A, Cooper A, Crumpler D, Dalen L, Grimshaw K, Kitchen E, Lok K, Porteous L, Prince E, Sonuga-Barke E, Warner JO, Stevenson J (2007) Food additives and hyperactive behavior in 3-year-old and 8/9-year-old children in the community: a randomized, double-blinded, placebo-controlled trial. Lancet 370:1560–1567CrossRefGoogle Scholar
  22. 22.
    Ravichandran M, Hettiarachchy NS, Ganesh V, Ricke SC, Singh S (2011) Enhancement of antimicrobial activities of naturally occuring phenolic compounds by nanoscale delivery against Listeria monocytogenes, Escherichia coli O157:h7 and Salmonella typhimurium in broth and chicken meat system. J Food Saf 31:462–471CrossRefGoogle Scholar
  23. 23.
    Sivarooban T, Hettiarachchy NS, Johnson MG (2008) Physical and antimicrobial properties of grape seed extract, nisin, and EDTA incorporated soy protein edible films. Food Res Int 41:781–785CrossRefGoogle Scholar
  24. 24.
    O’Donnell PB, McGinity JW (1997) Preparation of microspheres by the solvent evaporation technique. Adv Drug Deliv Rev 28:25–42CrossRefGoogle Scholar
  25. 25.
    Bodmeier R, McGinity JW (1987) The preparation and evaluation of drug-containing poly(dl-lactide) microspheres formed by the solvent evaporation method. Pharm Res 4(6):465–471CrossRefGoogle Scholar
  26. 26.
    Freitas S, Merkle HP, Gander B (2005) Microencapsulation by solvent extraction/evaporation: reviewing the state of the art of microsphere preparation process technology. J Control Release 102:313–332CrossRefGoogle Scholar
  27. 27.
    Archana R, Yoshikata N, Yutaka N, Toru M, Kumar DS (2014) Hollow polymeric (PLGA) nano capsules synthesized using solvent emulsion evaporation method for enhanced drug encapsulation and release efficiency. Mater Res Express 1:045407CrossRefGoogle Scholar
  28. 28.
    Hiraku T, Yukako K, Kenji Y, Daisuke K, Kentaro N, Yoshiaki W (2012) Fabrication of polylactic acid (PLA) microcapsules and release of the internal hydrophilic substance under ultrasound irradiation. In: IOP conference series: materials science engineering, vol 42, p 012012Google Scholar
  29. 29.
    Li Y, Liu L, Shi Y, Xiang F, Huang T, Wang Y, Zhou Z (2011) Morphology, rheological, crystallization behavior, and mechanical properties of poly(l-lactide)/ethylene-co-vinyl acetate blends with different VA contents. J Appl Polym Sci 121:2688–2698CrossRefGoogle Scholar
  30. 30.
    Guthery BE (2012) Nasal, wound and skin formulations and methods for control of antibiotic-resistant staphylococci and other gram-positive bacteria. EP2477619A2Google Scholar
  31. 31.
    Balouiri M, Sadiki M, Ibnsouda SK (2016) Methods for in vitro evaluating antimicrobial activity: a review. J Pharm Anal 6:71–79CrossRefGoogle Scholar
  32. 32.
    Tahir Ansari F, Saquib Hasnain M, Niyaz Hoda M, Nayak AK (2012) Microencapsulation of pharmaceuticals by solvent evaporation technique: a review. Elixir Pharm 47:8821–8827Google Scholar
  33. 33.
    NampoothiriMK Nair NR, John RP (2010) An overview of the recent developments in polylactide (PLA) research. Bioresour Technol 101:8493–8501CrossRefGoogle Scholar
  34. 34.
    Kharel S, Lee WL, Lee XY, Loo SCJ (2017) Osmogen-mediated one-step technique of fabricating hollow microparticles for encapsulation and delivery of bioactive molecules. Macromol Biosci 17:1600328CrossRefGoogle Scholar
  35. 35.
    Lee WL, WeeP Nugraha C, Loo SCJ (2013) Gastric-floating microcapsules provide controlled and sustained release of multiple cardiovascular drugs. J Mater Chem B 1(8):1090–1095CrossRefGoogle Scholar
  36. 36.
    Lee WL, Tan JWM, Tan CN, Loo SCJ (2014) Modulating drug release from gastric-floating microcapsules through spray-coating layers. PLoS ONE 9(12):e114284CrossRefGoogle Scholar
  37. 37.
    Yagnesh DAS, Bhatt A (2011) Effect of processing variables in formulation and development of biodegradable microparticles. Int J Pharm Pharm Sci 3(suppl 4):234–239Google Scholar
  38. 38.
    Dowding PJ, Atkin R, Vincent B, Bouillot P (2004) Oil core–polymer shell microcapsules prepared by internal phase separation from emulsion droplets. I. Characterization and release rates for microcapsules with polystyrene shells. Langmuir 20(26):11374–11379CrossRefGoogle Scholar
  39. 39.
    Yan H, Nishino M, Tsuboi Y, Kitamura N, Tsujii K (2005) Template-guided synthesis and individual characterization of poly(N-isopropylacrylamide)-based microgels. Langmuir 21:7076–7079CrossRefGoogle Scholar
  40. 40.
    Pagannone M, Fornari B, Mattei G (1987) Molecular structure and orientation of chemisorbed aromatic carboxylic acids: surface enhanced Raman spectrum of benzoic acid adsorbed on silver sol. Spectrochim Acta Mol Spectrosc 43:621–625CrossRefGoogle Scholar
  41. 41.
    Frederick BG, Ashton MR, Richardson NV, Jones TS (1993) Orientation and bonding of benzoic acid, phthalic anhydride and pyromellitic dianhydride on Cu(110). Surf Sci 292:33–46CrossRefGoogle Scholar
  42. 42.
    Kwon YJ, Son DH, Ahn SJ, Kim MS, Kim K (1994) Vibrational spectroscopic investigation of benzoic acid adsorbed on silver. J Phys Chem 98:8481–8487CrossRefGoogle Scholar
  43. 43.
    Gao J, Hu Y, Li S, Zhang Y, Chen X (2013) Adsorption of benzoic acid, phthalic acid on gold substrates studied by surface-enhanced Raman scattering spectroscopy and density functional theory calculations. Spectrochim Acta Mol Biomol Spectrosc 104:41–47CrossRefGoogle Scholar
  44. 44.
    Surnar B, Jayakannan M (2013) Stimuli-responsive poly(caprolactone) vesicles for dual drug delivery under the gastrointestinal tract. Biomacromolecules 14:4377–4387CrossRefGoogle Scholar
  45. 45.
    Siepmann J, Peppas NA (2001) Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev 48:139–157CrossRefGoogle Scholar
  46. 46.
    Yang YQ, Guo XD, Lin WJ, Zhang LJ, Zhang CY, Qian Y (2012) Amphiphilic copolymer brush with random pH-sensitive/hydrophobic structure: synthesis and self-assembled micelles for sustained drug delivery. Soft Matter 8:454–464CrossRefGoogle Scholar
  47. 47.
    Sanson C, Schatz C, Le Meins JF, Soum A, Thévenot J, Garanger E, Lecommandoux S (2010) A simple method to achieve high doxorubicin loading in biodegradable polymersomes. J Control Release 147:428–435CrossRefGoogle Scholar
  48. 48.
    Houga C, Giermanska J, Lecommandoux S, Borsali R, TatonD Gnanou Y, Le Meins JF (2009) Micelles and polymersomes obtained by self-assembly of dextran and polystyrene based block copolymers. Biomacromolecules 10:32–40CrossRefGoogle Scholar
  49. 49.
    Matsudo T, Ogawa K, Kokufuta E (2003) Intramolecular complex formation of poly(N-isopropylacrylamide) with human serum albumin. Biomacromolecules 4:728–735CrossRefGoogle Scholar
  50. 50.
    Makadia HK, Siegel SJ (2011) Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers 3:1377–1397CrossRefGoogle Scholar
  51. 51.
    Liu H, Finn N, Yates MZ (2005) Encapsulation and sustained release of a model drug, indomethacin, using CO2-based microencapsulation. Langmuir 21:379–385CrossRefGoogle Scholar
  52. 52.
    Burke J (1984) Solubility parameters: theory and application. The American Institute for Conservation, Washington, vol 3Google Scholar
  53. 53.
    Roy S, Riga AT, Alexander KS (2002) Experimental design aids the development of a differential scanning calorimetry standard test procedure for pharmaceuticals. Thermochim Acta 392:399–404CrossRefGoogle Scholar
  54. 54.
    Mistry P, Mohapatra S, Gopinath T, Vogt FG, Suryanarayanan R (2015) Role of the strength of drug-polymer interactions on the molecular mobility and crystallization inhibition in ketoconazole solid dispersions. Mol Pharm 12:3339–3350CrossRefGoogle Scholar
  55. 55.
    Dong Y, Feng SS (2007) In vitro and in vivo evaluation of methoxy polyethylene glycol-polylactide (MPEG-PLA) nanoparticles for small-molecule drug chemotherapy. Biomaterials 28:4154–4160CrossRefGoogle Scholar
  56. 56.
    Singla RK, Maiti SN, Ghosh AK (2016) Fabrication of super tough poly(lactic acid)/ethylene-co-vinyl-acetate blends via a melt recirculation approach: static-short term mechanical and morphological interpretation. RSC Adv 6:14580–114588CrossRefGoogle Scholar
  57. 57.
    Lin Y, Zhang KY, Dong ZM, Dong LS, Li YS (2007) Study of hydrogen-bonded blend of polylactide with biodegradable hyperbranched poly(ester amide). Macromolecules 40:6257–6267CrossRefGoogle Scholar
  58. 58.
    Fischer EW, Sterzel HJ, Wegner G (1973) Investigation of the structure of solution grown crystals of lactide copolymers by means of chemical reactions. Kolloid Z Z Polym 251:980–990CrossRefGoogle Scholar
  59. 59.
    Homklin R, Hongsriphan N (2013) Mechanical and thermal properties of PLA/PBA co-continuous blends adding nucleating agent. Energy Proc 3:871–879CrossRefGoogle Scholar
  60. 60.
    Jiang L, Wolcott MP, Zhang J (2006) Study of biodegradable polylactide/poly(butylene adipate-co-terephthalate) blends. Biomacromolecules 7:199–207CrossRefGoogle Scholar
  61. 61.
    Liu D, Li H, Zhou G, Yuan M, Qin Y (2015) Biodegradable poly(lactic-acid)/poly(trimethylenecarbonate)/laponite composite film: development and application to the packaging of mushrooms (Agaricus bisporus). Polym Adv Technol 26:1600–1607CrossRefGoogle Scholar
  62. 62.
    Fehri S, Cinelli P, Coltelli MB, Anguillesi I, Lazzeri A (2016) Thermal properties of plasticized poly (lactic acid) (PLA) containing nucleating agent. Int J Chem Eng Appl 7(2):85–88Google Scholar
  63. 63.
    Chadha R, Kapoor V, Kumar A (2006) Analytical techniques used to characterize drug-polyvinylpyrrolidone systems in solid and liquid states—an overview. J Sci Ind Res 65:459Google Scholar
  64. 64.
    Coughlan DC, Corrigan IO (2006) Drug–polymer interactions and their effect on thermoresponsive poly(N-isopropylacrylamide) drug delivery systems. Int J Pharm 313:163–174CrossRefGoogle Scholar
  65. 65.
    Jorgensen JH, Ferraro MJ (2009) Antimicrobial susceptibility testing: a review of generalprinciples and contemporary practices. Clin Infect Dis 49:1749–1755CrossRefGoogle Scholar
  66. 66.
    Manoharan A, Pai R, Shankar V, Thomas K, Lalitha MK (2003) Comparison of disc diffusion and E test methods with agar dilution for antimicrobial susceptibility testing of Haemophilus influenzaeIndian. J Med Res 117:81–87Google Scholar
  67. 67.
    Ambaye A, Kohner PC, Wollan PC, Roberts KL, Glenn D, Roberts GD, Cockerill FR (1997) Comparison of agar dilution, broth microdilution, disk diffusion, e-test, and bactec radiometric methods for antimicrobial susceptibility testing of clinical isolates of the nocardia asteroides complex. J Clin Microbiol 35:847–852Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Centre for Polymer Science and EngineeringIndian Institute of TechnologyDelhiIndia
  2. 2.Department of Biochemical Engineering and BiotechnologyIndian Institute of TechnologyDelhiIndia

Personalised recommendations