In SITU Gelling System as a Vaccine Carrier

Authors(4) :-Chandra HS, Basant Malik, Goutam Rath, Amit K. Goyal

The delivery of protein and peptides remain challenging task for the researchers in order to maintain integrity and stability of such molecules. Therefore, during formulation development phase it passes through various stress and loss their integrity due to configuration change. Thus, the quality of vaccine adjuvant plays a major role in addition to some other factors. Therefore, the adjuvant of formulation must satisfy compatibility issues apart from degree of immune stimulation. In this paper we are describing aluminum salt as adjuvant which is widely used in commercial available vaccine formulations. Despite immunomodulatory activity it has a lot of drawbacks viz. it is attractive but weak adjuvants, induces IgE production, allergenicity and neurotoxicity. In children it also causes azotemia and severe osteomalacia intoxication devoid of renal dialysis but it is only used in parenteral, and not for mucosal vaccination. In situ gelling system is most widely studied carrier system having characteristic of depot formation by different principle same as aluminum salt. The depot system is reported by various scientists for vaccine delivery and suggesting that it is good carrier for such types of sensitive material. In situ gelling system having various advantages viz. ease of administration and reduced frequency of administration, comfort and improved patient compliance. The material used for in situ gelling also provides lot of reward like biodegradable in nature, formulation stability, and particle size uniformity, sustained, prolonged and controlled release from depot, and biocompatibility characteristics. Those drugs which are sensitive to pH and enzymatic degradations it maintained potency of the drug and provides high interaction with tissues and biological fluids. Therefore, main advantage of it is that we can achieve mucosal as well as systemic immune response by administering antigen via. mucosal and non-mucosal sites. Thus, the use of in situ gel as vaccine adjuvant could be prevents infectious disease associated with pathogens.

Authors and Affiliations

Chandra HS
Panacea Biotec Limited, Vaccine Formulation Plant, Baddi, Himachal Pradesh, India
Basant Malik
Panacea Biotec Limited, Lalru, Punjab, India
Goutam Rath
Nanomedicine Research Centre, Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, India
Amit K. Goyal
Nanomedicine Research Centre, Department of Pharmaceutics, ISF College of Pharmacy, Moga, Punjab, India

In-situ Gel, Depot System, Vaccine Adjuvant, Depot Forming Polymers

  1. Abdi, S. I. H., J. Y. Choi, et al. (2012). "In Vivo study of a blended hydrogel composed of pluronic F-127-alginate-hyaluronic acid for its cell injection application." Tissue Engineering and Regenerative Medicine 9(1): 1-9.
  2. Abraham, S., S. Furtado, et al. (2009). "Sustained ophthalmic delivery of ofloxacin from an ion-activated in situ gelling system." Pakistan journal of pharmaceutical sciences 22(2).
  3. Agrawal, A., P. Gupta, et al. (2010). "Development and characterization of in situ gel system for nasal insulin delivery." Die Pharmazie-An International Journal of Pharmaceutical Sciences 65(3): 188-193.
  4. Aguilar, M., C. Elvira, et al. (2007). "Smart polymers and their applications as biomaterials." Topics in tissue engineering 3: 1-27.
  5. Anderson, D. P. (1997). "Adjuvants and immunostimulants for enhancing vaccine potency in fish." Dev Biol Stand 90: 257-265.
  6. Asasutjarit, R., S. Thanasanchokpibull, et al. (2011). "Optimization and evaluation of thermoresponsive diclofenac sodium ophthalmic in situ gels." Int J Pharm 411(1-2): 128-135.
  7. Audibert, F. M. and L. D. Lise (1993). "Adjuvants: current status, clinical perspectives and future prospects." Trends Pharmacol Sci 14(5): 174-178.
  8. Bernkop-Schnürch, A. and M. E. Krajicek (1998). "Mucoadhesive polymers as platforms for peroral peptide delivery and absorption: synthesis and evaluation of different chitosan–EDTA conjugates." Journal of controlled release 50(1): 215-223.
  9. Bertram, U., M. C. Bernard, et al. (2010). "In situ gelling nasal inserts for influenza vaccine delivery." Drug Dev Ind Pharm 36(5): 581-593.
  10. Besson, V., B. M. Yapo, et al. (2014). "Macromolecular and Viscoelastic Properties of Low Methoxy Pectin from Cashew Apple Pomace."
  11. Bilensoy, E., M. A. Rouf, et al. (2006). "Mucoadhesive, thermosensitive, prolonged-release vaginal gel for clotrimazole: β-cyclodextrin complex." AAPS PharmSciTech 7(2): E54-E60.
  12. Brewer, J. M., M. Conacher, et al. (1996). "In interleukin-4-deficient mice, alum not only generates T helper 1 responses equivalent to freund's complete adjuvant, but continues to induce T helper 2 cytokine production." Eur J Immunol 26(9): 2062-2066.
  13. Cao, S.-l., X.-w. Ren, et al. (2009). "In situ gel based on gellan gum as new carrier for nasal administration of mometasone furoate." International journal of pharmaceutics 365(1): 109-115.
  14. Cao, S.-l., Q.-z. Zhang, et al. (2007). "Preparation of ion-activated in situ gel systems of scopolamine hydrobromide and evaluation of its antimotion sickness efficacy." Acta Pharmacologica Sinica 28(4).
  15. Cao, Y., C. Zhang, et al. (2007). "Poly (< i> N</i>-isopropylacrylamide)–chitosan as thermosensitive in situ gel-forming system for ocular drug delivery." Journal of controlled release 120(3): 186-194.
  16. Carmen Chifiriuc, M., A. Mihai Grumezescu, et al. (2014). "Biomedical Applications of Natural Polymers for Drug Delivery." Current Organic Chemistry 18(2): 152-164.
  17. Cavalier, D. M., O. Lerouxel, et al. (2008). "Disrupting two Arabidopsis thaliana xylosyltransferase genes results in plants deficient in xyloglucan, a major primary cell wall component." The Plant Cell Online 20(6): 1519-1537.
  18. Chen, G., S. X. Hou, et al. (2006). "[In vivo distribution and pharmacokinetics of dexamethasone sodium phosphate thermosensitive in situ gel following intratympanic injection]." Sichuan Da Xue Xue Bao Yi Xue Ban 37(3): 456-459.
  19. Davis, N. E., S. Ding, et al. (2010). "Modular enzymatically crosslinked protein polymer hydrogels for in situ gelation." Biomaterials 31(28): 7288-7297.
  20. Dulay, M. T., H. N. Choi, et al. (2007). "Visible light?induced photopolymerization of an in situ macroporous sol–gel monolith." Journal of separation science 30(17): 2979-2985.
  21. Feldmann, B., D. Farber, et al. (1992). "[Aluminum poisoning caused by the phosphate binder in a non-dialysed child with chronic renal insufficiency]." Radiologe 32(7): 327-332.
  22. Gong, C., S. Shi, et al. (2009). "Biodegradable in situ gel-forming controlled drug delivery system based on thermosensitive PCL–PEG–PCL hydrogel. Part 2: Sol–gel–sol transition and drug delivery behavior." Acta biomaterialia 5(9): 3358-3370.
  23. Gordon, S., K. Young, et al. (2012). "Chitosan hydrogels containing liposomes and cubosomes as particulate sustained release vaccine delivery systems." Journal of liposome research 22(3): 193-204.
  24. Goto, N., H. Kato, et al. (1997). "Local tissue irritating effects and adjuvant activities of calcium phosphate and aluminium hydroxide with different physical properties." Vaccine 15(12-13): 1364-1371.
  25. Gupta, H. and A. Sharma (2011). "Ion activated bioadhesive in situ gel of clindamycin for vaginal application." International journal of drug Delivery 1(1).
  26. Gupta, H., R. M. Singh, et al. (2008). "pH-Induced In Situ Gel for Periodontal Anesthesia." Indian J Pharm Sci 70(6): 776-778.
  27. Gupta, R. K. (1998). "Aluminum compounds as vaccine adjuvants." Advanced Drug Delivery Reviews 32(3): 155-172.
  28. Gupta, S. and S. P. Vyas (2010). "Carbopol/chitosan based pH triggered in situ gelling system for ocular delivery of timolol maleate." Sci Pharm 78(4): 959-976.
  29. Haile, Y., K. Haastert, et al. (2007). "Culturing of glial and neuronal cells on polysialic acid." Biomaterials 28(6): 1163-1173.
  30. Harish, N. M., P. Prabhu, et al. (2009). "Formulation and Evaluation of in situ Gels Containing Clotrimazole for Oral Candidiasis." Indian J Pharm Sci 71(4): 421-427.
  31. Haynes, R. J., P. J. Tighe, et al. (1999). "Antimicrobial defensin peptides of the human ocular surface." Br J Ophthalmol 83(6): 737-741.
  32. Hoffman, A. S. (2013). "Stimuli-responsive polymers: Biomedical applications and challenges for clinical translation." Advanced Drug Delivery Reviews 65(1): 10-16.
  33. Itoh, K., R. Tsuruya, et al. (2010). "In situ gelling xyloglucan/alginate liquid formulation for oral sustained drug delivery to dysphagic patients." Drug Dev Ind Pharm 36(4): 449-455.
  34. Iyer, S., R. Robinett, et al. (2004). "Mechanism of adsorption of hepatitis B surface antigen by aluminum hydroxide adjuvant." Vaccine 22(11): 1475-1479.
  35. Jeong, B., Y. H. Bae, et al. (2000). "Drug release from biodegradable injectable thermosensitive hydrogel of PEG–PLGA–PEG triblock copolymers." Journal of controlled release 63(1): 155-163.
  36. Jeong, B., S. W. Kim, et al. (2002). "Thermosensitive sol–gel reversible hydrogels." Advanced Drug Delivery Reviews 54(1): 37-51.
  37. Khodaverdi, E., A. Golmohammadian, et al. (2012). "Biodegradable in situ gel-forming controlled drug delivery system based on thermosensitive poly (-caprolactone)-poly (ethylene glycol)-poly (-caprolactone) hydrogel." ISRN pharmaceutics 2012.
  38. Kubo, W., K. Itoh, et al. (2005). "Oral sustained delivery of theophylline and cimetidine from in situ gelling pectin formulations in rabbits." Drug Dev Ind Pharm 31(8): 819-825.
  39. Kubo, W., Y. Konno, et al. (2004). "In situ gelling pectin formulations for oral sustained delivery of paracetamol." Drug Dev Ind Pharm 30(6): 593-599.
  40. Kumar, D. and P. Kapoor (2014). "An Insight to In-Situ Gel Forming Stomach Specific Drug Delivery System." PharmaTutor 2(2): 25-32.
  41. Kushwaha, S. K., P. Saxena, et al. (2012). "Stimuli sensitive hydrogels for ophthalmic drug delivery: A review." Int J Pharm Investig 2(2): 54-60.
  42. Le Bourlais, C., L. Treupel-Acar, et al. (1995). "New ophthalmic drug delivery systems." Drug development and industrial pharmacy 21(1): 19-59.
  43. Leroux-Roels, G. (2010). "Unmet needs in modern vaccinology: adjuvants to improve the immune response." Vaccine 28 Suppl 3: C25-36.
  44. Li, H., S. B. Willingham, et al. (2008). "Cutting edge: inflammasome activation by alum and alum's adjuvant effect are mediated by NLRP3." J Immunol 181(1): 17-21.
  45. Li, X. Y., Z. J. Zhu, et al. (2008). "[Characteristics of poloxamer thermosensitive in situ gel of dexamethasone sodium phosphate]." Yao Xue Xue Bao 43(2): 208-213.
  46. Liang, H., C. Baudouin, et al. (2009). "Comparison of the ocular tolerability of a latanoprost cationic emulsion versus conventional formulations of prostaglandins: an in vivo toxicity assay." Mol Vis 15: 1690-1699.
  47. Lin, C., P. Zhao, et al. (2010). "Thermosensitive in situ-forming dextran–pluronic hydrogels through Michael addition." Materials Science and Engineering: C 30(8): 1236-1244.
  48. Little, S. S. R. (2005). Poly ([beta]-amino ester) s as pH sensitive biomaterials for microparticulate genetic vaccine delivery, Massachusetts Institute of Technology.
  49. Liu, Z., J. Li, et al. (2006). "Study of an alginate/HPMC-based in situ gelling ophthalmic delivery system for gatifloxacin." International journal of pharmaceutics 315(1): 12-17.
  50. Lo, Y. L., C. Y. Hsu, et al. (2013). "pH-and thermo-sensitive pluronic/poly(acrylic acid) in situ hydrogels for sustained release of an anticancer drug." J Drug Target 21(1): 54-66.
  51. Ma, W. D., H. Xu, et al. (2008). "Temperature-responsive, Pluronic-g-poly(acrylic acid) copolymers in situ gels for ophthalmic drug delivery: rheology, in vitro drug release, and in vivo resident property." Drug Dev Ind Pharm 34(3): 258-266.
  52. Madan, M., A. Bajaj, et al. (2009). "In situ forming polymeric drug delivery systems." Indian J Pharm Sci 71(3): 242-251.
  53. Mahoney, M. J. and K. S. Anseth (2006). "Three-dimensional growth and function of neural tissue in degradable polyethylene glycol hydrogels." Biomaterials 27(10): 2265-2274.
  54. Marrack, P., A. S. McKee, et al. (2009). "Towards an understanding of the adjuvant action of aluminium." Nat Rev Immunol 9(4): 287-293.
  55. Masson, C., M. Garinot, et al. (2004). "pH-sensitive PEG lipids containing orthoester linkers: new potential tools for nonviral gene delivery." Journal of controlled release 99(3): 423-434.
  56. Matia-Merino, L., K. Lau, et al. (2004). "Effects of low-methoxyl amidated pectin and ionic calcium on rheology and microstructure of acid-induced sodium caseinate gels." Food Hydrocolloids 18(2): 271-281.
  57. Mengesha, A. E., R. J. Wydra, et al. (2013). "Binary Blend of Glyceryl Monooleate and Glyceryl Monostearate for Magnetically Induced Thermo-Responsive Local Drug Delivery System." Pharmaceutical research 30(12): 3214-3224.
  58. Miyazaki, S., K. Endo, et al. (2003). "Oral sustained delivery of paracetamol from in situ gelling xyloglucan formulations." Drug Dev Ind Pharm 29(2): 113-119.
  59. Miyazaki, S., H. Murofushi, et al. (2013). "The influence of the degree of esterification on the release characteristics of in situ gelling pectin formulations for oral sustained delivery of paracetamol." Pharm Dev Technol 18(5): 1259-1264.
  60. Miyazaki, S., S. Suzuki, et al. (2001). "In situ gelling xyloglucan formulations for sustained release ocular delivery of pilocarpine hydrochloride." Int J Pharm 229(1-2): 29-36.
  61. Mottu, F., P. Gailloud, et al. (2000). "In vitro assessment of new embolic liquids prepared from preformed polymers and water-miscible solvents for aneurysm treatment." Biomaterials 21(8): 803-811.
  62. Moura, M. J., H. Faneca, et al. (2011). "In situ forming chitosan hydrogels prepared via ionic/covalent co-cross-linking." Biomacromolecules 12(9): 3275-3284.
  63. Nanjwade, B. K., A. Manjappa, et al. (2009). "A novel pH-triggered in situ gel for sustained ophthalmic delivery of ketorolac tromethamine." Asian J Pharm Sci 4(3): 189-199.
  64. Ni, Y., D. Turner, et al. (2004). "Isolation and characterization of structural components of< i> Aloe vera</i> L. leaf pulp." International Immunopharmacology 4(14): 1745-1755.
  65. Owens, D. E., Y. Jian, et al. (2007). "Thermally responsive swelling properties of polyacrylamide/poly (acrylic acid) interpenetrating polymer network nanoparticles." Macromolecules 40(20): 7306-7310.
  66. Patel, R., B. Dadhani, et al. (2011). "Formulation, evaluation and optimization of stomach specific in situ gel of clarithromycin and metronidazole benzoate." International journal of drug Delivery 2(2).
  67. Patel, R. B., M. A. Chauhan, et al. (2012). "Floating In Situ Gel: New Trends in Controlled and Sustained Gastroretentive Drug Delivery System." Research Journal of Pharmacy and Technology 5(7): 889-893.
  68. Petrovsky, N. and J. C. Aguilar (2004). "Vaccine adjuvants: current state and future trends." Immunol Cell Biol 82(5): 488-496.
  69. Priya James, H., R. John, et al. (2014). "Smart polymers for the controlled delivery of drugs–a concise overview." Acta Pharmaceutica Sinica B.
  70. Qiu, Y. and K. Park (2001). "Environment-sensitive hydrogels for drug delivery." Advanced Drug Delivery Reviews 53(3): 321-339.
  71. Rajas, N. J., T. Gounder, et al. (2011). "In situ opthalmic gels: a developing trend." International Journal of Pharmaceutical Sciences Review & Research 7(1).
  72. Rinaudo, M. (2006). "Chitin and chitosan: properties and applications." Progress in polymer science 31(7): 603-632.
  73. Rojas, R., S. Nishidomi, et al. (2013). "Glutamate transport and xanthan gum production in the plant pathogen Xanthomonas axonopodis pv. citri." World Journal of Microbiology and Biotechnology 29(11): 2173-2180.
  74. Rozier, A., C. Mazuel, et al. (1989). "Gelrite< sup>®</sup>: A novel, ion-activated, in-situ gelling polymer for ophthalmic vehicles. Effect on bioavailability of timolol." International journal of pharmaceutics 57(2): 163-168.
  75. Sahoo, S., R. Sahoo, et al. (2010). "Mucoadhesive nanopolymer-A novel drug carrier for topical ocular drug delivery." Eur J Sci Res 46: 401-409.
  76. Sargeant, T. D., A. P. Desai, et al. (2012). "An in situ forming collagen-PEG hydrogel for tissue regeneration." Acta Biomater 8(1): 124-132.
  77. Schirmbeck, R., K. Melber, et al. (1994). "Antibody and cytotoxic T-cell responses to soluble hepatitis B virus (HBV) S antigen in mice: implication for the pathogenesis of HBV-induced hepatitis." J Virol 68(3): 1418-1425.
  78. Shanbhag, P. P. and P. P. Pandhare "In situ gelling polymeric drug delivery system."
  79. Shaw, C. A., Y. Li, et al. (2013). "Administration of aluminium to neonatal mice in vaccine-relevant amounts is associated with adverse long term neurological outcomes." J Inorg Biochem 128: 237-244.
  80. Singh, V., S. S. Bushetti, et al. (2010). "Stimuli-sensitive hydrogels: a novel ophthalmic drug delivery system." Indian J Ophthalmol 58(6): 477-481.
  81. Tan, H., J. P. Rubin, et al. (2010). "Injectable in situ forming biodegradable chitosan-hyaluronic acid based hydrogels for adipose tissue regeneration." Organogenesis 6(3): 173-180.
  82. Tiwari, S., A. K. Goyal, et al. (2009). "Liposome in situ gelling system: Novel carrier based vaccine adjuvant for intranasal delivery of recombinant protein vaccine." Procedia in Vaccinology 1(1): 148-163.
  83. Tobin, J. M., D. Cooper, et al. (1984). "Uptake of metal ions by Rhizopus arrhizus biomass." Applied and Environmental Microbiology 47(4): 821-824.
  84. Traquina, P., M. Morandi, et al. (1996). "MF59 adjuvant enhances the antibody response to recombinant hepatitis B surface antigen vaccine in primates." J Infect Dis 174(6): 1168-1175.
  85. Ulanova, M., A. Tarkowski, et al. (2001). "The Common vaccine adjuvant aluminum hydroxide up-regulates accessory properties of human monocytes via an interleukin-4-dependent mechanism." Infect Immun 69(2): 1151-1159.
  86. Ulmer, J. B., C. M. DeWitt, et al. (1999). "Enhancement of DNA vaccine potency using conventional aluminum adjuvants." Vaccine 18(1-2): 18-28.
  87. Ur-Rehman, T., S. Tavelin, et al. (2011). "Chitosan in situ gelation for improved drug loading and retention in poloxamer 407 gels." Int J Pharm 409(1-2): 19-29.
  88. VENKATESH, M., P. KAMLESH L, et al. (2013). "DEVELOPMENT AND EVALUATION OF CHITOSAN BASED THERMOSENSITIVE IN SITU GELS OF PILOCARPINE." International Journal of Pharmacy & Pharmaceutical Sciences 5(1).
  89. Wang, W., L. Deng, et al. (2012). "Adjustable degradation and drug release of a thermosensitive hydrogel based on a pendant cyclic ether modified poly (ε-caprolactone) and poly (ethylene glycol) co-polymer." Acta biomaterialia 8(11): 3963-3973.
  90. Watarai, S., T. Iwase, et al. (2013). "Efficiency of pH-Sensitive Fusogenic Polymer-Modified Liposomes as a Vaccine Carrier." The Scientific World Journal 2013.s
  91. Winther?Jensen, O., V. Armel, et al. (2010). "In situ photopolymerization of a gel ionic liquid electrolyte in the presence of iodine and its use in dye sensitized solar cells." Macromolecular rapid communications 31(5): 479-483.
  92. Wu, H., Z. Liu, et al. (2011). "Design and evaluation of baicalin-containing in situ pH-triggered gelling system for sustained ophthalmic drug delivery." International journal of pharmaceutics 410(1): 31-40.

Publication Details

Published in : Volume 2 | Issue 4 | July-August 2016
Date of Publication : 2016-08-30
License:  This work is licensed under a Creative Commons Attribution 4.0 International License.
Page(s) : 801-814
Manuscript Number : IJSRSET1624177
Publisher : Technoscience Academy

Print ISSN : 2395-1990, Online ISSN : 2394-4099

Cite This Article :

Chandra HS, Basant Malik, Goutam Rath, Amit K. Goyal, " In SITU Gelling System as a Vaccine Carrier, International Journal of Scientific Research in Science, Engineering and Technology(IJSRSET), Print ISSN : 2395-1990, Online ISSN : 2394-4099, Volume 2, Issue 4, pp.801-814, July-August-2016.
Journal URL :

Article Preview