ABSTRACT The paper describes the synthesis of pH sensitive interpenetrating polymeric network (IPN) beads composed of chi-tosan, glycine, glutamic acid, cross linked with glutaraldehyde and their use for controlled drug release. The drug was loaded into beads by varying their composition such as, amount of crosslinker glutaraldehyde, ratio of chitosan, glycine and glutamic acid. The beads were characterized by fourier transform infrared (FTIR) spectroscopy to confirm the cross linking reaction and drug interaction with crosslinked polymer in beads, Scanning Electron Microscopy (SEM) to understand the surface morphology and Differential scanning calorimetry (DSC) to find out the thermal stability of beads. X-Ray Diffraction (XRD) investigation was carried out to determine the crystalline nature of drug after loading into chitosan-glycine-glutamic acid IPN beads. Results indicated amorphous dispersion of chlorpheniramine maleate (CPM) in the polymeric matrix. The swelling behavior of the beads at different time intervals was monitored in solutions of pH 2.0 and pH 7.4. The release experiments were performed in solutions of pH 2.0 and pH 7.4 at 37oC using chlorpheniramine maleate (CPM) as a model drug. The swelling behavior and release of drug were observed to be dependent on pH, degree of cross linking and their composition. The results indicate that the cross linked IPN beads of chitosan-glycine-glutamic acid might be useful as a vehicle for controlled release of drug. The kinetics of drug release from beads was best fitted by Higuchi’s model in which release rate is largely governed by rate of diffusion through the matrix.
Cite this paper
nullM. Rani, A. Agarwal and Y. Negi, "Characterization and Biodegradation Studies for Interpenetrating Polymeric Network (IPN) of Chitosan-Amino Acid Beads," Journal of Biomaterials and Nanobiotechnology, Vol. 2 No. 1, 2011, pp. 71-84. doi: 10.4236/jbnb.2011.21010.
 J. Jagur-Grodzinski, “Biomedical Application of Functional Polymers,” Reactive Functional Polymers, Vol. 39, 1999, pp. 99-138.
K. E. Uhrich, S. M. Cannizzaro, R. S. Langer and K. M. Shakesheff, “Polymeric Systems for Controlled Drug Release,” Chemical Reviews, Vol. 99, No. 11, 1999, pp. 3181-3198. doi:10.1021/cr940351u
V. Kumar and S. H. Kothari, “Effect of Compressional Force on the Crystallinity of Directly Compressible Cellulose Excipients,” International Journal of Pharmaceutics, Vol. 177, No. 2, 1999, pp. 173-182.
M. George and T. E. Abraham, “Polyionic Hydrocolloids for the Intestinal Delivery of Protein Drugs, Alginate and Chitosan — A Review,” Journal of Controlled Release, Vol. 114, No. 1, 2006, pp. 1-14.
Q. Gan, T. Wang, C. Cochrane and P. McCarron, “Modulation of Surface Charge Particle Size and Morphological Properties of Chitosan — TPP Nanoparticles Intended for Gene Delivery,” Colloids and Surfaces B: Biointerfaces, Vol. 44, No. 2-3, 2005, pp. 65-73.
P. He, S. S. Davis and L. Illum, “In vitro Evaluation of the Mucoadhesive Properties of Chitosan Microspheres,” International Journal of Pharmaceutics, Vol. 166, No. 1, 1998, pp. 75-88. doi:10.1016/S0378-5173(98)00027-1
A. B. Schnurch, C. Humenberger, C. Valenta, “Basic Studies on Bioadhesive Delivery Systems for Peptide and Protein Drugs,” International Journal of Pharmaceutics, Vol. 165, No. 2, 1998, pp. 217-225.
M. Yalpani, F. Johnson, L. E. Robinson, “Chitin, Chitosan: Sources, Chemistry, Biochemistry, Physical Properties and Applications,” Elsevier, Amsterdam, 1992.
H. Tseng, K. Furhata and M. Sakamoto, “Bromination of Regenerated Chitin with N-Bromosuccinimide and Triphenylphosphine under Homogeneous Conditions in Lithium Bromide-N,N-Dimethylacetamide,” Carbohydrate Research, Vol. 270, No. 2, 1995, pp. 149-161.
W. M. Hou, S. Miyazaki, M. Takada and T. Komai, “Sustained Release of Indomethacin from Chitosan Granules,” Chemical & Pharmaceutical Bulletin, Vol. 33, No. 9, 1985, pp. 3986-3992.
S. Miyazaki, K. Ishii and T. Nadai, “The Use of Chitin and Chitosan as Drug Carriers,” Chemical & Pharmaceutical Bulletin, Vol. 29, No. 10, 1981, pp. 3067-3069.
L. Illum, “Chitosan and Its Use as Pharmaceutical Excipient,” Pharmaceutical Research, Vol. 15, No. 9, 1998, pp. 1326-1331. doi:10.1023/A:1011929016601
T. Chandy and C. P. Sharma, “Chitosan — As a Biomaterial," Biomaterials, Artificial Cells and Artificial Organs, Vol. 18, No. 1, 1990, pp. 1-24.
T. Chandy and C. P. Sharma, “Biodegradable Chitosan Matrix for the Controlled Release of Steroids,” Biomaterials, Artificial Cells and Immobilization Biotechnology, Vol. 19, No. 4, 1991, pp. 745-760.
N. B. Graham, “Controlled Drug Delivery Systems,” Chemical Industries, Vol. 15, 1990, pp. 482-486.
T. Chandy and C. P. Sharma, “Chitosan Beads and Granules for Oral Sustained Delivery of Nifedipine: In vitro studies,” Biomaterials, Vol. 13, No. 13, 1992, pp. 949-952.
K. C. Gupta and M. N. V. Ravi Kumar, “Drug Release Behavior of Beads and Microgranules of Chitosan,” Biomaterials, Vol. 21, No. 11, 2000, pp. 1115-1119.
F. L. Mi, H. W. Sung and S. S. Shyu, “Drug Release from Chitosan – Alginate Complex Beads Reinforced by a Naturally Occurring Crosslinking Agent,” Carbohydrate Polymers, Vol. 48, No. 1, 2002, pp. 61-72.
M. V. D. Lubben, F. A. C. Van Opdorp, M. R. Hengeveld, J. J. M. Onderwater, H. K. Koerten, J. C. Verhoef, G. Borchard and H. E. Junginger, “Transport of Chitosan Microparticles for Mucosal Vaccine Delivery in a Human Intestinal M-Cell Model,” Journal of Drug Target, Vol. 10, No. 6, 2002, pp. 449-456.
M. Amidi, S. G. Romeijn, J. C. Verhoef, H. E. Junginger, L. Bungener, A. Huckriede, D. J. A. Crommelin and W. Jiskoot, “N-Trimethyl Chitosan (TMC) Nanoparticles Loaded with Influenza Subunit Antigen for Intranasl VacCination: Biological Properties and Immunogenicity in a Mouse Model,” Vaccine, Vol. 25, No. 1, 2007, pp. 144-153.
S. Danielsen, K. M. Varum and B. T. Stokke, “Structural Analysis of Chitosan Medicated DNA Condensation by AFM: Influence of Chitosan Molecular Parameters,” Biomacromolecules, Vol. 5, No. 3, 2004, pp. 928-936.
S. Mansouri, P. Lavigne, K. Corsi, M. Benderdour, E. Beaumont, et al. “Chitosan–DNA Nanoparticles as Non Viral Vectors in Gene Therapy: Strategies to Improve Transfection Efficacy,” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 57, No. 1, 2004, pp. 1-8.
K. Wong, G. Sun, X. Zhang, H. Dai, Y. Liu, C. He, et al. “PEI-g-Chitosan, a Novel Gene Delivery System with Transfection Efficiency Comparable to Polyethyleneimine in Vitro and after Liver Administration in Vivo,” Bioconjugate Chemistry, Vol. 17, No. 1, 2006, pp. 152-158.
N. Iwasaki, S. T. Yamane, T. Majima, Y. Kasahara, A. Minami, K. Harada, et al. “Feasibility of Polysaccharide Hybrid Materials for Scaffolds in Cartilage Tissue Engineering: Evaluation of Chondrocyte Adhesion to Polyion Complex Fibres Prepared from Alginate and Chitosan,” Biomacromolecules, Vol. 5, No. 3, 2004, pp. 828-833.
A. P. Zhu, Z. Ming and S. Jian, “Blood Compatibility of Chitosan/Heparin Complex Surface Modified ePTFE Vascular Graft,” Applied Surface Science, Vol. 241, No. 3-4, 2005, pp. 485-492. doi:10.1016/j.apsusc.2004.07.055
D. A. Zaharoff, C. J. Rogers, K. W. Hance, J. Schlom and J. W. Greiner, “Chitosan Solution Enhances Both Humoral and Cell-Medicated Immune Responses to Subcutaneous Vaccination,” Vaccine, Vol. 25, No. 11, 2007, pp. 2085-2094. doi:10.1016/j.vaccine.2006.11.034
J. Berger, M. Reist, J. M. Mayer, O. Felt and R. Gurny, “Structure and Interactions in Chitosan Hydrogels Formed by Complexation or Aggregations for Biomedical Applications,” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 57, No. 1, 2004, pp. 35-52.
J. Berger, M. Reist, J. M. Mayer, O. Felt, N. A. Peppas and R. Gurny, “Structure and Interactions in Covalently and Ionically Crosslinked Chitosan Hydrogels for Biomedical Applications,” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 57, No. 1, 2004, pp. 19-34.
M. N. V. Ravi kumar, “A Review of Chitin and Chitosan Applications,” Reactive and Functional Polymers, Vol. 46, No. 1, 2000, pp. 1-27.
J. Kost and R. Langer, “(…)” In: N. A. Peppas, Ed., Hydrogels in Medicines and Pharmacy, CRC Press, Boca Raton, 1987, p. 95.
K. D. Yao, T. Peng, H. B. Feng, Y. Y. He, “Swelling Kinetics and Release Characteristics of Crosslinked Chitosan-Polyether Polymer Network (semi IPN) Hydrogels,” Journal of Polymer Science Part A: Polymer Chemistry, Vol. 32, No. 7, 1994, pp. 1213-1223.
I. F. Amaral, M. Lamghari, S. R. Sousa, P. Sampaio and M. A. Barbosa, “Rat Bone Marrow Stromal Cell Osteogenic Differentiation and Fibronecetin Adsorption on Chitosan Membranes: The Effect of Degree of Acetylation,” Journal of Biomedical Materials Research, Vol. 75A, No. 2, 2005, pp. 387-397. doi:10.1002/jbm.a.30436
I. F. Amaral, P. Sampaio and M. A. Barbosa, “Three-Dimensional Culture of Human Osteoblastic Cells in Chitosan Sponges: The Effect of the Degree of Acetylation,” Journal of Biomedical Materials Research, Vol. 76A, No. 2, 2005, pp. 335-346.
T. Jung, W. Kamm, A. Breitenbach, E. Kaiserling, J. X. Xiao and T. Kissel, “Biodegradable Nanoparticles for Oral Delivery of Peptides: Is There a Role for Polymers to affect Mucosal Uptake?” European Journal of Pharmaceutics and Biopharmaceutics, Vol. 50, No. 1, 2000, pp. 147-160. doi:10.1016/S0939-6411(00)00084-9
M. K. S. Batista, L. F. Pinto, C. A. L. Gomes and P. Gomes, “Novel Highly-Soluble Peptide – Chitosan Polymer: Chemical Synthesis and Spectral Characterization,” Carbohydrate polymers, Vol. 64, No. 2, 2006, pp. 299-305.
P. Gomes, C. A. R. Gomes, M. K. S. Batista, L. F. Pinto and P. A. P. Silva, “Synthesis, Structural Characterization and Properties N-(Propanoyl-amino acid )-Chitosan,” Carbohydrate Polymers, Vol. 71, No. 1, 2008, pp. 54-65.
M. Rani, A. Agarwal, T. Maharana and Y. S. Negi, “A Comparative Study for Interpenetrating Polymeric Network (IPN) of Chitosan-amino Acid Beads for Controlled Drug Release,” African Journal of Pharmacy and Pharmacology, Vol. 4, No. 2, 2010, pp. 35-54.
S. A. Agnihotri, N. N. mallikarjuna and T. M. Aminabhavi, “Review on Recent Advances on Chitosan Based Micro and Nanoparticles in Drug Delivery,” Journal of Controlled Release, Vol. 100, No. 1, 2004, pp. 5-28.
E. Laszlo, L. Vlase and S. E. Leucuta, “Kinetic Modeling of Drug Release from Experimental Pharmaceutical Gels Containing Clotrimazole,” Farmacia, Vol. 54, No. 3, 2006, pp. 25-32.
T. Higuchi, “Mechanism of Sustained Action Medication,” Journal of Pharmaceutical Sciences, Vol. 52, No. 12, 1963, pp. 1145-1149.
K. Kumari and P. P. Kundu, “Studies on in Vitro Release of CPM from Semi-Interpenetrating Polymer Network (IPN) Composed of Chitosan and Glutamic Acid,” Bulletin of Materials Science, Vol. 31, No. 2, 2008, pp. 159-167. doi:10.1007/s12034-008-0028-y
K. Kumari and P. P. Kundu, “Semiinterpenetrating Polymer Networks (IPN) of Chitosan and L-Alanine for Monitoring the Release of Chlorpheniramine Maleate,” Journal of Applied Polymer Science, Vol. 103, No. 6, 2007, pp. 3751-3757. doi:10.1002/app.25432
T. Yoshioka, R. Hirano, T. Shioya and M. Kako, “Encapsulation of Mammalian Cell with Chitosan-CMC capsule,” Biotechnology and Bioengineering, Vol. 35, No. 1, 1990, pp. 66-72. doi:10.1002/bit.260350110
T. Peng, K. D. Yao, C. Yuan and M. F. Goosan, “Structural Changes of PH Sensitive Chitosan/Polyether Hydrogels in Different PH Solution,” Journal of Polymer Science.Part A: Polymer chemistry, Vol. 32, No. 3, 1994, pp. 591-596. doi:10.1002/pola.1994.080320322
T. Sannan, K. Kurita, K. Ogura and Y. Iwakura, “Studies on Chitin: 7. IR Spectroscopic Determination of Degree of Deacetylation,” Polymer, Vol. 19, 1978, pp. 458- 459.
L. J. Bellamy, “The Infrared Spectra of Complex Molecles,” Chapman & Hall, London, New York, 1980.
J. W. Lee, S. Y. Kim, S. G. Kim, Y. M. Lee, K. H. Lee and S. J. Kim, “Synthesis and Characteristics of Interpenetrating Polymer Network Hydrogel Composed of Chitosan and Poly Acrylic Acid,” Journal of Applied Polymer Science, Vol. 73, No. 1, 1999, pp. 113-120.
A. P. Rokhade, N. B. Shelke, S. A. Patil and T. M. Aminabhavi, “Novel Interpenetrating Polymer Network Microspheres of Chitosan and Methylcellulose for Controlled Release of Theophylline,” Carbohydrate polymer, Vol. 69, No. 4, 2007, pp. 678-687.
K. S. V. K. Rao, B. V. K. Naidu, M. C. S. Subha, M. Sairam and T. M. “Aminabhavi, Novel Chitosan-Based Ph–Sensitive Interpenetrating Network Microgels for the Controlled Release of Cefadroxil,” Carbohydrate Polymers, Vol. 66, No. 3, 2006, pp. 333-344.
S. A. Agnihotri and T. M. Aminabhavi, “Novel Interpenetrating Network Chitosan-Poly (Ethylene Oxide-g-Acryl Amide) Hydrogel Microspheres for the Controlled Release of Capecitabine,” International Journal of Pharmaceutics, Vol. 324, No. 2, 2006, pp. 103-115.
V. H. Kulkarni, P. V. Kulkarni and J. Keshavayya, “Glutaraldehyde-crosslinked Chitosan Beads for Controlled Release of Diclofenac Sodium,” Journal of Applied Polymer Science, Vol. 103, No. 1, 2007, pp. 211-217.
S. R. Jameela, T. V. Kumary, A. V. Lal and A. Jayakrishna, “Progesterone Loaded Chitosan Microspheres: A Long Acting Biodegradable Controlled Delivery System,” Journal of Control release, Vol. 52, No. 1-2, 1998, pp. 17-24.
I. Orienti, K. Aiedeh, E. Gianasi, V. Bertasi and V. Zecchi, “Indomethacin Loaded Chitosan Microspheres Correlation between the Erosion Process and Release Kinetics,” Journal of Microencapsulation, Vol. 13, No. 4, 1996, pp. 463-472. doi:10.3109/02652049609026031
A. Ganza-Gonzalez, S. Anguiano-igea, F. J. Otero-Espinar and J. Blanco Mendez, “Chitosan and Chondroitin Microspheres for Oral Administration Controlled Release of Metoclopramide,” European journal of pharmaceutics and Biopharmaceutics, Vol. 48, No. 2, 1999, pp. 149-155.