Health  Vol.6 No.11 , May 2014
Pharmacokinetic Evaluation of Chitosan-Succinyl-Prednisolone Conjugate Microparticles as a Colonic Delivery System: Comparison with Enteric-Coated Conjugate Microparticles
Abstract: In the previous study, chitosan-succinyl-prednisolone conjugate microparticles (MP) were found to exhibit good efficacy and reduced toxicity nearly as well as their Eudragit L-coated microparticles (MP/EuL). This proposes a question whether enteric-coating of MP is necessary or not. Although MP/EuL were already examined for their pharmacokinetic and gastrointestinal behaviors, MP have not been done yet. Therefore, in this study, MP were evaluated by investigating pharmacokinetic features in detail. MP with the in vitro features equivalent to those of the previous conjugate microparticles could be produced more readily in the modified preparative method. Pharmacokinetic and gastrointestinal behaviors of MP were investigated by intragastric dosing (5 mg PD eq./kg) to rats with 2,4,6-trinitrobenzenesulfonic acid-induced ulcerative colitis. The plasma concentration was suppressed extensively in MP as well as MP/EuL, supporting the reduction of PD systemic toxic side effects. However, the plasma level increased gradually up to 7 h in MP, but not in MP/EuL. At 8 h after dosing, MP were detected in the stomach to a fair extent, and free PD was found there, indicating that MP were subjected to trapping in the stomach probably due to positive charge of chitosan molecules. For MP, such prolonged localization and slow release of PD in the stomach were probably associated with the gradual increase in plasma concentration. Therefore, MP/EuL were evaluated to be superior to MP for effective targeting to ulcerative colitis. It is concluded that enteric-coating is very important for the targeting system using MP.
Cite this paper: Onishi, H. (2014) Pharmacokinetic Evaluation of Chitosan-Succinyl-Prednisolone Conjugate Microparticles as a Colonic Delivery System: Comparison with Enteric-Coated Conjugate Microparticles. Health, 6, 1286-1295. doi: 10.4236/health.2014.611157.

[1]   Karlinger, K., Györke, T., Makö, E., Mester, A. and Tarján, Z. (2000) The Epidemiology and the Pathogenesis of In-flammatory Bowel Disease. European Journal of Radiology, 35, 154-167.

[2]   Fiocchi, C. (2002) Inflammatory Bowel Disease. Current Concepts of Pathogenesis and Implications for Therapy. Minerva Gastroenterologica e Dietologica, 48, 215-226.

[3]   Danese S. and Fiocchi, C. (2006) Etiopathogenesis of Inflammatory Bowel Diseases. World Journal of Gastroenterology, 12, 4807-4812.

[4]   Troskot, B. and Simunic, M. (2013) Side Effects and Contraindications for Biological Therapy in Inflammatory Bowel Disease. Acta Medica Croatica, 67, 131-143.

[5]   Neef, H.C., Riebschleger, M.P. and Adler, J. (2013) Meta-Analysis: Rapid Infliximab Infusions Are Safe. Alimentary Pharmacology and Therapeutics, 38, 365-376.

[6]   Gionchetti, P., Rizzello, F., Habal, F., Morselli, C., Amadini, C., Romagnoli, R. and Campieri, M. (2003) Standard Treatment of Ulcerative Colitis. Digestive Diseases, 21, 157-167.

[7]   Kühbacher, T., Schreiber, S. and Fölsch, U.R. (2004) Ulcerative Colitis: Conservative Management and Long-Term Effects. Langenbeck’s Archives of Surgery, 389, 350-353.

[8]   Tominaga, K., Nakano, M., Hoshino, M., Kanke, K. and Hiraishi, H. (2013) Efficacy, Safety and Cost Analyses in Ulcerative Colitis Patients Undergoing Granulocyte and Monocyte Adsorption or Receiving Prednisolone. BMC Gastroenterology, 13, 41.

[9]   Tanaka, T., Sugiyama, S., Goishi, H., Kajihara, T., Akagi, M. and Miura, T. (2013) Treatment of Children and Adolescents with Ulcerative Colitis by Adsorptive Depletion of Myeloid Lineage Leucocytes as Monotherapy or in Combination with Low Dose Prednisolone after Failure of First-Line Medications. BMC Gastroenterology, 13, 130.

[10]   Nakajima, A., Doki, K., Homma, M., Sagae, T., Saito, R., Ito, S., Sumida, T. and Kohda, Y. (2009) Investigation of Glucocorticoid-Induced Side Effects in Patients with Autoimmune Diseases. Yakugaku Zasshi, 129, 445-450.

[11]   Mazzantini, M., Torre, C., Miccoli, M., Baggiani, A., Talarico, R., Bombardieri, S. and Di Munno, O. (2012) Adverse Events during Longterm Low-Dose Glucocorticoid Treatment of Polymyalgia Rheumatica: A Retrospective Study. Journal of Rheumatology, 39, 552-557.

[12]   Harris, M.S. and Lichtenstein, G.R. (2011) Review Article: Delivery and Efficacy of Topical 5-Aminosalicylic Acid (Mesalazine) Therapy in the Treatment of Ulcerative Colitis. Alimentary Pharmacology and Therapeutics, 33, 996-1009.

[13]   McLeod, A.D., Friend, D.R. and Tozer, T.N. (1994) Glucocorticoid-Dextran Conjugates as Potential Prodrugs for Colon-Specific Delivery: Hydrolysis in Rat Gastrointestinal Tract Contents. Journal of Pharmaceutical Sciences, 83, 1284-1288.

[14]   Wittaya-areekul, S., Kruenate, J. and Prahsarn, C. (2006) Preparation and in Vitro Evaluation of Mucoadhesive Properties of Alginate/Chitosan Microparticles Containing Prednisolone. International Journal of Pharmaceutics, 312, 113-118.

[15]   Tozaki, H., Komoike, J., Tada, C., Maruyama, T., Terabe, A., Suzuki, T., Yamamoto, A. and Muranishi, S. (1997) Chitosan Capsules for Colon-Specific Drug Delivery: Improvement of Insulin Absorption from the Rat Colon. Journal of Pharmaceutical Sciences, 86, 1016-1021.

[16]   Alvarez-Fuentes, J., Fernández-Arévalo, M., González-Rodríguez, M.L., Cirri, M. and Mura, P. (2004) Development of Enteric-Coated Timed-Release Matrix Tablets for Colon Targeting. Journal of Drug Targeting, 12, 607-612.

[17]   Yamamoto, A. (2007) Study on the Colon Specific Delivery of Prednisolone Using Chitosan Capsules. Yakugaku Zasshi, 127, 621-630.

[18]   Kaur, K. and Kim, K. (2009) Studies of Chitosan/Organic Acid/Eudragit RS/RL-Coated System for Colonic Delivery. International Journal of Pharmaceutics, 366, 140-148.

[19]   Lamprecht, A., Ubrich, N., Yamamoto, H., Schäfer, U., Takeuchi, H., Maincent, P., Kawashima, Y. and Lehr, C.M. (2001) Biodegradable Nanoparticles for Targeted Drug Delivery in Treatment of Inflammatory Bowel Disease. Journal of Pharmacology and Experimental Therapeutics, 299, 775-781.

[20]   Yano, H., Hirayama, F., Kamada, M., Arima, H. and Uekama, K. (2002) Colon-Specific Delivery of Prednisolone-Appended Alpha-Cyclodextrin Conjugate: Alleviation of Systemic Side Effect after Oral Administration. Journal of Controlled Release, 79, 103-112.

[21]   Onishi, H., Kikuchi, H. and Machida, Y. (2012) Comparison of Simple Eudragit Microparticles Loaded with Prednisolone and Eudragit-Coated Chitosan-Succinyl-Prednisolone Conjugate Microparticles: Part I. Particle Characteristics and in Vitro Evaluation as a Colonic Delivery System. Drug Development and Industrial Pharmacy, 38, 800-807.

[22]   Lamprecht, A., Schäfer, U. and Lehr, C.M. (2001) Size-Dependent Bioadhesion of Micro- and Nanoparticulate Carriers to the Inflamed Colonic Mucosa. Pharmaceutical Research, 18, 788-793.

[23]   Onishi, H., Oosegi, T., Machida, Y. and McGinity, J.W. (2007) Eudragit Coating of Chitosan-Prednisolone Conjugate Microspheres and in Vitro Evaluation of Coated Microspheres. Drug Development and Industrial Pharmacy, 33, 848-354.

[24]   Oosegi, T., Onishi, H. and Machida, Y. (2008) Novel Preparation of Enteric-Coated Chitosan-Prednisolone Conjugate Microspheres and in Vitro Evaluation of Their Potential as a Colonic Delivery System. European Journal of Pharmaceutics and Biopharmaceutics, 68, 260-266.

[25]   Oosegi, T., Onishi, H. and Machida, Y. (2008) Gastrointestinal Distribution and Absorption Behavior of Eudragit-Coated Chitosan-Prednisolone Conjugate Microspheres in Rats with TNBS-Induced Colitis. International Journal of Pharmaceutics, 348, 80-88.

[26]   Onishi, H., Oosegi, T. and Machida, Y. (2008) Efficacy and Toxicity of Eudragit-Coated Chitosan-Succinyl-Prednisolone Conjugate Microspheres Using Rats with 2,4,6-Trinitrobenzeneesulfonic Acid-Induced Colitis. International Journal of Pharmaceutics, 358, 296-302.

[27]   Onishi, H., Isoda, Y. and Matsuyama, M. (2013) In Vivo Evaluation of Chondroitin Sulfate-Glycyl-Prednisolone for Anti-Arthritic Effectiveness and Pharmacokinetic Characteristics. International Journal of Pharmaceutics, 456, 113-120.

[28]   Yamaoka, K., Tanigawara, Y., Nakagawa, T. and Uno, T. (1981) A Pharmacokinetic Analysis Program (Multi) for Microcomputer. Journal of Pharmacobio-Dynamics, 4, 879-885.