Colon delivery of 5 – Fluoro uracil using cross-linked chitosan microspheres coated with eudragit S 100
Keywords:
5-FU, colon-targeting, chitosan, microspheres, Eudragit S-100Abstract
5-Fluorouracil though recommended as a chemotherapeutic agent for colorectal cancer, suffers from severe systemic toxicity and so needs site-specific delivery. Objective of present investigation is to design slow release enteric coated solid formulations to avoid drug release in stomach and upper small intestine but slowly to build up required drug concentration in the colon. Chitosan microspheres were prepared by emulsification method using gluteraldehyde as cross linking agent. The microspheres were then coated with Eudragit S – 100 by emulsion solvent evaporation method. The coated microspheres were characterized for particle size, entrapment efficiency and surface characteristics. In-vitro drug release profile was studied by changing pH media as per USP protocol and the data was subjected to kinetic interpretations. The optimized microspheres showed particle size in the range of 62 to 65 μm with 65 ± 2% drug entrapment. Eudragit coated chitosan microspheres showed particle size increase upto 390 ± 2 μm with nearly spherical shape and smooth surface. In vitro drug release profile of uncoated microspheres was typical like conventional dosage forms with 38 %, 62 % and 88 % drug release at the end of 2 hrs, 6 hrs and 10 hrs respectively. Coated microspheres showed no drug release in SGF (2hrs), negligible release (8 %) in 6hrs but substantial release of 95% in 24 hours in simulated colon media. Drug distribution in GI following oral administration of coated microspheres in wistar rats showed 84% of the drug accumulation in colon.
References
Diasio RB, Harris BE. Clinical
Pharmacology of 5 – fluorouracil. Clin
Pharmacokinet 1989;16:215–237.
Meissner Y, Lamprecht A. Alternative drug
delivery approaches for the therapy of
inflammatory bowel disease. J Pharm Sci
;97(8):2878-2891.
Jain SK, Jain A, Gupta Y, Ahirwar M.
Design and Development of Hydrogel
Beads for Targeted Drug Delivery to the
Colon. AAPS Pharm Sci Tech
;8(3):Article 56.
Friend DR. Colon specific drug delivery,
Adv Drug Del Rev 1991;7(1):149-199.
Makhlof A, Tozuka YT. pH-Sensitive
nanospheres for colon-specific drug
delivery in experimentally induced colitis
rat model. Eur J Pharmaceut Biopharm
;72(1):1-8.
Controlled drug delivery. In: Bruck SD,
editor. Vol. 2. CRC Press; 1982;p. 190.
Uekama M, Horikawa T, Yamanaka M,
Hiramaya F. Peracylated b-cyclodextrins as
novel sustained release carries for a water
soluble drug, molsidomine. J Pharm
Pharmacol 1994;46:714-717.
Patel HK, Nagle A, Murthy R.
Characterization of calcium alginate beads
of 5-fluorouracil for colon delivery. Asian J
Pharm 2008;2:241-5.
Mooter GVD, Samyn C, Kinget R. In vivo
evaluation of a colon – specific drug
delivery system: An absorption study of
Theophylline from capsules coated with
Azo polymers in Rats. Pharm Res
;12(2):244 – 47.
Thanoo BC, Sunny MC, Jayakrishnan A.
Cross-linked chitosan microspheres:
preparation and evaluation as a matrix for
the controlled release of pharmaceuticals. J
Pharm Pharmacol 1992;44:283-286.
Gohel MC, Amin AF, Studies in the
preparation of diclofenac sodium
microspheres by emulsion solvent
evaporation technique by response surface
analysis. Ind J Pharm Sci 1999;61(1):48-53.
Paharia A, Yadav AK, Rai G, Jain SK,
Pancholi SS, Agrawal GP. Eudragit-coated
Pectin Microspheres of 5-Fluorouracil for
Colon Targeting. AAPS Pharm Sci Tech
;8(1):E1:E7:Article 12.
Adel NM, Shirazi FH, Cripps CM, Shereeni
V, Molepo MJ, Obrocea M, Diedre R,
Bates S, Fry D, Stewart DJ, Goel R. An
HPLC method for the measurement of 5-
fluorouracil in human plasma with a low
detection limit and a high extraction yield.
Int J Mol Med 2002;10(4):513-6.
Wan NWS, Endud CS, Mayamar R. Effect
of crosslinking agents on chitosan
microspheres in controlled release of
diclofenac sodium. Reac Func Polymers
;50:181-190.
Gonçalves VL, Laranjeira MCM, Fávere
VT, Pedrosa RC. Effect of crosslinking
agents on chitosan microspheres in
controlled release of diclofenac sodium.
Polímeros: Ciência e Tecnologia
;15(1):6-12.