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AAPS PharmSciTech. 2006 June; 7(2): E113–E121.
Published online 2006 May 26. doi:  10.1208/pt070247
PMCID: PMC2750274

Characterization of 5-fluorouracil microspheres for colonic delivery

Abstract

The purpose of this investigation was to prepare and evaluate the colon-specific microspheres of 5-fluorouracil for the treatment of colon cancer. Core microspheres of alginate were prepared by the modified emulsification method in liquid paraffin and by cross-linking with calcium chloride. The core microspheres were coated with Eudragit S-100 by the solvent evaporation technique to prevent drug release in the stomach and small intestine. The microspheres were characterized by shape, size, surface morphology, size distribution, incorporation efficiency, and in vitro drug release studies. The outer surfaces of the core and coated microspheres, which were spherical in shape, were rough and smooth, respectively. The size of the core microspheres ranged from 22 to 55 μm, and the size of the coated microspheres ranged from 103 to 185 μm. The core microspheres sustained the drug release for 10 hours. The release studies of coated microspheres were performed in a pH progression medium mimicking the conditions of the gastrointestinal tract. Release was sustained for up to 20 hours in formulations with core microspheres to a Eudragit S-100 coat ratio of 1[ratio]7, and there were no changes in the size, shape, drug content, differential scanning calorimetry thermogram, and in vitro drug release after storage at 40°C/75% relative humidity for 6 months.

Keywords: 5-FU, colon-specific, microspheres, alginate, Eudragit S-100, DSC, HPLC

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Heidelberger C, Chaudhuri NK, Danneburg P, et al. Fluorinated pyrimidine. A new class of tumor inhibitory compounds. Nature. 1957;179:663–666. doi: 10.1038/179663a0. [PubMed] [Cross Ref]
2. Langenbach RJ, Dancenberg PV, Heidelberger C. Thymidylate synthetase: mechanism of inhibition of 5-fluorouracil-2-deoxyuridylate. Biochem Biophys Res Commun. 1972;48:1565–1571. doi: 10.1016/0006-291X(72)90892-3. [PubMed] [Cross Ref]
3. Parker WB, Cheng YC. Metabolism and mechanism of action of 5-fluorouracil. Pharmacol Ther. 1990;48:381–395. doi: 10.1016/0163-7258(90)90056-8. [PubMed] [Cross Ref]
4. Hahn RG, Moertel CG, Schutt AJ, Bruckner HW. A double-blind comparison of intensive course 5-fluorouracil by oral vs. intravenous route in the treatment of colorectal carcinoma. Cancer. 1975;35:1031–1035. doi: 10.1002/1097-0142(197504)35:4<1031::AID-CNCR2820350403>3.0.CO;2-N. [PubMed] [Cross Ref]
5. Liu G, Fraussen E, Fitch MI, Warner E. Patient preferences for oral vs intravenous palliative chemotherapy. J Clin Oncol. 1997;15:110–115. [PubMed]
6. Van Cutsem E, Peeters M, Verslype C, Filez L, Haustermans K, Janssens J. The medical treatment of colorectal cancer: actual status and new developments. Hepatogastroenterology. 1999;46:709–716. [PubMed]
7. Labianca RF, Beretta GD, Pessi MA. Disease management consideration. Drugs. 2001;61:1751–1764. doi: 10.2165/00003495-200161120-00006. [PubMed] [Cross Ref]
8. Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet. 1989;16:215–237. doi: 10.2165/00003088-198916040-00002. [PubMed] [Cross Ref]
9. Yang L, Chu JS, Fix JA. Colon-specific drug delivery: new approaches and in vitro/in vivo evaluation. Int J Pharm. 2002;235:1–15. doi: 10.1016/S0378-5173(02)00004-2. [PubMed] [Cross Ref]
10. Shun YL, Ayres JW. Calcium alginate beads as core carriers of 5-aminosalicylic acid. Pharm Res. 1992;9:714–790. [PubMed]
11. Krishnaiah YSR, Satyanarayana V, Kumar DB, Karthikeyan RS, Bhaskar P. In vivo pharmacokinetics in human volunteers: oral administered guar gum-based colon-targeted 5-fluorouracil tablets. Eur J Pharm Sci. 2003;19:355–362. doi: 10.1016/S0928-0987(03)00139-8. [PubMed] [Cross Ref]
12. Madajewicz S, Petrelli N, Rustum YM, et al. Phase I–II trial of high dose calcium leucovorin and 5-fluorouracil in advanced colorectal cancer. Cancer Res. 1984;44:4667–4669. [PubMed]
13. Cortesi E, Aschelter AM, Gioacchini N, et al. Efficiency and toxicity of 5-fluorouracil and folates in advanced colon cancer. J Chemother. 1990;2:47–50. [PubMed]
14. O’Connell MJ, Mailliard JA, Kahn MJ, et al. Controlled trial of fluorouracil and low dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol. 1997;15:246–250. [PubMed]
15. Watts PJ, Barrow L, Steed KP, et al. The transit rate of different-sized model dosage forms through the human colon and effects of a lactulose induced catharsis. Int J Pharm. 1992;87:215–221. doi: 10.1016/0378-5173(92)90245-W. [Cross Ref]
16. Calis S, Arica B, Kas HS, Hincal AA. 5-Fluorouracil-loaded alginate microspheres in chitosan gel for local therapy of breast cancer. In: Muzzarelli RAA, Muzzarelli C, editors. Chitosan in Pharmacy and Chemistry. Grottammare, Italy: Atec; 2002. pp. 65–69.
17. Lorenzo-Lamosa ML, Remunan-Lopez C, Vila-Jato JL, Alonso MJ. Design of microencapsulated chitosan microspheres for colonic drug delivery. J Control Release. 1998;52:109–118. doi: 10.1016/S0168-3659(97)00203-4. [PubMed] [Cross Ref]
18. Martel P, Petit I, Pinguet S, Poujol S, Astre C, Fabbro M. Long term stability of 5-fluorouracil stored in PVC bags and in ambulatory pump reservoirs. J Pharm Biomed Anal. 1996;14:395–399. doi: 10.1016/0731-7085(95)01635-X. [PubMed] [Cross Ref]
19. Matthews BR. Regulatory aspects of stability testing in Europe. Drug Dev Ind Pharm. 1999;25:831–856. doi: 10.1081/DDC-100102245. [PubMed] [Cross Ref]
20. Lin S, Kao Y. Solid particulates of drug-β-cyclodextrin inclusion complexes directly prepared by a spray-drying technique. Int J Pharm. 1989;56:249–259. doi: 10.1016/0378-5173(89)90022-7. [Cross Ref]
21. Lemoine D, Wauters F, Bouchend S, Preat V. Preparation and characterization of alginate microspheres containing model antigen. Int J Pharm. 1998;176:9–19. doi: 10.1016/S0378-5173(98)00303-2. [Cross Ref]
22. Wagner JG. Interpretation of percent dissolved-time plots derived from in-vitro testing of conventional tablets and capsules. J Pharm Sci. 1969;58:1253–1257. doi: 10.1002/jps.2600581021. [PubMed] [Cross Ref]
23. Higuchi T. Mechanism of sustained action medication. J Pharm Sci. 1963;52:1145–1149. doi: 10.1002/jps.2600521210. [PubMed] [Cross Ref]
24. Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983;15:25–35. doi: 10.1016/0378-5173(83)90064-9. [Cross Ref]
25. Dubernet C. Thermo analysis of microspheres. Thermochim Acta. 1995;248:259–269. doi: 10.1016/0040-6031(94)01947-F. [Cross Ref]
26. Mu L, Feng SS. Fabrication characterization and in vitro release of paclitaxel (Taxol) loaded poly (lactic-co-glycolic acid) microspheres prepared by spray drying technique with lipid/cholesterol emulsifiers. J Control Release. 2001;76:239–254. doi: 10.1016/S0168-3659(01)00440-0. [PubMed] [Cross Ref]
27. Costa P, Labo JSMS. Modelling and comparison of dissolution profiles. Eur J Pharm Sci. 2001;13:123–133. doi: 10.1016/S0928-0987(01)00095-1. [PubMed] [Cross Ref]
28. Food and Drug Administration. Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms; 1997. Rockville, MD.

Articles from AAPS PharmSciTech are provided here courtesy of American Association of Pharmaceutical Scientists