Investigation of in situ gelling alginate formulations as a sustained release vehicle for co-precipitates of dextromethrophan and Eudragit S 100

Open access

Abstract

Alginate vehicles are capable of forming a gel matrix in situ when they come into contact with gastric medium in the presence of calcium ions. However, the gel structure is pH dependent and can break after gastric emptying, leading to dose dumping. The aim of this work was to develop modified in situ gelling alginate formulations capable of sustaining dextromethorphan release throughout the gastrointestinal tract. Alginate solution (2 %, m/m) was used as a vehicle for the tested formulations. Solid matrix of the drug and Eudragit S 100 was prepared by dissolving the drug and polymer in acetone. The organic solvent was then evaporated and the deposited solid matrix was micronized, sieved and dispersed in alginate solution to obtain candidate formulations. The release behavior of dextromethorphan was monitored and evaluated in a medium simulating the gastric and intestinal pH. Drug-polymer compatibility and possible solid-state interactions suggested physical interaction through hydrogen bonding between the drug and the polymer. A significant decrease in the rate and extent of dextromethorphan release was observed with increasing Eudragit S 100 concentration in the prepared particles. Most formulations showed sustained release profiles similar to that of a commercial sustained-release liquid based on ion exchange resin. The release pattern indicated strict control of drug release both under gastric and intestinal conditions, suggesting the potential advantage of using a solid dispersion of drug-Eudragit S 100 to overcome the problem of dose dumping after the rupture of the pH dependent alginate gels

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2. S. Miyazaki, H. Aoyama, N. Kawasaki, W. Kubo and D. Attwood, In situ-gelling gellan formulations as vehicles for oral drug delivery, J. Control. Release 60 (1999) 287-295; DOI: 10.1016/ S0168-3659(99)00084-X.

3. S. Miyazaki, W. Kubo and D. Attwood, Oral sustained delivery of theophylline using in situ gelation of sodium alginate, J. Control. Release 67 (2000) 275-280; DOI: 10.1016/s0168-3659(00) 00214-5.

4. S. Miyazaki, N. Kawasaki, W. Kubo, K. Endo and D. Attwood, Comparison of in situ gelling formulations for the oral delivery of cimetidine, Int. J. Pharm. 220 (2001) 161-168; DOI: 10.1016/ S0378-5173(01)00669-X.

5. W. Kubo, S. Miyazaki and D. Attwood, Oral sustained delivery of paracetamol from in situ- -gelling gellan and sodium alginate formulations, Int. J. Pharm. 258 (2003) 55-64; DOI: 10.1016/ S0378-5173(03)00163-7.

6. D. Schmaljohann, Thermo- and pH-responsive polymers in drug delivery, Adv. Drug Deliv. Rev. 58 (2006) 1655-1670; DOI: 10.1016/j.addr.2006.09.020.

7. T. Coviello, P. Matricardi, C. Marianecci and F. Alhaique, Polysaccharide hydrogels for modified release formulations, J. Control. Release 119 (2007) 5-24; DOI: S0168-3659(07)00039-9 [pii] 10.1016/j.jconrel.2007.01.004.

8. G. Rohith, B. K. Sridhar and A. Srinatha, Floating drug delivery of a locally acting H2-antagonist: an approach using an in situ gelling liquid formulation, Acta Pharm. 59 (2009) 345-354; DOI: 10.2478/v10007-009-0021-z.

9. L. Rodriguez, O. Caputo, M. Cini, C. Cavallari and R. Grecchi, In vitro release of theophylline from directly-compressed matrices containing methacrylic acid copolymers and/or dicalcium phosphate dehydrate, Farmaco 48 (1993) 1597-1604.

10. L. S. da Fonseca, R. P. Silveira, A.M. Deboni, E. V. Benvenutti, T. M. Costa, S. S. Guterres and A. R. Pohlmann, Nanocapsule@xerogel microparticles containing sodium diclofenac: a new strategy to control the release of drugs, Int. J. Pharm. 358 (2008) 292-295; DOI: S0378-5173(08)00118-X [pii] 10.1016/j.ijpharm.2008.02.005.

11. E. F. Reynolds James, Dextromethorphan Hydrobromide, Royal Pharmaceutical Society, London, 1996, p. 1066.

12. J. L. Bem and R. Peck, Dextromethorphan. An overview of safety issues, Drug Safety 7 (1992) 190-199.

13. E. S. Pender and B. R. Parks, Toxicity with dextromethorphan-containing preparations: a literature review and report of two additional cases, Pediatr. Emerg. Care 7 (1991) 163-165.

14. G. M. El Maghraby, Synergistic enhancement of itraconazole dissolution by ternary system formation with pluronic F68 and hydroxypropylmethylcellulose, Sci. Pharm. 77 (2009) 401-417; DOI: 10.3797/scipharm.0901-08.

15. F. K. Alanazi, M. El-Badry and I. A. Alsarra, Spray-dried HPMC microparticles of indomethacin impact of drug-polymer ratio and viscosity of the polymeric solution on dissolution, Saudi Pharm. J. 14 (2006) 100-107.

16. G. M. El Maghraby, E. M. Elzayat and F. K. Alanazi, Development of modified in situ gelling oral liquid sustained release formulation of dextromethorphan, Drug Dev. Ind. Pharm. (2011); DOI: 10.3109/03639045.2011.634811.

17. P. S. Rajinikanth and B. Mishra, Floating in situ gelling system of acetohydroxamic acid for clearance of H. pylori, Drug Dev. Ind. Pharm. 34 (2008) 577-587; DOI: 10.1080/03639040701831819

18. K. A. Khan, The concept of dissolution efficiency, J. Pharm. Pharmacol. 27 (1975) 48-49.

19. M. R. Louhaichi, S. Jebali, M. H. Loueslati, N. Adhoum and L. Monser, Simultaneous determination of pseudoephedrine, pheniramine, guaifenesin, pyrilamine, chlorpheniramine and dextromethorphan in cough and cold medicines by high performance liquid chromatography, Talanta 78 (2009) 991-997; DOI: 10.1016/j.talanta.2009.01.019.

20. F. Alanazi, H. Li, D. S. Halpern, S. Oie and D. R. Lu, Synthesis, preformulation and liposomal formulation of cholesteryl carborane esters with various fatty chains, Int. J. Pharm. 255 (2003) 189-197; DOI: S0378517303000887.

21. M. Malladi, R. Jukanti, R. Nair, S. Wagh, H. S. Padakanti and A. Mateti, Design and evaluation of taste masked dextromethorphan hydrobromide oral disintegrating tablets, Acta Pharm. 60 (2010) 267-280; DOI: 10.2478/v10007-010-0025-8.

22. R. P. Raffin, D. Jornada, S. Haas, A. R. Pohlmann and S. S. Guterres, “Pantoprazole sodium loaded controlled release microparticles,” in 15th International Symposium on Microencapsulation, Parma, ed. (Italy, 2005), pp. 7-8.

23. K. H. Kim, M. J. Frank and N. L. Henderson, Application of differential scanning calorimetry to the study of solid drug dispersions, J. Pharm. Sci. 74 (1985) 283-289.

24. R. J. Fessenden and J. S. Fessenden, Fessenden and Fessenden Organic Chemistry, Brooks/Cole publishing company, Pacific Grove, 1990, pp. 323-390.

25. Technical Information on EUDRAGIT L 100 and EUDRAGIT S 100, http://eudragit.evonik.com/product/eudragit/Documents/evonik-specification-eudragit-l-100-and-s-100.pdf; access date January 10, 2011.

26. M. R. Jenquin and J. W. McGinity, Characterization of acrylic resin matrix films and mechanisms of drug-polymer interaction, Int. J. Pharm. 101 (1994) 23-24.

27. K. O. R. Lehman, Chemistry and Application Properties of Polymethacrylate Coating Systems, Informa Healthcare USA, Inc., New York, 1990, pp. 101-174.

28. B. J. Lee, J. H. Cui, T. W. Kim, M. Y. Heo and C. K. Kim, Biphasic release characteristics of dual drug-loaded alginate beads, Arch. Pharm. Res. 21 (1998) 645-650.

29. T. Higuchi, Rate of release of medicaments from ointment bases containing drugs in suspension, J. Pharm. Sci. 50 (1961) 874-875.

30. G. M. Jantzen and J. R. Robinson, Sustained and Controlled Release Drug Delivery Systems, Marcel Dekker, New York, 1996, pp. 575-610.

31. S. Miyazaki, H. Aoyama, N. Kawasaki, W. Kubo and D. Attwood, In situ-gelling gellan formulations as vehicles for oral drug delivery, J. Control. Release 60 (1999) 287-295; DOI: 10.1016/ S0168-3659(99)00084-X.

32. S. Miyazaki, W. Kubo and D. Attwood, Oral sustained delivery of theophylline using in situ gelation of sodium alginate, J. Control Release 67 (2000) 275-280; DOI: 10.1016/s0168-3659(00)00214-5.

33. S. Miyazaki, N. Kawasaki, W. Kubo, K. Endo and D. Attwood, Comparison of in situ gelling formulations for the oral delivery of cimetidine, Int. J. Pharm. 220 (2001) 161-168; DOI: 10.1016/ S0378-5173(01)00669-X.

34. W. Kubo, S. Miyazaki and D. Attwood, Oral sustained delivery of paracetamol from in situ- -gelling gellan and sodium alginate formulations, Int. J. Pharm. 258 (2003) 55-64; DOI: 10.1016/ S0378-5173(03)00163-7.

35. D. Schmaljohann, Thermo- and pH-responsive polymers in drug delivery, Adv. Drug Deliv. Rev. 58 (2006) 1655-1670; DOI: 10.1016/j.addr.2006.09.020.

36. T. Coviello, P. Matricardi, C. Marianecci and F. Alhaique, Polysaccharide hydrogels for modified release formulations, J. Control. Release 119 (2007) 5-24; DOI: S0168-3659(07)00039-9 [pii] 10.1016/j.jconrel.2007.01.004.

37. G. Rohith, B. K. Sridhar and A. Srinatha, Floating drug delivery of a locally acting H2-antagonist: an approach using an in situ gelling liquid formulation, Acta Pharm. 59 (2009) 345-354; DOI: 10.2478/v10007-009-0021-z.

38. L. Rodriguez, O. Caputo, M. Cini, C. Cavallari and R. Grecchi, In vitro release of theophylline from directly-compressed matrices containing methacrylic acid copolymers and/or dicalcium phosphate dehydrate, Farmaco 48 (1993) 1597-1604.

39. L. S. da Fonseca, R. P. Silveira, A.M. Deboni, E. V. Benvenutti, T. M. Costa, S. S. Guterres and A.

R. Pohlmann, Nanocapsule@xerogel microparticles containing sodium diclofenac: a new strategy to control the release of drugs, Int. J. Pharm. 358 (2008) 292-295; DOI: S0378-5173(08) 00118-X [pii] 10.1016/j.ijpharm.2008.02.005.

40. E. F. Reynolds James, Dextromethorphan Hydrobromide, Royal Pharmaceutical Society, London, 1996, p. 1066.

41. J. L. Bem and R. Peck, Dextromethorphan. An overview of safety issues, Drug Safety 7 (1992) 190-199.

42. E. S. Pender and B. R. Parks, Toxicity with dextromethorphan-containing preparations: a literature review and report of two additional cases, Pediatr. Emerg. Care 7 (1991) 163-165.

43. G. M. El Maghraby, Synergistic enhancement of itraconazole dissolution by ternary system formation with pluronic F68 and hydroxypropylmethylcellulose, Sci. Pharm. 77 (2009) 401-417; DOI: 10.3797/scipharm.0901-08.

44. F. K. Alanazi, M. El-Badry and I. A. Alsarra, Spray-dried HPMC microparticles of indomethacin impact of drug-polymer ratio and viscosity of the Polymeric solution on dissolution, Saudi Pharm. J. 14 (2006) 100-107.

45. G. M. El Maghraby, E. M. Elzayat and F. K. Alanazi, Development of modified in situ gelling oral liquid sustained release formulation of dextromethorphan, Drug Dev. Ind. Pharm. (2011); DOI: 10.3109/03639045.2011.634811.

46. P. S. Rajinikanth and B. Mishra, Floating in situ gelling system of acetohydroxamic acid for clearance of H. pylori, Drug Dev. Ind. Pharm. 34 (2008) 577-587; DOI: 10.1080/03639040701831819.

47. K. A. Khan, The concept of dissolution efficiency, J. Pharm. Pharmacol. 27 (1975) 48-49.

48. M. R. Louhaichi, S. Jebali, M. H. Loueslati, N. Adhoum and L. Monser, Simultaneous determination of pseudoephedrine, pheniramine, guaifenesin, pyrilamine, chlorpheniramine and dextromethorphan in cough and cold medicines by high performance liquid chromatography, Talanta 78 (2009) 991-997; DOI: 10.1016/j.talanta.2009.01.019.

49. F. Alanazi, H. Li, D. S. Halpern, S. Oie and D. R. Lu, Synthesis, preformulation and liposomal formulation of cholesteryl carborane esters with various fatty chains, Int. J. Pharm. 255 (2003) 189-197; DOI: S0378517303000887.

50. M. Malladi, R. Jukanti, R. Nair, S. Wagh, H. S. Padakanti and A. Mateti, Design and evaluation of taste masked dextromethorphan hydrobromide oral disintegrating tablets, Acta Pharm. 60 (2010) 267-280; DOI: 10.2478/v10007-010-0025-8.

51. R. P. Raffin, D. Jornada, S. Haas, A. R. Pohlmann and S. S. Guterres, Pantoprazole sodiumloaded controlled release microparticles, in 15th International Symposium on Microencapsulation, Parma, ed. (Italy, 2005), pp. 7-8.

52. K. H. Kim, M. J. Frank and N. L. Henderson, Application of differential scanning calorimetry to the study of solid drug dispersions, J. Pharm. Sci. 74 (1985) 283-289.

53. R. J. Fessenden and J. S. Fessenden, Fessenden and Fessenden Organic Chemistry, Brooks/Cole publishing company, Pacific Grove, 1990, pp. 323-390.

54. Technical Information on EUDRAGIT L 100 and EUDRAGIT S 100, http://eudragit.evonik.com/product/eudragit/Documents/evonik-specification-eudragit-l-100-and-s-100.pdf; access date January 10, 2011.

55. M. R. Jenquin and J. W. McGinity, Characterization of acrylic resin matrix films and mechanisms of drug-polymer interaction, Int. J. Pharm. 101 (1994) 23-24.

56. K. O. R. Lehman, Chemistry and application properties of polymethacrylate coating systems, Informa Healthcare USA, Inc., New York, 1990, pp. 101-174.

57. B. J. Lee, J. H. Cui, T. W. Kim, M. Y. Heo and C. K. Kim, Biphasic release characteristics of dual drug-loaded alginate beads, Arch Pharm. Res. 21 (1998) 645-650.

58. T. Higuchi, Rate of release of medicaments from ointment bases containing drugs in suspension, J. Pharm. Sci. 50 (1961) 874-875.

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