Skip to main content
SpringerLink
Log in

Optimization and Evaluation of Gastroretentive Ranitidine HCl Microspheres by Using Factorial Design with Improved Bioavailability and Mucosal Integrity in Ulcer Model

  • Research Article
  • Theme: Recent Trends in the Development of Chitosan-Based Drug Delivery Systems
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The purpose of our investigation was to develop and optimize the drug entrapment efficiency and bioadhesion properties of mucoadhesive chitosan microspheres containing ranitidine HCl prepared by an ionotropic gelation method as a gastroretentive delivery system; thus, we improved their protective and therapeutic gastric effects in an ulcer model. A 3 × 22 full factorial design was adopted to study the effect of three different factors, i.e., the type of polymer at three levels (chitosan, chitosan/hydroxypropylmethylcellulose, and chitosan/methylcellulose), the type of solvent at two levels (acetic acid and lactic acid), and the type of chitosan at two levels (low molecular weight (LMW) and high molecular weight (HMW)). The studied responses were particle size, swelling index, drug entrapment efficiency, bioadhesion (as determined by wash-off and rinsing tests), and T 80% of drug release. Studies of the in vivo mucoadhesion and in vivo protective and healing effects of the optimized formula against gastric ulcers were carried out using albino rats (with induced gastric ulceration) and were compared to the effects of free ranitidine powder. A pharmacokinetic study in rabbits showed a significant, 2.1-fold increase in theAUC0–24of the ranitidine microspheres compared to free ranitidine after oral administration. The optimized formula showed higher drug entrapment efficiency and mucoadhesion properties and had more protective and healing effects on induced gastric ulcers in rats than ranitidine powder. In conclusion, the prolonged gastrointestinal residence time and the stability of the mucoadhesive microspheres of ranitidine as well as the synergistic healing effect of chitosan could contribute to increasing the potential of its anti-gastric ulcer activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Chaturvedi A, Kumar MM, Bhawani G, Chaturvedi H, Kumar M, Goel KR. Effect of ethanolic extract of Eugenia jambolana seeds on gastric ulceration and secretion in rats. Indian J Physiol Pharmacol. 2007;51(2):131–40.

    PubMed  Google Scholar 

  2. Wallace JL, Granger DN. The cellular and molecular basis of gastric mucosal defense. FASEB J. 1996;10(7):731–40.

    CAS  PubMed  Google Scholar 

  3. Bourdet DL, Pritchard JB, Thakker DR. Differential substrate and inhibitory activities of ranitidine and famotidine toward human organic cation transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). J Pharmacol Exp Ther. 2005;315(3):1288–90.

    Article  CAS  PubMed  Google Scholar 

  4. Chavda H, Patel C. Chitosan superporous hydrogel composite-based floating drug delivery system: a newer formulation approach. J Pharm Bioall Sci. 2010;2:124–31.

    Article  CAS  Google Scholar 

  5. Novak KM. Histamine H2 antagonists. In: Novak KM, editor. Drug facts and comparisons. 56th ed. MO: St. Louis; 2002. p. 1192–7.

    Google Scholar 

  6. McCarty-Dawson D, Sue SO, Morrill B, Murdock Jr RH. Ranitidine versus cimetidine in the healing of erosive esophagitis. Clin Ther. 1996;18(6):1150–60.

    Article  CAS  PubMed  Google Scholar 

  7. Grant SM, Langtry HD, Brogden RN. Ranitidine: an updated review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in peptic ulcer and other allied diseases. Drugs. 1989;37:801–70.

    Article  CAS  PubMed  Google Scholar 

  8. Lauritsen K, Laursen LS, Rask-Madsen J. Clinical pharmacokinetics of drugs used in the treatment of gastrointestinal diseases (part II). Clin Pharmacokinet. 1990;19:94–125.

    Article  CAS  PubMed  Google Scholar 

  9. Gramattι T, el Desoky E, Klotz U. Site-dependent small intestinal absorption of ranitidine. Eur J Clin Pharmacol. 1994;46:253–9.

    Article  Google Scholar 

  10. Basit AW, Lacey LF. Colonic metabolism of ranitidine: implications for its delivery and absorption. Int J Pharm. 2001;227:157–65.

    Article  CAS  PubMed  Google Scholar 

  11. Gnanaprakash K. Formulation and evaluation of floating drug delivery system of anti ulcer drugs. Ph D Thesis 2013, Jawaharlal Nehru Technological University, Anantapuram.

  12. Hagerstorm H. Polymer gels as pharmaceutical dosage forms. Ph.D. Thesis 2003, Faculty of Pharmacy, uppasala University, Sweden.

  13. Dua K, Trivedi P. Formulation and evaluation of mucoadhesive microspheres of ranitidine hydrochloride using chitosan and sodium carboxymethyl cellulose as polymers. Int J Pharm Biomed Res. 2013;4(2):140–4.

    CAS  Google Scholar 

  14. Ben HL, Leeuw BJ, Perrad D. Bioadhesive polymers for the per-oral delivery of peptide drugs. J Control Release. 1994;29:329–38.

    Article  Google Scholar 

  15. Ben HL, Leeuw BJ, Perrad D. Mucoadhesive excipients for the per-oral delivery of peptide drugs. Eur J Pharm Biopharm. 1996;4:117–28.

    Google Scholar 

  16. Chen CJ, Jacob J, Klein, AB,Chayapruks T, Mathiowitz E. Bioadhesive polymers for stomach targeted drug delivery. Proceedings of the 24th International Symposium on Controlled Release of Bioactive Materials, Stockholm. 1997; 259–260.

  17. Nagahara N, Akiyama Y, Tada M, Nakao M, Kitano M, Ogawa Y. Mucoadhesive microspheres containing amoxycillin for clearance of Helicobacter pylori. Antimicrob Agents Chemother. 1998;42:2492–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Harding SE, Davis SS, Deacon MP, Fiebrig I. Biopolymer mucoadhensives. In: Harding, SE. Biotechnology and Genetic Engineering Reviews. 1999; 16:41-86.

  19. Cuna M, Alonso MJ, Torres D. Preparation and in vivo evaluation of mucoadhesive microparticles containing amoxicillin–resin complexes for drug delivery to the gastric mucosa. Eur J Pharm Biopharm. 2001;51:199–205.

    Article  CAS  PubMed  Google Scholar 

  20. Bardonnet PL, Faivre V, Pugh WJ, Piffaretti JC, Falson F. Gastroretentive dosage forms: overview and special case of Helicobacter pylori. J Control Release. 2006;111:1–18.

    Article  CAS  PubMed  Google Scholar 

  21. Henriksen I, Green KL, Smart JD, Smistad G, Karlsen J. Bioadhesion of hydrated chitosans: an in vitro and in vivo study. Int J Pharm. 1996;145:231–40.

    Article  CAS  Google Scholar 

  22. Rao SB, Sharma CP. Use of chitosan as biomaterial: studies on its safety and haemostatic potential. Bio Med Mater Res. 1997;34:21–8.

    Article  CAS  Google Scholar 

  23. Chowdary KPR, Rao YS. Design and in vitro and in vivo evaluation of mucoadhesive microcapsules of glipizid for oral controlled release a technical note. AAPS Pharm Sci Tech. 2003;4:E39.

    Article  CAS  Google Scholar 

  24. Thanoo BC, Sunny MC, Jayakrishnan A. Cross-linked chitosan MS: preparation and evaluation as a matrix for the controlled release of pharmaceuticals. J Pharm Pharmacol. 1992;44:283–6.

    Article  CAS  PubMed  Google Scholar 

  25. Hari PR, Chandy T, Sharma CP. Chitosan/calcium alginate microcapsules for intestinal delivery of nitrofurantoin. J Microencapsul. 1996;13:319–29.

    Article  CAS  PubMed  Google Scholar 

  26. Liu LS, Liu SQ, Ng SY, Froix M, Heller J. Controlled release of interleukin 2 for tumour immunotherapy using alginate/chitosan porous microspheres. J Control Release. 1997;43:65–74.

    Article  CAS  Google Scholar 

  27. Patel JK, Bodar MS, Amin AF, Patel MM. Formulation and optimization of mucoadhesivemicrospheres of metoclopramide. Ind J Pharm Sci. 2004;66:300–5.

    CAS  Google Scholar 

  28. Dubey RR, Parikh RH. Two-stage optimization process for formulation of chitosan icrospheres. AAPS Pharm Sci Tech. 2004;5:E5.

    Article  Google Scholar 

  29. Takka S, Ocak OH, Acarturk F. Formulation and investigation of nicardipine HCl-alginate gel beads with factorial design-based studies. EurJ Pharm Sci. 1998;6(3):241–6.

    Article  CAS  Google Scholar 

  30. Shabaraya AR, Narayanacharyulu R. Design and evaluation of chitosan microspheres of metoprolol tartarate for sustained release. Indian J Pharm Sci. 2003;65(3):250–2.

    CAS  Google Scholar 

  31. Wong CF, Yuen KH, Peh KK. Formulation and evaluation of controlled release Eudragit buccal patches. Int J Pharm. 1999;(178): 11–22.

  32. Peh KK, Wong CF. Polymeric films as vehicle for buccal delivery: swelling mechanical and bioadhesive properties. J Pharm Pharm Sci. 1999;2(2):53–61.

    CAS  PubMed  Google Scholar 

  33. Qu X, Wirse’n A, Albertsson AC. Noval pH-sensitive chitosan hydrogels: swelling behavior and states of water. Polymer. 2000;41:4589–98.

    Article  CAS  Google Scholar 

  34. Lehr CM, Bowstra, JA, Tukker JJ, Junginger HE. Intestinal transit of bioadhesive microspheres in an in situ loop in the rat. J Control Release. 1990;(13): 51–62.

  35. RangaRao KV, Buri P. A novel in situ method to test polymers and coated microparticles for bioadhesion. Int J Pharm. 1989;52(3):265–70.

    Article  Google Scholar 

  36. Mastihlimath VS, Dandagi PM, Gadad AP, Rashi M, Kulkarni AR. In vitro and in vivo evaluation of ranitidine hydrochloride ethyl cellulose floating microparticles. J Microencapsulation. 2008;25(5):307–14.

    Article  Google Scholar 

  37. Dae-Kwon B, Dongsun P, Yun-Bae K. Different antiulcer activities of pantoprazole in stress, alcohol and pylorus ligation-induced ulcer models. Lab Anim Res. 2011;271:47–52.

    Google Scholar 

  38. Santucci L, Fioruci S, Giananti M, Brumoi PM, Dimatteo FN, Morelli A. Pentoxifylline prevents indomethacin induced acute mucosal damage in rats: role of tumor nicrosis factor alpha. J Am Pediatr Med Assoc Gut. 1994;35:909–15.

    CAS  Google Scholar 

  39. Maity S, Chaudhri T, Vedasiromoni JR, Ganguly DK. Cytoprotection mediated antiulcer effect of tea root extract. Ind Institute Chem Biol. 2003;35:213–9.

    Google Scholar 

  40. Ismail NM, Jaarin K, Ahmad A, Marzuki A, Ng WK, Gapor MT. Palm vitamin E and the healing of ethanol induced gastric lesions. Asia Pac J Clin Nutri. 1999;8:258–62.

    Article  CAS  Google Scholar 

  41. Bancroft JD, Stevens A. The haematoxylin and eosin. theory and practice of histological techniques. 1996; 4th ed, Ch 6: 99–112. Churchill Livingstone, London, New York & Tokyo.

  42. Nishioka, Y, Kyotani S, Okamura M, Miyazaki M, Okazaki K, Ohnishi S, Yamamoto Y, Ito K. Release characteristics of cisplatin chitosan microspheres and effect of containing chitin. Chem Pharm Bull (Tokyo). 1990; (38): 2871–2873.

  43. Berthold A, Cremer K, Kreuter J. Preparation and characterization of chitosan microspheres as drug carrier for prednisolone sodium phosphate as model for anti-inflammatory drugs. J Control Release. 1996;39:17–25.

    Article  CAS  Google Scholar 

  44. Berthold A, Cremer K, Kreuter J. Influence of crosslinking on the acid stability and physicochemical properties of chitosan microspheres. AAPSTech Pharm Sci. 1996; (6): 358–364.

  45. Aslani P, Kennedy RA. Effect of gelation condition and dissolution media on the release of paracetamol from alginate gel beads. J Microenscapsul. 1996;13(5):601–14.

    Article  CAS  Google Scholar 

  46. Kumar V, Lewis SA, Mutalik S, Shenoy DB, Udupa N. Biodegradable microspheres of curcumin for treatment of inflammation. Indian J Physiol Pharmacol. 2002;46:209–17.

    CAS  PubMed  Google Scholar 

  47. Sanat KB, Kunchu K, Mani R. Evaluation of ketorolac tromethamine microspheres by chitosan/gelatin B complex coacervation. Sci Pharm. 2010;78:79–92.

    Article  Google Scholar 

  48. Adusumilli PS, Bolten SM. Evaluation of chitosan citrate complexes as matrices for controlled release formulations using a 32 full factorial designs. Drug Devand Pharm. 1991;17:1931–45.

    Article  CAS  Google Scholar 

  49. Desai H, Park HJ. Preparation and characterization of drug-loaded chitosan–tripolyphosphate microspheres by spray drying. Drug Dev Res. 2005;64:114–28.

    Article  CAS  Google Scholar 

  50. Patel JK, Patel MM. Stomach specific anti Helicobacter pylori therapy: preparation and evaluation of rantidine HCl loaded chitosan mucoadhesive microspheres. Curr Drug Deliv. 2007;64:41–50.

    Article  Google Scholar 

  51. Shi XZ, Tan TW. Preparation of chitosan/ethyl cellulose complex microcapsule and its application in controlled release of vitamin D2. Biomaterials. 2002;23:4469–73.

    Article  CAS  PubMed  Google Scholar 

  52. Kavita D, Piyush T. Formulation and evaluation of mucoadhesive microspheres of rantidine hydrochloride using chitosan and sodium carboxymehyl cellulose as polymers. In J Pharm Biomed Res. 2013;4(2):140–4.

    Google Scholar 

  53. Huikari A, Karlsson A. Viscosity stability of methyl cellulose solutions at different pH and temperature. Acta Pharm Fenn. 1989;984:231–8.

    Google Scholar 

  54. Tonnesen HH, Karisen J. Alginate in drug delivery systems. Drug Dev Ind Pharm. 2002;28(6):621–30.

    Article  CAS  PubMed  Google Scholar 

  55. Shu XZ, Zhu KJ, Song W. Noval pH-sensitive citrate cross-linked chitosan film for drug controlled release. Int J Pharm. 2001;212(1):19–28.

    Article  CAS  PubMed  Google Scholar 

  56. Shu XZ, Zhu KJ. Controlled drug release properties of ionically cross-linked chitosan beads: the influence of anion structure. Int J Pharm. 2002;233(1-2):217–25.

    Article  CAS  PubMed  Google Scholar 

  57. Vanessa A, Eduardo R. Enacpsulation of naproxen in nanostructured system: structural characterization and in vitro release studies. Quim Nova. 2011;6:1–13.

    Google Scholar 

  58. Al-Howiriny T, Al-Sohaibani M, El-Tahir K, Rafatullah S. Prevention of experimentally-induced gastric ulcers in rats by an ethanolic extract of “Parsley” Petroselinum crispum. Am J Chin Med. 2003;31(5):699–711.

    Article  PubMed  Google Scholar 

  59. Olaibi OK, Ijomone OM, Olawuni IJ, Adewole SO, Akinsomisoye SO. Mucus secreting activity and nitric oxide concentrations of ethanol-injured pylorus and duodenum of rats pretreated with Moringa oleifera. J ExpIntegr Med. 2014; 4(2):123-130.

  60. Vinothapooshan G, Sundar K. Anti-ulcer activity of Mimosa pudica leaves against gastric ulcer in rats. RJPBCS. 2010;1(4):606–14.

    Google Scholar 

  61. Choudhary M, Kumar V, Singh S. Gastric antisecretory and cytoprotective effects of hydroalcoholic extracts of Plumeria alba Linn. leaves in rats. J Integr Med. 2014;12(1):42–51.

    Article  PubMed  Google Scholar 

  62. Jude EO, Paul A. Antiulcer and anticonvulsant activity of Croton zambesicus. J Pharm Sci. 2009;22:384–90.

    Google Scholar 

  63. Raju D, Ilango K, Chitra V, Ashish K. Evaluation of anti-ulcer activity of methanolic extract of Terminalia chebula fruits in experimental rats. J Pharm Sci Res. 2009;3:101–7.

    Google Scholar 

  64. Mastiholimath VS, Dandagi PM, Gadad AP, Rashmi M, Kulkarni AR. In vitro and in vivo evaluation of rantidine hydrochloride ethyl cellulose floating microparticles. 2008; 25(2):307–314.

  65. Wang J, Tabata Y, Bi D, Morimoto K. Evaluation of gastric mucoadhesive properties of animated gelatin microsphere. J Contr Rel. 2001;73:223–31.

    Article  CAS  Google Scholar 

  66. Nagai T, Machida Y. Mucosal adhesive dosage forms. Pharm Int. 1985;6:196–200.

    Google Scholar 

  67. Hemant KSY, Singh MN, Shivakumar HG. Chitosan/sodium tripolyphosphate cross linked microspheres for the treatment of gastric ulcer. Pharm Lett. 2010;2(6):106–13.

    CAS  Google Scholar 

  68. Repetto MG, Llesuy SF. Antioxidant properties of natural compounds used in popular medicine for gastric ulcers. Braz J Med Biol Res. 2002;35(5):523–34.

    Article  CAS  PubMed  Google Scholar 

  69. Nashwah IZ, Lobna AH, Abeer MK. Evaluation of newly formulated antiulcer drug on experimental ulcer model. J Drug Res. 2014;35(1):81–93.

    Google Scholar 

  70. Penissi A, Piezzi R. Effect of dehydroleucodine on mucus production: a quantitative study. Dig Dis Sci. 1999;44(4):708–12.

    Article  CAS  PubMed  Google Scholar 

  71. Dashputre NL, Naikwade NS. Evaluation of anti-ulcer activity of methanolic extract of Abutilon indicum Linn leaves in experimental rats. IJPSDR. 2011;3(2):97–100.

    Google Scholar 

  72. Ishihara M, Ono K, Sato M, Nakanishi K, Saito Y, Yura H, et al. Acceleration of wound contraction and healing with photocrosslinkable chitosan hydrogel. Wound Repair Regenn. 2001;9(6):513–21.

    Article  CAS  Google Scholar 

  73. Ito M, Bann, Ishihara M. Anti–ulcer effects of chitin and chitosan healthy foods in rats. J Pharmacol. 2000;82:218–25.

    CAS  Google Scholar 

  74. Xiao D, Wang Y, Liu G, He J, Qiu W, et al. Effects of chitosan on intestinal inflammation in weaned pigs challenged by enterotoxigenic Escherichia coli. PLoS ONE. 2014;9(8):e104192.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are thankful to the National Organization for Drug Control and Research for the financial support. Authors are thankful to Alexandria Company, Egypt, for the gift samples of drug and excipients.

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, National Organization for Drug Control and Research, Giza, Egypt

    Abeer Khattab

  2. Department of Physiology, National Organization for Drug Control and Research, Giza, Egypt

    Nashwah Zaki

Authors
  1. Abeer Khattab
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nashwah Zaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Abeer Khattab.

Ethics declarations

All the animal experimental protocols were approved by the Institutional Animal Ethics Committee (IAEC), National Organization for Drug Control and Research, Egypt.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Additional information

Guest Editors: Claudio Salomon, Francisco Goycoolea, and Bruno Moerschbacher

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khattab, A., Zaki, N. Optimization and Evaluation of Gastroretentive Ranitidine HCl Microspheres by Using Factorial Design with Improved Bioavailability and Mucosal Integrity in Ulcer Model. AAPS PharmSciTech 18, 957–973 (2017). https://doi.org/10.1208/s12249-017-0744-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-017-0744-y

KEY WORDS

Search

Navigation