AAPS PharmSciTech

, 20:306 | Cite as

New Perspective Enteric-Coated Tablet Dosage Form for Oral Administration of Ceftriaxone: In Vitro and In Vivo Assessments

  • Amir E. MaghrabiaEmail author
  • Mariza F. Boughdady
  • Mahasen M. Meshali
Research Article


Ceftriaxone (CTX) is a widely used injectable third-generation cephalosporin that exhibits broad-spectrum antibacterial activity. Unfortunately, the oral route of this drug suffers different encumbrances, such as instability in the upper part of the GIT and enzymatic degradation, as well as poor permeability. There is no reported tablet dosage form for this drug. In this respect, the authors investigated the possibility of developing an enteric-coated oral tablet of CTX that would be helpful for better patient compliance. The tablet consists of directly compressed core of CTX, citric acid (CA), sodium chloride (NaCl), and two biopolymers—chitosan (CH), a permeation enhancer, and silicified microcrystalline cellulose (SMCC), a wicking agent. Both biopolymers are naturally occurring polysaccharides that are biodegradable in the colon and able to incorporate acid labile drugs. CA is a pH modulator to protect CTX from protease enzymes, while NaCl is a translocation enhancer that helps drug penetration. The enteric coat of the core was shellac (SH) with plasticizer glycerol tristearate (GTS) and CA that was applied by direct compression (dry coating). The solventless heat curable coat resulted in an enteric-coated tablet that complies with the USP pharmacopeia. The optimized formula was further subjected to in vitro release and stability studies, as well as ingredient compatibility. In vivo oral bioavailability of the enteric-coated tablets in rabbits gave promising results (absolute bioavailability of about 80%). Synergistically, all ingredients together augmented oral bioavailability of CTX. This developed formula could be a perspective delivery system for those drugs intended to be absorbed from the colon such as peptides and peptide-like drugs.


ceftriaxone chitosan shellac colon targeting enteric coated 



  1. 1.
    Hirzel C, Hirzberger L, Furrer H, Endimiani A. Bactericidal activity of penicillin, ceftriaxone, gentamicin and daptomycin alone and in combination against Aerococcus urinae. Int J Antimicrob Ag. 2016;48(3):271–6.CrossRefGoogle Scholar
  2. 2.
    DeBrouse DR. (2009). Google Patents No.0123537 A. Retrieved from Accessed 9 May 2019.
  3. 3.
    Shah N, Seth A, Balaraman R, Aundhia C, Maheshwari R, Parmar G. Nanostructured lipid carriers for oral bioavailability enhancement of raloxifene: design and in vivo study. J Adv Res. 2016;7(3):423–34.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Lee S, Lee D, Chae S, Byun Y. Pharmacokinetics of a new orally available ceftriaxone formulation in physical complexation with a cationic analogue of bile acid in rats. Anti Microb Ag Chemo. 2006;50(5):1869–71.CrossRefGoogle Scholar
  5. 5.
    Neelam S, Arundhati B, Puneet G. Enhancement of intestinal absorption of poorly absorbed ceftriaxone sodium by using mixed micelles of polyoxy ethylene (20) cetyl ether & oleic acid as peroral absorption enhancers. Schol Res Lib. 2010;2(3):131–42.Google Scholar
  6. 6.
    Beskid G, Unowsky J, Behl C, Siebelist J, Tossounian J, McGarry C, et al. Enteral, oral, and rectal absorption of ceftriaxone using glyceride enhancers. Chemotherapy. 1988;34(2):77–84.PubMedCrossRefGoogle Scholar
  7. 7.
    Patel N, Lalwani D, Gollmer S, Injeti E, Sari Y, Nesamony J. Development and evaluation of a calcium alginate based oral ceftriaxone sodium formulation. Progress in Biomaterials. 2016;5(2):117–33.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Zaki N, Hafez M. Enhanced antibacterial effect of ceftriaxone sodium-loaded chitosan nanoparticles against intracellular Salmonella typhimurium. AAPS PharmSciTech. 2012;13(2):411–21.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Philip A, Philip B. Colon targeted drug delivery systems: a review on primary and novel approaches. Oman Med J. 2010;25(2):70–8.CrossRefGoogle Scholar
  10. 10.
    Bernkop-Schnürch A, Dünnhaupt S. Chitosan-based drug delivery systems. Eur J Pharm Biopharm. 2012;81(3):463–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Sun W, Mao S, Wang Y, Junyaprasert VB, Zhang T, Na L, et al. Bioadhesion and oral absorption of enoxaparin nanocomplexes. Int J Pharm. 2010;386(1–2):275–81.PubMedCrossRefGoogle Scholar
  12. 12.
    Grabovac V, Guggi D, Bernkop-Schnürch A. Comparison of the mucoadhesive properties of various polymers. Adv Drug Deliv Rev. 2005;57(11):1713–23.PubMedCrossRefGoogle Scholar
  13. 13.
    Gupta S, Vyas SP. Carbopol/chitosan based pH triggered in situ gelling system for ocular delivery of timolol maleate. J Pharm Sci. 2010;78(1):959–76.Google Scholar
  14. 14.
    Sakloetsakun J, Bernkop-Schnürch A. In situ gelling properties of chitosan–thioglycolic acid conjugate in the presence of oxidizing agents. Biomaterials. 2009;30(1):6151–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Kubbinga M, Augustijns P, García MA, Heinen C, Wortelboer HM, Verwei M, et al. The effect of chitosan on the bioaccessibility and intestinal permeability of acyclovir. Euro J Pharm Biopharm. 2019;136(1):147–55.PubMedCrossRefGoogle Scholar
  16. 16.
    Föger F, Bernkop-Schnürch A. In vivo evaluation of an oral delivery system for P-gp substrates based on thiolated chitosan. Biomaterials. 2006;27(23):4250–5.PubMedCrossRefGoogle Scholar
  17. 17.
    Newton A, Prabakaran L. Comparative efficacy of chitosan, pectin based mesalamine colon targeted drug delivery systems on TNBS-induced IBD model rats. Anti-inflam Anti-allerg Med Chem. 2019;18(1):1–14.CrossRefGoogle Scholar
  18. 18.
    Mohammed M, Syeda J, Wasan K, Wasan E. An overview of chitosan nanoparticles and its application in non-parenteral drug delivery. Pharmaceutics. 2017;9(4):53.PubMedCentralCrossRefGoogle Scholar
  19. 19.
    Almukainzi M, Araujo G, Löbenberg R. Orally disintegrating dosage forms. J Pharm Inves. 2019;49(2):229–43.CrossRefGoogle Scholar
  20. 20.
    Bose S, Bogner R. Solventless pharmaceutical coating processes: a review. Pharm Dev Technol. 2007;12(2):115–31.PubMedCrossRefGoogle Scholar
  21. 21.
    The United States pharmacopeia. National formulary. 40th revision. Rockville (MD)20852: United States Pharmacopeial Convention; 2017.Google Scholar
  22. 22.
    Sun X, Liu C, Omer A, Yang L-Y, Ouyang X-K. Dual-layered pH-sensitive alginate/chitosan/kappa-carrageenan microbeads for colon-targeted release of 5-fluorouracil. Int J Bio Mac Molec. 2019;132:487–94.CrossRefGoogle Scholar
  23. 23.
    Pudjiastuti P, Hendradi E, Wafiroh S, Darmokoesoemo H, Fauzi M, Nahar L, et al. First order kinetics of salicylamide release from κ-carrageenan hard shell capsules in comparison with gelatin. IOP Conf Series: Earth and Environmental Science. 2019;217(1):1–5.Google Scholar
  24. 24.
    Higuchi T. Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci. 1963;52(12):1145–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Korsmeyer R, Gurny R, Doelker E, Buri P, Peppas N. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983;15(1):25–35.CrossRefGoogle Scholar
  26. 26.
    Campos M, de Moura AJ, dos Santos ME, Oliveira J, Hussni C, Peccinini R. Ceftriaxone pharmacokinetics by new simple and sensitive ultra-high-performance liquid chromatography method. Diag Micro Infec Disease. 2017;88(1):95–9.CrossRefGoogle Scholar
  27. 27.
    Aman R, Meshali M, Ibrahim I. Novel chitosan-based solid-lipid nanoparticles to enhance the bio-residence of the miraculous phytochemical “apocynin”. Euro J Pharm Sci. 2018;124(1):304–18.CrossRefGoogle Scholar
  28. 28.
    Cardot J, Davit B. In vitro–in vivo correlations: tricks and traps. AAPS J. 2012;14(3):491–9.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Wagner J, Nelson E. Percent absorbed time plots derived from blood level and/or urinary excretion data. J Pharm Sci. 1963;52(6):610–1.PubMedCrossRefGoogle Scholar
  30. 30.
    Uranga J, Puertas A, Etxabide A, Dueñas M, Guerrero P, de la Caba K. Citric acid-incorporated fish gelatin/chitosan composite films. Food Hydrocoll. 2019;86:95–103.CrossRefGoogle Scholar
  31. 31.
    Snejdrova E, Dittrich M. Pharmaceutical applications of plasticized polymers. Rec Adv Plast. 2012;4:70–90.Google Scholar
  32. 32.
    Osman Z. Investigation of different shellac grades and improvement of release from air suspension coated pellets. PhD [dissertation]. Mainz: Universitätsbibliothek Mainz; 2012. Available from: Accessed 9 May 2019.
  33. 33.
    Farag Y, Leopold C. Physicochemical properties of various shellac types. Dissolut Technol. 2009;16:33–9.CrossRefGoogle Scholar
  34. 34.
    Kapoor D, Gupta P. A malleable technique for future coating process solventless coating. J Critic Rev. 2016;3(2):55–9.Google Scholar
  35. 35.
    Saigal N, Baboota S, Ahuja A, Ali J. Microcrystalline cellulose as a versatile excipient in drug research. J Young Pharmacists. 2009;1(1):6–12.CrossRefGoogle Scholar
  36. 36.
    Marczyński Z, Zgoda M, Jambor J. Application of silicified microcrystalline cellulose (Prosolv) as a polymer carrier of Epilobium parviflorum Schreb. extract in oral solid drug form. Polim Med. 2007;37(2):21–32.PubMedGoogle Scholar
  37. 37.
    Owens H, Dash A. Ceftriaxone sodium: comprehensive profile. In: Harry B. Profiles of drug substances, excipients and related methodology. USA. 2003;30:21–57.Google Scholar
  38. 38.
    Awadeen R, Boughdady M, Meshali M. New in-situ gelling biopolymer-based matrix for bioavailability enhancement of glimepiride; in-vitro/in-vivo X-ray imaging and pharmacodynamic evaluations. Pharm Dev Technol. 2018;2(5):539–49.CrossRefGoogle Scholar
  39. 39.
    Shantha K, Harding D. Synthesis and characterisation of chemically modified chitosan microspheres. Carbohydr Polym. 2002;48(3):247–53.CrossRefGoogle Scholar
  40. 40.
    Guinesi L, Cavalheiro E. The use of DSC curves to determine the acetylation degree of chitin/chitosan samples. Thermochim Acta. 2006;444(2):128–33.CrossRefGoogle Scholar
  41. 41.
    Theismann E-M, Keppler JK, Knipp J-R, Fangmann D, Appel E, Gorb SN, et al. Adjustment of triple shellac coating for precise release of bioactive substances with different physico-chemical properties in the ileocolonic region. Int J Pharm. 2019;564(1):472–84.PubMedCrossRefGoogle Scholar
  42. 42.
    Limmatvapirat S, Limmatvapirat C, Puttipipatkhachorn S, Nunthanid J, Luangtana-anan M, Sriamornsak P. Modulation of drug release kinetics of shellac-based matrix tablets by in-situ polymerization through annealing process. Eur J Pharm Biopharm. 2008;69(3):1004–13.PubMedCrossRefGoogle Scholar
  43. 43.
    Borg T, Mohamed E, El Naggar E, El-Sheakh A, Hamed M. Colon targeting of naringin for cytoprotection against ulcerative colitis: in vitro-in vivo study. IOSR J Pharm Bio Sci. 2017;12(2):23–9.Google Scholar
  44. 44.
    Asghar L, Chure C, Chandran S. Colon specific delivery of indomethacin: effect of incorporating pH sensitive polymers in xanthan gum matrix bases. AAPS PharmSciTech. 2009;10(2):418–29.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Abdelbary A, El-Gazayerly O, El-Gendy N, Ali A. Floating tablet of trimetazidine dihydrochloride: an approach for extended release with zero-order kinetics. AAPS PharmSciTech. 2010;11(3):1058–67.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Sexton D, Faucette R. (2019). Google Patents US0022641A1. Retrieved from Accessed 9 May 2019.
  47. 47.
    Bonferoni MC, Sandri G, Rossi S, Ferrari F, Gibin S, Caramella C. Chitosan citrate as multifunctional polymer for vaginal delivery: evaluation of penetration enhancement and peptidase inhibition properties. Euro J Pharm Sci. 2008;33(2):166–76.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Amir E. Maghrabia
    • 1
    Email author
  • Mariza F. Boughdady
    • 1
  • Mahasen M. Meshali
    • 1
  1. 1.Department of Pharmaceutics, Faculty of PharmacyMansoura UniversityMansouraEgypt

Personalised recommendations