In vitro–in vivo evaluation of in situ gelling and thermosensitive ketoprofen liquid suppositories

  • Işık Özgüney
  • Anita Kardhiqi
  • Gülbeyaz Yıldız
  • Gökhan Ertan
Original Paper
First Online:
Received:
Accepted:

Abstract

The main objective of this study was to investigate the release and pharmacokinetic profiles of ketoprofen (KP) from developed thermosensitive and mucoadhesive liquid suppositories. Thermosensitive liquid suppositories were prepared using KP, poloxamer 407 (P 407), poloxamer 188 (P 188) and various amounts of different mucoadhesive polymers. In vitro release studies was monitored by the USP XXVI paddle method. The results thus obtained were evaluated kinetically and mechanism of release was analyzed. Identification of poloxamer gel localization in vivo was conducted using white male rabbits by adding 1 % methylene blue. For in vivo studies, twenty-four white male rabbits were randomly divided into three groups. The rabbits in each group were administered with liquid suppository F1 [P407/P188/KP (4/20/2.5 %)], F5 [P407/P188/KP/C (4/20/2.5/0.8 %)] or conventional suppository (F–C) into the rectum. The plasma concentration of KP was analyzed by high performance liquid chromatography (HPLC). C max, AUC, MRT and T max were evaluated. The release of KP was variously affected by the mucoadhesive polymers. In vitro release studies showed that Carbopol 934 P(C) has significant effect on release rate among the mucoadhesive polymers. When the formulations were evaluated kinetically, different kinetic models were obtained. Formulation F6 [P407/P188/KP/C (4/20/2.5/1.6 %)] which contains the highest C concentration and very high viscosity, shows a significantly better fit with Higuchi kinetic model. n value of this formulation was also found approximately 0.5. n exponent results of the other formulations showed that KP might be released from the suppositories by non-Fickian diffusion. Identification of poloxamer gel localization in vivo showed that the suppositories remain in the rectum without leakage after administration. With regard to the results of in vivo studies, the AUC6→14 values of KP in liquid suppository containing C are significantly higher than those in liquid suppository without C. MRT0→24 and MRT0→∞ values of liquid suppository containing C are significantly higher than those in liquid suppository without C and conventional suppository. Conventional suppository and liquid suppository without C significantly gave faster time to reach the maximum plasma concentrations of KP. With regard to the in vitro and in vivo experiments, liquid suppository formulation F5 might be a promising formulation for the development of an effective rectal dosage form.

Keywords

Ketoprofen Thermosensitive gel In situ gelling Liquid suppository Sustained release In vivo 
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Notes

Acknowledgments

The authors wish to thank Research Foundation of Ege University for financial support given to this study. Project number: 06/ECZ/005.

References

  1. Choi HG, Oh YK, Kim CK (1998a) In-situ gelling and mucoadhesive liquid suppository containing acetaminophen: enhanced bioavailability. Int J Pharm 165:23–32CrossRefGoogle Scholar
  2. Choi HG, Jung JH, Ryu JM, Yoon SJ, Oh YK, Kim CK (1998b) Development of in situ-gelling and mucoadhesive acetaminophen liquid suppository. Int J Pharm 165:33–44CrossRefGoogle Scholar
  3. Ege MA, Karasulu HY, Karasulu E, Ertan G (2001) A computer program designed for in vitro dissolution kinetics, in vitro–in vivo kinetic correlations and routine application. In: Proceedings of the 4th Central European Symposium on Pharmaceutical Technology, Vienna, Scientia Pharmaceutica Supplement 1 Band 69, pp S127–S128. http://pharm.ege.edu.tr/applications
  4. Huang CH, Tokumura T, Machida Y, Nagai T (1987) Formulation of double-layered suppository for prolonged stay in lower rectum. Yakuzaigaku 47:42–48Google Scholar
  5. Karasulu E, Karasulu HY, Ertan G, Kırılmaz L, Güneri T (2003) Extended release lipophilic indomethacin microspheres: formulation factors and mathematical equations fitted drug release rates. Eur J Pharm Sci 19:99–104PubMedCrossRefGoogle Scholar
  6. Miyazaki S, Suisha F, Kawasaki N, Shirakawa M, Yamatoya K, Attwood D (1998) Thermally reversible xyloglucan gels as vehicles for rectal drug delivery. J Control Release 56:75–83PubMedCrossRefGoogle Scholar
  7. Özgüney I, Özcan İ, Ertan G, Güneri T (2007) The preparation and evaluation of sustained release suppositories containing ketoprofen and Eudragit RL 100 by using factorial design. Pharm Dev Tech 12:97–107CrossRefGoogle Scholar
  8. Park YJ, Yong CS, Kim HM, Rhee JD, Oh YK, Kim CK, Choi HG (2003) Effect of sodium chloride on the release, absorption and safety of diclofenac sodium delivered by poloxamer gel. Int J Pharm 263:105–111PubMedCrossRefGoogle Scholar
  9. Peppas NA (1985) Analysis of fickian and non-fickian drug release polymers. Pharm Acta Helv 60:110–111PubMedGoogle Scholar
  10. Ryu JM, Chung SJ, Lee MH, Kim CK, Shim CK (1999) Increased bioavailability of propranolol in rats by retaining thermally gelling liquid suppositories in the rectum. J Control Release 59:163–172PubMedCrossRefGoogle Scholar
  11. Tarımcı N, Ermis D (1997) Sustained release characteristics and pharmacokinetic parameters of ketoprofen suppositories using chitosan. Int J Pharm 147:71–77CrossRefGoogle Scholar
  12. Thomas G, Kantor MD (1986) Ketoprofen: a review of its pharmacological and clinical properties. Pharmacotherapy 6:93–103Google Scholar
  13. Yamada T, Onishi H, Machida Y (2001) Sustained release ketoprofen microparticles with ethylcellulose and carboxymethylethylcellulose. J Control Release 75:271–282PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag France 2013

Authors and Affiliations

  • Işık Özgüney
    • 1
  • Anita Kardhiqi
    • 1
  • Gülbeyaz Yıldız
    • 2
    • 3
  • Gökhan Ertan
    • 1
  1. 1.Department of Pharmaceutical Technology, Faculty of PharmacyEge UniversityBornovaTurkey
  2. 2.Department of Biopharmaceutics and Pharmacokinetics, Faculty of PharmacyEge UniversityBornovaTurkey
  3. 3.Ege University Center For Drug Research and Development and Pharmacokinetic Applications (ARGEFAR)BornovaTurkey

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