Skip to main content

Advertisement

Log in

Silica-Lipid Hybrid (SLH) Versus Non-lipid Formulations for Optimising the Dose-Dependent Oral Absorption of Celecoxib

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

ABSTRACT

Purpose

To investigate the dose linearity of celecoxib (CEL) pharmacokinetics from various non-lipid and lipid-based formulations; to probe the mechanisms of CEL absorption from a nano-structured silica-lipid hybrid (SLH) microparticle dosage form.

Methods

Single-dose pharmacokinetic parameters of CEL were determined in fasted rats at dose levels of 5, 20 and 50 mg/kg in aqueous suspensions of pure CEL, Celebrex® and CEL-SLH microparticles formulated using medium-chain lipids (Miglyol 812 or Capmul MCM) and Aerosil® silica nanoparticles. An in vitro lipolysis model was used to characterise the dynamic solubilisation state of CEL under digesting conditions.

Results

CEL-SLH formulations and Celebrex® consistently produced a 2-fold higher maximum plasma concentration (C max) and bioavailability (AUC 0→∞) than pure CEL in a dose-linear manner within the dose range of 5–50 mg/kg CEL (R2 > 0.8). Lipolysis drug phase partition data indicate a 2.5–7.5-fold higher CEL solubilising capacity resulting from the digestion of SLH microparticles as compared to the simulated fasted state endogenous micelles. Strong correlations were obtained between maximum CEL solubilisation levels during lipolysis and in vivo pharmacokinetic parameters (R2 > 0.9).

Conclusions

Collectively, the results highlight the potential of the SLH microparticles in enhancing the bioavailability of CEL in a dose-linear manner as facilitated by supersaturated solubilisation of CEL in the intestinal milieu.

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

Access this article

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

Similar content being viewed by others

REFERENCES

  1. US Food and Drug Administration. Celebrex® (celecoxib) capsules; 1998 December 31. Available from http://www.fda.gov/cder/foi/label/2005/020998s018,019lbl.pdf.

  2. US Food and Drug Administration. COX-2 selective (includes Bextra, Celebrex, and Vioxx) and non-selective non-steroidal anti-Inflammatory drugs (NSAIDs); 2005 July 4. Available from http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103420.htm.

  3. Australian Therapeutic Goods Administration. Medicines Regulator cancels registration of anti-inflammatory drug, Lumiracoxib (Prexige); 2007 August 11. Available from http://www.tga.gov.au/media/2007/070811-lumiracoxib.htm.

  4. Paulson SK, Vaughn MB, Jessen SM, Lawal Y, Gresk CJ, Yan B, et al. Pharmacokinetics of celecoxib after oral administration in dogs and humans: effect of food and site of absorption. J Pharmacol Exp Ther. 2001;297(2):638–45.

    PubMed  CAS  Google Scholar 

  5. Dixit RP, Nagarsenker MS. In vitro and in vivo advantage of celecoxib surface solid dispersion and dosage form development. Indian J Pharm Sci. 2007;69(3):370–7.

    Article  CAS  Google Scholar 

  6. Mamidi RNVS, Mullangi R, Kota J, Bhamidipati R, Khan AA, Katneni K, et al. Pharmacological and pharmacokinetics evaluation of celecoxib prodrugs in rats. Biopharm Drug Dispos. 2002;23(7):273–82.

    Article  PubMed  CAS  Google Scholar 

  7. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, Fitzgerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. P Natl Acad Sci USA. 1999;96(1):272–7.

    Article  CAS  Google Scholar 

  8. Humberstone AJ, Charman WN. Lipid-based vehicles for the oral delivery of poorly water soluble drugs. Adv Drug Deliv Rev. 1997;25(1):103–28.

    Article  CAS  Google Scholar 

  9. Pouton CW. Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci. 2006;29(3–4):278–87.

    Article  PubMed  CAS  Google Scholar 

  10. Hauss DJ. Oral lipid-based formulations. Adv Drug Deliv Rev. 2007;59(7):667–76.

    Article  PubMed  CAS  Google Scholar 

  11. Ghouchi Eskandar N, Simovic S, Prestidge CA. Synergistic effect of silica nanoparticles and charged surfactants in the formation and stability of submicron oil-in-water emulsions. Phys Chem Chem Phys. 2007;9(48):6426–34.

    Article  PubMed  CAS  Google Scholar 

  12. Ghouchi Eskandar N, Simovic S, Prestidge CA. Chemical stability and phase distribution of all-trans-retinol in nanoparticle-coated emulsions. Int J Pharm. 2009;376(1-2):186–94.

    Article  Google Scholar 

  13. Mohanraj VJ, Barnes TJ, Prestidge CA. Silica nanoparticle coated liposomes: a new type of hybrid nanocapsule for proteins. Int J Pharm. 2010;392(1–2):285–93.

    Article  PubMed  CAS  Google Scholar 

  14. Tan A, Simovic S, Davey AK, Rades T, Prestidge CA. Silica-lipid hybrid (SLH) microcapsules: a novel oral delivery system for poorly soluble drugs. J Control Release. 2009;134(1):62–70.

    Article  PubMed  CAS  Google Scholar 

  15. Simovic S, Heard P, Hui H, Song Y, Peddie F, Davey AK, et al. Dry hybrid lipid-silica microcapsules engineered from submicron lipid droplets and nanoparticles as a novel delivery system for poorly soluble drugs. Mol Pharm. 2009;6(3):861–72.

    Article  PubMed  CAS  Google Scholar 

  16. Ghouchi Eskandar N, Simovic S, Prestidge CA. Nanoparticle coated submicron emulsions: sustained in-vitro release and improved dermal delivery of all-trans-retinol. Pharm Res. 2009;26(7):1764–75.

    Article  PubMed  CAS  Google Scholar 

  17. Simovic S, Hui H, Song Y, Davey AK, Rades T, Prestidge CA. An oral delivery system for indomethicin engineered from cationic lipid emulsions and silica nanoparticles. J Control Release. 2010;143(3):367–73.

    Article  PubMed  CAS  Google Scholar 

  18. Sanganwar GP, Gupta RB. Dissolution-rate enhancement of fenofibrate by adsorption onto silica using supercritical carbon dioxide. Int J Pharm. 2008;360(1–2):213–8.

    Article  PubMed  CAS  Google Scholar 

  19. Mellaerts R, Mols R, Jammaer JAG, Aerts CA, Annaert P, Van Humbeeck J, et al. Increasing the oral bioavailability of the poorly water soluble drug itraconazole with ordered mesoporous silica. Eur J Pharm Biopharm. 2008;69(1):223–30.

    Article  PubMed  CAS  Google Scholar 

  20. Wang F, Hui H, Barnes TJ, Barnett C, Prestidge CA. Oxidized mesoporous silicon microparticles for improved oral delivery of poorly soluble drugs. Mol Pharm. 2010;7(1):227–36.

    Article  PubMed  CAS  Google Scholar 

  21. Prestidge CA, Barnes TJ, Lau C-H, Barnett C, Loni A, Canham L. Mesoporous silicon: a platform for the delivery of therapeutics. Expert Opin Drug Deliv. 2007;4(2):101–10.

    Article  PubMed  CAS  Google Scholar 

  22. Brouwers J, Brewster ME, Augustijns P. Supersaturating drug delivery systems: the answer to solubility-limited oral bioavailability? J Pharm. Sci. 2009;98(8):2549–72.

    CAS  Google Scholar 

  23. Guzman HR, Tawa M, Zhang Z, Ratanabanangkoon P, Shaw P, Gardner CR, et al. Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. J Pharm Sci. 2007;96(10):2686–702.

    Article  PubMed  CAS  Google Scholar 

  24. Adeyeye MC, Brittain HG. Preformulation in solid dosage form development. New York: Informa Healthcare; 2008.

    Google Scholar 

  25. Sek L, Porter CJH, Charman WN. Characterisation and quantification of medium chain and long chain triglycerides and their in vitro digestion products, by HPTLC coupled with in situ densitometric analysis. J Pharmaceut Biomed. 2001;25(3–4):651–61.

    Article  CAS  Google Scholar 

  26. Schoenwald RD, editor. Pharmacokinetics in drug discovery and development. Boca Raton: CRC; 2002.

    Google Scholar 

  27. Shchipunov YA. Lecithin organogel: a micellar system with unique properties. Colloid Surface A. 2001;183–185:541–54.

    Article  Google Scholar 

  28. Constantinides PP, Scalart J-P, Lancaster C, Marcello J, Marks G, Ellens H, et al. Formulation and intestinal absorption enhancement evaluation of water-in-oil microemulsions incorporating medium-chain glycerides. Pharm Res. 1994;11(10):1385–90.

    Article  PubMed  CAS  Google Scholar 

  29. Puranajoti P, Patil RT, Sheth PD, Bommareddy G, Dondeti P, Egbaria K. Design and development of topical microemulsion for poorly water-soluble antifungal agents. J Appl Res. 2002;2(1):XXVII–XXVIII.

    Google Scholar 

  30. Sari P, Razzak M, Tucker IG. Isotropic medium chain mono–diglyceride/oil/water formulations for solubilization of lipophilic and hydrophilic drugs. Int J Pharm. 2004;270(1–2):287–96.

    Article  PubMed  CAS  Google Scholar 

  31. Pieroni G, Verger R. Hydrolysis of mixed monomolecular films of triglyceride/lecithin by pancreatic lipase. J Biol Chem. 1979;254(20):10090–4.

    PubMed  CAS  Google Scholar 

  32. Seedher N, Bhatia S. Solubility enhancement of COX-2 inhibitors using various solvent systems. AAPS PharmSciTech. 2003;4(3):1–9.

    Article  Google Scholar 

  33. Dressman JB, Lennernas H. Oral drug absorption: prediction and asessment. New York: Marcel Dekker; 2000.

    Google Scholar 

  34. Tan A, Simovic S, Davey AK, Rades T, Boyd BJ, Prestidge CA. Silica nanoparticles to control the lipase-mediated digestion of lipid-based oral delivery systems. Mol Pharm. 2010;7(2):522–32.

    Article  PubMed  CAS  Google Scholar 

  35. Urum K, Pekdemir T. Evaluation of biosurfactants for crude oil contaminated soil washing. Chemosphere. 2004;57(9):1139–50.

    Article  PubMed  CAS  Google Scholar 

  36. Sek L, Porter CJH, Kaukonen AM, Charman WN. Evaluation of the in-vitro digestion profiles of long and medium chain glycerides and the phase behaviour of their lipolytic products. J Pharm Pharmacol. 2002;54(1):29–41.

    Article  PubMed  CAS  Google Scholar 

  37. Grubbs CJ, Lubet RA, Koki AT, Leahy KM, Masferrer JL, Steele VE, et al. Celecoxib inhibits N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder cancers in male B6D2F1 mice and female Fischer-344 rats. Cancer Res. 2000;60(20):5599–602.

    PubMed  CAS  Google Scholar 

  38. Friedman MI, Ramirez I, Tordoff MG. Gastric emptying of ingested fat emulsion in rats: implications for studies of fat-induced satiety. Am J Physiol - Reg I. 1996;270(3 39-3):R688–R92.

    CAS  Google Scholar 

  39. Porter CJH, Charman WN. In vitro assessment of oral lipid based formulations. Adv Drug Deliv Rev. 2001;50 Suppl 1:S127–S47.

    Article  PubMed  CAS  Google Scholar 

  40. Kaukonen AM, Boyd BJ, Porter CJH, Charman WN. Drug solubilization behavior during in vitro digestion of simple triglyceride lipid solution formulations. Pharm Res. 2004;21(2):245–53.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

The authors would like to thank Miss Kathy Lee (Monash Institute of Pharmaceutical Sciences) for technical support on the lipolysis work and Dr. Mihail Popescu (Ian Wark Research Institute) for useful discussion. Financial support of the Australian Research Council, Bio Innovation SA and Itek Pty. Ltd. are also gratefully acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Clive A. Prestidge.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tan, A., Davey, A.K. & Prestidge, C.A. Silica-Lipid Hybrid (SLH) Versus Non-lipid Formulations for Optimising the Dose-Dependent Oral Absorption of Celecoxib. Pharm Res 28, 2273–2287 (2011). https://doi.org/10.1007/s11095-011-0458-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-011-0458-x

KEY WORDS

Navigation