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.
Similar content being viewed by others
REFERENCES
US Food and Drug Administration. Celebrex® (celecoxib) capsules; 1998 December 31. Available from http://www.fda.gov/cder/foi/label/2005/020998s018,019lbl.pdf.
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.
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.
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.
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.
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.
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.
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.
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.
Hauss DJ. Oral lipid-based formulations. Adv Drug Deliv Rev. 2007;59(7):667–76.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Adeyeye MC, Brittain HG. Preformulation in solid dosage form development. New York: Informa Healthcare; 2008.
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.
Schoenwald RD, editor. Pharmacokinetics in drug discovery and development. Boca Raton: CRC; 2002.
Shchipunov YA. Lecithin organogel: a micellar system with unique properties. Colloid Surface A. 2001;183–185:541–54.
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.
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.
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.
Pieroni G, Verger R. Hydrolysis of mixed monomolecular films of triglyceride/lecithin by pancreatic lipase. J Biol Chem. 1979;254(20):10090–4.
Seedher N, Bhatia S. Solubility enhancement of COX-2 inhibitors using various solvent systems. AAPS PharmSciTech. 2003;4(3):1–9.
Dressman JB, Lennernas H. Oral drug absorption: prediction and asessment. New York: Marcel Dekker; 2000.
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.
Urum K, Pekdemir T. Evaluation of biosurfactants for crude oil contaminated soil washing. Chemosphere. 2004;57(9):1139–50.
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.
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.
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.
Porter CJH, Charman WN. In vitro assessment of oral lipid based formulations. Adv Drug Deliv Rev. 2001;50 Suppl 1:S127–S47.
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.
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
Corresponding author
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-011-0458-x