Advertisement

AAPS PharmSciTech

, 20:90 | Cite as

Preparation, Pre-clinical and Clinical Evaluation of a Novel Rapidly Absorbed Celecoxib Formulation

  • Réka Angi
  • Tamás SolymosiEmail author
  • Nikoletta Erdősi
  • Tamás Jordán
  • Balázs Kárpáti
  • Orsolya Basa-Dénes
  • Andrea Ujhelyi
  • John McDermott
  • Chris Roe
  • Stuart Mair
  • Zsolt Ötvös
  • László Molnár
  • Hristos Glavinas
Research Article
  • 14 Downloads

Abstract

Celecoxib (Celebrex®) is the only widely used NSAID that selectively inhibits the COX-2 isoenzyme. Celebrex® is absorbed slowly in the fasted state and food intake further delays absorption. In this work, an amorphous water dispersible granule formulation of celecoxib is described with in vitro characterization, preclinical and clinical data. The formulation exhibited very high passive permeability and apparent solubility, significantly outperforming the micronized celecoxib and the drug product Celebrex®. The granule formulation remained stable for at least 1 year in stability tests. In dog studies, tmax was 1 h with over 50% of Cmax reached within 15 min regardless of food intake. A phase 1 clinical trial was conducted with 12 volunteers at 100- and 200-mg doses. Celecoxib plasma concentrations reached 250 ng/ml, the effective therapeutic plasma level, in less than 15 min regardless of food or dose. The novel celecoxib formulation is rapidly absorbed, demonstrating the potential utility as an acute treatment offering advantages over the currently marketed product.

KEY WORDS

celecoxib solid dispersion amorphous faster onset of action clinical trial 

Abbreviations

CI

Confidence interval

Cmax

Maximal plasma concentration

AUC

Area under the concentration curve

COX

Cyclooxygenase

ECG

Electrocardiography

FaSSIF

Fasted state simulating intestinal fluid

FeSSIF

Fed state simulating intestinal fluid

GI tract

Gastrointestinal tract

GMR

Geometric mean ratio

HPMC

Hydroxypropylmethylcellulose

IMP

Investigational medicinal product

LOQ

Limit of quantification

MS

Mass spectrometry

NSAID

Non-steroidal anti-inflammatory drug

PES

Polyethersulfonate

PiB

Powder in bottle

PVDF

Polyvinylidene fluoride

PVP

Polyvinylpyrrolidone

S

Solubility

SAE

Serious adverse event

SDS

Sodium dodecyl sulfate

SGF

Simulated gastric fluid

Notes

References

  1. 1.
    Grossman SA, Olson J, Batchelor T, Peereboom D, Lesser G, Desideri S, et al. Effect of phenytoin on celecoxib pharmacokinetics in patients with glioblastoma. Neuro-Oncology. 2008;10(2):190–8.CrossRefGoogle Scholar
  2. 2.
    Nasr M. Influence of microcrystal Formulation on In Vivo absorption of celecoxib in rats. AAPS PharmSciTech. 2013;14(2):719–26.CrossRefGoogle Scholar
  3. 3.
    Shono Y, Jantratid E, Janssen N, Kesisoglou F, Mao Y, Vertzoni M, et al. Prediction of food effects on the absorption of celecoxib based on biorelevant dissolution testing coupled with physiologically based pharmacokinetic modeling. Eur J Pharm Biopharm. 2009;73(1):107–14.CrossRefGoogle Scholar
  4. 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.PubMedGoogle Scholar
  5. 5.
    Lu GW, Hawley M, Smith M, Geiger BM, Pfund W. Characterization of a novel polymorphic form of celecoxib. J Pharm Sci. 2006;95(2):305–17.CrossRefGoogle Scholar
  6. 6.
    Chawla G, Gupta P, Thilagavathi R, Chakraborti AK, Bansal AK. Characterization of solid-state forms of celecoxib. Eur J Pharm Sci. 2003;20(3):305–17.CrossRefGoogle Scholar
  7. 7.
    Gupta P, Bansal AK. Devitrification of amorphous celecoxib. AAPS PharmSciTech. 2005;6(2):E223–30.CrossRefGoogle Scholar
  8. 8.
    Xie T, Taylor LS. Dissolution performance of high drug loading celecoxib amorphous solid dispersions formulated with polymer combinations. Pharm Res. 2016;33(3):739–50.CrossRefGoogle Scholar
  9. 9.
    Homayouni A, Sadeghi F, Nokhodchi A, Varshosaz J, Afrasiabi Garekani H. Preparation and characterization of celecoxib solid dispersions; comparison of poloxamer-188 and PVP-K30 as carriers. Iran J Basic Med Sci. 2014;17(5):322–31.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Lee JH, Kim MJ, Yoon H, Shim CR, Ko HA, Cho SA, et al. Enhanced dissolution rate of celecoxib using PVP and/or HPMC-based solid dispersions prepared by spray drying method. J Pharm Investig. 2013;43(3):205–13.CrossRefGoogle Scholar
  11. 11.
    Abu-Diak OA, Jones DS, Andrews GP. An investigation into the dissolution properties of celecoxib melt extrudates: understanding the role of polymer type and concentration in stabilizing supersaturated drug concentrations. Mol Pharm. 2011;8(4):1362–71.CrossRefGoogle Scholar
  12. 12.
    Andrews GP, Abu-Diak O, Kusmanto F, Hornsby P, Hui Z, Jones DS. Physicochemical characterization and drug-release properties of celecoxib hot-melt extruded glass solutions. J Pharm Pharmacol. 2010;62(11):1580–90.CrossRefGoogle Scholar
  13. 13.
    Remenar JF, Peterson ML, Stephens PW, Zhang Z, Zimenkov Y, Hickey MB. Celecoxib:nicotinamide dissociation: using excipients to capture the cocrystal’s potential. Mol Pharm. 2007;4(3):386–400.CrossRefGoogle Scholar
  14. 14.
    Bolla G, Mittapalli S, Nangia A. Celecoxib cocrystal polymorphs with cyclic amides: synthons of sulfonamide drug with carboxamide coformers. CrysEngComm 2014;16:24-27.Google Scholar
  15. 15.
    Almansa C, Mercè R, Tesson N, Farran J, Tomàs J, Plata-Salamán CR. Co-crystal of tramadol hydrochloride–celecoxib ( ctc ): a novel API–API co-crystal for the treatment of pain. Cryst Growth Des. 2017;17:1884–92.CrossRefGoogle Scholar
  16. 16.
    Reddy MN, Rehana T, Ramakrishna S, Chowdary KPR, Diwan PV. Beta-cyclodextrin complexes of celecoxib: molecular-modeling, characterization, and dissolution studies. AAPS J. 2004;6(1):68–76.CrossRefGoogle Scholar
  17. 17.
    Sinha VR, Anitha R, Ghosh S, Nanda A, Kumria R. Complexation of celecoxib with β-cyclodextrin: characterization of the interaction in solution and in solid state. J Pharm Sci. 2005;94(3):676–87.CrossRefGoogle Scholar
  18. 18.
    Rawat S, Jain SK. Solubility enhancement of celecoxib using β-cyclodextrin inclusion complexes. Eur J Pharm Biopharm. 2004;57(2):263–7.CrossRefGoogle Scholar
  19. 19.
    Kansy M, Senner F, Gubernator K. Screening : Parallel artificial membrane permeation assay in the description of. J Med Chem. 1998;41(7):1007–10.CrossRefGoogle Scholar
  20. 20.
    Bendels S, Tsinman O, Wagner B, Lipp D, Parrilla I, Kansy M, et al. PAMPA-excipient classification gradient map. Pharm Res. 2006;23(11):2525–35.CrossRefGoogle Scholar
  21. 21.
    Oh MH, Lee HJ, Jo SH, Park BB, Park SB, Kim EY, et al. Development of cassette PAMPA for permeability Screening. Biol Pharm Bull. 2017;40(4):419–24.CrossRefGoogle Scholar
  22. 22.
    Mehatha AK, Suryadevara V, Sasidhar R, Deshmukh AM, Sambath LP. Formulation and Optimization of ezetimibe containing solid dispersions using Kollidon VA64. Int J Pharm Life Sci. 2014;11(2):113–25.Google Scholar
  23. 23.
    Shakeel F, Baboota S, Ahuja A, Ali J, Shafiq S. Celecoxib nanoemulsion for transdermal drug delivery: characterization and in vitro evaluation. J Dispers Sci Technol. 2009;30(6):834–42.CrossRefGoogle Scholar
  24. 24.
    Zhang Y, Lam YM. Study of mixed micelles and interaction parameters for polymeric nonionic and Normal surfactants. J Nanosci Nanotechnol. 2006;6(12):3877–81.CrossRefGoogle Scholar
  25. 25.
    Kumar N, Tyagi R. Analysis of the interactions of Polyvinylpyrrolidone with conventional anionic and dimeric anionic surfactant. J Dispers Sci Technol. 2015;36(11):1601–6.CrossRefGoogle Scholar
  26. 26.
    Prasad M, Palepu R, Moulik SP. Interaction between sodium dodecyl sulfate (SDS) and polyvinylpyrrolidone (PVP) investigated with forward and reverse component addition protocols employing tensiometric, conductometric, microcalorimetric, electrokinetic, and DLS techniques. Colloid Polym Sci. 2006;284(8):871–8.CrossRefGoogle Scholar
  27. 27.
    Liu C, Chen Z, Chen Y, Lu J, Li Y, Wang S, et al. Improving Oral bioavailability of Sorafenib by optimizing the “spring” and “parachute” based on molecular interaction mechanisms. Mol Pharm. 2016;13(2):599–608.CrossRefGoogle Scholar
  28. 28.
    He J, Han Y, Xu G, Yin L, Ngandeu Neubi M, Zhou J, et al. Preparation and evaluation of celecoxib nanosuspensions for bioavailability enhancement. RSC Adv. 2017;7(22):13053–64.CrossRefGoogle Scholar
  29. 29.
    Liu Y, Sun C, Hao Y, Jiang T, Zheng L, Wang S. Mechanism of dissolution enhancement and bioavailability of poorly water soluble celecoxib by preparing stable amorphous nanoparticles. J Pharm Pharm Sci. 2010;13(4):589–606.CrossRefGoogle Scholar
  30. 30.
    Fong SYK, Martins SM, Brandl M, Bauer-Brandl A. Solid phospholipid dispersions for Oral delivery of poorly soluble drugs: investigation into celecoxib incorporation and solubility-In Vitro permeability enhancement. J Pharm Sci. 2016;105(3):1113–23.CrossRefGoogle Scholar
  31. 31.
    Ha E-S, Choo G-H, Baek I-H, Kim M-S. Formulation, characterization, and in Vivo evaluation of celecoxib-PVP solid dispersion nanoparticles using supercritical Antisolvent process. Molecules. 2014;19(12):20325–39.CrossRefGoogle Scholar
  32. 32.
    Dhumal RS, Shimpi SL, Paradkar AR. Development of spray-dried co-precipitate of amorphous celecoxib containing storage and compression stabilizers. Acta Pharma. 2007;57(3):287–300.CrossRefGoogle Scholar
  33. 33.
    Gupta P, Bansal AK. Molecular interactions in celecoxib-PVP-meglumine amorphous system. J Pharm Pharmacol. 2005;57(3):303–10.CrossRefGoogle Scholar
  34. 34.
    Ghanavati R, Taheri A, Homayouni A. Anomalous dissolution behavior of celecoxib in PVP/Isomalt solid dispersions prepared using spray drier. Mater Sci Eng C. 2017;72:501–11.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Réka Angi
    • 1
  • Tamás Solymosi
    • 1
    Email author
  • Nikoletta Erdősi
    • 1
  • Tamás Jordán
    • 1
  • Balázs Kárpáti
    • 1
  • Orsolya Basa-Dénes
    • 1
  • Andrea Ujhelyi
    • 1
  • John McDermott
    • 2
  • Chris Roe
    • 2
  • Stuart Mair
    • 2
  • Zsolt Ötvös
    • 1
  • László Molnár
    • 1
  • Hristos Glavinas
    • 1
  1. 1.NanGenex Inc.BudapestHungary
  2. 2.Quotient SciencesNottinghamUK

Personalised recommendations