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

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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.

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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

References

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Nasr M. Influence of microcrystal Formulation on In Vivo absorption of celecoxib in rats. AAPS PharmSciTech. 2013;14(2):719–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  7. Gupta P, Bansal AK. Devitrification of amorphous celecoxib. AAPS PharmSciTech. 2005;6(2):E223–30.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  18. Rawat S, Jain SK. Solubility enhancement of celecoxib using β-cyclodextrin inclusion complexes. Eur J Pharm Biopharm. 2004;57(2):263–7.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  33. Gupta P, Bansal AK. Molecular interactions in celecoxib-PVP-meglumine amorphous system. J Pharm Pharmacol. 2005;57(3):303–10.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. NanGenex Inc., 47-49 Madarász Viktor str, Budapest, 1138, Hungary

    Réka Angi, Tamás Solymosi, Nikoletta Erdősi, Tamás Jordán, Balázs Kárpáti, Orsolya Basa-Dénes, Andrea Ujhelyi, Zsolt Ötvös, László Molnár & Hristos Glavinas

  2. Quotient Sciences, Mere Way, Ruddington, Nottingham, NG11 6JS, UK

    John McDermott, Chris Roe & Stuart Mair

Authors
  1. Réka Angi
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  2. Tamás Solymosi
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Correspondence to Tamás Solymosi.

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Appendices

Appendix 1

Table VIII Comparative PAMPA tabular data
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Appendix 2

Table IX Formulation stability test - PAMPA tabular data
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Angi, R., Solymosi, T., Erdősi, N. et al. Preparation, Pre-clinical and Clinical Evaluation of a Novel Rapidly Absorbed Celecoxib Formulation. AAPS PharmSciTech 20, 90 (2019). https://doi.org/10.1208/s12249-018-1270-2

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  • DOI: https://doi.org/10.1208/s12249-018-1270-2

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