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AAPS PharmSciTech

, Volume 19, Issue 8, pp 3571–3583 | Cite as

Novel Self-Assembled Ibrutinib-Phospholipid Complex for Potently Peroral Delivery of Poorly Soluble Drugs with pH-Dependent Solubility

  • Qiujun Qiu
  • Mei Lu
  • Cong Li
  • Xiang Luo
  • Xinrong Liu
  • Ling Hu
  • Mingqi Liu
  • Huangliang Zheng
  • Hongxia Zhang
  • Min Liu
  • Chaoyang Lai
  • Yanzhi Song
  • Yihui Deng
Research Article Theme: Lipid-Based Drug Delivery Strategies for Oral Drug Delivery
  • 64 Downloads
Part of the following topical collections:
  1. Theme: Lipid-Based Drug Delivery Strategies for Oral Drug Delivery

Abstract

As an irreversible small-molecule kinase inhibitor, ibrutinib (IBR) exhibits excellent tumor suppression in various tumor cells. However, IBR is insoluble at neutral pH and can dissolve only at low pH: thus, commercial IBR products present poor bioavailability and weakened in vivo antitumor activity. Therefore, we aimed to develop a stable IBR-phospholipid complex (IBR-PC) using egg phosphatidylglycerol (EPG) as excipients to improve the bioavailability of IBR and further enhance its antitumor effects. IBR-PC was characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray powder diffraction (XPRD), and molecular docking and simulation test, which all explained the interactions of two components. Solubility tests demonstrate that the novel formulation can maintain excellent solubility (above 5 mg/mL) at various pH levels. Storage stability tests show that no change in particle size or content of IBR-PC was observed during the experimental period. In vivo pharmacokinetic results demonstrated that the relative bioavailability of IBR-PC was a 9.14-fold improvement relative to that of IBR suspension (IBR-susp). Furthermore, IBR-PC was associated with enhanced cytotoxic activity in vitro and superior tumor growth suppression in vivo compared to that resulting from the free IBR. Thus, the proposed IBR-PC system is a promising drug delivery system that enhances the oral bioavailability of IBR, resulting in its improved in vivo antitumor effect.

KEY WORDS

ibrutinib phospholipid complex egg phosphatidylglycerol bioavailability antitumor activity 

Notes

Acknowledgements

This research was supported by the National Natural Science Foundation of China (No. 81373334 and No. 81573375).

Compliance with Ethical Standards

All animal experiments were performed in accordance with the guidelines of the Animal Welfare Committee of Shenyang Pharmaceutical University. The protocol numbers of the animal studies were SYPU-IACUC-C2018-1-24-201 and SYPU-IACUC- C2018-4-4-101.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120(6):1175–84.CrossRefGoogle Scholar
  2. 2.
    Rauf F, Festa F, Park JG, Magee M, Eaton S, Rinaldi C, et al. Ibrutinib inhibition of ERBB4 reduces cell growth in a WNT5A-dependent manner. Oncogene. 2018;37(17):2237–50.CrossRefGoogle Scholar
  3. 3.
    Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2012;31(1):88–94.CrossRefGoogle Scholar
  4. 4.
    Barrientos J, Rai K. Ibrutinib: a novel Bruton’s tyrosine kinase inhibitor with outstanding responses in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2013;54(8):1817–20.CrossRefGoogle Scholar
  5. 5.
    Nalley C. Ibrutinib granted breakthrough therapy designation by FDA for cGVHD treatment. Oncology Times. 2016;38(14):5–6.Google Scholar
  6. 6.
    Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci. 2010;107(29):13075–80.CrossRefGoogle Scholar
  7. 7.
    Berglöf A, Hamasy A, Meinke S, Palma M, Krstic A, Månsson R, et al. Targets for ibrutinib beyond B cell malignancies. Scand J Immunol. 2015;82(3):208–17.CrossRefGoogle Scholar
  8. 8.
    Wang X, Wong J, Sevinsky CJ, Kokabee L, Khan F, Sun Y, et al. Bruton’s tyrosine kinase inhibitors prevent therapeutic escape in breast cancer cells. Molecular cancer therapeutics. 2016:molcanther. 0813.2015.Google Scholar
  9. 9.
    Cohen MS, Zhang C, Shokat KM, Taunton J. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science. 2005;308(5726):1318–21.CrossRefGoogle Scholar
  10. 10.
    Leproult E, Barluenga S, Moras D, Wurtz J-M, Winssinger N. Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. J Med Chem. 2011;54(5):1347–55.CrossRefGoogle Scholar
  11. 11.
    Use CfMPfH. Guideline on the investigation of bioequivalence. London: European Medicines Agency; 2010.Google Scholar
  12. 12.
    Zvonicek V, Skorepova E, Dusek M, Babor M, Zvatora P, Soos M. First crystal structures of pharmaceutical ibrutinib: systematic solvate screening and characterization. Cryst Growth Des. 2017;17(6):3116–27.CrossRefGoogle Scholar
  13. 13.
    de Jésus NP, Kabamba B, Dahlqvist G, Sempoux C, Lanthier N, Shindano T, et al. Occult HBV reactivation induced by ibrutinib treatment: a case report. Acta Gastro-Enterol Belg. 2015;78Google Scholar
  14. 14.
    Atluri H, Chong CW, Kuehl R, Shu C, Tay PS-C, Hulvat JF, et al. Novel formulations of a Bruton’s tyrosine kinase inhibitor. Google Patents; 2017.Google Scholar
  15. 15.
    Chen M, Zhang Y, Chaohui Y, Zhang X, Wang P, Li P, et al. Crystalline form I of ibrutinib. Google Patents; 2017.Google Scholar
  16. 16.
    Sebastian R, Erdmann M, Albrecht W. Acid addition salt of ibrutinib. Google Patents; 2017.Google Scholar
  17. 17.
    Shakeel F, Iqbal M, Ezzeldin E. Bioavailability enhancement and pharmacokinetic profile of an anticancer drug ibrutinib by self-nanoemulsifying drug delivery system. J Pharm Pharmacol. 2016;68(6):772–80.CrossRefGoogle Scholar
  18. 18.
    Mukherjee P, Maiti K, Kumar V. Value added drug delivery systems with botanicals: approach for dosage development from natural resources. Pharm Rev. 2007;6:57–60.Google Scholar
  19. 19.
    Samuni A, Chong PL, Barenholz Y, Thompson T. Physical and chemical modifications of adriamycin: iron complex by phospholipid bilayers. Cancer Res. 1986;46(2):594–9.Google Scholar
  20. 20.
    Tanhuanpää K, Cheng KH, Anttonen K, Virtanen JA, Somerharju P. Characteristics of pyrene phospholipid/γ-cyclodextrin complex. Biophys J. 2001;81(3):1501–10.CrossRefGoogle Scholar
  21. 21.
    Raju TP, Reddy MS, Reddy VP. Phytosomes: a novel phyto-phospholipid carrier for herbal drug delivery. Int Res J Pharm. 2011;2(6):28–33.Google Scholar
  22. 22.
    Loguercio C, Andreone P, Brisc C, Brisc MC, Bugianesi E, Chiaramonte M, et al. Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Free Radic Biol Med. 2012;52(9):1658–65.CrossRefGoogle Scholar
  23. 23.
    Semalty A, Semalty M, Rawat B, Singh D, Rawat M. Pharmacosomes: the lipid-based new drug delivery system. Expert Opin Drug Deliv. 2009;6(6):599–612.CrossRefGoogle Scholar
  24. 24.
    Lu M, Qiu Q, Luo X, Liu X, Sun J, Wang C, et al. Phyto-phospholipid complexes (phytosomes): a novel strategy to improve the bioavailability of active constituents. Asian J Pharm Sci. 2018.  https://doi.org/10.1016/j.ajps.2018.05.011.
  25. 25.
    Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31(2):455–61.Google Scholar
  26. 26.
    Zhou S, Zhang T, Peng B, Luo X, Liu X, Hu L, et al. Targeted delivery of epirubicin to tumor-associated macrophages by sialic acid-cholesterol conjugate modified liposomes with improved antitumor activity. Int J Pharm. 2017;523(1):203–16.CrossRefGoogle Scholar
  27. 27.
    Shi J, Zhou S, Kang L, Ling H, Chen J, Duan L, et al. Evaluation of the antitumor effects of vitamin K2 (menaquinone-7) nanoemulsions modified with sialic acid-cholesterol conjugate. Drug Deliv Transl Res. 2018;8(1):1–11.CrossRefGoogle Scholar
  28. 28.
    Abdelwahed W, Degobert G, Stainmesse S, Fessi H. Freeze-drying of nanoparticles: formulation, process and storage considerations. Adv Drug Deliv Rev. 2006;58(15):1688–713.CrossRefGoogle Scholar
  29. 29.
    Jiang Q, Yang X, Du P, Zhang H, Zhang T. Dual strategies to improve oral bioavailability of oleanolic acid: enhancing water-solubility, permeability and inhibiting cytochrome P450 isozymes. Eur J Pharm Biopharm. 2016;99:65–72.CrossRefGoogle Scholar
  30. 30.
    Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK. Curcumin–phospholipid complex: preparation, therapeutic evaluation and pharmacokinetic study in rats. Int J Pharm. 2007;330(1–2):155–63.CrossRefGoogle Scholar
  31. 31.
    Jena SK, Singh C, Dora CP, Suresh S. Development of tamoxifen-phospholipid complex: novel approach for improving solubility and bioavailability. Int J Pharm. 2014;473(1–2):1–9.CrossRefGoogle Scholar
  32. 32.
    Zhang Z, Chen Y, Deng J, Jia X, Zhou J, Lv H. Solid dispersion of berberine–phospholipid complex/TPGS 1000/SiO2: preparation, characterization and in vivo studies. Int J Pharm. 2014;465(1–2):306–16.CrossRefGoogle Scholar
  33. 33.
    Singh C, Bhatt TD, Gill MS, Suresh S. Novel rifampicin–phospholipid complex for tubercular therapy: synthesis, physicochemical characterization and in-vivo evaluation. Int J Pharm. 2014;460(1–2):220–7.CrossRefGoogle Scholar
  34. 34.
    Roderick SL, Chan WW, Agate DS, Olsen LR, Vetting MW, Rajashankar K, et al. Structure of human phosphatidylcholine transfer protein in complex with its ligand. Nat Struct Mol Biol. 2002;9(7):507.Google Scholar
  35. 35.
    Beg S, Raza K, Kumar R, Chadha R, Katare O, Singh B. Improved intestinal lymphatic drug targeting via phospholipid complex-loaded nanolipospheres of rosuvastatin calcium. RSC Adv. 2016;6(10):8173–87.CrossRefGoogle Scholar
  36. 36.
    Khan J, Alexander A, Saraf S, Saraf S. Recent advances and future prospects of phyto-phospholipid complexation technique for improving pharmacokinetic profile of plant actives. J Control Release. 2013;168(1):50–60.CrossRefGoogle Scholar
  37. 37.
    O’Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48–58.CrossRefGoogle Scholar
  38. 38.
    Tan Q, Liu S, Chen X, Wu M, Wang H, Yin H, et al. Design and evaluation of a novel evodiamine-phospholipid complex for improved oral bioavailability. AAPS PharmSciTech. 2012;13(2):534–47.CrossRefGoogle Scholar
  39. 39.
    Awasthi R, Kulkarni G, Pawar VK. Phytosomes: an approach to increase the bioavailability of plant extracts. Int J Pharm Pharm Sci. 2011;3(2):1–3.Google Scholar
  40. 40.
    Peng Q, Zhang Z-R, Sun X, Zuo J, Zhao D, Gong T. Mechanisms of phospholipid complex loaded nanoparticles enhancing the oral bioavailability. Mol Pharm. 2010;7(2):565–75.CrossRefGoogle Scholar
  41. 41.
    Cui F, Shi K, Zhang L, Tao A, Kawashima Y. Biodegradable nanoparticles loaded with insulin–phospholipid complex for oral delivery: preparation, in vitro characterization and in vivo evaluation. J Control Release. 2006;114(2):242–50.CrossRefGoogle Scholar
  42. 42.
    Byrne JD, Betancourt T, Brannon-Peppas L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv Drug Deliv Rev. 2008;60(15):1615–26.CrossRefGoogle Scholar
  43. 43.
    Luo X, Hu L, Zheng H, Liu M, Liu X, Li C, et al. Neutrophil-mediated delivery of pixantrone-loaded liposomes decorated with poly (sialic acid)–octadecylamine conjugate for lung cancer treatment.Google Scholar
  44. 44.
    Moreau T, Barlogis V, Bardin F, Nunes J, Calmels B, Chabannon C, et al. Development of an enhanced B-specific lentiviral vector expressing BTK: a tool for gene therapy of XLA. Gene Ther. 2008;15(12):942–52.CrossRefGoogle Scholar
  45. 45.
    Hendriks RW, Yuvaraj S, Kil LP. Targeting Bruton’s tyrosine kinase in B cell malignancies. Nat Rev Cancer. 2014;14(4):219–32.CrossRefGoogle Scholar
  46. 46.
    Cui H, Li T, Wang L, Su Y, Xian CJ. Dioscorea bulbifera polysaccharide and cyclophosphamide combination enhances anti-cervical cancer effect and attenuates immunosuppression and oxidative stress in mice. Sci Rep. 2016;6:19185.CrossRefGoogle Scholar
  47. 47.
    Yu F, Yu F, McGuire P, Li R, Wang R. Effects of Hydrocotyle sibthorpioides extract on transplanted tumors and immune function in mice. Phytomedicine. 2007;14(2–3):166–71.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Qiujun Qiu
    • 1
  • Mei Lu
    • 1
  • Cong Li
    • 1
  • Xiang Luo
    • 1
  • Xinrong Liu
    • 1
  • Ling Hu
    • 1
  • Mingqi Liu
    • 1
  • Huangliang Zheng
    • 1
  • Hongxia Zhang
    • 1
  • Min Liu
    • 1
  • Chaoyang Lai
    • 1
  • Yanzhi Song
    • 1
  • Yihui Deng
    • 1
  1. 1.College of PharmacyShenyang Pharmaceutical UniversityShenyangChina

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