Advertisement

Drug Delivery and Translational Research

, Volume 9, Issue 1, pp 344–356 | Cite as

Effect of supersaturation on the oral bioavailability of paclitaxel/polymer amorphous solid dispersion

  • Linlin Miao
  • Yuheng Liang
  • Wenli Pan
  • Jingxin Gou
  • Tian Yin
  • Yu Zhang
  • Haibing He
  • Xing TangEmail author
Original Article
  • 96 Downloads

Abstract

The aim of the present investigation was to evaluate the effect of supersaturation on the oral absorption of paclitaxel (PTX) in vivo. To achieve this, a PTX amorphous solid dispersion (ASD) was prepared by the solvent cast method. Among the enteric polymers tested, hypromellose acetate succinate (HPMCAS) MF was found to be the most suitable polymer for maintaining PTX supersaturation and inhibiting crystallization in vitro. The dissolution rate and extent of the ASD was remarkably improved compared with a physical mixture (PM) of PTX, HPMCAS-MF, and Poloxamer 188 (F68), reaching an apparent drug concentration of 25–30 μg/mL and maintaining it for more than 2 h. The liquid–liquid phase separation (LLPS) concentration of PTX in the presence of HPMCAS-MF was determined to be 23 μg/mL, which was different to that of 40 μg/mL in the absence of polymer. It indicated that HPMCAS was substantially incorporated into the drug-rich phase. Also, HPMCAS could absorb to the PTX surface and provided an interfacial barrier for crystal growth, as well as retard the incorporation of PTX from solution into the growing crystal lattice. The results of X-ray diffraction, differential scanning calorimetry analysis, and transmission electron microscopy confirmed that PTX existed in the amorphous state in the solid dispersion. Compared with the PM group, the ASD prepared with HPMCAS-MF and F68 achieved a 1.78-fold increase in relative oral bioavailability, while PTX solution yielded a 1.56-fold increase, which could be explained that the solubility and the permeability of PTX were not increased simultaneously through supersaturation in vivo. Likely, it was because Cremophor inhibited P-glycoprotein in the intestine to some extent and maintained PTX at a higher concentration for a longer time.

Keywords

Supersaturation Bioavailability Amorphous solid dispersion Polymer PTX 

Notes

Funding information

This work was supported by the National Basic Research Program of China (973 Program, No. 2015CB932103), National Natural Science Foundation of China (No. 81673378), and China Postdoctoral Science Foundation (2016M600216).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All institutional and national guidelines for the care and use of laboratory animals were followed.

References

  1. 1.
    Batlle JF, et al. Oral chemotherapy: potential benefits and limitations. Rev Oncol. 2004;6(6):335–40.Google Scholar
  2. 2.
    Rao VM, Stella VJ. When can cyclodextrins be considered for solubilization purposes? J Pharm Sci. 2003;92(5):927–32.Google Scholar
  3. 3.
    Dahan A, Beig A, Lindley D, Miller JM. The solubility-permeability interplay and oral drug formulation design: two heads are better than one. Adv Drug Deliv Rev. 2016;101:99–107.Google Scholar
  4. 4.
    Dahan A, Miller JM. The solubility-permeability interplay and its implications in formulation design and development for poorly soluble drugs. Aaps J. 2012;14(2):244–51.Google Scholar
  5. 5.
    Green MC, Buzdar AU, Smith T, Ibrahim NK, Valero V, Rosales MF, et al. Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23(25):5983–92.Google Scholar
  6. 6.
    Rowinsky EK, et al. Taxol: the first of the taxanes, an important new class of antitumor agents. Semin Oncol. 1992;19(6):646.Google Scholar
  7. 7.
    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.Google Scholar
  8. 8.
    Mo R, Jin X, Li N, Ju C, Sun M, Zhang C, et al. The mechanism of enhancement on oral absorption of paclitaxel by N-octyl-O-sulfate chitosan micelles. Biomaterials. 2011;32(20):4609–20.Google Scholar
  9. 9.
    Feng SS, Zhao L, Zhang Z, Bhakta G, Yin Win K, Dong Y, et al. Chemotherapeutic engineering: vitamin E TPGS-emulsified nanoparticles of biodegradable polymers realized sustainable paclitaxel chemotherapy for 168h in vivo. Chem Eng Sci. 2007;62(23):6641–8.Google Scholar
  10. 10.
    Wang XX, et al. The antitumor efficacy of functional paclitaxel nanomicelles in treating resistant breast cancers by oral delivery. Biomaterials. 2011;32(12):3285.Google Scholar
  11. 11.
    Lv PP, Wei W, Yue H, Yang TY, Wang LY, Ma GH. Porous quaternized chitosan nanoparticles containing paclitaxel nanocrystals improved therapeutic efficacy in non-small-cell lung cancer after oral administration. Biomacromolecules. 2011;12(12):4230–9.Google Scholar
  12. 12.
    Liu F, Park JY, Zhang Y, Conwell C, Liu Y, Bathula SR, et al. Targeted cancer therapy with novel high drug-loading nanocrystals. J Pharm Sci. 2010;99(8):3542–51.Google Scholar
  13. 13.
    Lee E, Lee J, Lee IH, Yu M, Kim H, Chae SY, et al. Conjugated chitosan as a novel platform for oral delivery of paclitaxel. J Med Chem. 2008;51(20):6442–9.Google Scholar
  14. 14.
    Jain S, Kumar D, Swarnakar NK, Thanki K. Polyelectrolyte stabilized multilayered liposomes for oral delivery of paclitaxel. Biomaterials. 2012;33(28):6758–68.Google Scholar
  15. 15.
    Mazzaferro S, Bouchemal K, Ponchel G. Oral delivery of anticancer drugs I: general considerations. Drug Discov Today. 2013;18(1–2):25–34.Google Scholar
  16. 16.
    Roger E, Lagarce F, Garcion E, Benoit JP. Lipid nanocarriers improve paclitaxel transport throughout human intestinal epithelial cells by using vesicle-mediated transcytosis. J Control Release. 2009;140(2):174–81.Google Scholar
  17. 17.
    Batrakova EV, Han HY, Alakhov VY, Miller DW, Kabanov AV. Effects of pluronic block copolymers on drug absorption in Caco-2 cell monolayers. Pharm Res. 1998;15(6):850–5.Google Scholar
  18. 18.
    Sue May L, et al. Enhancement of docetaxel solubility using binary and ternary solid dispersion systems. Drug Dev Ind Pharm. 2015;41(11):1.Google Scholar
  19. 19.
    Warren DB, Benameur H, Porter CJH, Pouton CW. Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: a mechanistic basis for utility. J Drug Target. 2010;18(10):704–31.Google Scholar
  20. 20.
    Seeballuck F, Ashford MB, O'Driscoll CM. The effects of pluronics block copolymers and Cremophor EL on intestinal lipoprotein processing and the potential link with P-glycoprotein in Caco-2 cells. Pharm Res. 2003;20(7):1085–92.Google Scholar
  21. 21.
    Curatolo W, Nightingale JA, Herbig SM. Utility of hydroxypropylmethylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug Supersaturation in the GI milieu. Pharm Res. 2009;26(6):1419–31.Google Scholar
  22. 22.
    Sawicki E, Schellens JHM, Beijnen JH, Nuijen B. Inventory of oral anticancer agents: pharmaceutical formulation aspects with focus on the solid dispersion technique. Cancer Treat Rev. 2016;50:247–63.Google Scholar
  23. 23.
    Amidon GL, Lennernäs H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12(3):413–20.Google Scholar
  24. 24.
    Rabizzoni P. Development of a rebamipide solid dispersion system with improved dissolution and oral bioavailability. Arch Pharm Res. 2015;38(4):522.Google Scholar
  25. 25.
    Shuai S, Yue S, Huang Q, Wang W, Yang J, Lan K, et al. Preparation, characterization and in vitro/vivo evaluation of tectorigenin solid dispersion with improved dissolution and bioavailability. Eur J Drug Metab Pharmacokinet. 2016;41(4):413–22.Google Scholar
  26. 26.
    Miller JM, Beig A, Carr RA, Spence JK, Dahan A. A win-win solution in oral delivery of lipophilic drugs: supersaturation via amorphous solid dispersions increases apparent solubility without sacrifice of intestinal membrane permeability. Mol Pharm. 2012;9(7):2009–16.Google Scholar
  27. 27.
    Beig A, Fine-Shamir N, Lindley D, Miller JM, Dahan A. Advantageous solubility-permeability interplay when using amorphous solid dispersion (ASD) formulation for the BCS class IV P-gp substrate Rifaximin: simultaneous increase of both the solubility and the permeability. Aaps J. 2017;19(3):806–13.Google Scholar
  28. 28.
    Blandizzi C, Viscomi GC, Scarpignato C. Impact of crystal polymorphism on the systemic bioavailability of rifaximin, an antibiotic acting locally in the gastrointestinal tract, in healthy volunteers. Drug Des Devel Ther. 2014;9:1–11.Google Scholar
  29. 29.
    Walle UK, Walle T. Taxol transport by human intestinal epithelial Caco-2 cells. Drug Metab Dispos. 1998;26(4):343.Google Scholar
  30. 30.
    Sandström M, et al. The pharmacokinetics of epirubicin and docetaxel in combination in rats. Cancer Chemother Pharmacol. 1999;44(6):469–74.Google Scholar
  31. 31.
    Peltier S, Oger JM, Lagarce F, Couet W, Benoît JP. Enhanced oral paclitaxel bioavailability after administration of paclitaxel-loaded lipid nanocapsules. Pharm Res. 2006;23(6):1243–50.Google Scholar
  32. 32.
    Artursson P. Coexistence of passive and carrier-mediated processes in drug transport. Nat Rev Drug Discov. 2010;9(8):597–614.Google Scholar
  33. 33.
    Abuasal BS, Bolger MB, Walker DK, Kaddoumi A. In silico modeling for the nonlinear absorption kinetics of UK-343,664: a P-gp and CYP3A4 substrate. Mol Pharm. 2012;9(3):492–504.Google Scholar
  34. 34.
    Cisternino S, Bourasset F, Archimbaud Y, Sémiond D, Sanderink G, Scherrmann JM. Nonlinear accumulation in the brain of the new taxoid TXD258 following saturation of P-glycoprotein at the blood-brain barrier in mice and rats. Br J Pharmacol. 2003;138(7):1367–75.Google Scholar
  35. 35.
    Varma MVS, Khandavilli Sateesh A, Panchagnula R. Functional role of P-glycoprotein in limiting intestinal absorption of drugs: contribution of passive permeability to P-glycoprotein mediated efflux transport. Mol Pharm. 2005;2(1):12–21.Google Scholar
  36. 36.
    Moes J, Koolen S, Huitema A, Schellens J, Beijnen J, Nuijen B. Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel. Eur J PharmBiopharm. 2013;83(1):87–94.Google Scholar
  37. 37.
    Huizing MT, Rosing H, Koopman F, Keung ACF, Pinedo HM, Beijnen JH. High-performance liquid chromatographic procedures for the quantitative determination of paclitaxel (Taxol) in human urine. J Chromatogr B Biomed Appl. 1995;664(2):373–82.Google Scholar
  38. 38.
    Piao H, et al. A pre-formulation study of a polymeric solid dispersion of paclitaxel prepared using a quasi-emulsion solvent diffusion method to improve the oral bioavailability in rats. Drug Dev Ind Pharm. 2016;42(3):1–11.Google Scholar
  39. 39.
    Ilevbare GA, Taylor LS. Liquid–liquid phase separation in highly supersaturated aqueous solutions of poorly water-soluble drugs: implications for solubility enhancing formulations. Cryst Growth Des. 2013;13(4):1497–509.Google Scholar
  40. 40.
    Jackson MJ, Toth SJ, Kestur US, Huang J, Qian F, Hussain MA, et al. Impact of polymers on the precipitation behavior of highly supersaturated aqueous danazol solutions. Mol Pharm. 2014;11(9):3027–38.Google Scholar
  41. 41.
    Chen Y, et al. Sodium lauryl sulphate competitively interacts with HPMC-AS and consequently reduces oral bioavailability of posaconazole/HPMC-AS amorphous solid dispersion. Mol Pharm. 2016;13(8)Google Scholar
  42. 42.
    Ueda K, Higashi K, Moribe K. Direct NMR monitoring of phase separation behavior of highly supersaturated Nifedipine solution stabilized with Hypromellose derivatives. Mol Pharm. 2017;14(7):2314–22.Google Scholar
  43. 43.
    Ilevbare GA, Liu H, Pereira J, Edgar KJ, Taylor LS. Influence of additives on the properties of nanodroplets formed in highly supersaturated aqueous solutions of ritonavir. Mol Pharm. 2013;10(9):3392–403.Google Scholar
  44. 44.
    Ilevbare GA, et al. Effect of binary additive combinations on solution crystal growth of the poorly water-soluble drug, Ritonavir. Cryst Growth Des. 2017;12(12):6050–60.Google Scholar
  45. 45.
    Raina SA, Zhang GGZ, Alonzo DE, Wu J, Zhu D, Catron ND, et al. Impact of solubilizing additives on supersaturation and membrane transport of drugs. Pharm Res. 2015;32(10):3350–64.Google Scholar
  46. 46.
    Sun DD, Lee PI. Evolution of supersaturation of amorphous pharmaceuticals: the effect of rate of supersaturation generation. Mol Pharm. 2013;10(11):4330–46.Google Scholar
  47. 47.
    Lahav M, Leiserowitz L. The effect of solvent on crystal growth and morphology. Chem Eng Sci. 2001;56(7):2245–53.Google Scholar
  48. 48.
    Prasad D, Chauhan H, Atef E. Role of molecular interactions for synergistic precipitation inhibition of poorly soluble drug in supersaturated drug-polymer-polymer ternary solution. Mol Pharm. 2016;13(3):756–65.Google Scholar
  49. 49.
    Puel F, Verdurand E, Taulelle P, Bebon C, Colson D, Klein JP, et al. Crystallization mechanisms of acicular crystals. J Cryst Growth. 2008;310(1):110–5.Google Scholar
  50. 50.
    Tomaru A, Takeda-Morishita M, Maeda K, Banba H, Takayama K, Kumagai Y, et al. Effects of Cremophor EL on the absorption of orally administered saquinavir and fexofenadine in healthy subjects. Drug Metab Pharmacokinet. 2015;30(3):221–6.Google Scholar
  51. 51.
    Taylor LS, Zhang GG. Physical chemistry of supersaturated solutions and implications for oral absorption. Adv Drug Deliv Rev. 2016;101:122–42.Google Scholar
  52. 52.
    Frenkel YV, Clark AD, Das K, Wang YH, Lewi PJ, Janssen PAJ, et al. Concentration and pH dependent aggregation of hydrophobic drug molecules and relevance to oral bioavailability. J Med Chem. 2005;48(6):1974–83.Google Scholar
  53. 53.
    Indulkar AS, Gao Y, Raina SA, Zhang GGZ, Taylor LS. Exploiting the phenomenon of liquid–liquid phase separation for enhanced and sustained membrane transport of a poorly water-soluble drug. Mol Pharm. 2016;13(6):2059–69.Google Scholar

Copyright information

© Controlled Release Society 2018

Authors and Affiliations

  1. 1.Department of Pharmaceutics, School of PharmacyShenyang Pharmaceutical UniversityShenyangChina
  2. 2.School of Functional Food and WineShenyang Pharmaceutical UniversityShenyangChina

Personalised recommendations