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AAPS PharmSciTech

, Volume 19, Issue 5, pp 1957–1970 | Cite as

Improved Vemurafenib Dissolution and Pharmacokinetics as an Amorphous Solid Dispersion Produced by KinetiSol® Processing

  • Daniel J. Ellenberger
  • Dave A. Miller
  • Sandra U. Kucera
  • Robert O. WilliamsIII
Research Article Theme: Applications of KinetiSol Dispersing for Advanced Amorphous Solid Dispersions
Part of the following topical collections:
  1. Theme: Applications of KinetiSol Dispersing for Advanced Amorphous Solid Dispersions

Abstract

Vemurafenib is a poorly soluble, low permeability drug that has a demonstrated need for a solubility-enhanced formulation. However, conventional approaches for amorphous solid dispersion production are challenging due to the physiochemical properties of the compound. A suitable and novel method for creating an amorphous solid dispersion, known as solvent-controlled coprecipitation, was developed to make a material known as microprecipitated bulk powder (MBP). However, this approach has limitations in its processing and formulation space. In this study, it was hypothesized that vemurafenib can be processed by KinetiSol into the same amorphous formulation as MBP. The KinetiSol process utilizes high shear to rapidly process amorphous solid dispersions containing vemurafenib. Analysis of the material demonstrated that KinetiSol produced amorphous, single-phase material with acceptable chemical purity and stability. Values obtained were congruent to analysis conducted on the comparator material. However, the materials differed in particle morphology as the KinetiSol material was dense, smooth, and uniform while the MBP comparator was porous in structure and exhibited high surface area. The particles produced by KinetiSol had improved in-vitro dissolution and pharmacokinetic performance for vemurafenib compared to MBP due to slower drug nucleation and recrystallization which resulted in superior supersaturation maintenance during drug release. In the in-vivo rat pharmacokinetic study, both amorphous solid dispersions produced by KinetiSol exhibited mean AUC values at least two-fold that of MBP when dosed as a suspension. It was concluded that the KinetiSol process produced superior dosage forms containing vemurafenib with the potential for substantial reduction in patient pill burden.

KEY WORDS

vemurafenib kinetiSol microprecipitated bulk powder amorphous solid dispersion solubility enhancement 

References

  1. 1.
    Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, et al. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov. 2012;11(11):873–86.CrossRefGoogle Scholar
  2. 2.
    Budha N, Frymoyer A, Smelick G, Jin J, Yago M, Dresser M, et al. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clinical Pharmacology & Therapeutics. 2012;92(2):203–13.CrossRefGoogle Scholar
  3. 3.
    Schilling B, Sucker A, Griewank K, Zhao F, Weide B, Görgens A, et al. Vemurafenib reverses immunosuppression by myeloid derived suppressor cells. Int J Cancer. 2013;133(7):1653–63.CrossRefGoogle Scholar
  4. 4.
    Shah N, Iyer RM, Mair HJ, Choi DS, Tian H, Diodone R, et al. Improved human bioavailability of vemurafenib, a practically insoluble drug, using an amorphous polymer-stabilized solid dispersion prepared by a solvent-controlled coprecipitation process. J Pharm Sci. 2013;102(3):967–81.CrossRefGoogle Scholar
  5. 5.
    Dahan A, Miller JM, Amidon GL. Prediction of solubility and permeability class membership: provisional BCS classification of the world’s top oral drugs. AAPS J. 2009;11(4):740–6.CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Amidon GL, Lennernäs H, Shah VP, Crison JRA. 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.CrossRefGoogle Scholar
  7. 7.
    Zelboraf® Tablets, Roche 2011 [cited FDA. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202429Orig1s000ClinPharmR.pdf.
  8. 8.
    Bergström CA, Charman WN, Porter CJ. Computational prediction of formulation strategies for beyond-rule-of-5 compounds. Adv Drug Deliv Rev. 2016;101:6–21.CrossRefGoogle Scholar
  9. 9.
    He Y, Ho C. Amorphous solid dispersions: utilization and challenges in drug discovery and development. J Pharm Sci. 2015;104(10):3237–58.CrossRefGoogle Scholar
  10. 10.
    Goldinger SM, Rinderknecht J, Dummer R, Kuhn FP, Yang KH, Lee L, et al. A single-dose mass balance and metabolite-profiling study of vemurafenib in patients with metastatic melanoma. Pharmacol Res Perspect. 2015;3(2):e00113.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Mosharraf M, Nyström C. The effect of particle size and shape on the surface specific dissolution rate of microsized practically insoluble drugs. Int J Pharm. 1995;122(1–2):35–47.CrossRefGoogle Scholar
  12. 12.
    Dokoumetzidis A, Macheras P. A century of dissolution research: from Noyes and Whitney to the biopharmaceutics classification system. Int J Pharm. 2006;321:1):1–11.CrossRefGoogle Scholar
  13. 13.
    Brough C, Williams Iii RO. Amorphous solid dispersions and nano-crystal technologies for poorly water-soluble drug delivery. Int J Pharm. 2013;453(1):157–66.CrossRefGoogle Scholar
  14. 14.
    Kalepu S, Manthina M, Padavala V. Oral lipid-based drug delivery systems–an overview. Acta Pharm Sin B. 2013;3(6):361–72.CrossRefGoogle Scholar
  15. 15.
    Fricker G, Kromp T, Wendel A, Blume A, Zirkel J, Rebmann H, et al. Phospholipids and lipid-based formulations in oral drug delivery. Pharm Res. 2010;27(8):1469–86.CrossRefGoogle Scholar
  16. 16.
    Xi N, Zhang Y, Wang Z, Lin T. Wang Q. AACR: Vemurafenib prodrugs suitable for oral and IV administration; 2014.Google Scholar
  17. 17.
    Horbert R, Pinchuk B, Davies P, Alessi D, Peifer C. Photoactivatable prodrugs of antimelanoma agent vemurafenib. ACS Chem Biol. 2015;10(9):2099–107.CrossRefGoogle Scholar
  18. 18.
    Vo CL-N, Park C, Lee B-J. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. Eur J Pharm Biopharm. 2013;85(3:799–813.CrossRefGoogle Scholar
  19. 19.
    Benet LZ, Wu C-Y, Custodio JM. Predicting drug absorption and the effects of food on oral bioavailability. Bulletin Technique Gattefosse. 2006;99:9–16.Google Scholar
  20. 20.
    Van den Mooter G. The use of amorphous solid dispersions: a formulation strategy to overcome poor solubility and dissolution rate. Drug Discov Today Technol. 2012;9(2):e79-e85.Google Scholar
  21. 21.
    Serajuddin A. Solid dispersion of poorly water-soluble drugs: early promises, subsequent problems, and recent breakthroughs. J Pharm Sci. 1999;88(10):1058–66.CrossRefGoogle Scholar
  22. 22.
    Miller DA, Ellenberger D, Gil M. Spray-drying technology. Formulating Poorly Water Soluble Drugs: Springer; 2016. p. 437–525.Google Scholar
  23. 23.
    Paudel A, Worku ZA, Meeus J, Guns S, Van den Mooter G. Manufacturing of solid dispersions of poorly water soluble drugs by spray drying: formulation and process considerations. Int J Pharm. 2013;453(1):253–84.CrossRefGoogle Scholar
  24. 24.
    Gu S, Cai R, Luo T, Chen Z, Sun M, Liu Y, et al. A soluble and highly conductive ionomer for high-performance hydroxide exchange membrane fuel cells. Angew Chem Int Ed. 2009;48(35):6499–502.CrossRefGoogle Scholar
  25. 25.
    Witschi C, Doelker E. Residual solvents in pharmaceutical products: acceptable limits, influences on physicochemical properties, analytical methods and documented values. Eur J Pharm Biopharm. 1997;43(3):215–42.CrossRefGoogle Scholar
  26. 26.
    Haser A, DiNunzio JC, Martin C, McGinity JW, Zhang F. Melt extrusion. Formulating Poorly Water Soluble Drugs: Springer. 2016:383–435.Google Scholar
  27. 27.
    Brown C, DiNunzio J, Eglesia M, Forster S, Lamm M, Lowinger M, et al. Hot-melt extrusion for solid dispersions: composition and design considerations. Amorphous Solid Dispersions: Springer; 2014. p. 197–230.Google Scholar
  28. 28.
    LaFountaine JS, McGinity JW, Williams RO III. Challenges and strategies in thermal processing of amorphous solid dispersions: a review. AAPS PharmSciTech. 2016;17(1):43–55.CrossRefGoogle Scholar
  29. 29.
    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.CrossRefGoogle Scholar
  30. 30.
    Sarode AL, Obara S, Tanno FK, Sandhu H, Iyer R, Shah N. Stability assessment of hypromellose acetate succinate (HPMCAS) NF for application in hot melt extrusion (HME). Carbohydr Polym. 2014;101:146–53.CrossRefGoogle Scholar
  31. 31.
    Janssens S, Nagels S, HNd A, D’Autry W, Van Schepdael A, Van den Mooter G. Formulation and characterization of ternary solid dispersions made up of Itraconazole and two excipients, TPGS 1000 and PVPVA 64, that were selected based on a supersaturation screening study. Eur J Pharm Biopharm. 2008;69(1):158–66.CrossRefGoogle Scholar
  32. 32.
    Albano AA, Desai D, Dinunzio J, Go Z, Iyer RM, Sandhu HK, et al. Pharmaceutical composition with improved bioavailability for high melting hydrophobic compound. Google Patents; 2013.Google Scholar
  33. 33.
    Food and Drug Administration. Center for Drug Evaluation and Research. Clinical Pharmacology and Biopharmaceutics Review (s). 2011;202–429(0).Google Scholar
  34. 34.
    Shah N, Sandhu H, Phuapradit W, Pinal R, Iyer R, Albano A, et al. Development of novel microprecipitated bulk powder (MBP) technology for manufacturing stable amorphous formulations of poorly soluble drugs. Int J Pharm. 2012;438(1):53–60.CrossRefGoogle Scholar
  35. 35.
    Hughey JR, Keen JM, Brough C, Saeger S, McGinity JW. Thermal processing of a poorly water-soluble drug substance exhibiting a high melting point: the utility of KinetiSol® dispersing. Int J Pharm. 2011;419(1):222–30.CrossRefGoogle Scholar
  36. 36.
    Miller DA, Keen JM, Kucera SU. Inventors; DisperSol technologies, LLC, assignee. Formulations of deferasirox and methods of making the same. United States patent application. 2016 Jun 17;15(/185):888.Google Scholar
  37. 37.
    Miller DA. Improved oral absorption of poorly water-soluble drugs by advanced solid dispersion systems: University of Texas 2007.Google Scholar
  38. 38.
    DiNunzio JC, Brough C, Hughey JR, Miller DA, Williams RO, McGinity JW. Fusion production of solid dispersions containing a heat-sensitive active ingredient by hot melt extrusion and Kinetisol® dispersing. Eur J Pharm Biopharm. 2010;74(2):340–51.CrossRefGoogle Scholar
  39. 39.
    Hughey JR, DiNunzio JC, Bennett RC, Brough C, Miller DA, Ma H, et al. Dissolution enhancement of a drug exhibiting thermal and acidic decomposition characteristics by fusion processing: a comparative study of hot melt extrusion and KinetiSol® dispersing. AAPS PharmSciTech. 2010;11(2):760–74.CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Jain S, Patel N, Lin S. Solubility and dissolution enhancement strategies: current understanding and recent trends. Drug Dev Ind Pharm. 2015;41(6):875–87.CrossRefGoogle Scholar
  41. 41.
    Chhabda PJ, Balaji M, Srinivasarao V. Rao KCA. Development and validation of a new simple and stability indicating RP-HPLC method for the determination of vemurafenib in presence of degradant products. Google Scholar
  42. 42.
    Qian F, Huang J, Hussain MA. Drug–polymer solubility and miscibility: stability consideration and practical challenges in amorphous solid dispersion development. J Pharm Sci. 2010;99(7):2941–7.CrossRefGoogle Scholar
  43. 43.
    Hancock BC, Shamblin SL, Zografi G. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharm Res. 1995;12(6):799–806.CrossRefGoogle Scholar
  44. 44.
    Yoshioka M, Hancock BC, Zografi G. Crystallization of indomethacin from the amorphous state below and above its glass transition temperature. J Pharm Sci. 1994;83(12):1700–5.CrossRefGoogle Scholar
  45. 45.
    Hughey JR, Keen JM, Miller DA, Brough C, McGinity JW. Preparation and characterization of fusion processed solid dispersions containing a viscous thermally labile polymeric carrier. Int J Pharm. 2012;438(1):11–9.CrossRefGoogle Scholar
  46. 46.
    LaFountaine JS, Prasad LK, Brough C, Miller DA, McGinity JW, Williams RO III. Thermal processing of PVP-and HPMC-based amorphous solid dispersions. AAPS PharmSciTech. 2016;17(1):120–32.CrossRefGoogle Scholar
  47. 47.
    Huang S, Williams RO. Effects of the preparation process on the properties of amorphous solid dispersions. AAPS PharmSciTech. 2017;Google Scholar
  48. 48.
    Hu J, Rogers TL, Brown J, Young T, Johnston KP, Williams Iii RO. Improvement of dissolution rates of poorly water soluble APIs using novel spray freezing into liquid technology. Pharm Res. 2002;19(9):1278–84.CrossRefGoogle Scholar
  49. 49.
    Tam JM, McConville JT, Williams RO, Johnston KP. Amorphous cyclosporin nanodispersions for enhanced pulmonary deposition and dissolution. J Pharm Sci. 2008;97(11):4915–33.CrossRefGoogle Scholar
  50. 50.
    Dong Z, Chatterji A, Sandhu H, Choi DS, Chokshi H, Shah N. Evaluation of solid state properties of solid dispersions prepared by hot-melt extrusion and solvent co-precipitation. Int J Pharm. 2008;355(1):141–9.CrossRefGoogle Scholar
  51. 51.
    Wurster DE, Taylor PW. Dissolution rates. J Pharm Sci. 1965;54(2):169–75.CrossRefGoogle Scholar
  52. 52.
    Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983;15(1):25–35.CrossRefGoogle Scholar
  53. 53.
    Cardamone JM. Keratin sponge/hydrogel II: active agent delivery. Text Res J. 2013;83(9):917–27.CrossRefGoogle Scholar
  54. 54.
    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.CrossRefGoogle Scholar
  55. 55.
    Tuleu C, Andrieux C, Boy P, Chaumeil J. Gastrointestinal transit of pellets in rats: effect of size and density. Int J Pharm. 1999;180(1):123–31.CrossRefGoogle Scholar
  56. 56.
    Horspool K, Lee C-M, editors. KinetiSol® processed ASDs: performance in vivo and in non-clinical safety studies. San Diego: AAPS Annual Meeting; 2017.Google Scholar
  57. 57.
    Miller DA, Keen, Justin M, Brough, Chris, Kucera, Sandra U, and Ellenberger, Daniel J, Inventor improved formulations of vemurafenib and methods of making the same 2016.Google Scholar
  58. 58.
    Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50(1):47–60.CrossRefGoogle Scholar
  59. 59.
    Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867–76.CrossRefGoogle Scholar
  60. 60.
    Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6.CrossRefGoogle Scholar
  61. 61.
    Hong DS, Morris VK, Fu S, Overman MJ, Piha-Paul SA, Kee BK, et al. Phase 1B study of vemurafenib in combination with irinotecan and cetuximab in patients with BRAF-mutated advanced cancers and metastatic colorectal cancer. Proc Am Soc Clin Oncol; 2014.Google Scholar
  62. 62.
    Flaherty KT, Yasothan U, Kirkpatrick P. Vemurafenib. Nat Rev Drug Discov. 2011;10(11):811–3.CrossRefGoogle Scholar
  63. 63.
    Ellenberger DJ, Miller DA, Williams RO. Expanding the Application and Formulation Space of Amorphous Solid Dispersions with KinetiSol®: A Review. AAPS PharmSciTech. 2018 (In-Review).Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Daniel J. Ellenberger
    • 1
    • 2
  • Dave A. Miller
    • 1
  • Sandra U. Kucera
    • 1
  • Robert O. WilliamsIII
    • 2
  1. 1.DisperSol Technologies, LLCGeorgetownUSA
  2. 2.College of PharmacyThe University of Texas at AustinAustinUSA

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