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Development Considerations for Nanocrystal Drug Products

  • Review Article
  • Theme: Nanotechnology in Complex Drug Products: Learning from the Past, Preparing for the Future
  • Published:
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ABSTRACT

Nanocrystal technology has emerged as a valuable tool for facilitating the delivery of poorly water-soluble active pharmaceutical ingredients (APIs) and enhancing API bioavailability. To date, the US Food and Drug Administration (FDA) has received over 80 applications for drug products containing nanocrystals. These products can be delivered by different routes of administration and are used in a variety of therapeutic areas. To aid in identifying key developmental considerations for these products, a retrospective analysis was performed on the submissions received by the FDA to date. Over 60% of the submissions were for the oral route of administration. Based on the Biopharmaceutics Classification System (BCS), most nanocrystal drugs submitted to the FDA are class II compounds that possess low aqueous solubility and high intestinal permeability. Impact of food on drug bioavailability was reduced for most nanocrystal formulations as compared with their micronized counterparts. For all routes of administration, dose proportionality was observed for some, but not all, nanocrystal products. Particular emphasis in the development of nanocrystal products was placed on the in-process tests and controls at critical manufacturing steps (such as milling process), mitigation and control of process-related impurities, and the stability of APIs or polymorphic form (s) during manufacturing and upon storage. This emphasis resulted in identifying challenges to the development of these products including accurate determination of particle size (distribution) of drug substance and/or nanocrystal colloidal dispersion, identification of polymorphic form (s), and establishment of drug substance/product specifications.

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REFERENCES

  1. Shegokar R, Muller RH. Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. Intern J Pharm. 2010;399:129–39.

    Article  CAS  Google Scholar 

  2. Muller RH, Gohla S, Keck CM. State of the art of nanocrystals—special features, production, nanotoxicology aspects and intracellular delivery. Euro J Pharm Biopharm. 2011;78:1–9.

    Article  Google Scholar 

  3. Junghanns JAH, Muller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomedicine. 2008;3:295–309.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Moschwitzer JP. Drug nanocrystals in the commercial pharmaceutical development process. Intern J Pharm. 2013;453:142–56.

    Article  Google Scholar 

  5. Muller RH, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy—rationale for development and what we can expect for the future? Adv Drug Rev. 2001;47:3–19.

    Article  CAS  Google Scholar 

  6. Rabinow BE. Nanosuspensions in drug delivery. Nature Rev/Drug Discovery. 2004;3:785–96.

    Article  CAS  Google Scholar 

  7. Pawar VK, Singh Y, Meher JG, Siddharth G, Chourasia MK. Engineered nanocrystal technology: in vivo fate, targeting and application in drug delivery. J Control Release. 2014;183:51–66.

    Article  CAS  PubMed  Google Scholar 

  8. Peltonen L, Strachan C. Understanding critical quality attributes for nanocrystals from preparation to delivery. Molecules. 2015;20:22286–300.

    Article  CAS  PubMed  Google Scholar 

  9. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry: considering whether an FDA-regulated product involves the application of nanotechnology 2014. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM401695.pdf. Accessed 21 Jan 2016.

  10. Liversidge GC. Drug nanocrystals for improved drug delivery, in: Int Symp Control Release Bioact Matter, workshop on particulate drug delivery systems. Vol. 1996;23

  11. Duchene D, Ponchel G. Bioadhesion of solid oral dosage forms, why and how? Eur J Pharm Biopharm. 1997;44:15–23.

    Article  CAS  Google Scholar 

  12. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Draft guidance for industry: waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system May 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070246.pdf. Accessed 20 Jan 2016.

  13. Wu C-Y, Benet L. Predicting drug disposition via application of BCS: transport/absorption/elimination interplay and development of a biopharmaceutics drug disposition classification system. Pharm Res. 2005;22:11–23.

    Article  CAS  PubMed  Google Scholar 

  14. Hu J, Johnston KP, Williams III RO. Nanoparticle engineering processes for enhancing the dissolution rate of poorly water-soluble drugs. Drug Develop Indus Pharm. 2004;30:233–45.

    Article  Google Scholar 

  15. De Waard H, Frijlink HW, Hinrichs WLJ. Bottom-up preparation techniques for nanocrystals of lipophilic drugs. Pharm Res. 2011;28:1220–3.

    Article  CAS  PubMed  Google Scholar 

  16. Sinha B, Muller RH, Moschwitzer JP. Bottom-up approaches for preparing drug nanocrystals: formulations and factors affecting particle size. International J Pharm. 2013;453:126–41.

    Article  CAS  Google Scholar 

  17. De Waard H, Grasmeijer N, Hinrichs WL, Eissens AC, Pfaffenbach PP, Frijlink HW. Preparation of drug nanocrystals by controlled crystallization: application of a 3-way nozzle to prevent premature crystallization for large scale production. Eur J Pharm Sci. 2009;38:224–9.

    Article  CAS  PubMed  Google Scholar 

  18. Kapoor M, Lee SL, Tyner KM. Considerations for liposomal drug product development from a chemistry, manufacturing, and control perspective. AAPS J. 2017. doi.10.1208/s12248-017-0049-9.

  19. Physicians’ Desk Reference, 70th Edition, 2016.

  20. Butler JM, Dressman JB. The developability classification system: application of biopharmaceutics concepts to formulation development. J Pharm Sci. 2010;99:4940–54.

    Article  CAS  PubMed  Google Scholar 

  21. Butler JM. The optimal use of biorelevant media & simple modeling for the prediction of in vivo oral behavior. June 2011. www.apsgb.co.uk/Events/PastEvents/20110609/James%20Butler.pdf Accessed 23 Jan 2016.

  22. Wu Y, Loper A, Landis E, Hettrick L, Novak L, Lynn K, Chen C, Thompson K, Higgins R, Batra U, Shelukar S, Kwei G, Storey D. The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a beagle dog model predicts improved bioavailability and diminished food effect absorption in human. Int J Pharm. 2004;285:135–46.

    Article  CAS  PubMed  Google Scholar 

  23. Takano R, Takata N, Shiraki K, Higo S, Hayashi Y, Yamashita S. A theoretical-empirical analysis on the initial dissolution rate of drugs from polydispersed particles. Biol Pharm Bull. 2009;32:1885–91.

    Article  CAS  PubMed  Google Scholar 

  24. Shono Y, Jantratid E, Kesisoglou F, Reppas C, Dressman J. Forecasting in vivo oral absorption and food effect of micronized and nanosized aprepitant formulations in humans. Eur J Pharm Biopharm. 2010;76:95–104.

    Article  CAS  PubMed  Google Scholar 

  25. Schmidt LE, Dalhoff K. Food-drug interactions. Drugs. 2002;62:1481–502.

    Article  CAS  PubMed  Google Scholar 

  26. Bijanzadeh M, Mahmoudian M, Salehian P, Khazainia T, Eshghi L, Khosravy A. The bioavailability of griseofulvin from micronized and ultramicronized tablets in nonfasting volunteers. Indian J Physiol Pharmacol. 1990;34:157–61.

    CAS  PubMed  Google Scholar 

  27. Majumdar AK, Howard L, Goldberg MR, Hickey L, Constanzer M, Rothenberg PL, Crumley TM, Panebianco D, Bradstreet TE, Bergman AJ, Waldman SA, Greenberg HE, Butler K, Knops A, Lepeleire ID, Michiels N, Petty KJ. Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers. J Clin Pharmacol. 2006;46:291–300.

    Article  CAS  PubMed  Google Scholar 

  28. Merisko-Liversidge EM, Liversidge GG. Drug nanoparticles: formulating poorly water-soluble compounds. Toxicol Pathol. 2008;36:43–8.

    Article  CAS  PubMed  Google Scholar 

  29. Juenemann D, Jantratid E, Wagner C, Reppas C, Vertzoni M, Dressman JB. Biorelevant in vitro dissolution testing of products containing micronized or nanosized fenofibrate with a view to predicting plasma profiles. Eur J Pharm Biopharm. 2011;77:257–64.

    Article  CAS  PubMed  Google Scholar 

  30. Deschamps B, Musaji N, Gillespie JA. Food effect on the bioavailability of two distinct formulations of megestrol acetate oral suspension. Int J Nanomedicine. 2009;4:185–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Liversidge G. Application of Nanocrystal® technology to poorly water soluble compounds. AAPS Annual Meeting and Exposition, November 8–12, 2009, Los Angeles, California.

  32. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry: extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations 1997.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070239.pdf. Accessed 6 Sept. 2016

  33. Heng D, Cutler DJ, Chan H-K, Yun J, Raper JA. What is a suitable dissolution method for drug nanoparticles? Pharm Res. 2008;25:1696–701.

    Article  CAS  PubMed  Google Scholar 

  34. Juenemann D, Dressman JB. Analytical methods for dissolution testing of nanosized drugs. J Pharmacy Pharmacol. 2012;64:931–43.

    Article  CAS  Google Scholar 

  35. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry: analytical procedures and methods validation for drugs and biologics. July 2015 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm386366.pdf. Accessed 30 Sept. 2016.

  36. International Organization for Standardization (ISO) Technical Committee 24, Subcommittee 4 on Particle Characterization. http://www.iso.org/iso/standards_development/technical_committees/other_bodies/iso_technical_committee.htm?commid=47176. Accessed 30 Sept. 2016

  37. American Society for Testing and Materials (ASTM) erican Society for Testing and Materials (ASTM) International Technical Committee E56 on Nanotechnology. http://www.astm.org/COMMITTEE/E56.htm. Accessed 30 Sept. 2016.

  38. The Nanotechnology Characterization Laboratory (NCL), National Cancer Institute (NCI), National Institutes of Health (NIH). Protocols on physicochemical, in vitro, and in vivo characterization. http://ncl.cancer.gov/working_assay-cascade.asp. Accessed 30 Sept. 2016.

  39. National Institute of Standards and Technology (NIST). Protocols for sample preparation, physicochemical measurements, and biological measurements. http://www.nist.gov/mml/nanoehs-protocols.cfm. Accessed 30 Sept. 2016.

  40. ISO/TS 16195:2013. Nanotechnologies—generic requirements for reference materials for development of methods for characteristic testing, performance testing and safety testing of nano-particle and nano-fiber powders. http://www.iso.org/iso/iso_catalogue/catalogue_tc/catalogue_detail.htm?csnumber=55825

  41. Roebben G, Ramirez-Garcia S, Hackley VA, Roesslein M, Klaessig F, Kestens V, Kestens V, Lynch I, Garner CM, Rowle A, et al. Interlaboratory comparison of size surface charge measurements on nanoparticles prior to biological impact assessment. J Nanopart Res. 2011;13:2675–87.

    Article  Google Scholar 

  42. Patel VR, Agrawal YK. Nanosuspension: an approach to enhance solubility of drugs. J Adv Pharm Tech Res. 2011;2:81–7.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA

    Mei-Ling Chen, Mathew John, Sau L. Lee & Katherine M. Tyner

Authors
  1. Mei-Ling Chen
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  2. Mathew John
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  3. Sau L. Lee
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  4. Katherine M. Tyner
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Correspondence to Katherine M. Tyner.

Additional information

Guest Editors: Katherine Tyner, Sau (Larry) Lee, and Marc Wolfgang

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Chen, ML., John, M., Lee, S.L. et al. Development Considerations for Nanocrystal Drug Products. AAPS J 19, 642–651 (2017). https://doi.org/10.1208/s12248-017-0064-x

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