Nanocrystalization: An Emerging Technology to Enhance the Bioavailability of Poorly Soluble Drugs

Author(s): Kavita Joshi, Akhilesh Chandra, Keerti Jain, Sushama Talegaonkar*.

Journal Name: Pharmaceutical Nanotechnology

Volume 7 , Issue 4 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Most of the active pharmaceutical ingredient used in the management of disease have poor water solubility and offer grueling problems in drug formulation development since low solubility is generally associated with poor dissolution characteristics which leads to poor oral bioavailability. The great challenge for the development of a pharmaceutical product is to create its new formulation and drug delivery system to limit solubility problems of existing drug candidate. Limited drug-loading capacity requires a large amount of carrier material to get appropriate encapsulation of the drug, which is another major challenge in the development of pharmaceutical product which could be resolved by developing nanocrystals (NCs). A significant research in the past few years has been done to develop NCs which helps in the delivery of poorly water soluble drugs via different routes. The technology could continue to thrive as a useful tool in pharmaceutical sciences for the improvement of drug solubility, absorption and bioavailability. Many crystalline compounds have pulled in incredible consideration much of the time, due to their ability to show good physical and chemical properties when contrasted with their amorphous counterparts. Nanocrystals have been proven to show atypical properties compared to the bulk. This review article explores the principles of the important nanocrystallization techniques including NCs characterization and its application.

Keywords: Application, crystalline state, dissocube, dissolution, high pressure homogenization, milling, nanocrystal (NCs), nanoPure.

[1]
Heimbach T, Fleisher D, Kaddoumi A. Overcoming poor aqueous solubility of drugs for oral delivery. In: Prodrugs:. Springer New York; 2007; pp. 157-215.
[2]
Nagarwal RC, Kumar R, Dhanawat M, Das N, Pandit JK. Nanocrystal technology in the delivery of poorly soluble drugs: an overview. Curr Drug Deliv 2011; 8(4): 398-406.
[3]
Zhang H, Li Q, Liu R, Zhang X, Li Z, Luan Y. A versatile prodrug strategy to in situ encapsulate drugs in mof nanocarriers: a case of cytarabine‐ir820 pro-drug encapsulated zif‐8 toward chemo‐photothermal therapy. Adv Funct Mater 2018; 28(35)1802830
[4]
Zhang D, Zhang J, Li Q, et al. pH- and enzyme-sensitive IR820-paclitaxel conjugate self-assembled nanovehicles for near-infrared fluorescence imaging-guided chemo-photothermal therapy. ACS Appl Mater Interfaces 2018; 10(36): 30092-102.
[5]
Zhao L, Li N, Wang K, Shi C, Zhang L, Luan Y. A review of polypeptide-based polymersomes. Biomaterials 2013; 35(4): 1284-301.
[6]
Bhatt V, Shete G, Bansal AK. Mechanism of generation of drug nanocrystals in celecoxib: man-nitol nanocrystalline solid dispersion. Int J Pharm 2015; 495(1): 132-9.
[7]
Uekama K. Design and evaluation of cyclodextrin-based drug formulation. Chem Pharm Bull 2004; 52(8): 900-15.
[8]
Alam MA, Al-Jenoobi FI, Al-mohizea AM. Commercially bioavailable proprietary technologies and their marketed products. Drug Discov Today 2013; 18(19-20): 936-49.
[9]
Monkare J, Hakala RA, Korhonen H, Kiviniemi A, Seppala JV, Jarvinen K. Controlled drug release from crosslinked poly(ester-anhydrides). Eur J Pharm Sci 2008; 34(1): S35-6.
[10]
Keck C, Muller R. Drug nanocrystals of poorly soluble drugs produced by high pressure homo-genisation. Eur J Pharm Biopharm 2006; 62(1): 3-16.
[11]
Armijo LM, Brandt YI, Withers NJ, et al. Multifunctional superparamagnetic nanocrystals for imaging and targeted drug delivery to the lung. In: Parak WJ, Yamamoto K, Osinski M, Eds. Colloidal Nanocrystals for Biomedical Applications.. Bellingham: International Society for Optics and Photonics 2012; p. 82320M.
[12]
Junghanns J-UAH, Müller RH. Nanocrystal tech-nology, drug delivery and clinical applications. Int J Nanomedicine 2008; 3(3): 295-309.
[13]
Elan drug technologies. Technology focus. http://www.farmtech.com
[14]
Zhao J, Liu Y, Wang L, Zhou Y, Du J, Wang Y. Functional and modified nanocrystals technology for target drug delivery. J Nanosci Nanotechnol 2018; 18(8): 5207-21.
[15]
Kettunen R, Peltonen L, Karjalainen M, Hirvonen J. Nanocrystallization of indomethacin by wet ball-milling technique. Eur J Pharm Sci 2008; 34(1): S35.
[16]
Masuda Y. Nanocrystals. Intechopen:. London 2010.
[17]
Merisko-Liversidge E, Liversidge GG, Cooper ER. Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci 2003; 18(2): 113-20.
[18]
Gao L, Zhang D, Chen M. Drug nanocrystals for the formulation of poorly soluble drugs and its application as a potential drug delivery system. J Nanopart Res 2008; 10(5): 845-62.
[19]
Rabinow BE. Nanosuspensions in drug delivery. Nat Rev Drug Discov 2004; 3(9): 785-96.
[20]
What is nanocrystal?Available from: . http: //whatis.techtarget.com/definition/nanocrystal
[21]
Weber M, Westendorf S, Märker B, Braun K, Scheele M. Opportunities and challenges for electrochemistry in studying the electronic structure of nanocrystals. Phys Chem Chem Phys 2019; 21(18): 8992-9001.
[22]
Chen H, Khemtong C, Yang X, Chang X, Gao J. Nanonization strategies for poorly water-soluble drugs. Drug Discov Today 2011; 16(7-8): 354-60.
[23]
Guo S, Huang L. Nanoparticles containing insoluble drug for cancer therapy. Biotechnol Adv 2014; 32(4): 778-88.
[24]
Müller RH, Gohla S, Keck CM. State of the art of nanocrystals-special features, production, nanotoxico-logy aspects and intracellular delivery. Eur J Pharm Biopharm 2011; 78(1): 1-9.
[25]
Bhuyan B, Rajak P, Nath LK. Cremophor-free aqueous paclitaxel nanosuspension-production and chemical stability. World J Pharma Res 2004; 3(2): 2940-71.
[26]
Jinno J, Kamada N, Miyake M, et al. Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs. J Control Release 2006; 111(1-2): 56-64.
[27]
Müller RH, Gohla S, Keck CM. State of the art of nanocrystals-special features, production, nanotoxico-logy aspects and intracellular delivery. Eur J Pharm Biopharm 2011; 78(1): 1-9.
[28]
Fontana F, Figueiredo P, Zhang P, Hirvonen JT, Liu D, Santos HA. Production of pure drug nanocrystals and Nano Co -crystals by confinement methods. Adv Drug Deliv Rev 2018; 131: 3-21.
[29]
Arunkumar N, Deecaraman M, Rani C. Nanosus-pension technology and its applications in drug delivery. Asian J Pharm 2014; 3(3)
[30]
Peltonen L, Hirvonen J. Drug nanocrystals-versatile option for formulation of poorly soluble materials. Int J Pharm 2018; 537(1-2): 73-83.
[31]
Shegokar R, Müller RH. Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. Int J Pharm 2010; 399(1-2): 129-39.
[32]
Liversidge GG, Cundy KC, Bishop JF, Czekai DA. Surface modified drug nanoparticles. US Patent 5145684. 1992.
[33]
Malamatari M, Taylor KMG, Malamataris S, Douroumis D, Kachrimanis K. Pharmaceutical nanocrystals: production by wet milling and applications. Drug Discov Today 2018; 23(3): 534-47.
[34]
Salazar J, Muller RH, Moschwitzer JP. Performance comparison of two novel combinative particle-size-reduction technologies. J Pharm Sci 2013; 102(5): 1636-49.
[35]
Merisko-Liversidge E, Liversidge GG. Nanosizing for oral and parenteral drug delivery: a perspective on formulating poorly-water soluble compounds using wet media milling technology. Adv Drug Deliv Rev 2011; 63(6): 427-40.
[36]
Bruno R, McIlwrick R. Microfluidizer processor technology for high performance particle size reduction, mixing and dispersion. Eur J Pharm Biopharm 1999; 56: 26-36.
[37]
Sun B, Yeo Y. Nanocrystals for the parenteral delivery of poorly water-soluble drugs. Curr Opin Solid State Mater Sci 2012; 16(6): 295-301.
[38]
Muller RH, Jacobs CKO. Nanosuspensions as particulate drug formulations in therapy. Rationale for development and what we can expect for the future. Adv Drug Deliv Rev 2001; 47(1): 3-19.
[39]
Müller RH, Peters K. Nanosuspensions for the formulation of poorly soluble drugs: I. Preparation by a size-reduction technique. Int J Pharm 1998; 160(2): 229-37.
[40]
Müller R, Jacobs C, Kayser O. Nanosuspensions as particulate drug formulations in therapy: rationale for development and what we can expect for the future. Adv Drug Deliv Rev 2001; 47(1): 3-19.
[41]
Peltonen L, Hirvonen J. Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods. J Pharm Pharmacol 2010; 62(11): 1569-79.
[42]
Serrano D, Gallagher K, Healy A. Emerging nanonisation technologies: tailoring crystalline versus amorphous nanomaterials. Curr Top Med Chem 2015; 15(22): 2327-40.
[43]
Agarwal A, Lvov Y, Sawant R, Torchilin V. Stable nanocolloids of poorly soluble drugs with high drug content prepared using the combination of sonication and layer-by-layer technology. J Control Release 2008; 128(3): 255-60.
[44]
Asahi T, Sugiyama T, Masuhara H. Laser fabrication and spectroscopy of organic nanoparticles. Acc Chem Res 2008; 41(12): 1790-8.
[45]
Sylvestre J-P, Tang M-C, Furtos A, Leclair G, Meunier M, Leroux J-C. Nanonization of megestrol acetate by laser fragmentation in aqueous milieu. J Control Release 2011; 149(3): 273-80.
[46]
Sverdlov Arzi R, Sosnik A. Electrohydrodynamic atomization and spray-drying for the production of pure drug nanocrystals and co-crystals. Adv Drug Deliv Rev 2018; 131: 79-100.
[47]
Soliman KA, Ibrahim HK, Ghorab MM. Effects of different combinations of nanocrystallization technologies on avanafil nanoparticles: in vitro, in vivo and stability evaluation. Int J Pharm 2017; 517(1-2): 148-56.
[48]
Bosselmann S, Nagao M, Chow KT, Williams RO III. Influence of formulation and processing variables on properties of itraconazole nanoparticles made by advanced evaporative precipitation into aqueous solution. AAPS PharmSciTech 2012; 13(3): 949-60.
[49]
Padrela L, Rodrigues MA, Duarte A, Dias AMA, Braga MEM, de Sousa HC. Supercritical carbon dioxide-based technologies for the production of drug nanoparticles/nanocrystals - a comprehensive review. Adv Drug Deliv Rev 2018; 131: 22-78.
[50]
Spitzer D, Pichot V, Pessina F, Schnell F, Klaumünzer M, Blas L. Continuous and reactive nanocrystallization: new concepts and processes for dual-use advances. Comptes Rendus Chim 2017; 20(4): 339-45.
[51]
Nordmann J, Buczka S, Voss B, Haase M, Mummenhoff K. In vivo analysis of the size- and time-dependent uptake of NaYF 4: Yb, Er upconversion nanocrystals by pumpkin seedlings. J Mater Chem B 2015; 3(1): 144-50.
[52]
Fateminia SMA, Wang Z, Goh CC, et al. Nanocrystallization: a unique approach to yield bright organic nanocrystals for biological applications. Adv Mater 2017; 29(1)1604100
[53]
Raghava Srivalli KM, Mishra B. Drug nanocrystals: a way toward scale-up. Saudi Pharm J 2016; 24(4): 386-404.
[54]
Müller RH, Keck CM. Second generation of drug nanocrystals for delivery of poorly soluble drugs: smart crystal technology. Eur J Pharm Sci 2008; 34(1): S20-1.
[55]
Sarnes A, Kovalainen M, Hakkinen MR, et al. Nanocrystal-based per-oral itraconazole delivery: superior in vitro dissolution enhancement versus sporanox® is not realized in in vivo drug absorption. J Control Release 2014; 180: 109-16.
[56]
George M, Ghosh I. Identifying the correlation between drug/stabilizer properties and critical quality attributes (CQAs) of nanosuspension formulation prepared by wet media milling technology. Eur J Pharm Sci 2013; 48(1-2): 142-52.
[57]
Tuomela A, Liu P, Puranen J, et al. Brinzolamide nanocrystal formulations for ophthalmic delivery: reduction of elevated intraocular pressure in vivo. Int J Pharm 2014; 467(1-2): 34-41.
[58]
Gaunia Anju, Mazumder R, Pathak K. Formulation, optimization and characterization of ziprasidone nanocrystals prepared by media milling technique. Int J Pharm Pharm Sci 2015; 7(8): 146-50.
[59]
Liu P, Viitala T, Kartal-Hodzic A, et al. Interaction studies between indomethacin nanocrystals and peo/ ppo copolymer stabilizers. Pharm Res 2015; 32(2): 628-39.
[60]
Liu P, Rong X, Laru J, et al. Nanosuspensions of poorly soluble drugs: preparation and development by wet milling. Int J Pharm 2011; 411(1-2): 215-22.
[61]
Van Eerdenbrugh B, Vermant J, Martens JA, et al. A screening study of surface stabilization during the production of drug nanocrystals. J Pharm Sci 2009; 98(6): 2091-103.
[62]
Ahuja BK, Jena SK, Paidi SK, Bagri S, Suresh S. Formulation, optimization and in vitro-in vivo evaluation of febuxostat nanosuspension. Int J Pharm 2015; 478(2): 540-52.
[63]
Shegokar R, Müller RH. Nanocrystals: industrially feasible multifunctional formulation technology for poorly soluble actives. Int J Pharm 2010; 399(1-2): 129-39.
[64]
Hecq J, Deleers M, Fanara D, Vranckx H, Amighi K. Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement of nifedipine. Int J Pharm 2005; 299(1-2): 167-77.
[65]
Valo HK, Laaksonen PH, Peltonen LJ, Linder MB, Hirvonen JT, Laaksonen TJ. Multifunctional hydrophobin: toward functional coatings for drug nanoparticles. ACS Nano 2010; 4(3): 1750-8.
[66]
Tuomela A, Laaksonen T, Laru J, et al. Solid formulations by a nanocrystal approach: critical process parameters regarding scale-ability of nanocrystals for tableting applications. Int J Pharm 2015; 485(1-2): 77-86.
[67]
Laaksonen T, Limnell T, Santos H, et al. Drug dissolution studies on mesoporous silicon particles-a theoretical approach. Eur J Pharm Sci 2008; 34(1): S35.
[68]
Zhou Y, Du J, Wang L, Wang Y. Nanocrystals technology for improving bioavailability of poorly soluble drugs: a mini-review. J Nanosci Nanotechnol 2017; 17(1): 18-28.
[69]
Kesisoglou F, Panmai S, Wu Y. Nanosizing - Oral formulation development and biopharmaceutical evaluation. Adv Drug Deliv Rev 2007; 59(7): 631-44.
[70]
Mauludin R, Müller RH, Keck CM. Kinetic solubility and dissolution velocity of rutin nanocrystals. Eur J Pharm Sci 2009; 36(4-5): 502-10.
[71]
Junyaprasert VB, Morakul B. Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian J Pharm Sci 2015; 10(1): 13-23.
[72]
Möschwitzer J, Müller R. Drug nanocrystals-the universal formulation approach for poorly soluble drugs. In: Thassu D, Deleers M, Pathak YV, Eds. Nanoparticulate drug delivery systems.. CRC Press: Florida 2007; pp. 71-88.
[73]
Ponchel G, Montisci M-J, Dembri A, Durrer C, Duchêne D. Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract. Eur J Pharm Biopharm 1997; 44(1): 25-31.
[74]
Colombo M, Staufenbiel S, Rühl E, Bodmeier R. In situ determination of the saturation solubility of nanocrystals of poorly soluble drugs for dermal application. Int J Pharm 2017; 521(1-2): 156-66.
[75]
Junghanns J-UAH, Muller RH. Nanocrystal technology, drug delivery and clinical applications. Int J Nanomedicine 2008; 3(3): 295-309.
[76]
Jacobs C, Kayser O, Müller RH. Nanosuspensions as a new approach for the formulation for the poorly soluble drug tarazepide. Int J Pharm 2000; 196(2): 161-4.
[77]
Liversidge GG, Conzentino P. Drug particle size reduction for decreasing gastric irritancy and enhancing absorption of naproxen in rats. Int J Pharm 1995; 125(2): 309-13.
[78]
Müller RH, Jacobs C. Buparvaquone mucoadhesive nanosuspension: preparation, optimisation and long-term stability. Int J Pharm 2002; 237(1-2): 151-61.
[79]
Jacobs C, Kayser O, Müller RH. Production and characterisation of mucoadhesive nanosuspensions for the formulation of bupravaquone. Int J Pharm 2001; 214(1-2): 3-7.
[80]
Sarnes A, Østergaard J, Jensen SS, et al. Dissolution study of nanocrystal powders of a poorly soluble drug by UV imaging and channel flow methods. Eur J Pharm Sci 2013; 50(3-4): 511-9.
[81]
Peters K, Leitzke S, Diederichs JE, et al. Preparation of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic efficacy in murine Mycobacterium avium infection. J Antimicrob Chemother 2000; 45(1): 77-83.
[82]
Tuomela A, Saarinen J, Strachan CJ, Hirvonen J. Production, applications and in vivo fate of drug nanocrystals. J Drug Deliv Sci Technol 2016; 34: 21-31.
[83]
Ostrander KD, Bosch HW, Bondanza DM. An in-vitro assessment of a NanoCrystal beclomethasone dipropionate colloidal dispersion via ultrasonic nebulization. Eur J Pharm Biopharm 1999; 48(3): 207-15.
[84]
Mainardes RM, Urban MCC, Cinto PO, et al. Colloidal carriers for ophthalmic drug delivery. Curr Drug Targets 2005; 6(3): 363-71.
[85]
Müller RH, Shegokar R, Keck CM. 20 years of lipid nanoparticles (SLN and NLC): present state of development and industrial applications. Curr Drug Discov Technol 2011; 8(3): 207-27.
[86]
Patel V, Sharma OP, Mehta T. Nanocrystal: a novel approach to overcome skin barriers for improved topical drug delivery. Expert Opin Drug Deliv 2018; 15(4): 351-68.
[87]
Müller RH, Jacobs C. Buparvaquone mucoadhesive nanosuspension: preparation, optimisation and long-term stability. Int J Pharm 2002; 237(1-2): 151-61.
[88]
Tran PT, Anderson GP, Mauro JM, Mattoussi H. Use of luminescent CdSe-ZnS nanocrystal bioconjugates in quantum dot-based nanosensors. Phys Status Solidi 2002; 229(1): 427-32.
[89]
Dubertret B, Skourides P, Norris DJ, Noireaux V, Brivanlou AH, Libchaber A. In vivo imaging of quantum dots encapsulated in phospholipid micelles. Science 2002; 298(5599): 1759-62.
[90]
Parak WJ, Boudreau R, Le Gros M, et al. Cell motility and metastatic potential studies based on quantum dot imaging of phagokinetic tracks. Adv Mater 2002; 14(12): 882.
[91]
Taylor JR, Fang MM, Nie S. Probing specific sequences on single DNA molecules with bioconjugated fluorescent nanoparticles. Anal Chem 2000; 72(9): 1979-86.
[92]
Parak WJ, Pellegrino T, Plank C. Labelling of cells with quantum dots. Nanotechnology 2005; 16(2): R9-R25.
[93]
Ren L, Zhou Y, Wei P, Li M, Chen G. Preparation and pharmacokinetic study of aprepitant-sulfobutyl ether-β-cyclodextrin complex. AAPS PharmSciTech 2014; 15(1): 121-30.
[94]
Möschwitzer JP. Drug nanocrystals in the commercial pharmaceutical development process. Int J Pharm 2013; 453(1): 142-56.
[95]
Tilley MR, Gu HH. The effects of methylphenidate on knockin mice with a methylphenidate-resistant dopamine transporter. J Pharmacol Exp Ther 2008; 327(2): 554-60.
[96]
Sirolimus formulation. 2008.Available from: . https: //patents.google.com/patent/US8053444
[97]
Henry PD. Comparative pharmacology of calcium antagonists: Nifedipine, verapamil and diltiazem. Am J Cardiol 1980; 46(6): 1047-58.
[98]
Diltiazem - an overview | ScienceDirect Topics. Available from: . https: //www.sciencedirect.com/ topics/neuroscience/diltiazem
[99]
Yekkirala AS, Kalyuzhny AE, Portoghese PS. Standard opioid agonists activate heteromeric opioid receptors: evidence for morphine and [d-Ala2 -MePhe 4-Glyol5]enkephalin as selective μ-δ agonists. ACS Chem Neurosci 2010; 1(2): 146-54.
[100]
Ohno S, Kawana K, Nakajin S. Contribution of udp-glucuronosyltransferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic properties. Drug Metab Dispos 2008; 36(4): 688-94.
[101]
Abildskov K, Weldy P, Garland M. Molecular cloning of the baboon UDP-glucuronosyltransferase 2b gene family and their activity in conjugating morphine. Drug Metab Dispos 2010; 38(4): 545-53.
[102]
Jang K, Yoon S, Kim S-E, et al. Novel nanocrystal formulation of megestrol acetate has improved bioavailability compared with the conventional micronized formulation in the fasting state. Drug Des Devel Ther 2014; 8: 851-8.
[103]
Novalic Z, van der Wal AM, Leonhard WN, et al. Dose-dependent effects of sirolimus on mTOR signaling and polycystic kidney disease. J Am Soc Nephrol 2012; 23(5): 842-53.
[104]
Rapamune (sirolimus) Oral Solution and Tablets. Available from: . https: //www.fda.gov/ohrms/dockets/ ac/02/briefing/3832b1_03_FDA-RapamuneLabel.htm
[105]
Australian Public Assessment Report for Paliperidone palmitate. 2010. Available from: . 2010.http: //www.ag.gov. au/cca
[106]
Preissner S, Kroll K, Dunkel M, et al. SuperCYP: a comprehensive database on cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res 2010; 38(Suppl. 1): D237-43.
[107]
Thakkar AL, Hirsch CA, Page JG. Solid dispersion approach for overcoming bioavailability problems due to polymorphism of nabilone, a cannabinoid derivative. J Pharm Pharmacol 1977; 29(1): 783-4.
[108]
Pharmacokinetics in Special Populations. Available from: . https: //www.accessdata.fda.gov/drugsatfda_ docs/label/2008/021350s005lbl.pdf
[109]
Holsapple MP, Farland WH, Landry TD, Monteiro-Riviere NA, Carter JM, Walker NJ. Research strategies for safety evaluation of nanomaterials, part ii: toxicological and safety evaluation of nanomaterials, current challenges and data needs. Toxicol Sci 2005; 88: 12-7.
[110]
Patravale V, Dandekar P, Jain R. Nanoparticulate drug delivery : perspectives on the transition from laboratory to market. Elsevier London 2012.
[111]
Lu Y, Li Y, Wu W. Injected nanocrystals for targeted drug delivery. Acta Pharm Sin B 2016; 6(2): 106-13.
[112]
Sanjay B, Meena B, Rachna K. Nanocrystals: current strategies and trends. Int J Res Pharm Biomed Sci 2012; 3(1): 407-19.
[113]
Amenta V, Aschberger K, Arena M, et al. Regulatory aspects of nanotechnology in the agri/feed/food sector in EU and non-EU countries. Regul Toxicol Pharmacol 2015; 73(1): 463-76.
[114]
Commissioner O of the. Nanotechnology - FDA’s Approach to Regulation of Nanotechnology Products. Office of the Commissioner Available from: . https: //www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/ucm301114.htm


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 7
ISSUE: 4
Year: 2019
Page: [259 - 278]
Pages: 20
DOI: 10.2174/2211738507666190405182524

Article Metrics

PDF: 18
HTML: 3
EPUB: 1
PRC: 1