Abstract
Pharmaceutical nanocrystals were developed at the beginning of the 1990s and entered the pharmaceutical market in the year 2000. With less than one decade, they belong to the most successful nanosystems. In 2005 the first dermal cosmetic products were put on the market. Nanocrystals consist of 100 % active, surrounded by a stabilizer layer. They enhance penetration into the skin via physical effects of increased kinetic solubility (supersaturation), thus increasing concentration gradient, fast dissolution from the nanocrystal depot on the skin, adhesive properties, and size-dependent localization in hair follicles. Nanocrystals do not need to penetrate themselves into the skin. Production is possible on a large industrial scale by bead milling or high-pressure homogenization. Nanocrystal concentrates are on the market available which can easily be incorporated into dermal products by admixing in the production process. By formulation as nanocrystals, poorly soluble molecules are made biologically active in the skin, which were not active before as microcrystals (e.g., flavonoids, up to factor 1000 bioactivity enhancement). First cosmetic products with nanocrystals are meanwhile marketed worldwide, and identical to liposomes the dermal pharmaceutical applications are expected to come. The nanocrystals belong to class I or II of the nanotoxicological classification system (NCS); therefore, they are well tolerated.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Amidon GL, Lennernas H, Shah VP, Crison JR (1995) A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 12(3):413–420
Auweter H, Bohn H, Heger R, Horn D, Siegel B, Siemensmeyer K (2002) Precipitated water-insoluble colorants in colloid disperse form. USA. United States Patent 6,494,924
Bangham AD (1963) Physical structure and behavior of lipids and lipid enzymes. Adv Lipid Res 1:65–104
Bangham AD (1972) Lipid bilayers and biomembranes. Annu Rev Biochem 41:753–776
Bangham AD (1978) Properties and uses of lipid vesicles: an overview. Ann N Y Acad Sci 308:2–7
Bangham AD, Horne RW (1964) Negative staining of phospholipids and their structural modification by surface-active agents as observed in the electron microscope. J Mol Biol 8:660–668
Blache D, Devaux S, Joubert O, Loreau N, Schneider M, Durand P et al (2006) Long-term moderate magnesium-deficient diet shows relationships between blood pressure, inflammation and oxidant stress defense in aging rats. Free Radic Biol Med 41(2):277–284
Buckton G, Beezer AE (1992) The relationship between particle size and solubility. Int J Pharm 82(3):R7–R10
Calistro P (1987) Deliverance from wrinkles?: Liposomes and ‘anti-aging’ products are the great new hope for smoother skin. Los Angeles Times, 08 Mar 1987
Cevc G (1996) Transfersomes, liposomes and other lipid suspensions on the skin: permeation enhancement, vesicle penetration, and transdermal drug delivery. Crit Rev Ther Drug Carrier Syst 13(3–4):257–388
Chen R (2013) Tailor-made antioxidative nanocrystals: production and in vitro efficacy. Ph.D. thesis, Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin, Germany
Chen R, Sauer M, Durand P, Müller RH, Schäfer K-H, Prost M, et al (2013) Rutin nanocrystals: production, antioxidative capacity, neuroprotection. Controlled Release Society Local Chapter 2013, Ludwigshafen, 21–22 March 2013
EU – European Commission Recommendation on the definition of nanomaterial (2011/696/EU), L 275/38, https://ec.europa.eu/research/industrial_technologies/pdf/policy/commission-recommendation-on-the-definition-of-nanomater-18102011_en.pdf)
Fernandez M (2007) Nanotechnologies, level 2 – details on nanotechnologies. Greenfacts – Facts on Health and the Environment, Health & Consumer Protection DG of the European Commission. http://ec.europa.eu/health/opinions2/en/nanotechnologies/about-nanotechnologies.htm#7. Accessed 20 04 2013
Gassmann P, List M, Schweitzer A, Sucker H (1994) Hydrosols – alternatives for the parenteral application of poorly water soluble drugs. Eur J Pharm Biopharm 40:64–72
Horne RW, Bangham AD, Whittaker VP (1963) Negatively stained lipoprotein membranes. Nature 200:1340
Keck CM, Müller RH (2006) Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm 62(1):3–16
Keck CM, Müller RH (2013a) Auf den Spuren von Kleopatras Schönheit – und warum Nanotechnologie noch schöner macht. Labor More 13(1):8–14
Keck CM, Müller RH (2013b) Nanotoxicological classification system (NCS) – a guide for the risk-benefit assessment of nanoparticulate drug delivery systems. Eur J Pharm Biopharm 84(3):445–448
Kipp JE, Wong JCT, Doty MJ, Rebbeck CL (2003) Microprecipitation method for preparing submicron suspensions. USA. United States Patent 6,607,784
Kipp JE, Wong JCT, Doty MJ, Werling J, Rebbeck CL, Brynjelsen S (2005) Method for preparing submicron particle suspensions. USA. 6,884,436
Küchler S, Abdel-Mottaleb M, Lamprecht A, Radowski MR, Haag R, Schäfer-Korting M (2009) Influence of nanocarrier type and size on skin delivery of hydrophilic agents. Int J Pharm 377(1–2):169–172
Lademann J, Otberg N, Richter H, Weigmann HJ, Lindemann U, Schaefer H et al (2001) Investigation of follicular penetration of topically applied substances. Skin Pharmacol Appl Skin Physiol 14(Suppl 1):17–22
Lademann J, Otberg N, Jacobi U, Hoffman RM, Blume-Peytavi U (2005) Follicular penetration and targeting. J Investig Dermatol Symp Proc 10(3):301–303
Lademann J, Richter H, Teichmann A, Otberg N, Blume-Peytavi U, Luengo J et al (2007) Nanoparticles--an efficient carrier for drug delivery into the hair follicles. Eur J Pharm Biopharm 66(2):159–164
Lasic DD (1995) Application of liposomes. In: Lipowsky R, Sackmann E (eds) Handbook of biological physics, volume 1A: structure and dynamics of membranes: from cells to vesicles. Elsevier, Amsterdam, pp 491–519
List M, Sucker H (1988) Pharmaceutical colloidal hydrosols for injection. GB Patent 2,200,048
Liversidge GG, Cundy KC, Bishop JF, Czekai DA (1992) Surface modified drug nanoparticles. USA. United States Patent 5,145,684
Möschwitzer J, Lemke A (2007) Method for carefully producing ultrafine particle suspensions and ultrafine particles and use thereof. PCT/EP2006/003377
Müller RH, Möschwitzer J (2007) Method and device for producing very fine particles and coating such particles. PCT/EP2006/009930
Müller RH, Becker R, Kruss B, Peters K (1999) Pharmaceutical nanosuspensions for medicament administration as systems with increased saturation solubility and rate of solution. United States Patent 5,858,410
Müller RH, Mäder K, Krause K (2000) Verfahren zur schonenden Herstellung von hochfeinen Micro-/Nanopartikeln. Germany. PCT Application PCT/EP00/06535
Müller RH, Hanisch J, Mauludin R, Petersen R, Keck CM (2007) Rutin drug nanocrystals for dermal cosmetic application. AAPS annual meeting, San Diego, 9th–15th Nov 2007
Müller RH, Gohla S, Keck CM (2011a) State of the art of nanocrystals – special features, production, nanotoxicology aspects and intracellular delivery. Eur J Pharm Biopharm 78:1–9
Müller RH, Shegokar R, Gohla S, Keck CM (2011b) Nanocrystals: production, cellular drug delivery, current and future products. In: Prokop A (ed) Intracellular delivery: fundamentals and applications, fundamental biomedical technologies. Springer Science + Business Media, B.V. Dordrecht, pp 411–432
Patzelt A, Richter H, Knorr F, Schafer U, Lehr CM, Dahne L et al (2011) Selective follicular targeting by modification of the particle sizes. J Control Release 150(1):45–48
Petersen RD (2006) Nanocrystals for use in topical formulations and method of production thereof. Germany. PCT/EP2007/009943
Prost M (1989) Utilisation de générateur de radicaux libres dans le domaine des dosages biologiques. FR Patent 2,642,526
Prost M (1992) Process for the determination by means of free radicals of the antioxidant properties of a living organism or potentially aggressive agents. US Patent 5,135,850
Sinambela P, Loeffler BM, Egorov E, Shegokar R, Keck CM, Müller RH (2012) Antioxidant rutin nanocrystals for anti-aging treatment – an in vivo study. Annual meeting of the American Association of Pharmaceutical Scientists, Chicago, 2012
US Food and Drug Administration (FDA) (2011) Guidance for industry, Considering whether an FDA-regulated product involves the application of nanotechnology, www.fda.gov./RegulatoryInformation/Guidances/ucm257698.htm
Xing M, Zhong W, Xu X, Thomson D (2010) Adhesion force studies of nanofibers and nanoparticles. Langmuir 26(14):11809–11814
Acknowledgments
We thank Prof. Michel Prost and the company Kirial International/Laboratoires Spiral, France (www.nutriteck.com/sunyatakrl.html), for performing the in vitro tests of the antioxidant capacity of rutin nanocrystals and PharmaSol GmbH Berlin for the provision of production equipment.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Müller, R.H., Zhai, X., Romero, G.B., Keck, C.M. (2016). Nanocrystals for Passive Dermal Penetration Enhancement. In: Dragicevic, N., Maibach, H. (eds) Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-47862-2_18
Download citation
DOI: https://doi.org/10.1007/978-3-662-47862-2_18
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-47861-5
Online ISBN: 978-3-662-47862-2
eBook Packages: MedicineMedicine (R0)