Skip to main content
SpringerLink
Log in
Book cover

Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement pp 161–185Cite as

Nanostructured Lipid Carriers (NLC): The Second Generation of Solid Lipid Nanoparticles

  • Chapter

Abstract

Solid lipid nanoparticles (SLN) were invented in 1991 as a delivery system combining advantages of other nanoparticulate systems and at the same time avoiding/minimizing some of their limitations. In 1999/2000 the second generation of nano(structured) lipid carriers (NLC) was developed, showing improved properties such as increased drug loading and physical stability. Differences to the first generation are discussed. Large-scale production, incorporation of NLC concentrates in final dermal products, and accepted regulatory status of excipients – as prerequisites for market introduction – are presented. Special emphasis is also given to the problem of nanotoxicity/nanotolerability, considering the increasing concern in the public perception. The mechanisms of action are presented. As the most important criterion for the performance of a delivery system, in vivo data in the literature are reviewed. An overview of marketed dermal products (cosmetics) is given and the future for dermal pharma products and cosmetics forecasted.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Almeida AJ, Runge S, Müller RH (1997) Peptide-loaded solid lipid nanoparticles (SLN): influence of production parameters. Int J Pharm 149(2):255–265

    Article  CAS  Google Scholar 

  • Baiseng N (2013) Ultra-small Nanostructured Lipid Carriers (usNLC). PhD-thesis, Freie Universität Berlin; (in preparation)

    Google Scholar 

  • Bargoni A, Cavalli R, Zara GP, Fundaro A, Caputo O, Gasco MR (2001) Transmucosal transport of tobramycin incorporated in solid lipid nanoparticles (SLN) after duodenal administration to rats. Part II–tissue distribution. Pharmacol Res 43(5):497–502

    Article  PubMed  CAS  Google Scholar 

  • Betzig E, Patterson GH, Sougrat R, Lindwasser OW, Olenych S, Bonifacino JS et al (2006) Imaging intracellular fluorescent proteins at nanometer resolution. Science 313(5793):1642–1645

    Article  PubMed  Google Scholar 

  • Bhaskar K, Anbu J, Ravichandiran V, Venkateswarlu V, Rao Y (2009a) Lipid nanoparticles for transdermal delivery of flurbiprofen: formulation, in vitro, ex vivo and in vivo studies. Lipids Health Dis 8:6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bhaskar K, Mohan CK, Lingam M, Mohan SJ, Venkateswarlu V, Rao YM et al (2009b) Development of SLN and NLC enriched hydrogels for transdermal delivery of nitrendipine: in vitro and in vivo characteristics. Drug Dev Ind Pharm 35(1):98–113

    Article  PubMed  CAS  Google Scholar 

  • Bunjes H, Westsen K, Koch MHJ (1996) Crystallization tendency and polymorphic transitions in triglyceride nanoparticles. Int J Pharm 129(1–2):159–173

    Article  CAS  Google Scholar 

  • Cavalli R, Gasco MR, Chetoni P, Burgalassi S, Saettone MF (2002) Solid lipid nanoparticles (SLN) as ocular delivery system for tobramycin. Int J Pharm 238(1–2):241–245

    Article  PubMed  CAS  Google Scholar 

  • del Pozo-Rodriguez A, Pujals S, Delgado D, Solinis MA, Gascon AR, Giralt E et al (2009a) A proline-rich peptide improves cell transfection of solid lipid nanoparticle-based non-viral vectors. J Control Release 133(1):52–59

    Article  PubMed  CAS  Google Scholar 

  • del Pozo-Rodriguez A, Solinis MA, Gascon AR, Pedraz JL (2009b) Short- and long-term stability study of lyophilized solid lipid nanoparticles for gene therapy. Eur J Pharm Biopharm 71(2):181–189

    Article  PubMed  CAS  Google Scholar 

  • Domb AJ (1993) Lipospheres for controlled delivery of substances. US Patent 5,188,837

    Google Scholar 

  • EU (2011) European Commission Recommendation on the definition of nanomaterial, Regulation (Ec) No. 1223/2009 of the european parliament and of the council on cosmetic products, L 342/59 (2009).

    Google Scholar 

  • Gasco MR (1993) Method for producing solid lipid microspheres having a narrow size distribution. US Patent 5,250,236

    Google Scholar 

  • Gasco MR (2002) Microparticles for drug delivery across mucosa and the blood–brain barrier. US Patent 6,419,949

    Google Scholar 

  • Gasco MR (2007) Lipid nanoparticles: perspectives and challenges. Adv Drug Deliv Rev 59(6):377–378

    Article  PubMed  CAS  Google Scholar 

  • Hess HF (2007) Far-field optical nanoscopy. Science 316(5828):1153–1158

    Article  CAS  Google Scholar 

  • Hess SM, Girirajan TPK, Mason MD (2006) Ultra-high resolution imaging by fluorescence photoactivation localization microscopy. Biophys J 91(11):4258–4272

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jenning V (1999) Feste Lipid-Nanopartikel (SLN®) als Trägersystem für die dermale Applikation von Retinol: Wirkstoffinkorporation, −freisetzung und Struktur (Solid lipid nanoparticles (SLN®) as carrier for the dermal application of Retinol: drug incorporation, release and structure of the carrier). PhD-thesis, Freie Universität Berlin

    Google Scholar 

  • Jenning V, Gohla S (2001) Encapsulation of retinoids in solid lipid nanoparticles (SLN). J Microencapsul 18(2):149–158

    Article  PubMed  CAS  Google Scholar 

  • Jores K, Mehnert W, Drechsler M, Bunjes H, Johann C, Mäder K (2004) Investigations on the structure of solid lipid nanoparticles (SLN) and oil-loaded solid lipid nanoparticles by photon correlation spectroscopy, field-flow fractionation and transmission electron microscopy. J Control Release 95(2):217–227

    Article  PubMed  CAS  Google Scholar 

  • Joshi M, Patravale V (2006) Formulation and evaluation of nanostructured lipid carrier (NLC)-based gel of valdecoxib. Drug Dev Ind Pharm 32(8):911–918

    Article  PubMed  CAS  Google Scholar 

  • Keck CM, Baisaeng N, Durand P, Prost M, Meinke MC, Muller RH (2014) Oil-enriched, ultra-small nanostructured lipid carriers (usNLC): A novel delivery system based on flip-flop structure. Int J Pharm 477(1–2):227–235

    Google Scholar 

  • Keck CM, Müller RH (2010) Silber-Lipid-Zwerge – Ein neues Therapiekonzept gegen Neurodermitis. Quantos 1:6–11

    Google Scholar 

  • Keck CM, Müller RH (2013) Nanotoxicological classification system (NCS) – a guide for the risk-benefit assessment of nanoparticulate drug delivery systems. Eur J Pharm Biopharm 84(3):445–448

    Article  PubMed  CAS  Google Scholar 

  • Keck CM, Schwabe K (2009) Silver-nanolipid complex for application to atopic dermatitis skin: rheological characterization, in vivo efficiency and theory of action. J Biomed Nanotechnol 5(4):428–436

    Article  PubMed  CAS  Google Scholar 

  • Keck CM, Schwabe K, Rimpler C (2008) Lipid nanoparticles for the enhancement of the dermal action of solid particles. European Patent Application No 08 019 3063, 4 Nov 2008

    Google Scholar 

  • Keck CM, Boreham T, Schlieter D, Peters D, Müller RH, Alexiev U (2013) Nanostructures and drug distribution within Nanostructured Lipid Carriers (NLC). Annual meeting of controlled release society, Honululu, p ID 100536

    Google Scholar 

  • Kim T-Y, Uji-i H, Moeller M, Muls B, Hofkens J, Alexiev U (2009) Monitoring the interaction of a single G-protein key binding site with rhodopsin disk membranes upon light activation. Biochemistry 48(18):3801–3803

    Article  PubMed  CAS  Google Scholar 

  • Kim T-Y, Schlieter T, Haase S, Alexiev U (2012) Activation and molecular recognition of the GPCR rhodopsin – insights from time-resolved fluorescence depolarisation and single molecule experiments. Eur J Cell Biol 91(4):300–310

    Article  PubMed  CAS  Google Scholar 

  • Kirchberg K, Kim T-Y, Haase S, Alexiev U (2010) Functional inter-action structures of the photochromic retinal protein rhodopsin. Photochem Photobiol Sci 9(2):226–233

    Article  PubMed  CAS  Google Scholar 

  • Küchler S, Radowski MR, Blaschke T, Dathe M, Plendl J, Haag R et al (2009) Nanoparticles for skin penetration enhancement–a comparison of a dendritic core-multishell-nanotransporter and solid lipid nanoparticles. Eur J Pharm Biopharm 71(2):243–250

    Article  PubMed  CAS  Google Scholar 

  • Lucks JS, Müller RH (1996) Inventors; Excipient of solid lipid particles (solid lipid nanospheres (SLN)), EP 0605497 B1

    Google Scholar 

  • Maia CS, Mehnert W, Schäfer-Korting M (2000) Solid lipid nanoparticles as drug carriers for topical glucocorticoids. Int J Pharm 196(2):165–167

    Article  PubMed  CAS  Google Scholar 

  • Maia CS, Mehnert W, Schaller M, Korting HC, Gysler A, Haberland A et al (2002) Drug targeting by solid lipid nanoparticles for dermal use. J Drug Target 10(6):489–495

    Article  CAS  Google Scholar 

  • Masters DB, Domb AJ (1998) Liposphere local anesthetic timed-release for perineural site application. Pharm Res 15(7):1038–1045

    Article  PubMed  CAS  Google Scholar 

  • Miglietta A, Cavalli R, Bocca C, Gabriel L, Gasco MR (2000) Cellular uptake and cytotoxicity of solid lipid nanospheres (SLN) incorporating doxorubicin or paclitaxel. Int J Pharm 210(1–2):61–67

    Article  PubMed  CAS  Google Scholar 

  • Mitri K, Shegokar R, Gohla S, Anselmi C, Müller RH (2011) Lipid nanocarriers for dermal delivery of lutein: preparation, characterization, stability and performance. Int J Pharm 414(1–2):267–275

    Article  PubMed  CAS  Google Scholar 

  • Müller BW (1998) Mikroemulsionen als neue Wirkstoffträgersysteme. In: Müller RH, Hildebrand GE (eds) Pharmazeutische Technologie: Moderne Arzneiformen. Wissenschaftliche Verlagsgesellschaft, Stuttgart, pp 161–169

    Google Scholar 

  • Müller R, Mehnert W, Lucks JS, Schwarz C, Zur Mühlen A, Meyhers H et al (1995) Solid lipid nanoparticles (SLN): an alternative colloidal carrier system for controlled drug delivery. Eur J Pharm Biopharm 41(1):62–69

    Google Scholar 

  • Müller RH, Jenning V, Mäder K, Lippacher A (2000a) Lipid particles on the basis of mixtures of liquid and solid lipids and the method for producing same. PCT/EP2000/004112

    Google Scholar 

  • Müller RH, Jenning V, Mäder K, Lippacher A (2000b) Lipidpartikel auf der Basis von Mischungen von flüssigen und festen Lipiden und Verfahren zu ihrer Herstellung. EP1176949A2

    Google Scholar 

  • Müller RH, Mäder K, Gohla S (2000c) Solid lipid nanoparticles (SLN) for controlled drug delivery – a review of the state of the art. Eur J Pharm Biopharm 50(1):161–177

    Article  PubMed  Google Scholar 

  • Müller RH, Radtke M, Wissing SA (2002a) Nanostructured lipid matrices for improved microencapsulation of drugs. Int J Pharm 242(1–2):121–128

    Article  PubMed  Google Scholar 

  • Müller RH, Radtke M, Wissing SA (2002b) Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) in cosmetic and dermatological preparations. Adv Drug Deliv Rev 54(Suppl 1):S131–S155

    Article  PubMed  Google Scholar 

  • Müller RH, Petersen RD, Hommoss A, Pardeike J (2007) Nanostructured lipid carriers (NLC) in cosmetic dermal products. Adv Drug Deliv Rev 59(6):522–530

    Article  PubMed  CAS  Google Scholar 

  • 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):1–9

    Article  PubMed  CAS  Google Scholar 

  • Müller RH, Shegokar R, Keck CM (2011b) 20 years of lipid nanoparticles (SLN and NLC): present state of development and industrial applications. Curr Drug Discov Technol 8(3):207–227

    Article  PubMed  Google Scholar 

  • Pardeike J, Müller RH (2007) Coenzyme Q10-loaded NLCs: preparation, occlusive properties and penetration enhancement. Pharm Tech Eur 19(7):46–49

    CAS  Google Scholar 

  • Pardeike J, Hommoss A, Müller RH (2009) Lipid nanoparticles (SLN, NLC) in cosmetic and pharmaceutical dermal products. Int J Pharm 366(1–2):170–184

    Article  PubMed  CAS  Google Scholar 

  • Pardeike J, Schwabe K, Müller RH (2010) Influence of nanostructured lipid carriers (NLC) on the physical properties of the Cutanova Nanorepair Q10 cream and the in vivo skin hydration effect. Int J Pharm 396(1–2):166–173

    Article  PubMed  CAS  Google Scholar 

  • Pople PV, Singh KK (2006) Development and evaluation of topical formulation containing solid lipid nanoparticles of vitamin A. AAPS PharmSciTech 7(4):91

    Article  PubMed  Google Scholar 

  • Puglia C, Blasi P, Rizza L, Schoubben A, Bonina F, Rossi C et al (2008) Lipid nanoparticles for prolonged topical delivery: an in vitro and in vivo investigation. Int J Pharm 357(1–2):295–304

    Article  PubMed  CAS  Google Scholar 

  • Radtke M (2003) Grundlegende Untersuchungen zur Arzneistoffinkorporation, −freisetzung und Struktur von SLN und NLC. Ph.D. thesis, Freie Universität Berlin, Berlin

    Google Scholar 

  • Rogiers V (2001) EEMCO guidance for the assessment of transepidermal water loss in cosmetic sciences. Skin Pharmacol Appl Skin Physiol 14:117–128

    Google Scholar 

  • Rust MJ, Bates M, Zhuang X (2006) Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nat Methods 3(10):793–795

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Schäfer-Korting M, Mehnert W, Korting H-C (2007) Lipid nanoparticles for improved topical application of drugs for skin diseases. Adv Drug Deliv Rev 59(6):427–443

    Article  PubMed  CAS  Google Scholar 

  • Schubert MA, Müller-Goymann CC (2005) Characterisation of surface-modified solid lipid nanoparticles (SLN): influence of lecithin and nonionic emulsifier. Eur J Pharm Biopharm 61(1–2):77–86

    Article  PubMed  CAS  Google Scholar 

  • Schwarz JC, Weixelbaum A, Pagitsch E, Low M, Resch GP, Valenta C (2012) Nanocarriers for dermal drug delivery: influence of preparation method, carrier type and rheological properties. Int J Pharm 437(1–2):83–88

    Article  PubMed  CAS  Google Scholar 

  • Sinambela P, Shegokar R, Gohla S, Müller RH (2011) Dermal nanostructured lipid carriers (NLC) – the invisible patch. AAPS annual meeting, Washington DC, p T2160

    Google Scholar 

  • Souto EB, Wissing SA, Barbosa CM, Müller RH (2004) Development of a controlled release formulation based on SLN and NLC for topical clotrimazole delivery. Int J Pharm 278(1):71–77

    Article  PubMed  CAS  Google Scholar 

  • Teeranachaideekul V, Boonme P, Souto EB, Müller RH, Junyaprasert VB (2008) Influence of oil content on physicochemical properties and skin distribution of Nile red-loaded NLC. J Control Release 128(2):134–141

    Article  PubMed  CAS  Google Scholar 

  • Üner M, Wissing SA, Yener G, Müller RH (2005a) Skin moisturizing effect and skin penetration of ascorbyl palmitate entrapped in solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) incorporated into hydrogel. Pharmazie 60(10):751–755

    PubMed  Google Scholar 

  • Üner M, Wissing SA, Yener G, Müller RH (2005b) Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for application of ascorbyl palmitate. Pharmazie 60:577–582

    PubMed  Google Scholar 

  • US Food and Drug Administration (FDA) (2011) Draft guidance, considering whether an FDA-regulated product involves the application of nanotechnology, Guidance for Industry

    Google Scholar 

  • von Nägeli CW (1893) Über oligodynamische Erscheinungen in lebenden Zellen. Neue Denksch 33:1–51

    Google Scholar 

  • Zara GP, Bargoni A, Cavalli R, Fundaro A, Vighetto D, Gasco MR (2002) Pharmacokinetics and tissue distribution of idarubicin-loaded solid lipid nanoparticles after duodenal administration to rats. J Pharm Sci 91(5):1324–1333

    Article  PubMed  CAS  Google Scholar 

  • zur Mühlen A, Schwarz C, Mehnert W (1998) Solid lipid nanoparticles (SLN) for controlled drug delivery–drug release and release mechanism. Eur J Pharm Biopharm 45(2):149–155

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Biopharmaceutics and NutriCosmetics, Freie Universität Berlin, Berlin, 14195, Germany

    Rainer H. Müller, Pricillia Sinambela & Cornelia M. Keck

  2. Faculty of Physics, Institute of Experimental Physics, Freie Universität Berlin, Berlin, 14195, Germany

    Ulrike Alexiev

  3. Applied Pharmacy, University of Applied Sciences Kaiserslautern – Campus Pirmasens, Carl-Schurz-Str. 10-16, Pirmasens, 66953, Germany

    Cornelia M. Keck

Authors
  1. Rainer H. Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ulrike Alexiev
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pricillia Sinambela
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cornelia M. Keck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cornelia M. Keck .

Editor information

Editors and Affiliations

  1. Department of Manufacturing, Apoteka "Beograd", Belgrade, Serbia

    Nina Dragicevic

  2. San Francisco, California, USA

    Howard I. Maibach

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Müller, R.H., Alexiev, U., Sinambela, P., Keck, C.M. (2016). Nanostructured Lipid Carriers (NLC): The Second Generation of Solid Lipid Nanoparticles. 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_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-47862-2_11

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-47861-5

  • Online ISBN: 978-3-662-47862-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation