Skip to main content
SpringerLink
Log in

Physicochemical Characteristics, Cytotoxicity, and Antioxidant Activity of Three Lipid Nanoparticulate Formulations of Alpha-lipoic Acid

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Exogenously supplied alpha-lipoic acid (LA) has proven to be effective as an antioxidant. In an effort to develop a water-soluble formulation for topical administration, LA was formulated in the form of solid lipid nanoparticles (SLN), nanostructure lipid carriers (NLC), and nanoemulsion (NE) and characterized in terms of physical and biological properties. Mean particle size of 113, 110, and 121 nm were obtained for NE, NLC, and SLN, respectively, with narrow size distribution. Zeta potential was approximately in the range of −25 to −40 mV. Disc and spherical structures of nanoparticles were observed by cryo-scanning electron microscopy. Entrapment efficiency of LA in three formulations was found to be more than 70%. After 120 days of storage at 25°C, physical stability of all formulations remained unchanged whereas the entrapment efficiency of SLN and NLC could be maintained, suggesting relative long-term stability. Prolonged release of LA formulation following the Higuchi model was found where a faster release was observed from NE compared with that of SLN and NLC. More than 80% of cell survivals were found up to 1 μM of LA concentrations. Antioxidant activity analysis demonstrated that all LA-loaded formulations expressed antioxidant activity at a similar magnitude as pure LA. These results suggest that chosen compositions of lipid nanoparticles play an important role on drug loading, stability, and biological activity of nanoparticles. Both SLN and NLC demonstrated their potential as alternative carriers for aqueous topical administration of LA.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

DHLA:

dihydrolipoic acid

LA:

alpha-lipoic acid

NE:

nanoemulsion

NLC:

nanostructure lipid carriers

SLN:

solid lipid nanoparticles

ROS:

reactive oxygen species

Z :

ave particle diameter

MW:

molecular weight

PDI:

polydispersity index

ZP:

zeta potential

PCS:

photon correlation spectroscopy

SEM:

scanning electron microscopy

TEM:

transmission electron microscope

DSC:

differential scanning calorimetry

ΔH :

melting enthalpy

RI:

recrystallization index

HPLC:

high-performance liquid chromatography

EE:

entrapment efficiency

FBS:

fetal bovine serum

NHF:

human foreskin fibroblast

DMEM:

Dulbecco’s modified Eagle’s medium

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide

PBS:

phosphate buffer saline

SD:

standard deviation

p value:

probability value

References

  1. U. Cakatay, A. Telci, R. Kayali, A. Sivas, and T. Akcay. Effect of lipoic acid supplementation on oxidative protein damage in the streptozotocin-diabetic rat. Res. Exp. Med. (Berl). 199:243–251 (2000).

    Article  CAS  Google Scholar 

  2. Y. Dincer, A. Telci, R. Kayal, C. Yılmazia, U. Cakatay, and T. Akcay. Effect of a-lipoic acid on lipid peroxidation and antioxidant enzyme activities in diabetic rats. Clin. Exp. Pharmacol. Physiol. 29:281–284 (2002).

    Article  PubMed  CAS  Google Scholar 

  3. M. A. Lovell, C. Xie, S. Xiong, and W. R. Markesbery. Protection against amyloid b peptide and iron/hydrogen peroxide toxicity by a-lipoic acid. J. Alzheimer Dis. 5:229–239 (2003).

    CAS  Google Scholar 

  4. G. H. Marracci, G. P. McKeon, W. E. Marquardt, R. W. Winter, M. K. Riscoe, and D. N. Bourdette. α-Lipoic acid inhibits human T cell migration: implications for multiple sclerosis. J. Neurosci. Res. 78:362–370 (2004).

    Article  PubMed  CAS  Google Scholar 

  5. A. R. Smith, S. V. Shenvi, M. Widlansky, J. H. Suh, and T. M. Hagen. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr. Med. Chem. 11:1135–1146 (2004).

    PubMed  CAS  Google Scholar 

  6. A. Baur, T. Harrer, M. Peukert, G. Jahn, J. R. Kalden, and B. Fleckenstein. Alpha-lipoic acid is an effective inhibitor of human immuno-deficiency virus (HIV-1) replication. J. Mol. Med. 69:722–724 (1991).

    CAS  Google Scholar 

  7. U. Cakatay. Pro-oxidant actions of a-lipoic acid and dihydrolipoic acid. Med. Hypotheses. 66:110–117 (2006).

    Article  PubMed  CAS  Google Scholar 

  8. A. Bliska, and L. Wlodek. Lipoic acid—the drug of the future? Pharmacol. Rep. 57:570–577 (2005).

    Google Scholar 

  9. L. Packer. α-Lipoic acid: a metabolic antioxidant, which regulates NF-κВ signal transduction and protects against oxidative injury. Drug Metab. Rev. 30:245–275 (1998).

    Article  PubMed  CAS  Google Scholar 

  10. D. Ziegler, and F. A. Gries. Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes. 46:S62–S66 (1997).

    PubMed  CAS  Google Scholar 

  11. S. D. Wollin, and P. J. Jones. Alpha-lipoic acid and cardiovascular disease. J. Nutr. 133:3327–3330 (2003).

    PubMed  CAS  Google Scholar 

  12. J. Fuchs, and R. Milbradt. Antioxidant inhibition of skin inflammation induced by reactive oxidants: Evaluation of the redox couple dihydrolipoate/lipoate. Skin Pharmacol. 7:278–284 (1994).

    Article  PubMed  CAS  Google Scholar 

  13. M. Podda, M. Rallis, M. G. Cuber, L. Packer, and H. Maibachl. Kinetic study of cutaneous and subcutaneous distribution following topical application of [7,8J4C] rac-cx-lipoic acid onto hairless mice. Biochem. Pharmacol. 52:627–633 (1996).

    Article  PubMed  CAS  Google Scholar 

  14. H. Beitner. Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% α-lipoic acid related to photoageing of facial skin. Br. J. Dermatol. 149:841–849 (2003).

    Article  PubMed  CAS  Google Scholar 

  15. R. H. Müller and J. S. Lucks. Medication vehicles made of solid lipid particles (solid lipid nanospheres—SLN). Eur. Patent 0605497 (1996).

  16. R. H. Müller, K. Mäder, and S. Gohla. Solid lipid nanoparticles (SLN) for controlled drug delivery—a review of the state of the art. Eur. J. Pharm. Biopharm. 50:161–177 (2000).

    Article  PubMed  Google Scholar 

  17. R. H. Müller, and C. M. Keck. Challenges and solutions for the delivery of biotech drugs—a review of drug nanocrystal technology and lipid nanoparticles. J. Biotech. 113:151–170 (2004).

    Article  CAS  Google Scholar 

  18. E. Ugazio, R. Cavalli, and M. R. Gasco. Incorporation of cyclosporin A in solid lipid nanoparticles (SLN). Int. J. Pharm. 241:341–344 (2002).

    Article  PubMed  CAS  Google Scholar 

  19. S. A. Wissing, and R. H. Müller. Cosmetic applications for solid lipid nanoparticles (SLN). Int. J. Pharm. 254:65–68 (2003).

    Article  PubMed  CAS  Google Scholar 

  20. S. A. Wissing, and R. H. Müller. The influence of solid lipid nanoparticles on skin hydration and viscoelasticity—in vivo study. Int. J. Pharm. 56:67–72 (2003).

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. W. Mehnert, and K. Mäder. Solid lipid nanoparticles: production, characterization and applications. Adv. Drug. Deliv. Rev. 47:165–196 (2001).

    Article  PubMed  CAS  Google Scholar 

  23. V. Teeranachaideekul, E. B. Souto, V. B. Junyaprasert, and R. H. Müller. Cetyl palmitate-based NLC for topical delivery of coenzyme Q10—development, physicochemical characterization and in vitro release studies. Eur. J. Pharm. Biopharm. 67:141–148 (2007).

    Article  PubMed  CAS  Google Scholar 

  24. C. Freitas, and R. H. Müller. Correlation between long-term stability of solid lipid nanoparticles (SLN™) and crystallinity of the lipid phase. Eur. J. Pharm. Sci. 47:125–132 (1999).

    CAS  Google Scholar 

  25. A. Ernst, A. Stolzing, G. Sandig, and T. Grune. Antioxidants effectively prevent oxidation-induced protein damage in OLN 93 cells. Arch. Biochem. Biophys. 421:54–60 (2004).

    Article  PubMed  CAS  Google Scholar 

  26. M. A. Schubert, and C. C. Müller-Goymann. Characterisation of surface-modified solid lipid nanoparticles (SLN): influence of lecithin and nonionic emulsifier. Eur. J. Pharm. Biopharm. 61:77–86 (2005).

    Article  PubMed  CAS  Google Scholar 

  27. A. Saupe, K. C. Gordon, and T. Rades. Structural investigations on nanoemulsions, solid lipid nanoparticles and nanostructured lipid carriers by cryo-field emission scanning electron microscopy and Raman spectroscopy. Int. J. Pharm. 314:56–62 (2006).

    Article  PubMed  CAS  Google Scholar 

  28. W. Tiyaboonchai, W. Tungpradit, and P. Plianbangchang. Formulation and characterization of curcuminoids loaded solid lipid nanoparticles. Int. J. Pharm. 337:299–306 (2007).

    Article  PubMed  CAS  Google Scholar 

  29. H. Bunjes, K. Westesen, and M. H. J. Koch. Crystallization tendency and polymorphic transitions in triglyceride nanoparticles. Int. J. Pharm. 129:159–173 (1996).

    Article  CAS  Google Scholar 

  30. A. Saupe, S. A. Wissing, A. Lenk, C. Schmidt, and R. H. Müller. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC)—structural investigations on two different carrier systems. Biomedical Mater. 15:393–402 (2005).

    CAS  Google Scholar 

  31. V. Jenning, A. F. Thünemann, and S. H. Gohla. Characterisation of a novel solid lipid nanoparticle carrier system based on binary mixtures of liquid and solid lipids. Int. J. Pharm. 199:167–177 (2000).

    Article  PubMed  CAS  Google Scholar 

  32. V. Jenning, and S. Gohla. Comparison of wax and glyceride solid lipid nanoparticles (SLN®). Int. J. Pharm. 196:219–222 (2000).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  34. E. B. Souto, S. A. Wissing, C. M. Barbosa, and R. H. Müller. Development of a controlled release formulation based on SLN and NLC for topical clotrimazole delivery. Int. J. Pharm. 278:71–77 (2004).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  36. R. H. Müller, D. Rühl, S. Runge, K. Schulze-Forster, and W. Mehnert. Cytotoxicity of solid lipid nanoparticles as a function of the lipid matrix and the surfactant. Pharm. Res. 14:458–462 (1997).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This research was financially supported by the National Nanotechnology Center (NANOTEC), Thailand (research grant number B22 CR0102).

Author information

Authors and Affiliations

  1. National Nanotechnology Center, National Science and Technology Development Agency, 111 Thailand Science Park, Paholyothin Road., Klong 1, Klong Luang, Pathumthani, 12120, Thailand

    Uracha Ruktanonchai, Piyawan Bejrapha & Usawadee Sakulkhu

  2. Faculty of Pharmacy, Silpakorn Univerity, Nakhonpathom, Thailand

    Praneet Opanasopit

  3. Department of Pharmacognosy, Faculty of Pharmacy, Mahidol University, Sri-ayudhya Road, Bangkok, 10400, Thailand

    Nuntavan Bunyapraphatsara, Varaporn Junyaprasert & Satit Puttipipatkhachorn

  4. Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Sri-ayudhya Road, Bangkok, 10400, Thailand

    Nuntavan Bunyapraphatsara, Varaporn Junyaprasert & Satit Puttipipatkhachorn

  5. Department of Manufacturing Pharmacy, Faculty of Pharmacy, Mahidol University, Sri-ayudhya Road, Bangkok, 10400, Thailand

    Nuntavan Bunyapraphatsara, Varaporn Junyaprasert & Satit Puttipipatkhachorn

Authors
  1. Uracha Ruktanonchai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Piyawan Bejrapha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Usawadee Sakulkhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Praneet Opanasopit
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nuntavan Bunyapraphatsara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Varaporn Junyaprasert
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Satit Puttipipatkhachorn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Uracha Ruktanonchai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ruktanonchai, U., Bejrapha, P., Sakulkhu, U. et al. Physicochemical Characteristics, Cytotoxicity, and Antioxidant Activity of Three Lipid Nanoparticulate Formulations of Alpha-lipoic Acid. AAPS PharmSciTech 10, 227–234 (2009). https://doi.org/10.1208/s12249-009-9193-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-009-9193-6

Key words

Search

Navigation