Skip to main content


Log in

Preparation of a novel lipid-core micelle using a low-energy emulsification method

  • Original Article
  • Published:
Drug Delivery and Translational Research Aims and scope Submit manuscript


High-energy methods for the manufacturing of nanomedicines are widely used; however, interest in low-energy methods is increasing due to their simplicity, better control over the process, and energy-saving characteristics during upscaling. Here, we developed a novel lipid-core micelle (LCM) as a nanocarrier to encapsulate a poorly water-soluble drug, nifedipine (NFD), by hot-melt emulsification, a low-energy method. LCMs are self-assembling colloidal particles composed of a hydrophobic core and a hydrophilic shell. Hybrid materials, such as Gelucire 44/14, are thus excellent candidates for their preparation. We characterized the obtained nanocarriers for their colloidal properties, drug loading and encapsulation efficiency, liquid state, stability, and drug release. The low-energy method hot-melt emulsification was successfully adapted for the manufacturing of small and narrowly dispersed LCMs. The obtained LCMs had a small average size of ~ 11 nm and a narrow polydispersity index (PDI) of 0.228. These nanocarriers were able to increase the amount of NFD dispersible in water more than 700-fold. Due to their sustained drug release profile and the PEGylation of Gelucire 44/14, these nanocarriers represent an excellent starting point for the development of drug delivery systems designed for long circulation times and passive targeting.

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

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

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

Similar content being viewed by others


  1. Kawakami K. Supersaturation and crystallization: non-equilibrium dynamics of amorphous solid dispersions for oral drug delivery. Expert Opin Drug Deliv. 2017;14:735–43.

    Article  CAS  PubMed  Google Scholar 

  2. Semalty A. Cyclodextrin and phospholipid complexation in solubility and dissolution enhancement: a critical and meta-analysis. Expert Opin Drug Deliv. 2014;11:1255–72.

    Article  CAS  PubMed  Google Scholar 

  3. Rehman FU, Shah KU, Shah SU, Khan IU, Khan GM, Khan A. From nanoemulsions to self-nanoemulsions, with recent advances in self-nanoemulsifying drug delivery systems (SNEDDS). Expert Opin Drug Deliv. 2017;14:1325–40.

    Article  PubMed  Google Scholar 

  4. Al-Kassas R, Bansal M, Shaw J. Nanosizing techniques for improving bioavailability of drugs. J Control Release. 2017;260:202–12.

    Article  CAS  PubMed  Google Scholar 

  5. Fahr A, Liu X. Drug delivery strategies for poorly water-soluble drugs. Expert Opin Drug Deliv. 2007;4:403–16.

    Article  CAS  PubMed  Google Scholar 

  6. Alam MI, Beg S, Samad A, Baboota S, Kohli K, Ali J, et al. Strategy for effective brain drug delivery. Eur J Pharm Sci. 2010;40:385–403.

    Article  CAS  PubMed  Google Scholar 

  7. Esposito E, Boschi A, Ravani L, Cortesi R, Drechsler M, Mariani P, et al. Biodistribution of nanostructured lipid carriers: a tomographic study. Eur J Pharm Biopharm. 2015;89:145–56.

    Article  CAS  PubMed  Google Scholar 

  8. Natarajan J, Baskaran M, Humtsoe LC, Vadivelan R, Justin A. Enhanced brain targeting efficacy of olanzapine through solid lipid nanoparticles. Artif Cells Nanomedicine Biotechnol. 2017;45:364–71.

    Article  CAS  Google Scholar 

  9. Prajapat MD, Patel NJ, Bariya A, Patel SS, Butani SB. Formulation and evaluation of self-emulsifying drug delivery system for nimodipine, a BCS class II drug. J Drug Deliv Sci Technol. 2017;39:59–68.

    Article  CAS  Google Scholar 

  10. Albekery MA, Alharbi KT, Alarifi S, Ahmad D, Omer ME, Massadeh S, et al. Optimization of a nanostructured lipid carriers system for enhancing the biopharmaceutical properties of valsartan. Dig J Nanomater BIOSTRUCTURES. 2017;12:381–9.

    Google Scholar 

  11. Patel RHP and Nanoemulsions RJ For intranasal delivery of riluzole to improve brain bioavailability: formulation development and pharmacokinetic studies. Curr Drug Deliv 2016. (accessed October 9, 2017).

  12. Jakubiak P, Thwala LN, Cadete A, Preat V, Jose Alonso M, Beloqui A, et al. Solvent-free protamine nanocapsules as carriers for mucosal delivery of therapeutics. Eur Polym J. 2017;93:695–705.

    Article  CAS  Google Scholar 

  13. Kumari P, Muddineti OS, Rompicharla SVK, Ghanta P, Karthik ABBN, Ghosh B, et al. Cholesterol-conjugated poly(D, L-lactide)-based micelles as a nanocarrier system for effective delivery of curcumin in cancer therapy. Drug Deliv. 2017;24:209–23.

    Article  CAS  PubMed  Google Scholar 

  14. Martins S, Sarmento B, Ferreira DC, Souto EB. Lipid-based colloidal carriers for peptide and protein delivery-liposomes versus lipid nanoparticles. Int J Nanomedicine. 2007;2:595.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Torchilin VP. Lipid-core micelles for targeted drug delivery. Curr Drug Deliv. 2005;2:319–27.

    Article  CAS  Google Scholar 

  16. Čerpnjak K, Zvonar A, Vrečer F, Gašperlin M. Development of a solid self-microemulsifying drug delivery system (SMEDDS) for solubility enhancement of naproxen. Drug Dev Ind Pharm. 2015;41:1548–57.

    Article  CAS  PubMed  Google Scholar 

  17. Hosny KM, Aljaeid BM. Sildenafil citrate as oral solid lipid nanoparticles: a novel formula with higher bioavailability and sustained action for treatment of erectile dysfunction. Expert Opin Drug Deliv. 2014;11:1015–22.

    Article  CAS  PubMed  Google Scholar 

  18. Friedrich I, Müller-Goymann C. Characterization of solidified reverse micellar solutions (SRMS) and production development of SRMS-based nanosuspensions. Eur J Pharm Biopharm. 2003;56:111–9.

    Article  CAS  PubMed  Google Scholar 

  19. Gao Z, Lukyanov AN, Singhal A, Torchilin VP. Diacyllipid-polymer micelles as nanocarriers for poorly soluble anticancer drugs. Nano Lett. 2002;2:979–82.

    Article  CAS  Google Scholar 

  20. Mu L, Chrastina A, Levchenko T, Torchilin VP. Micelles from poly(ethylene glycol)–phosphatidyl ethanolamine conjugates (peg-Pe) as pharmaceutical nanocarriers for poorly soluble drug camptothecin. J Biomed Nanotechnol. 2005;1:190–5.

    Article  CAS  Google Scholar 

  21. Wang J, Mongayt DA, Lukyanov AN, Levchenko TS, Torchilin VP. Preparation and in vitro synergistic anticancer effect of vitamin K3 and 1,8-diazabicyclo[5,4,0]undec-7-ene in poly(ethylene glycol)-diacyllipid micelles. Int J Pharm. 2004;272:129–35.

    Article  CAS  PubMed  Google Scholar 

  22. Kocbek P, Baumgartner S, Kristl J. Preparation and evaluation of nanosuspensions for enhancing the dissolution of poorly soluble drugs. Int J Pharm. 2006;312:179–86.

    Article  CAS  PubMed  Google Scholar 

  23. Vivek K, Reddy H, Murthy RS. Investigations of the effect of the lipid matrix on drug entrapment, in vitro release, and physical stability of olanzapine-loaded solid lipid nanoparticles. AAPS PharmSciTech. 2007;8:16–24.

    Article  Google Scholar 

  24. Harivardhan Reddy L, Vivek K, Bakshi N, Murthy RSR. Tamoxifen citrate loaded solid lipid nanoparticles (SLN™): preparation, characterization, in vitro drug release, and pharmacokinetic evaluation. Pharm Dev Technol. 2006;11:167–77.

    Article  CAS  PubMed  Google Scholar 

  25. Solans C, Izquierdo P, Nolla J, Azemar N, Garciacelma M. Nano-emulsions. Curr Opin Colloid Interface Sci. 2005;10:102–10.

    Article  CAS  Google Scholar 

  26. Yukuyama MN, Ghisleni DDM, Pinto TJA, Bou-Chacra NA. Nanoemulsion: process selection and application in cosmetics—a review. Int J Cosmet Sci. 2016;38:13–24.

    Article  CAS  PubMed  Google Scholar 

  27. Koroleva MY, Yurtov EV. Nanoemulsions: the properties, methods of preparation and promising applications. Russ Chem Rev. 2012;81:21–43.

    Article  CAS  Google Scholar 

  28. Lukyanov AN, Gao Z, Mazzola L, Torchilin VP. Polyethylene glycol-diacyllipid micelles demonstrate increased accumulation in subcutaneous tumors in mice. Pharm Res. 2002;19:1424–9.

    Article  CAS  PubMed  Google Scholar 

  29. Mandawgade SD, Sharma S, Pathak S, Patravale VB. Development of SMEDDS using natural lipophile: application to β-artemether delivery. Int J Pharm. 2008;362:179–83.

    Article  CAS  PubMed  Google Scholar 

  30. Sawant RR, Torchilin VP. Multifunctionality of lipid-core micelles for drug delivery and tumour targeting. Mol Membr Biol. 2010;27:232–46.

    Article  CAS  PubMed  Google Scholar 

  31. Behbahani ES, Ghaedi M, Abbaspour M, Rostamizadeh K. Optimization and characterization of ultrasound assisted preparation of curcumin-loaded solid lipid nanoparticles: application of central composite design, thermal analysis and X-ray diffraction techniques. Ultrason Sonochem. 2017;38:271–80.

    Article  CAS  PubMed  Google Scholar 

  32. Gumede TP, Luyt AS, Pérez-Camargo RA, Iturrospe A, Arbe A, Zubitur M, et al. Plasticization and cocrystallization in LLDPE/wax blends. J Polym Sci Part B Polym Phys. 2016;54:1469–82.

    Article  CAS  Google Scholar 

  33. Ran Y, He Y, Yang G, Johnson JL, Yalkowsky SH. Estimation of aqueous solubility of organic compounds by using the general solubility equation. Chemosphere. 2002;48:487–509.

    Article  CAS  Google Scholar 

  34. Weissleder R, Cheng H-C, Bogdanova A, Bogdanov A. Magnetically labeled cells can be detected by MR imaging. J Magn Reson Imaging. 1997;7:258–63.

    Article  CAS  Google Scholar 

  35. Moore A, Basilion JP, Chiocca EA, Weissleder R. Measuring transferrin receptor gene expression by NMR imaging. Biochim Biophys Acta BBA-Mol Cell Res. 1998;1402:239–49.

    Article  CAS  Google Scholar 

  36. Schoepf U, Marecos EM, Melder RJ, Jain RK, Weissleder R. Intracellular magnetic labeling of lymphocytes for in vivo trafficking studies. BioTechniques. 1998;24:642–51.

    Article  CAS  Google Scholar 

  37. Chou LYT, Ming K, Chan WCW. Strategies for the intracellular delivery of nanoparticles. Chem Soc Rev. 2011;40:233–45.

    Article  CAS  PubMed  Google Scholar 

  38. Otsuka H, Nagasaki Y, Kataoka K. PEGylated nanoparticles for biological and pharmaceutical applications. Adv Drug Deliv Rev. 2003;55:403–19.

    Article  CAS  PubMed  Google Scholar 

  39. Yoo HS, Park TG. Folate receptor targeted biodegradable polymeric doxorubicin micelles. J Control Release. 2004;96:273–83.

    Article  CAS  PubMed  Google Scholar 

  40. Patil YB, Toti US, Khdair A, Ma L, Panyam J. Single-step surface functionalization of polymeric nanoparticles for targeted drug delivery. Biomaterials. 2009;30:859–66.

    Article  CAS  PubMed  Google Scholar 

  41. Yuan H, Miao J, Du Y, You J, Hu F, Zeng S. Cellular uptake of solid lipid nanoparticles and cytotoxicity of encapsulated paclitaxel in A549 cancer cells. Int J Pharm. 2008;348:137–45.

    Article  CAS  PubMed  Google Scholar 

Download references


The authors acknowledge the funding support from FONDECYT 1181689, FONDAP 15130011, and STINT IB2015-6087.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Javier O. Morales.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material


(DOCX 44 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fritz, H.F., Ortiz, A.C., Velaga, S.P. et al. Preparation of a novel lipid-core micelle using a low-energy emulsification method. Drug Deliv. and Transl. Res. 8, 1807–1814 (2018).

Download citation

  • Published:

  • Issue Date:

  • DOI: