Advertisement

Preparation and Characterization of Simvastatin Nanocapsules: Encapsulation of Hydrophobic Drugs in Calcium Alginate

  • Mazaher Ahmadi
  • Tayyebeh Madrakian
  • Saeid GhavamiEmail author
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 2125)

Abstract

During past few years, development of methods for physical encapsulation of drugs in biocompatible materials in mild conditions for poorly water-soluble hydrophobic drugs which are sensitive to hydrolytic conditions is of high interest in biomedical and pharmaceutical industries. The encapsulation can improve the drug solubility while decreases its side effects besides controlling its pharmacokinetic profile which results in the overall improvement of the therapeutic efficacy. In the current paper, we provide a detailed protocol for encapsulation of poorly water-soluble hydrophobic drugs which is a development of the previously developed protocol of nanocapsule formation by complex formation on the interface of emulsion droplets. The newly developed protocol is based on nanocapsule formation by complex formation on the interface of emulsion droplets except using no organic solvent for potential targeted drug delivery to glioblastoma cells. Simvastatin as a model of hydrophobic drugs of high hydrolytic sensitivity was encapsulated in calcium alginate hydrogel as a biocompatible matrix using the developed protocol. Simvastatin belongs to a group of mevalonate cascade inhibitors (statins) which have recently been considered as a possible new approach in cancer treatment especially glioblastoma. As a cholesterol biosynthesis inhibitor, it is very important to deliver statins only to target cells and not intact cells using targeted drug delivery strategies to avoid dysregulation of cholesterol biosynthesis in normal tissue. To prepare the statin drug nanocarrier’s, the drug was first dissolved in polysorbate 20 nonionic surfactant solution, and then peptide modified calcium alginate was deposited on the micelles interface at neutral pH and 30 °C. The prepared nanocapsules were spherical in shape and very small in size (i.e., 17 ± 5 nm). The drug content of the nanocapsules was 117.3 mg g−1 and the drug loading efficiency for a 5-mg initial amount of the drug was 23.5% ± 3.1%.

Keywords

Calcium alginate Encapsulation Hydrophobic drugs Nanocapsules Simvastatin 

Notes

Acknowledgments

The project was supported by National Institute for Medical Research Development (NIMAD), operating grant number #943267. SG was also supported by Health Science Foundation general operating grant and Research Manitoba New Investigator Operating grant.

References

  1. 1.
    Kalepu S, Nekkanti V (2015) Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B 5(5):442–453.  https://doi.org/10.1016/j.apsb.2015.07.003CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Savjani KT, Gajjar AK, Savjani JK (2012) Drug solubility: importance and enhancement techniques. ISRN Pharm 2012:1–10.  https://doi.org/10.5402/2012/195727CrossRefGoogle Scholar
  3. 3.
    Singh D, Bedi N, Tiwary AK (2017) Enhancing solubility of poorly aqueous soluble drugs: critical appraisal of techniques. J Pharm Investig.  https://doi.org/10.1007/s40005-017-0357-1CrossRefGoogle Scholar
  4. 4.
    Messana L (2017) Nanotechnology in drug delivery: fundamentals, design, and applications. Scitus Academics LLCGoogle Scholar
  5. 5.
    Din F, Aman W, Ullah I, Qureshi OS, Mustapha O, Shafique S, Zeb A (2017) Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int J Nanomedicine 12:7291–7309.  https://doi.org/10.2147/IJN.S146315CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Loh ZH, Samanta AK, Sia Heng PW (2015) Overview of milling techniques for improving the solubility of poorly water-soluble drugs. Asian J Pharm Sci 10(4):255–274.  https://doi.org/10.1016/j.ajps.2014.12.006CrossRefGoogle Scholar
  7. 7.
    Singh R, Lillard JW (2009) Nanoparticle-based targeted drug delivery. Exp Mol Pathol 86(3):215–223.  https://doi.org/10.1016/j.yexmp.2008.12.004CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Srinivasarao M, Low PS (2017) Ligand-targeted drug delivery. Chem Rev 117(19):12133–12164.  https://doi.org/10.1021/acs.chemrev.7b00013CrossRefPubMedGoogle Scholar
  9. 9.
    Liu L, Jiang L, Xu GK, Ma C, Yang XG, Yao JM (2014) Potential of alginate fibers incorporated with drug-loaded nanocapsules as drug delivery systems. J Mater Chem B 2(43):7596–7604.  https://doi.org/10.1039/C4TB01392ACrossRefGoogle Scholar
  10. 10.
    Leong J-Y, Lam W-H, Ho K-W, Voo W-P, Lee MF-X, Lim H-P, Lim S-L, Tey B-T, Poncelet D, Chan E-S (2016) Advances in fabricating spherical alginate hydrogels with controlled particle designs by ionotropic gelation as encapsulation systems. Particuology 24:44–60.  https://doi.org/10.1016/j.partic.2015.09.004CrossRefGoogle Scholar
  11. 11.
    Paques JP, van der Linden E, van Rijn CJM, Sagis LMC (2014) Preparation methods of alginate nanoparticles. Adv Colloid Interface Sci 209:163–171.  https://doi.org/10.1016/j.cis.2014.03.009CrossRefPubMedGoogle Scholar
  12. 12.
    Reis CP, Neufeld RJ, Ribeiro AJ, Veiga F (2006) Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles. Nanomedicine 2(1):8–21.  https://doi.org/10.1016/j.nano.2005.12.003CrossRefPubMedGoogle Scholar
  13. 13.
    Mora-Huertas CE, Fessi H, Elaissari A (2010) Polymer-based nanocapsules for drug delivery. Int J Pharm 385(1):113–142.  https://doi.org/10.1016/j.ijpharm.2009.10.018CrossRefPubMedGoogle Scholar
  14. 14.
    Lertsutthiwong P, Noomun K, Jongaroonngamsang N, Rojsitthisak P, Nimmannit U (2008) Preparation of alginate nanocapsules containing turmeric oil. Carbohydr Polym 74(2):209–214.  https://doi.org/10.1016/j.carbpol.2008.02.009CrossRefGoogle Scholar
  15. 15.
    Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benita S (1989) Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm 55(1):R1–R4.  https://doi.org/10.1016/0378-5173(89)90281-0CrossRefGoogle Scholar
  16. 16.
    Alizadeh J, Zeki AA, Mirzaei N, Tewary S, Rezaei Moghadam A, Glogowska A, Nagakannan P, Eftekharpour E, Wiechec E, Gordon JW, Xu FY, Field JT, Yoneda KY, Kenyon NJ, Hashemi M, Hatch GM, Hombach-Klonisch S, Klonisch T, Ghavami S (2017) Mevalonate cascade inhibition by simvastatin induces the intrinsic apoptosis pathway via depletion of isoprenoids in tumor cells. Sci Rep 7:44841.  https://doi.org/10.1038/srep44841CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Likus W, Siemianowicz K, Bienk K, Pakula M, Pathak H, Dutta C, Wang Q, Shojaei S, Assaraf YG, Ghavami S, Cieslar-Pobuda A, Los MJ (2016) Could drugs inhibiting the mevalonate pathway also target cancer stem cells? Drug Resist Updat 25:13–25.  https://doi.org/10.1016/j.drup.2016.02.001CrossRefPubMedGoogle Scholar
  18. 18.
    Yeganeh B, Wiechec E, Ande SR, Sharma P, Moghadam AR, Post M, Freed DH, Hashemi M, Shojaei S, Zeki AA, Ghavami S (2014) Targeting the mevalonate cascade as a new therapeutic approach in heart disease, cancer and pulmonary disease. Pharmacol Ther 143(1):87–110.  https://doi.org/10.1016/j.pharmthera.2014.02.007CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ghavami S, Sharma P, Yeganeh B, Ojo OO, Jha A, Mutawe MM, Kashani HH, Los MJ, Klonisch T, Unruh H, Halayko AJ (2014) Airway mesenchymal cell death by mevalonate cascade inhibition: integration of autophagy, unfolded protein response and apoptosis focusing on Bcl2 family proteins. Biochim Biophys Acta 1843(7):1259–1271.  https://doi.org/10.1016/j.bbamcr.2014.03.006CrossRefPubMedGoogle Scholar
  20. 20.
    Murtaza G (2012) Solubility enhancement of simvastatin: a review. Acta Pol Pharm 69(4):581–590PubMedGoogle Scholar
  21. 21.
    Alvarez-Lueje A, Valenzuela C, Squella JA, Nunez-Vergara LJ (2005) Stability study of simvastatin under hydrolytic conditions assessed by liquid chromatography. J AOAC Int 88(6):1631–1636CrossRefGoogle Scholar
  22. 22.
    Nielsen SF, Nordestgaard BG, Bojesen SE (2013) Statin use and reduced cancer-related mortality. N Engl J Med 368(6):576–577.  https://doi.org/10.1056/NEJMc1214827CrossRefPubMedGoogle Scholar
  23. 23.
    Oberoi RK, Parrish KE, Sio TT, Mittapalli RK, Elmquist WF, Sarkaria JN (2016) Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma. Neuro Oncol 18(1):27–36.  https://doi.org/10.1093/neuonc/nov164CrossRefPubMedGoogle Scholar
  24. 24.
    Zhang M, Chen X, Ying M, Gao J, Zhan C, Lu W (2017) Glioma-targeted drug delivery enabled by a multifunctional peptide. Bioconjug Chem 28(3):775–781.  https://doi.org/10.1021/acs.bioconjchem.6b00617CrossRefPubMedGoogle Scholar
  25. 25.
    Montalbetti CAGN, Falque V (2005) Amide bond formation and peptide coupling. Tetrahedron 61(46):10827–10852.  https://doi.org/10.1016/j.tet.2005.08.031CrossRefGoogle Scholar
  26. 26.
    Bhowmik BB, Sa B, Mukherjee A (2006) Preparation and in vitro characterization of slow release testosterone nanocapsules in alginates. Acta Pharm 56(4):417–429PubMedGoogle Scholar
  27. 27.
    Santhi K, Dhanraj S, Nagasamyvenkatesh D, Sangeetha S, Suresh B (2005) Preparation and optimization of sodium alginate nanospheres of methotrexate. Indian J Pharm Sci 67(6):691–696Google Scholar

Copyright information

© Springer Science+Business Media New York 2018

Authors and Affiliations

  • Mazaher Ahmadi
    • 1
    • 5
  • Tayyebeh Madrakian
    • 1
  • Saeid Ghavami
    • 2
    • 3
    • 4
    Email author
  1. 1.Faculty of ChemistryBu-Ali Sina UniversityHamedanIran
  2. 2.Department of Human Anatomy and Cell Science, Max Rady College of MedicineUniversity of ManitobaWinnipegCanada
  3. 3.Biology of Breathing Theme, Children’s Hospital Research Institute of ManitobaUniversity of ManitobaWinnipegCanada
  4. 4.Health policy Research Center, Institute of HealthShiraz University of Medical SciencesShirazIran
  5. 5.Department of Clinical BiochemistryShiraz University of Medical SciencesShirazIran

Personalised recommendations