Skip to main content
SpringerLink
Log in

Intraoral Film Containing Insulin-Phospholipid Microemulsion: Formulation and In Vivo Hypoglycemic Activity Study

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

Abstract

Non-invasive administration of insulin is expected for better diabetes mellitus therapy. In this report, we developed intraoral preparation for insulin. Insulin was encapsulated into nanocarrier using self-assembly emulsification process. To increase lipophilicity of insulin, it was dispersed in phospholipid resulted in insulin-phospholipid solid dispersion. The microemulsion formula was established from our previous work which contained glyceryl monooleate (GMO), Tween 20, and polyethylene glycol (PEG 400) in a ratio of 1:8:1. To confirm the formation of insulin-phospholipid solid dispersion, PXRD, FTIR spectroscopy, and Raman spectroscopy were performed. Then, the microemulsion was evaluated for droplet size and distribution, zeta potential, entrapment efficiency, physical stability, and Raman spectroscopy. In addition, microemulsion with expected characteristic was evaluated for in vitro release, in vitro permeation, and in vivo activity. The droplets size of ∼100 nm with narrow distribution and positive charge of +0.56 mV were formed. The insulin encapsulated in the oil droplet was accounted of >90%. Water-soluble chitosan seems to be a promising film matrix polymer which also functioned as insulin release controller. Oral administration of insulin microemulsion to healthy Swiss-Webster mice showed hypoglycemic effect indicating the success of this protein against a harsh environment of the gastrointestinal tract. This effectiveness significantly increased by fourfold as compared to free insulin. Taken together, microemulsion seems to be a promising carrier for oral delivery of insulin.

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
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Triplitt CL, Reasner CA, Isle WL. Diabetes mellitus, 1205–1241 in book: pharmacotherapy: a pathophysiologic approach. 7th ed. New York: The McGraw-Hill Companies, Inc; 2008. p. 2597.

  2. Heineman L, Jacques Y. Oral insulin and buccal insulin: a critical reappraisal. J Diabetes Sci Tech. 2009;3(3):568–83.

    Article  Google Scholar 

  3. Heinemann L. New ways of insulin delivery. Int J Clin Pract. 2011;65:31–46.

    Article  Google Scholar 

  4. Lassmann-Vague V, Racca D. Alternatives routes of insulin delivery. Diabetes Metab. 2006;32:513–22.

    Article  CAS  PubMed  Google Scholar 

  5. Rekha MR, Sharma CP. Oral delivery of therapeutic protein/peptide for diabetes—future perspectives. Int J Pharm. 2013;440:48–52.

    Article  CAS  PubMed  Google Scholar 

  6. Pozzilli P, Raskin P, Parkin CG. Review of clinical trials: update on oral insulin spray formulation. Diabetes Obes Metab. 2010;12(2):1–8.

    Article  Google Scholar 

  7. Iyer H, Khedkar A, Verma M. Oral insulin—a review of current status. Diabetes Obes Metab. 2010;12(3):179–85.

    Article  CAS  PubMed  Google Scholar 

  8. Ramesan RM, Sharma CP. Challenges and advances in nanoparticle-based oral insulin delivery. Exp Rev Med Devices. 2009;6(6):665–76.

    Article  CAS  Google Scholar 

  9. Khafagy ES, Morishita M, Onuki Y, Takayama K. Current challenges in non-invasive insulin delivery systems: a comparative review. Adv Drug Del. 2007;59:1521–46.

    Article  CAS  Google Scholar 

  10. Banga AK, editor. Therapeutic peptides and proteins formulation, processing, and delivery systems. 2nd ed. Boca Raton: Taylor & Francis; 2006. p. 14–83.

    Google Scholar 

  11. Chen MC, Sonaje K, Chen KJ, Sung HW. A review of the prospects for polymeric nanoparticle platforms in oral insulin delivery. Biomat. 2011;32:9826–38.

    Article  CAS  Google Scholar 

  12. Li XY, Qi JP, Xie YC, Zhang X, Hu SW, Xu Y, et al. Microemulsions coated with alginate/chitosan as oral insulin delivery systems: preparation, characterization, and hypoglycemic effect in rats. Int J Nanomedicine. 2013;8:12–21.

    Google Scholar 

  13. Rao SVR, Shao J. Self-microemulsion drug delivery systems (SNEDDS) for oral delivery of protein drugs 1: formulation development. Int J Pharm. 2008;362(2–3):7–8.

    Google Scholar 

  14. Fryd MM, Mason TG. Advanced microemulsions. Annu Rev Phys Chem. 2012;6:493–518.

    Article  Google Scholar 

  15. Sadtler V, Galindo-Alvarez JM, and Marie-Bégué E. Low energy emulsification methods for nanoparticles synthesis, 509–524 dalam Hashim, A.A. The delivery of nanoparticles. InTech, Rijeka-Croatia. 2012:p. 540.

  16. Dogru ST, Calis S, Oner F. Oral multiple W/O/W emulsion formulation of a peptide salmon calcitonin: in vitro-in vivo evaluation. J Clin Pharm Ther. 2000;25(6):435–43.

    Article  CAS  PubMed  Google Scholar 

  17. Celebi N, Yetkin G, Ozer C, Can A, Gökçora N. Evaluation of microemulsion and liposomes as carriers for oral delivery of transforming growth factor alpha in rats. J Microencapsul. 2012;29(6):539–48.

    Article  CAS  PubMed  Google Scholar 

  18. Çilek A, Çelebi N, Tirnaksiz F. Lecithin-based microemulsion of a peptide for oral administration: preparation, characterization, and physical stability of the formulation. Drug Deliv. 2005;13(1):19–24.

    Article  Google Scholar 

  19. Çilek A, Çelebi N, Tirnaksiz F, Tay A. A lecithin-based microemulsion of Rh-insulin with aprotinin for oral administration: investigation of hypoglycemic effects in non-diabetic and STZ-induced diabetic rats. Int J Pharm. 2006;298(1):176–85.

    Article  Google Scholar 

  20. Toorisaka E, Ono H, Arimori K, Kamiya N, Goto M. Hypoglycemic effect of surfactant-coated insulin solubilized in a novel solid-in-oil-in-oil water (S/O/W) emulsion. Int J Pharm. 2003;252:271–4.

    Article  CAS  PubMed  Google Scholar 

  21. Morita T, Sakamura Y, Horikir Y, Suzuki T, Yoshino H. Protein encapsulation into biodegradable microspheres by a novel S/O/W emulsion method using poly(ethylene glycol) as a protein micronization adjuvant. J Con Rel. 2000;69:435–44.

    Article  CAS  Google Scholar 

  22. Rachmawati H, Haryadi DM. The influence of polymer structure on the physical characteristic of intraoral film containing BSA-loaded nanoemulsion. J Nanomed Nanotechnol. 2014;5(1):1–6.

    Google Scholar 

  23. Rachmawati H, Edityaningrum CA, Mauluddin R. Molecular inclusion complex of curcumin-β-cyclodextrin nanoparticle to enhance curcumin skin permeability from hydrophilic matrix gel. Am Assoc Pharm Scie Pharm Sci Tech. 2013;14(4):1303–12.

    CAS  Google Scholar 

  24. Cui FD, Shi K, Zhang LQ, Tao AJ, Kawashima Y. Biodegradable nanoparticles loaded with insulin-phospholipid complex for oral delivery: preparation, in vitro characterization and in vivo evaluation. J Con Rel. 2006;114:242–50.

    Article  CAS  Google Scholar 

  25. Peng Q, Zhang ZR, Gong T, Chen GQ, Sun X. A rapid-acting, long-acting insulin formulation based on a phospholipid complex loaded PHBHHx nanoparticles. Biomat. 2012;3:1583–8.

    Article  Google Scholar 

  26. Zhou CP, Xia XJ, Liu YL, Li L. The preparation of a complex of insulin-phospholipids and their interaction mechanism. J Pept Sci. 2012;18:541–8.

    Article  CAS  PubMed  Google Scholar 

  27. Pawar H, Douromumis D, Boateng JS. Preparation and optimization of PMAA-chitosan-PEG nanoparticle for oral drug delivery. Coll Surf B. 2012;90:102–8.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Ortiz C, Zhang DM, Xie Y, Davisson JV, dam Ben-Amotz D. Identification of insulin variants using Raman spectroscopy. Anal Biochem. 2004;332:245–52.

    Article  CAS  PubMed  Google Scholar 

  30. Tay SLM, Heng PWS, Chan LW. An investigation of the chick chorioallantoic membrane as an alternative model to various biological tissues for permeation studies. J Pharm Pharmacol. 2011;63:1283–9.

    Article  CAS  PubMed  Google Scholar 

  31. Haigh JM, Beyssac E, Chanet L, Aiache JM. In vitro permeation of progesterone from a gel through shed skin of three different snake species. Int J Pharm. 1998;170:151–6.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was financially supported by a research grant from the Bandung Institute of Technology, Indonesia, 2013.

Conflict of Interest

There is no conflict of interest to declare.

Author information

Authors and Affiliations

  1. School of Pharmacy, Bandung Institute of Technology, Ganesha 10, Bandung, 40132, Indonesia

    Heni Rachmawati, Bernard Manuel Haryadi & Kusnandar Anggadiredja

  2. Division of Nanomedicine, National Research Center for Nanotechnology, Bandung Institute of Technology, Ganesha 10, Bandung, 40132, Indonesia

    Heni Rachmawati & Veinardi Suendo

  3. Department of Chemistry, Faculty of Mathematics and Natural Sciences, Bandung Institute of Technology, Ganesha 10, Bandung, 40132, Indonesia

    Veinardi Suendo

Authors
  1. Heni Rachmawati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bernard Manuel Haryadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kusnandar Anggadiredja
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Veinardi Suendo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heni Rachmawati.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

ESM 1

(XLSX 701 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rachmawati, H., Haryadi, B.M., Anggadiredja, K. et al. Intraoral Film Containing Insulin-Phospholipid Microemulsion: Formulation and In Vivo Hypoglycemic Activity Study. AAPS PharmSciTech 16, 692–703 (2015). https://doi.org/10.1208/s12249-014-0258-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1208/s12249-014-0258-9

KEY WORDS

Search

Navigation