Pharmaceutical Research

, 35:82 | Cite as

Double or Simple Emulsion Process to Encapsulate Hydrophilic Oxytocin Peptide in PLA-PEG Nanoparticles

  • Betty Gourdon
  • Xavier Declèves
  • Jean-Manuel Péan
  • Caroline Chemin
Research Paper
  • 143 Downloads

Abstract

Purpose

Oral drug delivery using NPs is a current strategy for poorly absorbed molecules. It offers significant improvement in terms of bioavailability. However, the encapsulation of proteins and peptides in polymeric NPs is a challenge. Firstly, the present study focused on the double emulsion process in order to encapsulate the OXY peptide. Then the technique was challenged by a one-step simplified process, the simple emulsion.

Methods

In order to study the influence of formulation and process parameters, factorial experimental designs were carried on. The responses observed were the NP size (<200 nm in order to penetrate the intestinal mucus layer), the suspension stability (ZP < |30| mV) and the OXY loading.

Results

It was thus found that the amount and the nature of surfactant, the ratio between the phases, the amount of PLA-PEG polymer and OXY, the presence of a viscosifying agent, and the duration of the sonication could significantly influence the responses. Finally, OXY-loaded NPs from both processes were obtained with NP size of 195 and 226 nm and OXY loading of 4 and 3.3% for double and simple emulsions, respectively.

Conclusion

The two processes appeared to be suitable for OXY encapsulation and comparable in term of NP size, peptide drug load and release obtained.

KEY WORDS

emulsion process factorial experimental design oxytocin peptide polymer nanoparticles 

Abbreviations

ACN

Acetonitrile

ATFA

Trifluoroacetic acid

BSA

Bovine serum albumin

DCM

Dichloromethane

DL

Drug load

DLS

Dynamic light scattering

DMSO

Dimethyl sulfoxyde

EtAc

Ethyl acetate

EtOH

Ethanol

HBSS

Hanks buffer saline solution

HEC

Hydroxy ethyl cellulose

HLB

Hydrophilic-lipophilic balance

HPLC

High pressure liquid chromatography

MES

2-(N-morpholino)ethanesulfonic acid

NME

New molecular entity

NP

Nanoparticle

O

Organic phase

OXY

Oxytocin

PDLG

DL-lactide/glycolide copolymer

PEG

Poly-ethylene glycol

PLA

Polylactic acid

PLGA

Poly-D-L-lactide-co-glycolide

PVA

Poly(vinyl alcohol)

W

Aqueous phase

WE

External aqueous phase

WI

Internal aqueous phase

ZP

Zeta potential

Notes

Acknowledgments and Disclosures

The author reports no conflicts of interest in this work.

Supplementary material

11095_2018_2358_Fig1_ESM.jpg (83 kb)
Fig. S1 Apparent viscosity (Pas) of the viscofying agents HEC at 1% and 2.5% (w/v) and PEG 400 at (3:2) and (2:3) ratios with water, represented as function of shearing speed (1/s), in [water + poloxamer P188 1% (w/v)] aqueous phase (JPEG 83 kb)

References

  1. 1.
    Reis CP, Neufeld RJ, Ribeiro AJ. VeigaF. Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles. Nanomedicine. 2006;2:8–21.CrossRefPubMedGoogle Scholar
  2. 2.
    Mahapatro A, Singh DK. Biodegradable nanoparticles are excellent vehicle for site directed in-vivo delivery of drugs and vaccines. Journal of Nanobiotechnology. 2011;9:55.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Damgé C, Michel C, Aprahamian M, Couvreur P, Devissaguet JP. Nanocapsules as carriers for oral peptide delivery. J Control Release. 1990;13:233–9.CrossRefGoogle Scholar
  4. 4.
    Iqbal M, Zafar N, Fessi H, Elaissari A. Double emulsion solvent evaporation techniques used for drug encapsulation. Int J Pharm. 2015;496:173–90.CrossRefPubMedGoogle Scholar
  5. 5.
    Vauthier C, Bouchemal K. Methods for the preparation and manufacture of polymeric nanoparticles. Pharm Res. 2009;26:1025–58.CrossRefPubMedGoogle Scholar
  6. 6.
    Wang H, Zhao Y, Wu Y, Hu YL, Nan K, Nie G, et al. Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles. Biomaterials. 2011;32:8281–90.CrossRefPubMedGoogle Scholar
  7. 7.
    Mattos AC, Altmeyer C, Tominaga TT, Khalil NM, Mainardes RM. Polymeric nanoparticles for oral delivery of 5-fluorouracil: formulation optimization, cytotoxicity assay and pre-clinical pharmacokinetics study. Eur J Pharm Sci. 2016;84:83–91.CrossRefPubMedGoogle Scholar
  8. 8.
    Danafar H, Rostamizadeh K, Davaran S, Hamidi M. Drug-conjugated PLA-PEG-PLA copolymers: a novel approach for controlled delivery of hydrophilic drugs by micelle formation. Pharm Dev Technol. 2017;22(8):947–57.CrossRefPubMedGoogle Scholar
  9. 9.
    Tomar L, Tyagi C, Kumar M, Kumar P, Singh H, Choonara YE, et al. In vivo evaluation of a conjugated poly(lactide-ethylene glycol) nanoparticle depot formulation for prolonged insulin delivery in the diabetic rabbit model. Int J Nanomedicine. 2013;8:505–20.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Jain A, Jain SK. L-valine appended PLGA nanoparticles for oral insulin delivery. Acta Diabetol. 2015;52:663–76.CrossRefPubMedGoogle Scholar
  11. 11.
    Pirooznia N, Hasannia S, Lotfi AS, Ghanei M. Encapsulation of alpha-1 antitrypsin in PLGA nanoparticles: in vitro characterization as an effective aerosol formulation in pulmonary diseases. J Nanobiotechnology. 2012;10:20.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Essa S, Rabanel JM, Hildgen P. Characterization of rhodamine loaded PEG-g-PLA nanoparticles (NPs): effect of poly(ethylene glycol) grafting density. Int J Pharm. 2011;411:178–87.CrossRefPubMedGoogle Scholar
  13. 13.
    Ji S, Lu J, Liu Z, Srivastava D, Song A, Liu Y, et al. Dynamic encapsulation of hydrophilic nisin in hydrophobic poly (lactic acid) particles with controlled morphology by a single emulsion process. J Colloid Interface Sci. 2014;423:85–93.CrossRefPubMedGoogle Scholar
  14. 14.
    Ensign LM, Cone R, Hanes J. Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers. Adv Drug Deliv Rev. 2012;64:557–70.CrossRefPubMedGoogle Scholar
  15. 15.
    Hans ML, Lowman AM. Biodegradable nanoparticles for drug delivery and targeting. Curr Opinion Solid State Mater Sci. 2002;6:319–27.CrossRefGoogle Scholar
  16. 16.
    Budhian A, Siegel SJ, Winey KI. Haloperidol-loaded PLGA nanoparticles: systematic study of particle size and drug content. Int J Pharm. 2007;336:367–75.CrossRefPubMedGoogle Scholar
  17. 17.
    Görner T, Gref R, Michenot D, Sommer F, Tran MN, Dellacherie E. Lidocaine-loaded biodegradable nanospheres. I. Optimization of the drug incorporation into the polymer matrix. J Control Release. 1999;57:259–68.CrossRefPubMedGoogle Scholar
  18. 18.
    Pridgen EM, Alexis F, Kuo TT, Levy-Nissenbaum E, Karnik R, Blumberg RS, et al. Transepithelial transport of fc-targeted nanoparticles by the neonatal fc receptor for oral delivery. Sci Transl Med. 2013;5:213ra167.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Sharma N, Madan P, Lin S. Effect of process and formulation variables on the preparation of parenteral paclitaxel-loaded biodegradable polymeric nanoparticles: a co-surfactant study. Asian Journal of Pharmaceutical Sciences. 2016;11:404–16.CrossRefGoogle Scholar
  20. 20.
    Zweers ML, Grijpma DW, Engbers GH, Feijen J. The preparation of monodisperse biodegradable polyester nanoparticles with a controlled size. J Biomed Mater Res B Appl Biomater. 2003;66:559–66.CrossRefPubMedGoogle Scholar
  21. 21.
    Box GEP, Hunter WG, Hunter JS. Statistics for experimenters: an introduction to design, data analysis, and model building. Hoboken: Wiley; 1978.Google Scholar
  22. 22.
    Julienne MC, Alonso MJ, Gomez Amoza JL, Benoit JP. Preparation of poly(D,L-lactide/glycolide) nanoparticles of controlled particle size distribution: application of experimental designs. Drug DevIndPharm. 1992;18:1063–77.Google Scholar
  23. 23.
    Lewis GA, Mathieu D, Phan-Tan-Luu R. Pharmaceutical experimental design. New York: Marcel Dekker, Inc.; 1999. p. 186-191Google Scholar
  24. 24.
    Walls ZF, Gupta SV, Amidon GL, Lee KD. Synthesis and characterization of valyloxy methoxy luciferin for the detection of valacyclovirase and peptide transporter. Bioorg Med Chem Lett. 2014;24:4781–3.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bilati U, Allemann E, Doelker E. Development of a nanoprecipitation method intended for the entrapment of hydrophilic drugs into nanoparticles. Eur J Pharm Sci. 2005;24:67–75.CrossRefPubMedGoogle Scholar
  26. 26.
    Gourdon B, Chemin C, Moreau A, Arnauld T, Baumy P, Cisternino S, et al. Functionalized PLA-PEG nanoparticles targeting intestinal transporter PepT1 for oral delivery of acyclovir. Int J Pharm. 2017;529:357–70.CrossRefPubMedGoogle Scholar
  27. 27.
    Cheng J, Teply BA, Sherifi I, Sung J, Luther G, Gu FX, et al. Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery. Biomaterials. 2007;28:869–76.CrossRefPubMedGoogle Scholar
  28. 28.
    Budhian A, Siegel SJ, Winey KI. Production of haloperidol-loaded PLGA nanoparticles for extended controlled drug release of haloperidol. J Microencapsul. 2005;22:773–85.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Betty Gourdon
    • 1
    • 2
    • 3
  • Xavier Declèves
    • 2
    • 3
    • 4
  • Jean-Manuel Péan
    • 1
  • Caroline Chemin
    • 1
  1. 1.Technologie ServierOrléansFrance
  2. 2.Inserm, U1144ParisFrance
  3. 3.Faculté de Pharmacie de Paris, UMR-S 1144Université Paris DescartesParisFrance
  4. 4.Inserm UMR-S1144Universités Paris Descartes et Paris DiderotParisFrance

Personalised recommendations