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Combination of SEDDS and Preactivated Thiomer Technology: Incorporation of a Preactivated Thiolated Amphiphilic Polymer into Self-Emulsifying Delivery Systems

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Abstract

Purpose

The aim of the study was to create novel mucoadhesive drug delivery systems by incorporating amphiphilic hydrophobically modified, thiolated and preactivated polymers (preactivated thiomers) into self-emulsifying drug delivery systems (SEDDS).

Methods

L-Cysteine methyl ester was covalently attached to the polymeric backbone of Pemulen TR-2 and preactivated using 2-mercaptonicotinic acid (2-MNA). These thiomers were incorporated in a concentration of 0.3% (w/v) into SEDDS. The size distribution and the zeta potential of the emulsions were evaluated by dynamic light scattering. Mucoadhesive properties of thiomers-SEDDS spiked with FDA (fluorescein diacetate) were examined utilizing rheological measurement, permeation studies and in vitro residence time study on porcine mucosa. Cell viability tests were additionally performed.

Results

734 ± 58 μmol L-Cysteine methyl ester and 562 ± 71 μmol 2-MNA could be attached per gram polymer of Pemulen TR-2. Emulsions exhibited a droplet size range between 180 and 270 nm. Blank SEDDS possessed a zeta potential value between −5.7 and −8.6 mV, whereas thiomers-SEDDS between −14.6 and −17.2 mV. Viscous modulus of thiomer and preactivated thiomer containing SEDDS-mucus mixture was 8-fold and 11-fold increased in comparison to reference. The amount of FDA permeated the mucus layer was 2-fold lower in case of thiomers-SEDDS compared to blank SEDDS. A prolonged residence time was observed for thiomers-SEDDS over 45 min. During cell viability studies no severe toxic effects were detected.

Conclusion

The novel developed SEDDS with incorporated thiomers might be a promising tool for mucoadhesive oral drug delivery.

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Abbreviations

DTNB:

5,5´-Dithio-bis(2-nitrobenzoic acid

EDAC:

1-Ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride

FDA:

Fluorescein diacetate

2-MNA:

2-Mercaptonicotinic acid

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NHS:

N-hydroxysuccinimide

SEDDS:

Self-emulsifying drug delivery systems

TNBS:

2,4,6-Trinitrobenzene sulfonic acid

References

  1. Aungst BJ. Novel formulation strategies for improving oral bioavailability of drugs with poor membrane permeation or Presystemic metabolism. J Pharm Sci. 1993;82(10):979–87.

    Article  CAS  PubMed  Google Scholar 

  2. Karamanidou T, Karidi K, Bourganis V, Kontonikola K, Kammona O, Kiparissides C. Effective incorporation of insulin in mucus permeating self-nanoemulsifying drug delivery systems. Eur J Pharm Biopharm. 2015;97(Pt A):223–9.

    Article  CAS  PubMed  Google Scholar 

  3. Bruno BJ, Miller GD, Lim CS. Basics and recent advances in peptide and protein drug delivery. Ther Deliv. 2013;4(11):1443–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods. 2000;44(1):235–49.

    Article  CAS  PubMed  Google Scholar 

  5. Albrecht K, Bernkop-Schnürch A. Thiomers: forms, functions and applications to nanomedicine. Nanomedicine (London, England). 2007;2(1):41–50.

    Article  CAS  Google Scholar 

  6. Ijaz M, Bernkop-Schnürch A. Preactivated thiomers: their role in drug delivery. Expert Opin Drug Deliv. 2015;12(8):1269–81.

    Article  CAS  PubMed  Google Scholar 

  7. Nirosha M, Badarinath A, Hyndavi M, Prasad K, Naveen N, Anil Kumar B, et al. Recent advances in self-emulsifying drug delivery system. Int J Rev Life Sci. 2011;1(4):206–14.

    CAS  Google Scholar 

  8. Chatterjee B, Hamed Almurisi S, Ahmed Mahdi Dukhan A, Mandal UK, Sengupta P. Controversies with self-emulsifying drug delivery system from pharmacokinetic point of view. Drug Deliv. 2016:1–14.

  9. Friedl H, Dünnhaupt S, Hintzen F, Waldner C, Parikh S, Pearson JP, et al. Development and evaluation of a novel mucus diffusion test system approved by self-nanoemulsifying drug delivery systems. J Pharm Sci. 2013;102(12):4406–13.

    Article  CAS  PubMed  Google Scholar 

  10. Valicherla GR, Dave KM, Syed AA, Riyazuddin M, Gupta AP, Singh A, et al. Formulation optimization of Docetaxel loaded self-emulsifying drug delivery system to enhance bioavailability and anti-tumor activity. Sci Report. 2016;6:26895.

    Article  CAS  Google Scholar 

  11. Hintzen F, Perera G, Hauptstein S, Müller C, Laffleur F, Bernkop-Schnürch A. In vivo evaluation of an oral self-microemulsifying drug delivery system (SMEDDS) for leuprorelin. Int J Pharm. 2014;472(1–2):20–6.

    Article  CAS  PubMed  Google Scholar 

  12. Sakloetsakun D, Dünnhaupt S, Barthelmes J, Perera G, Bernkop-Schnürch A. Combining two technologies: multifunctional polymers and self-nanoemulsifying drug delivery system (SNEDDS) for oral insulin administration. Int J Biol Macromol. 2013;61:363–72.

    Article  CAS  PubMed  Google Scholar 

  13. Leonaviciute G, Trivic Adamovic N, Thanh Lam H, Rohrer J, Partenhauser A, Bernkop-Schnürch A. Self-emulsifying drug delivery systems (SEDDS): proof-of-concept how to make them mucoadhesive. Eur J Pharm Biopharm. 2017;112:51–7.

  14. Bonengel S, Haupstein S, Perera G, Bernkop-Schnürch A. Thiolated and S-protected hydrophobically modified cross-linked poly(acrylic acid)--a new generation of multifunctional polymers. Eur J Pharm Biopharm. 2014;88(2):390–6.

    Article  CAS  PubMed  Google Scholar 

  15. Iqbal J, Shahnaz G, Dünnhaupt S, Müller C, Hintzen F, Bernkop-Schnürch A. Preactivated thiomers as mucoadhesive polymers for drug delivery. Biomaterials. 2012;33(5):1528–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Müller C, Ma BN, Gust R, Bernkop-Schnürch A. Thiopyrazole preactivated chitosan: combining mucoadhesion and drug delivery. Acta Biomater. 2013;9(5):6585–93.

    Article  PubMed  Google Scholar 

  17. Rahmat D, Müller C, Barthelmes J, Shahnaz G, Martien R, Bernkop-Schnürch A. Thiolated hydroxyethyl cellulose: design and in vitro evaluation of mucoadhesive and permeation enhancing nanoparticles. Eur J Pharm Biopharm. 2013;83(2):149–55.

    Article  CAS  PubMed  Google Scholar 

  18. Karwal R, Garg T, Rath G, Markandeywar TS. Current trends in self-emulsifying drug delivery systems (SEDDSs) to enhance the bioavailability of poorly water-soluble drugs. Crit Rev Ther Drug Carrier Syst. 2016;33(1):1–39.

    Article  PubMed  Google Scholar 

  19. Leonaviciute G, Bernkop-Schnürch A. Self-emulsifying drug delivery systems in oral (poly)peptide drug delivery. Expert Opin Drug Deliv. 2015;12(11):1703–16.

    Article  CAS  PubMed  Google Scholar 

  20. Bonengel S, Hauptstein S, Leonaviciute G, Griessinger J, Bernkop-Schnürch A. Thiolated alkyl-modified carbomers: novel excipients for mucoadhesive emulsions. Eur J Pharm Sci. 2015;75:123–30.

    Article  CAS  PubMed  Google Scholar 

  21. He C, Hu Y, Yin L, Tang C, Yin C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials. 2010;31(13):3657–66.

    Article  CAS  PubMed  Google Scholar 

  22. Friedl HE, Dünnhaupt S, Waldner C, Bernkop-Schnürch A. Preactivated thiomers for vaginal drug delivery vehicles. Biomaterials. 2013;34(32):7811–8.

    Article  CAS  PubMed  Google Scholar 

  23. Köllner S, Dünnhaupt S, Waldner C, Hauptstein S, Pereira de Sousa I, Bernkop-Schnürch A. Mucus permeating thiomer nanoparticles. Eur J Pharm Biopharm. 2015;97(Pt A):265–272.

  24. Takeuchi H, Yamamoto H, Kawashima Y. Mucoadhesive nanoparticulate systems for peptide drug delivery. Adv Drug Deliv Rev. 2001;47(1):39–54.

    Article  CAS  PubMed  Google Scholar 

  25. Bonengel S, Bernkop-Schnürch A. Thiomers--from bench to market. J Control Release. 2014;195:120–9.

    Article  CAS  PubMed  Google Scholar 

  26. Griesser J, Hetényi G, Moser M, Demarne F, Jannin V, Bernkop-Schnürch A. Hydrophobic ion pairing: key to highly payloaded self-emulsifying peptide drug delivery systems. 2017 International Journal of Pharmaceutics (in press).

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Acknowledgements and Disclosures

The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 280,761.

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Authors and Affiliations

  1. Thiomatrix Forschungs-und Beratungs GmbH,, Innsbruck, Austria

    Gergely Hetényi, Janine Griesser, Isabelle Nardin & Andreas Bernkop-Schnürch

  2. Department of Pharmaceutical Technology, Center for Chemistry and Biomedicine, Institute of Pharmacy, Leopold-Franzens-University, Innrain 80/82, 6020, Innsbruck, Austria

    Andreas Bernkop-Schnürch

Authors
  1. Gergely Hetényi
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  2. Janine Griesser
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  3. Isabelle Nardin
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  4. Andreas Bernkop-Schnürch
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Corresponding author

Correspondence to Andreas Bernkop-Schnürch.

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Hetényi, G., Griesser, J., Nardin, I. et al. Combination of SEDDS and Preactivated Thiomer Technology: Incorporation of a Preactivated Thiolated Amphiphilic Polymer into Self-Emulsifying Delivery Systems. Pharm Res 34, 1171–1179 (2017). https://doi.org/10.1007/s11095-017-2131-5

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  • DOI: https://doi.org/10.1007/s11095-017-2131-5

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