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Alf Lamprecht Laboratory of Pharmaceutical Engineering (EA4267),

NP at the gastrointestinal barrier - aspects of bioadhesion. Alf Lamprecht Laboratory of Pharmaceutical Engineering (EA4267), University of Franche-Comté, Besançon, France http://galenique.univ-fcomte.fr Contact: alf.lamprecht@univ-fcomte.fr. site of action. drug. intestinal barrier.

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Alf Lamprecht Laboratory of Pharmaceutical Engineering (EA4267),

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  1. NP at the gastrointestinal barrier - aspects of bioadhesion Alf Lamprecht Laboratory of Pharmaceutical Engineering (EA4267), University of Franche-Comté, Besançon, France http://galenique.univ-fcomte.fr Contact:alf.lamprecht@univ-fcomte.fr

  2. site of action drug intestinal barrier target organs • Oral drug delivery aims for: • systemic absorption – bioavailability • local drug delivery – drug targeting • Nanoparticles for increased drug absorption • Nanoparticles for the selective drug targeting

  3. nanoparticulate drug delivery phenomena at intact barriers Absorption of - macromolecules - low bioavailability drugs

  4. Nanoparticles for oral absorption Heparin - treatment and prophylaxis of venous thrombosis - parenteral administration - no oral absorption Nanoparticles: - biocompatible polymers (cationic) - diameter: 50-500nm oral rel. F > 30%

  5. Nanoparticles for oral absorption Calcitonine - treatment of calcemia - parenteral administration - no oral absorption Nanoparticles: - emulsion technique (w/o/w) - biocompatible polymers (lipophilic) - diameter: 300-500nm oral rel. F  5% (Lamprecht et al., JCR, 2006)

  6. Nanoparticles for oral absorption Cell culture model for adsorption studies: 1. Absorption barrier (Caco-2 cells) 2. Mucus layer (mucin) apical compartment mucus layer epithelial cells basolateral comp.

  7. NP adhesion • LMWH adhesion correlates!!! (Lamprecht et al., Nanotechology, 2006)

  8. PEG-stearate lipid core Nanoparticles for oral absorption - no use of organic solvents  biocompatible - very small size (~20-50nm) - drug release includes distinct burst effect - slower release for higher drug loading (Lamprecht et al., IJP, 2004; JCR 2006)

  9. PEG-stearate PEG-stearate drug inhibitor D D D D drug D D Nanoparticles for oral absorption Applications to: - poorly water-soluble drugs - P-gp substrates - drugs with presystemic metabolism

  10. nanoparticulate drug delivery phenomena at inflamed barriers Specific bioadhesion to inflammation

  11. Nanoparticles in colitis • chronic, relapsing inflammation of the colon • swelling and ulceration of mucosa and submucosa • therapeutic principles: • induce remission of outbreaks • prevent outbreaks during remission • drug treatment • - oral (standard) • - rectal (limited use) • - intravenous (recent) • surgery ulcerative colitis Crohn’s disease

  12. Nanoparticles in colitis Histology of inflamed colon (TNBS-model in rats) healthy control colitis group colitis group oral small particle targeting by: - particle adhesion to the thicker mucus layer - uptake into the T cells in ulcerated regions Hypothesis:  selective accumulation in the inflamed tissue

  13. healthy control ulcerated tissue Nanoparticles in colitis - deposition in inflamed colon  selectivity - size dependent accumulation - unchanged deposition in other gut tissues Lamprecht et al., PharmRes, 2001)

  14. Nanoparticles in colitis Lamprecht et al., JPET, 2005)

  15. Nanoparticles in colitis FK506 after rectal administration  solution less efficient than NP

  16. Nanoparticles in colitis solution: NP: healthy inflamed healthy inflamed NP tissue penetration into inflamed tissue  into healthy tissue  …. ….

  17. Nanoparticles in colitis D D D D D healthy group D D D D D D D D D colitis group D D

  18. Nanoparticles in colitis Nanoparticles = large surface = difficulties to control the release Covalent coupling polymer - drug (Pertuit et al., JCR, 2007)

  19. Nanoparticles in colitis Covalent coupling silica NP - drug (Moulari et al., Biomaterials, 2008)

  20. Nanoparticles in colitis - specific adhesion - high therapeutic efficiency (Moulari et al., Biomaterials, 2008)

  21. Nanoparticles in gastric ulcer How about other inflamed tissues? example: gastric ulcer + helicobacter Pylori oral small particle targeting by: - particle adhesion to the thicker mucus layer? - uptake into cells in ulcerated regions?

  22. Nanoparticles in gastric ulcer • significant adhesion of NP • - higher NP adhesion in ulcerated regions • - therapy interval-dependent (Hassani et al., PharmRes, 2009)

  23. Nanoparticles in gastric ulcer targeting index increases with: - smaller NP - prolonged therapy (Hassani et al., PharmRes, 2009)

  24. Conclusion Is this a general therapeutic approach? there is an epithelial EPR-effect in the GI tract!

  25. Acknowledgements Besançon Y. Pellequer A. Béduneau B. Moulari T. Bautzova S. Hassani D. Pertuit Y. Meissner Bonn D. Allhenn M. Abdel Mottaleb W. Ulbrich P. Wachsmann A. Viehof S. Eggerstedt

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