. Shahbazi, Contrairement à la taille obtenue, identique à celle obtenue avec l'insuline, et ne variant pas d'un type d'héparine à l'autre, la charge de surface des NPs semble varier du SDS, Les trois héparines sélectionnées ont ainsi été encapsulées dans des NPs d'un diamètre d'environ 200 nm, 2013.

. Hoffart, En effet, chaque héparine selon son poids moléculaire ne possède pas le même nombre de groupements sulfates faisant varier la charge négative d'une héparine à l'autre, 2002.

. Hoffart, Cette hypothèse semble corréler avec la littérature qui comporte plusieurs études parlant d'héparine en surface au sein de micro ou nanocapsules et montrant une charge de surface fortement négative qui pourrait lui être attribuée, 2006.

, De plus, il est largement connu qu'il existe deux types d'encapsulation de principe actif au sein de nanocapsules : soit le principe actif est contenu au coeur des NPs soit il se trouve en surface (Ranjit, 2012.

R. A. Baughman, S. C. Kapoor, R. K. Agarwal, J. Kisicki, F. Catella-lawson et al., Oral delivery of anticoagulant doses of heparin. A randomized, double-blind, controlled study in humans, Circulation, vol.98, pp.1610-1615, 1998.

A. Bayat, B. Larijani, S. Ahmadian, H. E. Junginger, and M. Rafiee-tehrani, Preparation and characterization of insulin nanoparticles using chitosan and its quaternized derivatives, Nanomedicine, vol.4, 2008.

S. D. Berkowitz, V. J. Marder, G. Kosutic, and R. A. Baughman, Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty, J Thromb Haemost, vol.1, pp.1914-1919, 2003.

A. Bernkop-schnurch, Thiomers: a new generation of mucoadhesive polymers, Adv Drug Deliv Rev, vol.57, 2005.

U. Bilati, E. Allemann, and E. Doelker, Poly(D,L-lactide-co-glycolide) proteinloaded nanoparticles prepared by the double emulsion method--processing and formulation issues for enhanced entrapment efficiency, J Microencapsul, vol.22, pp.205-214, 2005.

B. M. Boddupalli, Z. N. Mohammed, R. A. Nath, and D. Banji, Mucoadhesive drug delivery system: An overview, J Adv Pharm Technol Res, vol.1, 2010.

H. B. Bosworth, B. B. Granger, P. Mendys, R. Brindis, R. Burkholder et al., Medication adherence: a call for action, Am Heart J, vol.162, 2011.

X. Boulenc, E. Marti, H. Joyeux, C. Roques, Y. Berger et al., Importance of the paracellular pathway for the transport of a new bisphosphonate using the human CACO-2 monolayers model, Biochem Pharmacol, vol.46, pp.1591-1600, 1993.

J. Brange and L. Langkjoer, Insulin structure and stability, Pharm Biotechnol, vol.5, pp.315-350, 1993.

L. Bueno, Regulatory mechanisms of tight junctions permeability of gut epithelial cells. Cahiers de Nutrition et de Diététique, vol.45, pp.72-77, 2010.

K. B. Chalasani, G. J. Russell-jones, S. K. Yandrapu, P. V. Diwan, and S. K. Jain, A novel vitamin B12-nanosphere conjugate carrier system for peroral delivery of insulin, J Control Release, vol.117, 2007.

M. C. Chen, K. Sonaje, K. J. Chen, and H. W. Sung, A review of the prospects for polymeric nanoparticle platforms in oral insulin delivery, Biomaterials, vol.32, pp.9826-9838, 2011.

Y. Chen, P. Li, J. A. Modica, R. J. Drout, and O. K. Farha, Acid-Resistant Mesoporous Metal-Organic Framework toward Oral Insulin Delivery: Protein Encapsulation, Protection, and Release, J Am Chem Soc, vol.140, pp.5678-5681, 2018.

Z. Chen, M. P. Caulfield, M. J. Mcphaul, R. E. Reitz, S. W. Taylor et al., Quantitative insulin analysis using liquid chromatography-tandem mass spectrometry in a high-throughput clinical laboratory, Clin Chem, vol.59, 2013.

J. S. Chia, J. L. Mcrae, S. Kukuljan, K. Woodford, R. B. Elliott et al., A1 beta-casein milk protein and other environmental pre-disposing factors for type 1 diabetes, Nutr Diabetes, vol.7, 2017.

K. Y. Choi, H. Chung, K. H. Min, H. Y. Yoon, K. Kim et al., Self-assembled hyaluronic acid nanoparticles for active tumor targeting, Biomaterials, vol.31, pp.106-114, 2010.

H. J. Chung, H. K. Kim, J. J. Yoon, and T. G. Park, Heparin immobilized porous PLGA microspheres for angiogenic growth factor delivery, Pharm Res, vol.23, 2006.

S. Clement, P. Dandona, J. G. Still, and G. Kosutic, Oral modified insulin (HIM2) in patients with type 1 diabetes mellitus: results from a phase I/II clinical trial, Metabolism, vol.53, pp.54-58, 2004.

S. Clement, J. G. Still, G. Kosutic, and R. G. Mcallister, Oral insulin product hexylinsulin monoconjugate 2 (HIM2) in type 1 diabetes mellitus: the glucose stabilization effects of HIM2, Diabetes Technol Ther, vol.4, pp.459-466, 2002.

H. Cortes, S. Alcala-alcala, A. Avalos-fuentes, N. Mendoza-munoz, D. Quintanar-guerrero et al., Nanotechnology As Potential Tool for siRNA Delivery in Parkinson's Disease, Curr Drug Targets, vol.18, 2017.

C. I. Crucho and M. T. Barros, Polymeric nanoparticles: A study on the preparation variables and characterization methods, Mater Sci Eng C Mater Biol Appl, vol.80, 2017.

E. Czuba, M. Diop, C. Mura, A. Schaschkow, A. Langlois et al., Oral insulin delivery, the challenge to increase insulin bioavailability: Influence of surface charge in nanoparticle system, Int J Pharm, vol.542, 2018.

E. D'adamo and S. Caprio, Type 2 diabetes in youth: epidemiology and pathophysiology, Diabetes Care, vol.34, issue.2, 2011.

F. Danhier, E. Ansorena, J. M. Silva, R. Coco, A. Le-breton et al., PLGA-based nanoparticles: an overview of biomedical applications, J Control Release, vol.161, 2012.

M. Debrincat, Medication adherence: patient education,communication and behaviour, Journal of the Malta College of Pharmacy Practice, vol.3, issue.5, 2012.

I. T. Degim, B. Gumusel, Z. Degim, T. Ozcelikay, A. Tay et al., Oral administration of liposomal insulin, J Nanosci Nanotechnol, vol.6, pp.2945-2949, 2006.

X. Delavenne, , 2013.

, Presse Med, vol.42, pp.1206-1212

R. Dinarvand, N. Sepehri, S. Manoochehri, H. Rouhani, A. et al., Polylactideco-glycolide nanoparticles for controlled delivery of anticancer agents, Int J Nanomedicine, vol.6, 2011.

C. Ding, L. , and Z. , A review of drug release mechanisms from nanocarrier systems, 2017.

, Mater Sci Eng C Mater Biol Appl, vol.76

M. Diop, N. Auberval, A. Viciglio, A. Langlois, W. Bietiger et al., Design, characterisation, and bioefficiency of insulinchitosan nanoparticles after stabilisation by freeze-drying or cross-linking, Int J Pharm, vol.491, 2015.

N. Duceppe and M. Tabrizian, Factors influencing the transfection efficiency of ultra low molecular weight chitosan/hyaluronic acid nanoparticles, Biomaterials, vol.30, pp.2625-2631, 2009.

I. Elalamy, Héparines: structure, propriétés pharmacologiques et activités, 2010.

D. Flevas, P. Megaloikonomos, L. Dimopoulos, E. Misiokapa, P. Koulouvaris et al., Thromboembolism prophylaxis in orthopaedics: an update, Effort open reviews, vol.3, pp.130-142, 2018.

C. Foged, B. Brodin, S. Frokjaer, and A. Sundblad, Particle size and surface charge affect particle uptake by human dendritic cells in an in vitro model, Int J Pharm, vol.298, pp.315-322, 2005.

X. Gao and J. Chorover, Adsorption of sodium dodecyl sulfate (SDS) at ZnSe and alpha-Fe2O3 surfaces: combining infrared spectroscopy and batch uptake studies, J Colloid Interface Sci, vol.348, pp.167-176, 2010.

L. E. Garcia-perez, M. Alvarez, T. Dilla, V. Gil-guillen, and D. Orozco-beltran, Adherence to therapies in patients with type 2 diabetes, Diabetes Ther, vol.4, 2013.

A. Gedawy, J. Martinez, H. Al-salami, and C. R. Dass, Oral insulin delivery: existing barriers and current counter-strategies, J Pharm Pharmacol, vol.70, 2018.

P. Gentile, V. Chiono, I. Carmagnola, and P. V. Hatton, An overview of poly(lacticco-glycolic) acid (PLGA)-based biomaterials for bone tissue engineering, Int J Mol Sci, vol.15, 2014.

K. T. Goodall, C. C. Chooi, and A. S. Gallus, Heparin stability: effects of diluent, heparin activity, container, and pH, J Clin Pathol, vol.33, pp.1206-1211, 1980.

N. Grabowski, H. Hillaireau, J. Vergnaud, L. A. Santiago, S. Kerdine-romer et al., Toxicity of surface-modified PLGA nanoparticles toward lung alveolar epithelial cells, Int J Pharm, vol.454, 2013.

E. Gray, B. Mulloy, and T. W. Barrowcliffe, Heparin and low-molecular-weight heparin, Thromb Haemost, vol.99, pp.807-818, 2008.

M. B. Guarnieri, Subcutaneous implants for long-acting drug therapy in laboratory animals may generate unintended drug reservoirs, J Pharm Bioallied, pp.38-42, 2014.

J. H. Hamman, G. M. Enslin, and A. F. Kotze, Oral delivery of peptide drugs: barriers and developments, BioDrugs, vol.19, pp.165-177, 2005.

L. Han, Y. Zhao, L. Yin, R. Li, Y. Liang et al., , 2012.

, Insulin-loaded pH-sensitive hyaluronic acid nanoparticles enhance transcellular delivery, AAPS PharmSciTech, vol.13

T. Hanslik and J. Prinseau, The use of vitamin K in patients on anticoagulant therapy: a practical guide, Am J Cardiovasc Drugs, vol.4, pp.43-55, 2004.

L. Heinemann, J. , and Y. , Oral insulin and buccal insulin: a critical reappraisal, J Diabetes Sci Technol, vol.3, 2009.

K. D. Hinds, K. M. Campbell, K. M. Holland, D. H. Lewis, C. A. Piche et al., , 2005.

, PEGylated insulin in PLGA microparticles. In vivo and in vitro analysis, J Control Release, vol.104

J. Hirsh and M. N. Levine, Low molecular weight heparin, Blood, vol.79, pp.1-17, 1992.

V. Hoffart, A. Lamprecht, P. Maincent, T. Lecompte, C. Vigneron et al., , 2006.

, Oral bioavailability of a low molecular weight heparin using a polymeric delivery system, J Control Release, vol.113

V. Hoffart, N. Ubrich, C. Simonin, V. Babak, C. Vigneron et al., Low molecular weight heparin-loaded polymeric nanoparticles: formulation, characterization, and release characteristics, Drug Dev Ind Pharm, vol.28, 2002.

R. Hoier and A. L. Jensen, Evaluation of an enzyme linked immunosorbent assay (ELISA) for determination of insulin in dogs, Zentralbl Veterinarmed A, vol.40, pp.26-32, 1993.

S. S. Ibrahim, R. Awad, G. A. Mortada, N. D. Geneidy, and A. S. , Low molecular weight heparins for current and future uses: approaches for micro-and nano-particulate delivery, Drug Delivery, p.23, 2016.

, ICHQ2(R1) (2005). ICH Q2 (R1): Validation of Analytical Procedures: Text and Methodology

M. Iqbal, N. Zafar, H. Fessi, and A. Elaissari, Double emulsion solvent evaporation techniques used for drug encapsulation, Int J Pharm, vol.496, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01958031

K. Iwanaga, S. Ono, K. Narioka, M. Kakemi, K. Morimoto et al., Application of surface-coated liposomes for oral delivery of peptide: effects of coating the liposome's surface on the GI transit of insulin, J Pharm Sci, vol.88, 1999.

H. Iyer, A. Khedkar, and M. Verma, Oral insulin -a review of current status, Diabetes Obes Metab, vol.12, pp.179-185, 2010.

S. R. Jameela, N. Suma, J. , and A. , Protein release from poly(epsiloncaprolactone) microspheres prepared by melt encapsulation and solvent evaporation techniques: a comparative study, J Biomater Sci Polym Ed, vol.8, pp.457-466, 1997.

Q. C. Jiao, Q. Liu, C. Sun, and H. He, Investigation on the binding site in heparin by spectrophotometry, Talanta, vol.48, pp.1095-1101, 1999.

Y. Jiao, N. Ubrich, V. Hoffart, M. Marchand-arvier, C. Vigneron et al., Anticoagulant activity of heparin following oral administration of heparin-loaded microparticles in rabbits, J Pharm Sci, vol.91, pp.760-768, 2002.

Y. Y. Jiao, N. Ubrich, M. Marchand-arvier, C. Vigneron, M. Hoffman et al., Preparation and in vitro evaluation of heparin-loaded polymeric nanoparticles, Drug Deliv, vol.8, 2001.

B. Jimmy, J. , and J. , Patient medication adherence: measures in daily practice, Oman Med J, vol.26, pp.155-159, 2011.

J. Jin, G. E. Sklar, V. Min-sen-oh, C. Li, and S. , Factors affecting therapeutic compliance: A review from the patient's perspective, Ther Clin Risk Manag, vol.4, pp.269-286, 2008.

J. F. Jin, L. L. Zhu, M. Chen, H. M. Xu, H. F. Wang et al., The optimal choice of medication administration route regarding intravenous, intramuscular, and subcutaneous injection, Patient Prefer Adherence, vol.9, 2015.

S. Jogala, S. S. Rachamalla, and J. Aukunuru, Development of subcutaneous sustained release nanoparticles encapsulating low molecular weight heparin, J Adv Pharm Technol Res, vol.6, 2015.

H. N. Keles, A. Clegg, F. Sammon, and C. , Investigation of factors influencing the hydrolytic degradation of single PLGA microparticles, Polymer Degradation and Stability, vol.119, pp.228-241, 2015.

J. S. Kelloway, R. A. Wyatt, and S. A. Adlis, Comparison of patients' compliance with prescribed oral and inhaled asthma medications, Arch Intern Med, vol.154, pp.1349-1352, 1994.

L. J. Kettler, S. M. Sawyer, H. R. Winefield, and H. W. Greville, Determinants of adherence in adults with cystic fibrosis, Thorax, vol.57, pp.459-464, 2002.

S. K. Kim, D. Y. Lee, E. Lee, Y. K. Lee, C. Y. Kim et al., Absorption study of deoxycholic acid-heparin conjugate as a new form of oral anti-coagulant, J Control Release, vol.120, 2007.

G. P. Koocher, M. L. Mcgrath, and L. J. Gudas, Typologies of nonadherence in cystic fibrosis, J Dev Behav Pediatr, vol.11, pp.353-358, 1990.

A. Kumari, S. K. Yadav, and S. C. Yadav, Biodegradable polymeric nanoparticles based drug delivery systems, Colloids Surf B Biointerfaces, vol.75, 2010.

C. K. Lai, Y. L. Lu, J. T. Hsieh, S. C. Tsai, C. L. Feng et al., Development of chitosan/heparin nanoparticle-encapsulated cytolethal distending toxin for gastric cancer therapy, Nanomedicine (Lond), vol.9, 2014.

S. P. Lamichhane, N. Arya, N. Ojha, E. Kohler, and V. P. Shastri, Glycosaminoglycanfunctionalized poly-lactide-co-glycolide nanoparticles: synthesis, characterization, cytocompatibility, and cellular uptake, Int J Nanomedicine, vol.10, 2015.

A. Lamouroux, A. Magnan, and D. Vervloet, , 2005.

, Rev Mal Respir, vol.22, pp.31-34

A. K. Lamprecht, P. Ubrich, P. Maincent, and D. Neumann, Low molecular weight heparin nanoparticles: mucoadhesion and behaviour in Caco-2 cells, Nanotechnology, p.17, 2006.

V. L. Lasalle, S. Rueda, E. Ferreira, and M. L. , An accurate UV/visible method to quantify proteins and enzymes: Impact of aggregation, buffer concentration and the nature of the standard, Current Topics in Analytical Chemistry, 2011.

B. Lask, Non-adherence to treatment in cystic fibrosis, J R Soc Med, vol.87, pp.25-27, 1994.

G. Y. Lee, J. H. Kim, K. Y. Choi, H. Y. Yoon, K. Kim et al., Hyaluronic acid nanoparticles for active targeting atherosclerosis, Biomaterials, vol.53, pp.341-348, 2015.

S. I. Lee and P. Narendran, Intraperitoneal insulin therapy for a patient with type 1 diabetes with insulin injection site inflammation, BMJ Case Rep, 2014.

Y. Lee, S. H. Kim, and Y. Byun, Oral delivery of new heparin derivatives in rats, Pharm Res, vol.17, pp.1259-1264, 2000.

X. Li, J. Qi, Y. Xie, X. Zhang, S. Hu et al., Nanoemulsions coated with alginate/chitosan as oral insulin delivery systems: preparation, characterization, and hypoglycemic effect in rats, Int J Nanomedicine, vol.8, 2013.

L. Liu, M. L. Fishman, J. Kost, and K. B. Hicks, Pectin-based systems for colon-specific drug delivery via oral route, Biomaterials, vol.24, pp.3333-3343, 2003.

Q. J. Liu and G. , Mechanism of methylene blue action and interference in the heparin assy. Spectroscopy letters: an international journal for rapid communication, pp.913-924, 1998.

J. D. Loike and S. C. Silverstein, A fluorescence quenching technique using trypan blue to differentiate between attached and ingested glutaraldehyde-fixed red blood cells in phagocytosing murine macrophages, J Immunol Methods, vol.57, pp.373-379, 1983.

M. Lopes, N. Shrestha, A. Correia, M. A. Shahbazi, B. Sarmento et al., Dual chitosan/albumin-coated alginate/dextran sulfate nanoparticles for enhanced oral delivery of insulin, J Control Release, vol.232, 2016.

M. A. Lopes, B. A. Abrahim, L. M. Cabral, C. R. Rodrigues, R. M. Seica et al., Intestinal absorption of insulin nanoparticles: contribution of M cells, Nanomedicine, vol.10, 2014.

P. Lundquist, A. , and P. , Oral absorption of peptides and nanoparticles across the human intestine: Opportunities, limitations and studies in human tissues, Adv Drug Deliv Rev, vol.106, pp.256-276, 2016.

K. M. Lybecker, The economic fundamentals of the U.S. pharmaceutical market, Manag Care, vol.13, pp.41-53, 2004.

H. K. Makadia and S. J. Siegel, Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier, Polymers (Basel), vol.3, 2011.

S. Malathi, P. Nandhakumar, V. Pandiyan, T. J. Webster, and S. Balasubramanian, , 2015.

, Novel PLGA-based nanoparticles for the oral delivery of insulin, Int J Nanomedicine, vol.10

S. K. Mansuri, P. Jain, K. Tekade, R. K. Jain, and N. K. , Mucoadhesion: A promising approach in drug delivery system, Reactive and functionnal polymers, vol.100, pp.151-172, 2016.

M. T. Masahiro-hayashi and A. Shoji, Transcellular and paracellular contribution to transport processes in the colorectal route, Advanced Drug Delivery Reviews, vol.28, pp.191-204, 1997.

D. J. Mcclements, G. Deloid, G. Pyrgiotakis, J. A. Shatkin, H. Xiao et al.,

, The Role of the Food Matrix and Gastrointestinal Tract in the assessment of biological properties of ingested engineered nanomaterials (iENMs): State of the science and knowledge gaps, NanoImpact, vol.3, issue.4

P. S. Mcnamara, P. Mccormack, A. J. Mcdonald, L. Heaf, and K. W. Southern, Open adherence monitoring using routine data download from an adaptive aerosol delivery nebuliser in children with cystic fibrosis, J Cyst Fibros, vol.8, 2009.

D. Mishra, J. R. Hubenak, and A. B. Mathur, Nanoparticle systems as tools to improve drug delivery and therapeutic efficacy, J Biomed Mater Res A, vol.101, 2013.

L. L. Mitic, C. M. Van-itallie, A. , and J. M. , Molecular physiology and pathophysiology of tight junctions I. Tight junction structure and function: lessons from mutant animals and proteins, Am J Physiol Gastrointest Liver Physiol, vol.279, 2000.

B. Moazed and L. M. Hiebert, An in vitro study with an ussing chamber showing that unfractionated heparin crosses rat gastric mucosa, J Pharmacol Exp Ther, vol.322, 2007.

A. C. Modi, C. S. Lim, N. Yu, D. Geller, M. H. Wagner et al., A multimethod assessment of treatment adherence for children with cystic fibrosis, J Cyst Fibros, vol.5, 2006.

A. Muheem, F. Shakeel, M. A. Jahangir, M. Anwar, N. Mallick et al., A review on the strategies for oral delivery of proteins and peptides and their clinical perspectives, Saudi Pharm J, vol.24, 2016.

N. Nafee, S. Taetz, M. Schneider, U. F. Schaefer, and C. M. Lehr, Chitosancoated PLGA nanoparticles for DNA/RNA delivery: effect of the formulation parameters on complexation and transfection of antisense oligonucleotides, Nanomedicine, vol.3, pp.173-183, 2007.

L. H. Nicoll and A. Hesby, Intramuscular injection: an integrative research review and guideline for evidence-based practice, Appl Nurs Res, vol.15, pp.149-162, 2002.

E. J. Oh, K. Park, K. S. Kim, J. Kim, J. A. Yang et al., Target specific and long-acting delivery of protein, peptide, and nucleotide therapeutics using hyaluronic acid derivatives, J Control Release, vol.141, 2010.

L. Osterberg and T. Blaschke, Adherence to medication, N Engl J Med, vol.353, pp.487-497, 2005.

D. R. Owens, New horizons--alternative routes for insulin therapy, Nat Rev Drug Discov, vol.1, 2002.

F. A. Oyarzun-ampuero, J. Brea, M. I. Loza, D. Torres, A. et al., Chitosanhyaluronic acid nanoparticles loaded with heparin for the treatment of asthma, Int J Pharm, vol.381, 2009.

B. Patel, V. Gupta, A. , and F. , PEG-PLGA based large porous particles for pulmonary delivery of a highly soluble drug, low molecular weight heparin, J Control Release, vol.162, 2012.

C. Pazzini, P. D. Marcato, L. B. Prado, A. M. Alessio, N. F. Hoehr et al., Polymeric Nanoparticles of Enoxaparin as a Delivery System: In Vivo Evaluation in Normal Rats and in a Venous Thrombosis Rat Model, J Nanosci Nanotechnol, vol.15, pp.4837-4843, 2015.

M. Petitou, P. Duchaussoy, P. A. Driguez, J. P. Herault, J. C. Lormeau et al., New synthetic heparin mimetics able to inhibit thrombin and factor Xa, Bioorg Med Chem Lett, vol.9, pp.1155-1160, 1999.

M. Petitou, J. P. Herault, A. Bernat, P. A. Driguez, P. Duchaussoy et al., , 1999.

, Ann Pharm Fr, vol.57, pp.232-239

, Euopean pharmacopeia 8.0, 20246, chromatographic separation techniques, 2008.

, European pharmacopeia human insulin 8.0, p.838, 2014.

L. Plapied, G. Vandermeulen, B. Vroman, V. Preat, and A. Des-rieux, Bioadhesive nanoparticles of fungal chitosan for oral DNA delivery, Int J Pharm, vol.398, pp.210-218, 2010.

Y. Qian, L. J. Zhang, Z. M. Wu, L. Y. Zhou, W. Jiang et al., , 2013.

, Enteric-coated capsule containing cationic nanoparticles for oral insulin delivery (USA)

M. Quaranta, O. Erez, S. A. Mastrolia, A. Koifman, E. Leron et al., The physiologic and therapeutic role of heparin in implantation and placentation, PeerJ, vol.3, 2015.

P. Ramalingam and Y. T. Ko, Improved oral delivery of resveratrol from N-trimethyl chitosan-g-palmitic acid surface-modified solid lipid nanoparticles, Colloids Surf B Biointerfaces, vol.139, 2016.

K. B. Ranjit and A. , Nanoparticle: an overview of preparation and characterization. International research journal of pharmacy, 2013.

Q. Rashid, M. Abid, and M. A. Jairajpuri, Elucidating the specificity of non-heparinbased conformational activators of antithrombin for factor Xa inhibition, J Nat Sci Biol Med, vol.5, 2014.

N. Reix, P. Guhmann, W. Bietiger, M. Pinget, N. Jeandidier et al., , 2012.

, Duodenum-specific drug delivery: in vivo assessment of a pharmaceutically developed entericcoated capsule for a broad applicability in rat studies, Int J Pharm, vol.422

N. Reix, A. Parat, E. Seyfritz, R. Van-der-werf, V. Epure et al., In vitro uptake evaluation in Caco-2 cells and in vivo results in diabetic rats of insulin-loaded PLGA nanoparticles, Int J Pharm, vol.437, 2012.

S. Sajeesh, K. Bouchemal, C. P. Sharma, and C. Vauthier, Surface-functionalized polymethacrylic acid based hydrogel microparticles for oral drug delivery, Eur J Pharm Biopharm, vol.74, pp.209-218, 2010.

S. Kumar, N. D. , R. Rani, and G. Bhanjana, Nanotechnology as Emerging Tool for Enhancing Solubility of Poorly Water-Soluble Drugs, 2012.

G. Sandri, S. Rossi, F. Ferrari, M. C. Bonferoni, N. Zerrouk et al., , 2004.

, Mucoadhesive and penetration enhancement properties of three grades of hyaluronic acid using porcine buccal and vaginal tissue, Caco-2 cell lines, and rat jejunum, J Pharm Pharmacol, vol.56

M. J. Santander-ortega, D. Bastos-gonzalez, J. L. Ortega-vinuesa, A. , and M. J. , , 2009.

, Insulin-loaded PLGA nanoparticles for oral administration: an in vitro physico-chemical characterization, J Biomed Nanotechnol, vol.5, pp.45-53

S. R. Saptarshi, A. Duschl, and A. L. Lopata, Interaction of nanoparticles with proteins: relation to bio-reactivity of the nanoparticle, J Nanobiotechnology, vol.11, 2013.

B. Sarmento, S. Martins, D. Ferreira, and E. B. Souto, Oral insulin delivery by means of solid lipid nanoparticles, Int J Nanomedicine, vol.2, pp.743-749, 2007.

C. Schimpel, B. Teubl, M. Absenger, C. Meindl, E. Frohlich et al., Development of an advanced intestinal in vitro triple culture permeability model to study transport of nanoparticles, Mol Pharm, vol.11, 2014.

G. Schliecker, C. Schmidt, S. Fuchs, R. Wombacher, and T. Kissel, Hydrolytic degradation of poly(lactide-co-glycolide) films: effect of oligomers on degradation rate and crystallinity, Int J Pharm, vol.266, pp.39-49, 2003.

B. S. Sekhon, Surfactants: Pharmaceutical and Medicinal Aspects, Journal of Pharmaceutical Technology, Research and Management, vol.1, pp.11-36, 2013.

J. Sequeira, A. Santos, S. J. Veiga, F. Ribeiro, and A. , Chapter 10 -Poly(lactic-co-glycolic acid) (PLGA) matrix implants. Nanostructures for the Engineering of Cells, Tissues and Organs: From Design to Applications, pp.375-402, 2018.

M. A. Shahbazi, M. Hamidi, and S. Mohammadi-samani, Preparation, optimization, and in-vitro/in-vivo/ex-vivo characterization of chitosan-heparin nanoparticles: drug-induced gelation, J Pharm Pharmacol, vol.65, 2013.

M. Shakweh, G. Ponchel, and E. Fattal, Particle uptake by Peyer's patches: a pathway for drug and vaccine delivery, Expert Opin Drug Deliv, vol.1, pp.141-163, 2004.

J. Sheng, L. Han, J. Qin, G. Ru, R. Li et al., , 2015.

, N-trimethyl chitosan chloride-coated PLGA nanoparticles overcoming multiple barriers to oral insulin absorption, ACS Appl Mater Interfaces, vol.7

J. Smith, E. Wood, and M. Dornish, Effect of chitosan on epithelial cell tight junctions, Pharm Res, vol.21, pp.43-49, 2004.

K. Sonaje, K. J. Lin, S. P. Wey, C. K. Lin, T. H. Yeh et al., Biodistribution, pharmacodynamics and pharmacokinetics of insulin analogues in a rat model: Oral delivery using pH-responsive nanoparticles vs. subcutaneous injection, Biomaterials, vol.31, pp.6849-6858, 2010.

K. S. Soppimath, T. M. Aminabhavi, A. R. Kulkarni, and W. E. Rudzinski, , 2001.

, Biodegradable polymeric nanoparticles as drug delivery devices, J Control Release, vol.70, pp.1-20

S. Sun, N. Liang, H. Yamamoto, Y. Kawashima, F. Cui et al., pH-sensitive poly(lactide-co-glycolide) nanoparticle composite microcapsules for oral delivery of insulin, Int J Nanomedicine, vol.10, 2015.

E. Szymanska and K. Winnicka, Stability of chitosan-a challenge for pharmaceutical and biomedical applications, Mar Drugs, vol.13, 2015.

D. M. Tarn, D. A. Paterniti, R. L. Kravitz, J. Heritage, H. Liu et al., How much time does it take to prescribe a new medication?, Patient Educ Couns, vol.72, 2008.

A. Taverner, R. Dondi, K. Almansour, F. Laurent, S. E. Owens et al., Enhanced paracellular transport of insulin can be achieved via transient induction of myosin light chain phosphorylation, J Control Release, vol.210, 2015.

M. Thanou, J. C. Verhoef, and H. E. Junginger, Chitosan and its derivatives as intestinal absorption enhancers, Adv Drug Deliv Rev, vol.50, pp.91-101, 2001.

M. Thanou, J. C. Verhoef, and H. E. Junginger, Oral drug absorption enhancement by chitosan and its derivatives, Adv Drug Deliv Rev, vol.52, pp.117-126, 2001.

M. F. Tsai and C. Miller, Substrate selectivity in arginine-dependent acid resistance in enteric bacteria, Proc Natl Acad Sci U S A, vol.110, 2013.

C. A. Van-itallie and J. M. , The molecular physiology of tight junction pores, Physiology, vol.19, pp.331-338, 2004.

J. K. Vasir and V. Labhasetwar, Quantification of the force of nanoparticle-cell membrane interactions and its influence on intracellular trafficking of nanoparticles, Biomaterials, vol.29, pp.4244-4252, 2008.

C. Vauthier and K. Bouchemal, Methods for the preparation and manufacture of polymeric nanoparticles, Pharm Res, vol.26, 2009.

A. Verma and F. Stellacci, Effect of surface properties on nanoparticle-cell interactions, Small, vol.6, pp.12-21, 2010.

T. Wang, J. Hou, C. Su, L. Zhao, and Y. Shi, Hyaluronic acid-coated chitosan nanoparticles induce ROS-mediated tumor cell apoptosis and enhance antitumor efficiency by targeted drug delivery via CD44, J Nanobiotechnology, vol.15, 2017.

M. Weiss, D. F. Steiner, and L. H. Philipson, Insulin Biosynthesis, Secretion, Structure, and Structure-Activity Relationships, 2000.

H. Wolf, Low-molecular-weight heparin, Med Clin North Am, vol.78, pp.733-743, 1994.

J. Xie, A. Li, L. , and J. , Advances in pH-Sensitive Polymers for Smart Insulin Delivery, Macromol Rapid Commun, vol.38, 2017.

X. Xing, X. Zhao, J. Ding, D. Liu, and G. Qi, Enteric-coated insulin microparticles delivered by lipopeptides of iturin and surfactin. Drug delivery, pp.22-34, 2018.

X. Xu and Y. Dai, Heparin: an intervenor in cell communication, J Cell Mol Med, vol.14, 2010.

Y. Cottin, L. L. , A. Gudjoncik, P. Buffet, C. Brulliarda et al., Medication compliance: concepts and determinants, Archives of Cardiovascular Diseases, vol.4, pp.291-298, 2012.

Y. Yun, Y. W. Cho, and K. Park, Nanoparticles for oral delivery: targeted nanoparticles with peptidic ligands for oral protein delivery, Adv Drug Deliv Rev, vol.65, 2013.

J. Zeilstra, S. P. Joosten, L. Vermeulen, J. Koster, J. P. Medema et al., CD44 expression in intestinal epithelium and colorectal cancer is independent of p53 status, PLoS One, vol.8, 2013.

G. H. Zhang, R. Zhan, Y. Cong, . J. Cheng-ja, and J. Fu, Fabrication of hollow porous PLGA microspheres for controlled protein release and promotion of cell compatibility, Chinese Chemical Letters, vol.24, pp.710-714, 2013.

Z. H. Zhang, S. Abbad, R. R. Pan, A. Y. Waddad, L. L. Hou et al., Noctyl-N-Arginine chitosan micelles as an oral delivery system of insulin, J Biomed Nanotechnol, vol.9, pp.601-609, 2013.

Y. Y. Zhou, Y. Z. Du, L. Wang, H. Yuan, J. P. Zhou et al., Preparation and pharmacodynamics of stearic acid and poly (lactic-co-glycolic acid) grafted chitosan oligosaccharide micelles for 10-hydroxycamptothecin, Int J Pharm, vol.393, 2010.

E. Czuba, S. Sigrist, E. Marchioni, Y. Frere, E. Maillard et al., The charge effect of insulin PLGA nanoparticles on cell uptake in vitro and bioavailability in vivo, 2018.

E. Czuba, insulin encapsulation for an oral administration (Scientific forum, Lycée Jean Rostand, 2018.

E. Czuba, M. Diop, C. Mura, W. Bietiger, C. Peronet et al.,

E. Jeandidier, E. Maillard, Y. Marchioni, S. Frere, and . Sigrist, New Nanoparticular systems formulation for oral administration of insulin

E. Czuba, M. Diop, C. Mura, W. Bietiger, C. Peronet et al.,

E. Jeandidier, E. Maillard, Y. Marchioni, S. Frere, and . Sigrist, Nanoparticular system: charge effect on cell uptake in vitro and bioavailability in vivo (international conference on bioencapsulation 2016

E. Czuba, M. Diop, C. Mura, W. Bietiger, C. Peronet et al.,

E. Jeandidier, E. Maillard, Y. Marchioni, S. Frere, and . Sigrist, Nanoparticular system formulation: influence of charge on cell uptake and bioavailability, 2016.

E. Czuba, M. Diop, E. Maillard, E. Marchioni, Y. Frere et al., ORAL INSULIN DELIVERY: charge effect on cell uptake in vitro and bioavailability in vivo, 2017.

E. Czuba, M. Diop, E. Maillard, Y. Frere, E. Marchioni et al., ORAL INSULIN DELIVERY, the challenge to increase insulin bioavailability: influence of surface charge in nanoparticle system, 2017.

, Cadre général et enjeux de votre thèse 1.1. Présentation succincte

, L'adhésion thérapeutique à un traitement est aujourd'hui un enjeu économique et sociétal majeur dans la prise en charge du patient. En effet, à l'échelle mondiale, on estime que les coûts évitables liés au manque d'adhésion thérapeutique dépassent les 470 milliards de dollars, soit environ 8% des dépenses de santé annuelles

, Les causes sont multiples : l'oubli, le manque d'information mais également l'impact réel du traitement sur la vie quotidienne (douleur, effets secondaires

C. Pourquoi, une des solutions pour palier à ce manque d'adhésion est le changement de voie d'administration de principe actif

, Cette thèse réalisée au Centre Européen d'Etude du Diabète entre donc dans le cadre d'un projet débuté il y a 15 ans sur l'encapsulation d'insuline pour une administration par voie orale

, De plus, cette thèse s'inscrit dans un contexte plutôt particulier « de transition ». En effet, un projet de montage d'une spin-off est en cours sur ce projet afin d'élargir les capacités du système d'encapsulation développé ayant fait l

, En parallèle de cette thèse et dans le cadre du projet de « spin-off », j'ai pour mission

L. De, . Projet, and . Qu, il fait appel à de nombreuses compétences se situant à l'interface de la chimie et de la biologie et faisant donc intervenir à la fois des chimistes et des biologistes issus du domaine privé (CEED)

. Dans-le,

, De plus, ce sujet de thèse m'a tout de suite plu par son caractère multidisciplinaire, à l'interface de la chimie et de la biologie correspondant parfaitement à ma formation universitaire (master chimie-biologie). Cette interface permet d'allier formulation (chimie), validation in vitro et manipulations sur le petit animal (biologie)

, Mon investissement dans la thèse

, Je n'ai pas été à l'origine de la programmation du projet étant un projet de longue date et ayant repris la fin d'une thèse en cours à l'époque où j'ai commencé

, Déroulement, gestion et coût estimé de mon projet

, Dans un projet de recherche tel qu'une thèse, l'aspect management semble être un pilier à

, Celui-ci se déroulait tous les 6 mois avec tous les partenaires associés au projet aussi

, En effet, la négociation afin que chaque partenaire nous laisse sa part du butin n'a pas été simple et montre tout l'enjeu à ce niveau d, C'est à ce moment-là que l'aspect propriété intellectuelle entre en jeu

, De plus, un brevet a été déposé au départ du projet en collaboration avec le CNRS

, L'idée de la création d'une spin-off durant mes 3