title: Enhancement of oral insulin bioavailability: in vitro and in vivo assessment of nanoporous stimuli-responsive hydrogel microparticles.
abstract: OBJECTIVE
  Oral insulin administration suffers gastrointestinal tract (GIT) degradation and inadequate absorption from the intestinal epithelium resulting in poor bioavailability. This study entails in vitro and in vivo assessment of stimuli-responsive hydrogel microparticles (MPs) in an attempt to circumvent GI barrier and enhance oral insulin bioavailability.
  
  
  METHODS
  Bacterial cellulose-g-poly(acrylic acid) (BC-g-P(AA)) hydrogel MPs were evaluated for morphology, swelling, entrapment efficiency (EE), in vitro insulin release and enzyme inhibition. The ex vivo mucoadhesion, insulin degradation and transport were investigated in excised intestinal tissues. The effect of MPs on paracellular transport was studied in Caco-2/HT29-MTX monolayers. The in vivo hypoglycemic effect and pharmacokinetics of insulin-loaded MPs were investigated in diabetic rats.
  
  
  RESULTS
  Hydrogel MPs efficiently entrapped insulin (EE up to 84%) and exhibited pH-responsive in vitro release. The MPs decreased the proteolytic activity of trypsin (up to 60%). Insulin transport across monolayers was increased up to 5.9-times by MPs. Histological assessment of GI tissues confirmed the non-toxicity of MPs. Orally administered insulin-loaded MPs showed higher hypoglycemic effect as compared to insulin solution and enhanced relative oral bioavailability of insulin up to 7.45-times.
  
  
  CONCLUSIONS
  These findings suggest that BC-g-P(AA) MPs are promising biomaterials to overcome the barriers of oral insulin delivery and enhancing its bioavailability.
authors.affiliation: a Centre for Drug Delivery Research, Faculty of Pharmacy , Universiti Kebangsaan Malaysia , Kuala Lumpur , Malaysia.
authors.forename: Naveed
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: a Centre for Drug Delivery Research, Faculty of Pharmacy , Universiti Kebangsaan Malaysia , Kuala Lumpur , Malaysia.
authors.forename: Mohd Cairul Iqbal
authors.initials: MC
authors.lastname: Mohd Amin
authors.affiliation: b Institute of Systems Biology (INBIOSIS) , Universiti Kebangsaan Malaysia , Bangi , Selangor , Malaysia.|c School of Biosciences and Biotechnology, Faculty of Science and Technology , Universiti Kebangsaan Malaysia , Bangi , Selangor , Malaysia.
authors.forename: Ismanizan
authors.initials: I
authors.lastname: Ismail
authors.affiliation: d Faculty of Pharmacy , Universiti Kebangsaan Malaysia , Kuala Lumpur , Malaysia.
authors.forename: Fhataheya
authors.initials: F
authors.lastname: Buang
mesh_terms: D000180:Acrylic Resins; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism; D018938:Caco-2 Cells / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005753:Gastric Mucosa / Q000378:metabolism; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D007328:Insulin / Q000493:pharmacokinetics* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D017208:Rats, Wistar
chemical_list: D000180:Acrylic Resins; D001786:Blood Glucose; D020100:Hydrogels; D007004:Hypoglycemic Agents; D007328:Insulin; C006903:carbopol 940
keywords: Hydrogel microparticles; mucoadhesion; oral insulin delivery; pH-responsive release; paracellular transport