Formulating insulin for oral administration: preparation of hyaluronan-insulin complex.
OBJECTIVE
To investigate the behaviour of peptides and hyaluronan in strong acid solutions containing electrolytes in the preparation of a new formulation of insulin, hyaluronan-insulin complex, and to evaluate the in vivo oral activity of the formulation.


METHODS
Individual processing parameters in the preparation of the insulin complex were first refined, and two formulations were subsequently investigated. The chemical structure, particle size and hydrophilic/hydrophobic properties of the insulin complex in these formulations were studied using light scattering techniques, amino acid analysis, atomic force microscopy and cryo-transmission electron microscopy. The in vivo activity of oral hyaluronan-insulin complex was then evaluated by measuring the decrease in blood glucose concentrations in streptozotocin diabetic rats.


RESULTS
Five of seven batches of the two insulin complex formulations fit the baseline criteria for approval of the new formulation. The formulation consists of a transparent aqua sol containing a solid hydrophobic phase as precipitate. Glucose-lowering activity was demonstrated after oral administration of the insulin complex'to diabetic rats.


CONCLUSIONS
A new insulin formulation, a hyaluronan-insulin complex, has been developed and oral activity has been demonstrated.
Jederstrom
Gustaf
G
Department of Pharmacy, Uppsala University, Biomedical Center, SE-751 23 Uppsala, Sweden. gustaf.jederstrom@farmaci.uu.se
Andersson
Arne
A
Gråsjö
Johan
J
Sjöholm
Ingvar
I
D000284:Administration, Oral; D000818:Animals; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D002627:Chemistry, Physical; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D008027:Light; D008297:Male; D046529:Microscopy, Electron, Transmission; D008970:Molecular Weight; D011786:Quality Control; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D012542:Scattering, Radiation; D012995:Solubility; D014783:Viscosity; D015032:Zinc / Q000737:chemistry
D007004:Hypoglycemic Agents; D007328:Insulin; D011994:Recombinant Proteins; D006820:Hyaluronic Acid; D015032:Zinc