ABSTRACT
The main purpose of this study was to investigate the nasal absorption of insulin from a new microemulsion spray preparation in rabbits. The bioavailability of insulin lispro via the nasal route using a W/O microemulsion was found to reach 21.5% relative to subcutaneous administration, whereas the use of an inverse microemulsion as well as a plain solution yielded less than 1% bioavailability. The profile of plasma glucose levels obtained after nasal spray application of the microemulsion (1IU/kg lispro) was similar to the subcutaneous profile of 0.5IU/kg at the first 90min after application and resulted in a 30-40% drop in glucose levels. The microemulsion system was characterized by DLS, TEM, viscosity measurements, and by construction of pseudo-ternary phase diagram. The average droplet size of an insulin-unloaded and insulin-loaded microemulsions containing 20% aqueous phase (surfactants-to-oil ratio=87:13) was 2nm and 2.26nm in diameter, respectively. In addition, the effect of the microemulsion on FITC-labeled insulin permeation was examined across the porcine nasal mucosa in vitro. The permeability coefficient of FITC-insulin via the microemulsion was 0.210±0.048cm/h with a lag time of 10.9±6.5min, whereas the permeability coefficient from a plain solution was 0.082±0.043cm/h with a lag time of 36.3±10.1min. In view of the absorption differences of insulin between 20%, 50% water-containing microemulsions and an aqueous solution obtained in vitro and in vivo, it has been concluded that the acceleration in the intramucosal transport process is the result of encapsulating insulin within the nano-droplet clusters of a W/O microemulsion, while the microemulsion ingredients seems to have no direct role.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Drug Carriers , Hypoglycemic Agents/administration & dosage , Insulin/analogs & derivatives , Administration, Intranasal , Aerosols , Animals , Biological Availability , Blood Glucose/drug effects , Chemistry, Pharmaceutical , Diabetes Mellitus, Experimental/blood , Disease Models, Animal , Drug Compounding , Emulsions , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Injections, Subcutaneous , Insulin/administration & dosage , Insulin/chemistry , Insulin/pharmacokinetics , Insulin Lispro , Light , Microscopy, Electron, Transmission , Nasal Mucosa/metabolism , Particle Size , Permeability , Rabbits , Scattering, Radiation , Surface Properties , Swine , Technology, Pharmaceutical/methods , ViscosityABSTRACT
The objective of this study was to evaluate the transdermal delivery potential of diclofenac-containing microemulsion system in vivo and in vitro. It was found that the transdermal administration of the microemulsion to rats resulted in 8-fold higher drug plasma levels than those obtained after application of Voltaren Emulgel. After s.c. administration (3.5 mg/kg), the plasma levels of diclofenac reached a peak of 0.94 microg/ml at t=1 h and decreased rapidly to 0.19 microg/ml at t=6 h, while transdermal administration of the drug in microemulsion maintained constant levels of 0.7-0.9 microg/ml for at least 8 h. The transdermal fluxes of diclofenac were measured in vitro using skin excised from different animal species. In three rodent species, penetration fluxes of 53.35+/-8.19 (furry mouse), 31.70+/-3.83 (hairless mouse), 31.66+/-4.45 (rat), and 22.89+/-6.23 microg/cm(2)/h (hairless guinea pig) were obtained following the application of the microemulsion. These fluxes were significantly higher than those obtained by application of the drug in aqueous solution. In contrast to these results, a 'flip-flop' phenomenon was observed when frozen porcine skin (but not fresh skin) was significantly more permeable to diclofenac-in-water than to the drug-in-microemulsion. In fact, the drug penetration from the microemulsion was not affected by the skin storage conditions, but it was increased when an aqueous solution was applied. However, this unusual phenomenon observed in non-freshly used porcine skin places a question mark on its relevancy for in vitro penetration studies involving aqueous vehicle systems.
