CommunicationsBiological Activity of Insulin in Microemulsion in Mice
Abstract
We have previously studied microemulsions as vehicles for peroral and rectal administration of peptides.1-3 Among the peptides we used, insulin in dogs had a pharmacologic availability of 6.2% when administered po in microemulsion form,4 and 20% when administered rectally in rabbits in the form of a microemulsion gel.5 In all our previous studies, freshly prepared microemulsion was used. In order to examine the stability of peptides in microemulsions, we investigated the potency of insulin in microemulsion according to the USP XXII,e but modified for mice.
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Cited by (12)
Formulation and characterization of an oily-based system for oral delivery of insulin
2009, European Journal of Pharmaceutics and BiopharmaceuticsThe present work explored the possibility of formulating an oral insulin delivery system by combining the advantages of nanoencapsulation and the use of oily vehicle. The parameters affecting formulation such as association efficiency were characterized. The preparation was evaluated for its chemical, physical and biological stability. The preparation has unimodal particle size distribution with a mean diameter of 108 ± 9 nm. Insulin was protected from gastric enzymes by incorporation into lipid-based formulation. The results of RP HPLC and ELISA indicated that insulin was able to withstand the preparation procedure. Insulin in the preparations was stable for a period of one month at storage temperatures of 4 and 25 °C. It was also biologically active and stable as demonstrated by the remarkable reduction of blood glucose levels of the STZ-diabetic rats after oral administration of the preparation. Moreover, hypoglycemic effect of nanoparticles administered orally was sustained for a longer period of time compared to the subcutaneous injection. These results clearly evidenced the ability of the nanoparticles to enhance the pharmacological response of insulin when given orally and could be used to deliver other peptides.
Effect of fiber length of carbon nanotubes on the absorption of erythropoietin from rat small intestine
2007, International Journal of PharmaceuticsErythropoietin (EPO) loaded carbon nanotubes (CNTs) with surfactant as an absorption enhancer were prepared for the oral delivery of EPO using two types of CNTs, long and short fiber length CNTs, and the effect of CNT fiber length on the absorption efficiency of EPO was studied. After Labrasol, PEG-8 caprylic/capric glycerides, as absorption enhancer was adsorbed into long fiber CNTs of which mean fiber length was 20–80 μm, as a carrier, EPO and casein as protease inhibitor and Explotab (sodium starch glycolate) as a disintegrating agent, were mixed. The resulting solid preparation was administered into the rat jejunum and serum EPO levels were measured by ELISA. The dose of EPO, CNTs, casein and Explotab were 100 IU/kg, 5 mg/kg, 25 mg/kg and 2.5 mg/kg, respectively. Serum EPO level reached to Cmax, 69.0 ± 3.9 mIU/ml, at 3.5 ± 0.1 h and AUC was 175.7 ± 13.8 mIU h/ml. These values were approximately half of that obtained with short fiber length CNTs of which Cmax was 143.1 ± 15.2 mIU/ml and AUC was 256.3 ± 9.7 mIU h/ml. When amphoteric surfactant, Lipomin LA, sodium β-alkylaminopropionic acid, was used to accelerate the disaggregation of long fiber length CNTs, Cmax was 36.0 ± 4.9 and AUC was 96.9 ± 11.9, which showed less bioavailability (BA) of EPO. These results suggest that the short fiber length CNTs deliver more both EPO and absorption enhancer to the absorptive cells of the rat small intestine and the aggregation of CNTs is not the critical factor for the oral delivery of EPO.
In the present study, an attempt was made to study the feasibility of nanoparticulate adsorbents in the presence of an absorption enhancer, as a drug delivery tool for the administration of erythropoietin (EPO) to the small intestine. Liquid filled nano- and micro-particles (LFNPS/LFMPS) were prepared using solid adsorbents such as porous silicon dioxide (Sylysia 550), carbon nanotubes (CNTs), carbon nanohorns, fullerene, charcoal and bamboo charcoal. Surfactants such as a saturated polyglycolysed C8–C18 glyceride (Gelucire 44/14), PEG-8 capryl/caprylic acid glycerides (Labrasol) and polyoxyethylene hydrogenated castor oil derivative (HCO-60) were used as an absorption enhancer at 50 mg/kg along with casein/lactoferrin as enzyme inhibitors. The absorption of EPO was studied by measuring serum EPO levels by an ELISA method after small intestinal administration of EPO-LFNPS preparation to rats at the EPO dose level of 100 IU/kg. Among the adsorbents studied, CNTs showed the highest serum EPO level of 62.7±11.6 mIU/ml. In addition, with the use of casein, EPO absorption was improved, 143.1±15.2 mIU/ml. Labrasol showed the highest absorption enhancing effect after intra-jejunum administration than Gelucire 44/14 and HCO-60, 25.6±3.2 and 22.2±3.6 mIU/ml, respectively. Jejunum was found to be the best absorption site for the absorption of EPO from LFNPS. The use of CNTs as LFNPS, improved the bioavailability of EPO to 11.5% following intra-small intestinal administration.
In vivo evaluation of a reverse water-in-fluorocarbon emulsion stabilized with a semifluorinated amphiphile as a drug delivery system through the pulmonary route
2004, International Journal of PharmaceuticsThe potential of a reverse water-in-fluorocarbon (w-in-FC) emulsion stabilized with a semifluorinated amphiphile, namely C8F17(CH2)11OP(O)[N(CH2CH2)2O]2 (F8H11DMP) for drug delivery through intrapulmonary administration was investigated in the mouse. This study involved assessment of the effect of single or repeated intranasal instillations of a plain emulsion on lung tissue integrity, and evaluation of blood glucose levels in mice treated with an insulin-loaded emulsion. When instilled intranasally to mice, the plain emulsion did not alter lung tissue integrity, as demonstrated by histological staining, and did not induce any airway inflammatory reaction. Treated mice exhibited decreased body weight within the 3–4 days that followed the first emulsion administration, but this decrease was reversible within few days. Mice instilled intranasally with the insulin-loaded emulsion displayed decreased blood glucose levels within the 20 min that followed the administration, thus demonstrating the potential of the reverse w-in-FC emulsion stabilized with F8H11DMP to systemically deliver drugs, including peptides, upon lung administration.
Possibility of a patch system as a new oral delivery system
2003, International Journal of PharmaceuticsA new oral patch system has been designed to increase the residence time of model drugs within the gastrointestinal tract. The system consisted of three layers (1) water-insoluble backing layer (2) drug-carrying adhesive layer composed of a model drug, fluorescein (FL) or fluorescein isothiocyanate-dextran (FD), and gel-forming polymer and (3) pH-sensitive enteric polymer. These three layers system was prepared as 3.0 mm diameter patches. As references, tablet containing FL or FD was prepared. In vitro dissolution studies showed that the mean dissolution time (MDT) of model drugs from patch preparation was 0.739±0.021 h for FL and 0.407±0.021 h for FD, which were longer than from tablet, 0.327±0.008 h for FL and 0.270±0.019 h for FD. The two test preparations were orally administered to beagle dogs in a crossover manner at a FL dose of 30 mg/dog and the measured plasma FL concentrations were used for pharmacokinetic analysis. With FL patch preparation, area under the plasma drug concentration vs. time curve (AUC) was 2.12±0.24 μg h/ml and mean residence time (MRT) was 4.60±0.18 h, which were greater than those of tablet, AUC was 1.52±0.16 μg h/ml and MRT was 3.18±0.09 h, respectively. Oral patch preparation also increased both AUC and MRT of FD, a model macromolecular drug, which was formulated into both patches and tablets and administered to dogs (30 mg/dog). The AUC and MRT of FD from the patch preparation were 1.11±0.13 μg h/ml and 5.58±0.55 h and from tablets were 0.53±0.08 μg h/ml and 4.09±0.29 h, respectively. These results suggest that oral patch preparation has as a potential a new oral delivery system to obtain a long residence time of drug in the gastrointestinal tract.
Preparation and characterization of a peptide containing w/o emulsion
1995, International Journal of PharmaceuticsHuman insulin as a model peptide drug was incorporated into a water-in-oil emulsion prepared by high-pressure homogenization. The formulation of the emulsion was developed with regard to oral compatibility and enhancing properties of the excipients. A fine and stable dispersion of the aqueous phase was achieved by a valid complex of emulsifiers dissolved in a mixture of triglycerides. The resulting droplet size distribution was determined by microscopical means and photon correlation spectroscopy (PCS). The stability of insulin in the formulation was examined by ELISA and HPLC methods over a period of 3 months. Human insulin as a high molecular mass peptide (5800 Da) stayed immunologically active after preparation and the formulation showed high compatibility with the peptide in longer term stability by HPLC. The emulsion was able to protect insulin against gastric degradation in vitro without further encapsulation. Simultaneous incorporation of aprotinin as a suitable protease inhibitor was performed.