Pharmacokinetics and pharmacodynamics of intranasal insulin administered to healthy subjects in escalating doses.

BACKGROUND: This exploratory study examined the pharmacokinetics and pharmacodynamics of a Bentley Pharmaceuticals, Inc. (North Hampton, NH) proprietary insulin formulation utilizing CPE-215 technology designed for intranasal administration. METHODS: Eight fasting healthy volunteers (four men, four women; body mass index, 23.6 +/- 1.7 kg/m2) received up to four doses of intranasal insulin at least 1 week apart. Serum insulin, C-peptide, and plasma glucose were measured in the 4-h period following administration. RESULTS: At doses of 18.75 IU and above, a rise in serum insulin levels accompanied by a decrease in plasma glucose and serum C-peptide levels was seen. Insulin levels peaked in 10-20 min and remained elevated for approximately 1 h, and the resultant hypoglycaemic effect peaked at 40 min and returned to normal 1.5-2 h post-dosing. At 25 IU (n = 11 doses; eight subjects with three replicates), there was a mean fall in plasma glucose of 20.49%; a greater fall in plasma glucose was seen with higher insulin doses. In addition, mean peak insulin levels increased with dose escalation. For the 25 IU dose (a single 90-microL spray), the maximum measured insulin concentration was 19.52 +/- 9.28 mIU/L, and the area under the concentration-time curve from 0 to 4 h was 19.06 +/- 5.56 mIU/L/h. Three subjects with repeated 25 IU doses demonstrated similarly reproducible peaks for maximum measured insulin concentration and for plasma glucose reductions. As seen with other insulin studies, the inter-individual responsiveness to insulin was variable. CONCLUSIONS: This intranasal formulation was generally well tolerated and demonstrated rapid onset of action and appropriate duration of action for the potential use in controlling postprandial hyperglycaemia.

Bioavailability of two new formulations of paracetamol, compared with three marketed formulations, in healthy volunteers.

The aim of this study was to compare the main pharmacokinetic characteristics of two new paracetamol formulations, powder sachet and tablet, with that of three commercially available paracetamol formulations: two conventional solid tablets and one effervescent tablet. Twelve healthy volunteers participated in an open, single dose (paracetamol 1,000 mg), randomized, five-way, crossover study. Formulations studied included: formulation A: 2 x 500 mg paracetamol tablets (Laboratorios Belmac S.A.); formulation B: 1 x 1,000 mg paracetamol powder sachets (Laboratorios Belmac, S.A.); formulation C: 2 x 500 mg paracetamol film-coated tablets (Panadol, SmithKline Beecham); formulation D: 2 x 500 mg paracetamol tablets (Tylenol, McNeil); and formulation E: 1 x 1,000 mg effervescent paracetamol tablets (Efferalgan, UPSA). The primary variables were area under the plasma concentration time curve extrapolated to infinity (AUC(0-infinity)), maximum plasma concentration (Cmax), and time to maximum plasma concentration (tmax). Mean AUC(0-infinity) ranged from 52.6 (B) to 56.3 microg x h/ml (D); mean Cmax varied between 17.98 (C) and 20.73 microg/ml (E); mean tmax ranged from 0.40 (E) to 0.88 h (C); and median t(1/2) varied between 2.65 (C) and 2.81 h (A). Formulations A, B and E showed significantly shorter tmax than formulation C. The tmax and Cmax values found for formulations A and B were very similar to that found for E, an effervescent tablet formulation. In conclusion, the two new formulations of paracetamol tested in this study were absorbed rapidly after a single oral dose in healthy volunteers, similar to an effervescent paracetamol formulation and significantly faster than two ordinary commercialized paracetamol tablets.