Morphine administered nasally to humans as a simple solution is only absorbed to a limited degree, with a bioavailability of the order of 10% compared with intravenous administration. This article describes the development of novel nasal morphine formulations based on chitosan, which, in the sheep model, provide a highly increased absorption with a 5-to 6-fold increase in bioavailability over simple morphine solutions. The chitosan-morphine nasal formulations have been tested in healthy volunteers in comparison with a slow i.v. infusion (over 30 min) of morphine. The results show that the nasal formulation was rapidly absorbed with a T max of 15 min or less and a bioavailability of nearly 60%. The shape of the plasma profile for nasal delivery of the chitosan-morphine formulation was similar to the one obtained for the slow i.v. administration of morphine. Furthermore, the metabolite profile obtained after the nasal administration of the chitosan-morphine nasal formulation was essentially identical to the one obtained for morphine administered by the intravenous route. The levels of both morphine-6-glucuronide and morphine-3-glucuronide were only about 25% of that found after oral administration of morphine. It is concluded that a properly designed nasal morphine formulation (such as one with chitosan) can result in a noninjectable opioid product capable of offering patients rapid and efficient pain relief.
The purpose of this investigation was to develop a pig model for colonic drug delivery and to validate the model by determining whether the physiology of the pig colon had been significantly altered after the surgical implantation of a gut cannula into the terminal ileum of the pig. A fistula was created in the terminal ileum of the pig, and a cannula fitted for the purpose of directly administering drug formulations to a point just anterior to the ileocaeco-colonic valve of the gastrointestinal tract. The cephalic vein of the pig was also cannulated to enable continued blood sampling. Sulphasalazine was used as the model drug for the validation study. In the intact colon, sulphasalazine is metabolized by the gut microflora to sulphapyridine which is then absorbed. Sulphasalazine was administered orally to non-fistulated and fistulated pigs and then ileally, via the gut cannula, to fistulated pigs. Absorption of sulphapyridine was monitored by HPLC analysis of plasma samples. There was no significant difference in the absorption obtained for the three groups. Thus it is demonstrated that the colon physiology had not been altered. The colonic pig model is ideal for studying factors affecting the colonic absorption of drugs and as a means for developing drug delivery systems with improved absorption properties.
The pharmacokinetics of indoramin (Baratol) have been studied in five male and five female healthy, middle-aged volunteers after intravenous administration (0.14 mg/kg). Elimination occurred in an apparently biexponential fashion with a mean elimination half-life of 4.0 h (+/- 0.25 SEM). The mean plasma clearance was 19.9 ml/min/kg (+/- 1.32 SEM) and the mean volume of distribution 7.4 l/kg (+/- 0.81 SEM). There were no significant differences in these parameters between male and female volunteers. Protein binding of indoramin ranged from 85.6% at 81 ng/ml to 72.2% at 129 micrograms/ml. Two classes of binding site were evident, with affinity constants of 6.85 X 10(4)M -1 and 4.30 X 10(3)M -1.
Indoramin was administered as a single 50 mg oral tablet to 5 elderly (aged 68-71 years) and 6 middle-aged (aged 46-55 years) healthy female volunteers. The mean half life of indoramin in elderly subjects (14.7 +/- 4.8 h, mean +/- SEM) was statistically significantly longer than that seen in middle-aged subjects (5.1 +/- 1.0 h). The mean plasma concentrations of indoramin and mean area under the plasma concentration/time curve were also greater in elderly than in middle-aged subjects, although this did not achieve statistical significance. In many elderly patients, therefore, a reduction in dosage may be required due to the apparent reduction in clearance of indoramin. However, because of the wide inter-subject variability observed in the oral pharmacokinetics of indoramin, individual titration of indoramin dosage in all patients may be desirable.
Oral administration of meptazinol (200 mg Meptid) to male and female geriatric patients (greater than 70 years) resulted in rapid absorption, with peak drug concentrations at 0.5 to 3 h after dosage. Subsequent elimination also proceeded rapidly with a half-life of 3.39 h (+/- 0.26 SEM) after a single dose and 4.97 h (+/- 0.80 SEM) after 13 consecutive 6-h doses. These values were not statistically different. There was no accumulation of meptazinol above that expected from the single-dose kinetics. Plasma protein binding of meptazinol was 33.8% (+/- 0.74 SEM). No sex difference was apparent in any of the pharmacokinetic parameters determined. Comparison of these results with those obtained in an earlier study in young volunteers showed that although the half-life of meptazinol was somewhat longer than the value of 2 h seen in the young, peak plasma concentrations after single and multiple dosing were similar for both age groups, implying that clearance remained largely unaltered. It was concluded that there was no pharmacokinetic basis for recommending a reduction in dosage when treating elderly patients with oral meptazinol.
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