Electroencephalographic effects and serum concentrations after intranasal and intravenous administration of diazepam to healthy volunteers.

AIMS: To evaluate the electroencephalographic (EEG) effects, blood concentrations, vehicle irritation and dose-effect relationships for diazepam administered nasally. METHODS: The study had a cross-over design with eight healthy volunteers (one drop out). It consisted of four legs with four different administrations: intranasal (i.n.) placebo, 4 mg diazepam i.n., 7 mg diazepam i.n. and 5 mg intravenous (i.v.) diazepam. Polyethylene glycol 300 (PEG300) was used as a vehicle in the nasal formulations to solubilize a clinically relevant dose of diazepam. Changes in N100, P200 and P300 brain event-related potentials (ERP) elicited by auditory stimulation and electroencephalographic beta-activity were used to assess effects on neurological activity. RESULTS: The mean [95% confidence intervals] differences between before and after drug administration values of P300-N100 amplitude differences were -0.9 [-6.5, 4.7], -6.4 [-10.1, -2,7], -8.6 [-11.4, -5.8] and -9.6 [-12.1, -7.1] for placebo, 4 mg i.n., 7 mg i.n. and 5 mg i.v. diazepam, respectively, indicating statistically significant drug induced effects. The bioavailabilities of 4 and 7 mg i.n. formulations, were found to be similar, 45% [32, 58] and 42% [22, 62], respectively. CONCLUSION: The present study indicates that it is possible to deliver a clinically effective nasal dose of diazepam for the acute treatment of epilepsy, using PEG300 as a solubilizer.

Intranasal bioavailability of buprenorphine in rabbit correlated to sheep and man.

The purpose of the present study of buprenorphine is to add information about the correlation between various animal models and nasal bioavailabilities in man. PEG 300 was added to one formulation to study whether the addition of the co-solvent results in the same absorption pattern as seen for sheep. The bioavailability of intranasal buprenorphine 0.6 mg in PEG 300 and 5% dextrose was assessed in a cross-over study in six rabbits. The mean bioavailabilities, Tmax and Cmax were 46% (S.D. +/-13) and 53% (S.D. +/-17), 8 and 12 min, 28 and 27 ng/ml for 30% PEG 300 and 5% dextrose, respectively. No significant differences were found between the nasal buprenorphine formulations. The bioavailabilities in rabbit and sheep, respectively, were approximately 2.5 and four times higher than for man. The absorption rate was faster for rabbit and sheep than for man. It appears that rabbit and sheep bioavailability differ from humans, especially with respect to rate. PEG 300 do not increase the bioavailability of buprenorphine.

Intranasal absorption of buprenorphine--in vivo bioavailability study in sheep.

The bioavailability of buprenorphine, HCl (BPP) in sheep after nasal administration of two formulations has been studied. 0.9 mg BPP in 150 microl was administered nasally and compared to 0.6 mg i.v. The test solutions were formulated with 30% polyethylene glycol 300 (PEG 300) and 5% dextrose, respectively. The bioavailability for PEG 300 was 70% (S.D.+/-27%, n=6), whereas the bioavailability for 5% dextrose was 89% (S.D.+/-23%, n=6). A two-compartment model with initial and terminal serum half-lives of 10 and 23 min, respectively, may describe the pharmacokinetics. The rate of absorption for both nasal formulations was very fast (t(max)=10 min). The C(max) was 37 ng/ml (S.D.+/-17) and 48 (S.D.+/-10) for PEG 300 and dextrose, respectively. No significant difference was found between the two formulations, but PEG 300 has advantages in relation to freezing point depression and solubility, which may be considered if further studies are going to be initiated. The high nasal bioavailability and short time to maximal plasma concentration suggests that it is possible to make a clinically relevant nasal formulation of BPP for the treatment of pain.

Intranasal absorption of melatonin in vivo bioavailability study.

The bioavailability of melatonin in rabbits after nasal administration of two formulations has been studied. In each case, a total amount of 1.5 mg melatonin in 50 microl was administered and compared with 1.5 mg i.v. The test solutions were formulated with 40% polyethylene glycol 300 (PEG 300), one with 1% sodium glycocholate (+GC) and one without (-GC). The bioavailability for +GC was 94% (S.D.+/-29%, n=4), whereas the bioavailability for -GC was 55% (S.D.+/-17%, n=6). These results indicate that GC has an enhancer effect (P<0.05). However, the relatively high bioavailability without GC shows that it might not be necessary to use an enhancer for a clinical relevant formulation. The pharmacokinetics of melatonin could be described by a one-compartment model, and the serum half-life was about 13 min. The absorption rate for both formulations was very fast (tmax=5 min) and Cmax mean was 493+/-290 ng/ml (n=4) and 249+/-125 ng/ml (n=6) for +GC and -GC, respectively.

High-performance liquid chromatographic analysis of melatonin in human plasma and rabbit serum with on-line column enrichment.

This paper describes the development of a simple and sensitive analytical method for the quantification of melatonin in human plasma and rabbit serum, using standard analytical equipment and on-line column enrichment without prior extraction, clean-up or derivatization. The analytical procedure was found to be accurate, precise and linear. For human plasma, the accuracy was 101% (range 89-106%), and the mean precision was 5% (range 2-9%) for all concentrations (0, 2, 10, 50 and 200 ng/ml) tested (n=6). The accuracy in rabbit serum was 101% (range 90-112%), and the mean precision was 13% (range 8-19%) for all concentrations (0, 2, 10, 50, 200 and 500 ng/ml) tested (n=6). The retention time of melatonin was about 8 min and the total recoveries were found to be approximately 65 and 85%, respectively, for human plasma and rabbit serum. The limit of detection was found to be lower than 1 ng/ml for human plasma and around 2 ng/ml for rabbit serum. The method is, therefore, found to be suitable for melatonin bioavailability studies in rabbits and presumably also in humans.