Therapeutic Intranasal Drug Delivery

The efficacy of antiviral drugs and vaccines administered intranasally may depend upon the technique of application. The distribution and time-course of removal of human serum albumin-technetium 99m (HSA-Tc 99m)-instilled intranasally were studied in eleven healthy volunteers using a gamma camera and an anterior sodium iodide scintillation detector. In 100 randomized studies material was delivered as drops in the supine position or as a spray to seated subjects. A significantly higher proportion of 'good' distributions (62 in 73 tests) was obtained with drops compared with spray (1 in 27). The volume administered was varied between 0.10 ml and 0.75 ml and the concentration of HSA was changed from 3 to 30% with no significant effect upon the distribution of time-course of removal; pertechnetate in isotonic saline was distributed and removed in a manner comparable to HSA-Tc 99m. Activity recorded by the detector showed an initial rapid fall associated with removal of most of the material from the nasal cavity, followed by a slower decline associated with the removal of material mainly from the anterior region of the nose. A multidose study confirmed that frequent administration by drops is required to maintain a high level of activity in the nasal cavity. Using this technique it should be possible to correlate measurements of antiviral efficacy and vaccines take-rates with certain characteristics of intranasal applicators; such studies may lead to the design of better devices.

The aim of this study was to determine the bioavailability and absorption kinetics of midazolam given as an intranasal (i.n.) spray. In addition, plasma concentrations of the active metabolite, 1-hydroxymidazolam, were measured to give an indication of enteral absorption. An i.v. and i.n. midazolam dose were given in a crossover study to 14 adult surgical patients. Individual uptake profiles of i.n. midazolam were estimated by numerical deconvolution. After an i.n. dose of 0.15 mg kg-1, maximum arterial plasma concentrations were 192 (SD 48) micrograms litre-1 at 14 (2) min. Uptake of midazolam was rapid and bioavailability was 83 (15)%. Formation of the 1-hydroxy metabolite after i.n. administration did not exceed that after the i.v. dose. This demonstrates that under optimal conditions absorption of midazolam via the nasal mucosa was virtually complete. In this case little midazolam was swallowed and subjected to first-pass metabolism in the liver and therefore pharmacologically important amounts of active metabolite were not produced. Routinely administering i.n. midazolam under the assumption that the bioavailability is approximately 50% (as reported previously in the literature) may lead to overdosing in some patients.

The distribution and nasal clearance of 99Tcm-labelled albumin (18.5 MBq), used as a mucosal vaccine surrogate for FluMist, was determined in three volunteers. The subjects were randomized in a cross-over clinical study design to receive either large-particle aerosal (nasal spray) followed by nose drops, or nose drops followed by the nasal spray, 1 week apart. Gamma scintigraphy was used to measure the distribution and clearance. The 'vaccine' delivered as drops was cleared from the nose into the oesophagus and upper stomach at very variable rates. In contrast, the nasal spray was uniformly distributed and cleared from the nasopharynx with a 50% mean clearance time of 50 min (range 40-60 min) and was not detected in the lungs.

AIMS: To measure and compare the systemic bioavailability of fluticasone propionate aqueous nasal spray and a new nasal drop formulation, using a sensitive analytical method and high dose regimen. METHODS: Volunteers received four 800 microg doses of fluticasone propionate as a nasal spray or drops over 2 days, separated by an 8 h dose interval. On day 2, blood samples were collected for assay of fluticasone propionate plasma concentrations. RESULTS: The mean systemic exposure, for both formulations was 8.5 pg x ml(-1) x h (drops) and 67.5 pg x ml(-1) x h (spray). Mean absolute bioavailabilities were estimated to be 0.06% (drops) and 0.51% (spray), by reference to historical intravenous data. CONCLUSIONS: Both formulations exhibited low systemic bioavailability, even at 12 times the normal daily dose. The bioavailability from the nasal drops was approximately eight times lower than from the nasal spray.

The bioavailability of progesterone (P) in terms of area under time-concentration curve and maximal concentration in the serum and cerebrospinal fluid was studied in adult ovariectomized rhesus monkeys following the administration of P as a nasal spray, i.v. or i.m. injections, nasal or eye drops. The bioavailability of P in both the body fluids was found to be considerably higher following its being sprayed intranasally.

A solution of 99mTc-labelled human serum albumin was administered into the nose as a spray and as one or three drops. The patterns of deposition and the rates of clearance in normal subjects were monitored by gamma scintigraphy. The spray was deposited mainly in the atrium, and cleared slowly into the pharynx. The single drop spread more extensively than the spray, while the three drops were sufficient to cover most of the walls of the nasal cavity. Clearance was faster following administration of the drops. These factors have implications when designing dosage regimens for drugs administered by the intranasal route.

The effect of methylcellulose on the particle size distribution and dosing accuracy of pre-metered spray pump devices containing the peptide desmopressin (DDAVP) was investigated. Using gamma scintigraphy, the influence of methylcellulose on the in vivo deposition and clearance of nasal solutions administered as drops or spray was studied. Nasal formulations containing 0, 0.25, and 0.50% methylcellulose produced a dose-related increase in average particle size from 51 micron for 0% to 81 and 200 micron for 0.25 and 0.50% methylcellulose, respectively. However, no effect was observed on the dosing accuracy of the spray pumps. The addition of methylcellulose gave a more localized in vivo deposition in the anterior region of the nasal vestibule. However, the net effect on clearance followed a biphasic pattern which showed an increase in retention time for the 0.25% solution, followed by a decrease in retention time and faster clearance time for the 0.50% solution. The spray delivers well-controlled doses to the nasal cavity. These findings show that viscosity, particle size, and nasal clearance are important parameters in the design of nasal delivery systems.

PURPOSE: The purpose of this investigation was to compare the pharmacokinetics of midazolam following intravenous, intranasal drop, and nasal-atomizer administration in beagle dogs. METHODS: Six animals weighing 9-13 kg were used in a repeated-measure design, group assignment based on route of drug administration. Midazolam (1.5 mg/kg) was administered with the delivery route based on group assignment. Blood samples were obtained at baseline and at 1, 3, 5, 7, 10, 15, 20, 30, and 45 min after administration. Cerebrospinal fluid samples (CSF) were obtained at 5 and 10 min after administration. Plasma and CSF concentrations of midazolam were determined by electron-capture gas-liquid chromatography. RESULTS: Comparison between groups and over time demonstrated that both nasal routes resulted in significantly higher CSF concentrations relative to corresponding plasma levels, and that nasal-atomizer administration produced significantly higher CSF concentrations compared to the drop approach.

Using a cast of the human nose the intranasal distribution of drugs, delivered from pressurized aerosols and nebulizers was studied. The results indicate that a pressurized aerosol should be used twice in each nostril to give an acceptable drug distribution, and also that an automized pump is preferable for a plastic-bottle nebulizer with regard to drug distribution.

The distribution of nasal drugs specifically to the middle meatus is of vital importance in the treatment of rhinosinusitis and nasal polyposis. It is widely assumed that the intranasal distribution is superior with nasal drops rather than spray delivery. However, a comparison of nasal spray and drop delivery specifically to this area has not been studied before. This study aims to compare semiquantitatively the intranasal distribution of nasal sprays and drops to the middle meatus in vivo. A novel method was used whereby a neurosurgical patty was placed in the middle meatus. Topical nasal drops and aqueous sprays dyed with methylene blue (0.1% v/v) were administered in a standardized fashion in normal volunteers. The subsequent absorption of administered dye was classified on a four-point scale. A randomized prospective cross-over design was used for the study. We found that there was no difference in the delivery of nasal drug to the middle meatus between either method of drug administration (P > 0.2). The perceived superiority of nasal drops may therefore be as a result of the acknowledged systemic effect of betamethasone drops.