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PURPOSE: The objective of this study was to investigate the effect of nasal cavity patency on the penetration, deposition, and clearance of an aqueous isotonic saline solution. METHODS: The study was carried out as a single center, open, randomized, 2-way cross-over in healthy volunteers. Nasal patency was assessed using misting patterns on a cold metal surface at the beginning and end of study. 100 microl of technetium-99m radiolabeled saline solution was introduced into either the most or least patent nasal cavity using a purpose designed spray device. The distribution and residence time of the radiolabel was followed for 2 hours using gamma scintigraphy. RESULTS: The mean times to 50% clearance were 34+/-7 and 28+/-12 minutes (+/- s.d.) for the side view of the least and most patent nasal cavity respectively. Total clearance of the radiolabelled saline from the nose was not affected by patency. Between 7 and 35% of the radiolabelled saline solution remained in the nasal cavity at the end of imaging. Using endoscopy to track the clearance of an aqueous solution of food dye using the same delivery procedure, identified this region as hair in the nasal vestibule. The dye was seen to dry in this region along with the mucus. CONCLUSIONS: Nasal patency affects the initial, but not total clearance of solutions, however, the remaining solution may not be available for drug delivery.

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The nose is becoming a common route of drug administration, however, little is known about the pH of the human nasal cavity. Local pH may have a direct effect on the rate and extent of absorption of ionizable compounds and hence this study was performed to investigate normal pH values and whether pH could be manipulated by various buffers. Twelve healthy volunteers participated in a study to measure pH in the anterior and posterior sites of the nasal cavity. Miniature pH electrodes were placed 3 cm apart in the nasal cavity and a baseline was recorded for 30 min once the pH had stabilized. One hundred microlitres of isotonic solution was sprayed into the nostril and the pH was measured for 4 h post-dose. The following five formulations were tested: formulation A--sodium chloride (0.9%) at pH 7.2; formulation B--sodium chloride (0.9%) at pH 5.8; formulation C--Sorensens phosphate buffer (0.06 M) at pH 5. 8; formulation D--Sorensens phosphate buffer (0.13 M) at pH 5.8 and formulation E--formulation as (c) but adjusted to pH 5.0. Each formulation also contained saccharin sodium (0.5%) as a taste marker for nasal clearance. The time at which each subject detected the taste of saccharin was noted. The 30-minute baseline recording prior to administration of the nasal spray formulation demonstrates that there was both considerable intersubject and intrasubject variation in nasal pH. The average pH in the anterior of the nose was 6.40 (+0. 11, -0.15 S.D.) when calculated from H(+) values. The pH in the posterior of the nasal cavity was 6.27 (+0.13, -0.18 S.D.). The overall range in pH was 5.17-8.13 for anterior pH and 5.20-8.00 for posterior pH. Formulation A caused the pH in the anterior part of the nasal cavity to reach a maximum of 7.06 in 11.25 min from the baseline of pH 6.14 (P<0.05). The mean baseline pH was 6.5 for the posterior part of the nose which did not change over the recording period. Formulation B caused the anterior pH to increase from pH 6. 60 to 7.25 within the first minute. This fell back to a mean pH of 7.07 over the first hour which was still significantly above the baseline. It remained at this value for the remainder of the recording period. The initial average posterior pH was 6.32 and again this did not significantly change over the recording period. Formulation C produced a sustained increase in anterior nasal pH from a baseline pH of 6.57-7.12. A small transient decrease was observed in the pH in the posterior of the nose but baseline pH of 6. 6 was re-established within 15 min post dose. Formulation D significantly reduced anterior nasal pH from 6.30 to 5.87 by 30 min reaching a pH of 5.95 by 90 min where it remained for the remainder of the recording period. The posterior baseline pH was 6.3 and introduction of the pH 5.8 buffer caused a slow increase over 90 min to pH 6.6. Formulation E increased anterior pH from 6.1 to 6.7 for the remainder of the recording period. It had an insignificant effect on posterior nasal pH. The mean (+/-S.D.) time to taste saccharin for formulations A to E was 13.42+/-10.21, 14.67+/-8.37, 11.67+/-8.08, 10.08+/-7.6, 9.80+/-6.73 min, respectively. There was no significant difference between the clearance times for the different formulations. In conclusion, average baseline human nasal pH is approximately 6.3. Nasal anterior pH can be decreased when buffers of 0.13 M and above are used. Mildly acidic solutions produce an increase in pH presumably due to reflux bicarbonate secretion. Posterior nasal pH was not altered by administration of any buffer except the 0.13 M buffer at pH 5.8. This produced a rise in posterior pH.

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The surface energies of four sulfonamides have been assessed from contact angle data, using the Lewis acid-base approach. From these data the free energy of adhesion between the drugs and sodium dodecyl sulfate (SDS) head groups and tails has been calculated. The most favored interaction was for adhesion to the SDS tails, rather than the head groups. The initial rotating disk dissolution rate (hereafter termed dissolution rate) of drug compacts has been measured in water and water with SDS micelles at a range of temperatures. The thermodynamic parameters of activation have been calculated from the rate data. Linear relationships exist between the enthalpy of transfer between water and SDS micelles and the free energy of adhesion between the drugs and both SDS head groups and SDS tails. The most nonpolar drugs had the most favored free energy of adhesion and the most favored enthalpy of transfer. The most polar drug had a disfavoured free energy of adhesion to the SDS head and a disfavoured enthalpy of transfer. This response demonstrates that the most important barrier to the passage from the aqueous fluid to the hydrophobic core of the micelle is the monopolar repulsion between the polar forces of the drug and head group surface energies. This provides a new insight into a possible mechanism of solubilization and offers the prospect of understanding even more complex partitioning behavior.

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