Determination of baseline human nasal pH and the effect of intranasally administered buffers

Abstract

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 — Sørensens phosphate buffer (0.06 M) at pH 5.8; formulation D — Sørensens 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 ≈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.

Introduction

Topical intranasal drug delivery is primarily employed to treat allergies and infections that cause local irritation, sneezing and congestion. Increasingly, however, it is being used to deliver drugs systemically, particularly large molecules and peptides. Nasal drug delivery has several advantages over conventional routes of administration. It avoids gut enzymes, hepatic ‘first-pass’ metabolism and invasive procedures such as injections, but clearance of the formulations can be highly variable (Andersen et al., 1971, Andersen et al., 1972).

A review of the medical literature reveals that there has been little, if any, scientific investigation into the pH characteristics of the human nasal cavity. This information is directly relevant to the delivery of drugs via the nasal route since local pH can significantly affect the rate and extent of absorption of ionizable compounds. This has been demonstrated in vitro and ex-vivo studies (Gibson and Olanoff, 1987). Buffering a solution to a target pH optimised for a particular drug should in theory, improve the absorption across the nasal epithelia.

The aims of this study were to determine baseline physiological pH of the nasal cavity in 12 healthy volunteer subjects and to investigate whether intranasally administered buffers could achieve and sustain a target pH within the nasal cavity. It was postulated that the pH of a solution may affect its clearance from the nasal cavity, hence this was also measured using the saccharin-taste test (Batts et al., 1991).