Determination of baseline human nasal pH and the effect of intranasally administered buffers☆
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).
Section snippets
Materials
The formulations investigated were:
- 1.
Sodium chloride (0.9%) adjusted to pH 7.2 with dilute sodium hydroxide+saccharin sodium (0.5%).
- 2.
Sodium chloride (0.9%) adjusted to pH 5.8 with dilute hydrochloric acid+saccharin sodium (0.5%).
- 3.
pH 5.8 Sørensens phosphate buffered solution (0.06 M)+saccharin sodium (0.5%).
- 4.
pH 5.8 Sørensens phosphate buffered solution (0.13 M)+saccharin sodium (0.5%).
- 5.
pH 5.8 Sørensens phosphate buffered solution (0.06 M) adjusted to pH 5.0 with dilute hydrochloric acid+saccharin
Methods
Twelve healthy volunteer subjects took part in the study, six males and six females within the age range 18–50 years. The exclusion criteria included the use of prescribed or over-the-counter medications which could influence the results of the study, current medical conditions which could influence the outcome of the study, participation in a clinical trial within the previous 3 months, habitual tobacco smoking and use of drugs of abuse.
Before entry into the study, the volunteers were given
Thirty minute baseline period prior to formulation administration
The average pH in the anterior of the nose was 6.40 (+0.11, −0.15 S.D.) when calculated from H+ values. The S.D. is not evenly spread due to conversion to the logarithmic pH scale. 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.
Effect of the formulations on nasal pH
Formulation A (pH 7.2 unbuffered saline solution) caused the pH in the anterior part of the nasal cavity to reach a maximum of 7.06 in 11.25 min (Fig. 1).
Discussion
None of the formulations appeared to significantly affect the clearance time as measured by the saccharin-taste test. These values compare with other values reported in the literature for this test e.g. 11.2±6.3 min with a range from 6 to 25 min (Ridley et al., 1995).
The effect of altering nasal pH on the absorption of certain drugs has been studied in animals and animal models by other groups. To date, enhanced absorption of vasopressin by a reduction in pH has been demonstrated in rats (
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Please note that AstraZeneca has no association with this work.