Comparison of the clinical efficacy of standard and mucoadhesive-based nasal decongestants

Abstract

Aims

To compare two xylometazoline 0.1% preparations: reference commercial solution (RS) and test mucoadhesive solution (TS).

Methods

Twenty subjects with perennial allergic rhinitis (age range 18–69 years, 5 atopic, 7 men) applied randomly in turn TS and RS for 5 days in a double-blind crossover clinical trial. Nasal airflow resistance (NAR), nasal symptoms (6 grade scoring), frequency of application (times/day), and side-effects were recorded.

Results

Mean ratio TS/RS of areas under the resistance/time curves for NAR ±90% CI: 3.56 ± 0.92; mean TS-RS differences ±95% CI: for congestion: −1.12 ± 0.59, for frequency of application: −1.10 ± 0.20. Subjects experienced fewer side-effects with TS.

Conclusions

A mucoadhesive solution with a decongestant had a greater and longer lasting effect on nasal congestion in subjects with perennial allergic rhinitis than the commercially available decongestant solution. It also caused fewer side effects.

Introduction

Over the past few years we have developed a nontoxic and nonirritating liquid mucoadhesive carrier for nasally applied drugs. We used it as a vehicle for a nasal test preparation of xylometazoline 0.1%. The end test solution (TS) was isotonic and characterized in regard to its rheological and mucoadhesive properties [1, 2].

Our clinical study was designed to compare the effect of TS with a commercial nonadhesive 0.1% xylometazoline product (Rhinoxilin, Sopharma, Bulgaria) used as reference solution (RS) in subjects with nasal obstruction.

Methods

Subjects

Twenty subjects (7 men, aged between 18 and 69 years, 5 atopic) from among the outpatients of the Clinical Center of Allergology in Sofia diagnosed with perennial allergic rhinitis gave informed consent to participate in the study. They all indicated persistant nasal congestion as their main symptom. The objective examination (nasendoscopy and ultrasound examination) excluded nasal polyps, septum deviations or sinus disease, which could interfere with the results of the study. None of them took other medications throughout the study.

Study design

In this double-blind cross-over study each subject was randomly assigned to receive either TS or RS for a period of 5 days, switching to the alternative preparation after a 7 day wash-out period. On the morning of days 1 and 5 of each treatment arm we measured the nasal airflow resistance (NAR) before application (t₀) and at intervals until the 6th hour (t₁₅, t₃₀, t₆₀, t₉₀, t₁₂₀, t₁₈₀, t₂₄₀ and t₃₆₀) after application of the preparations. On days 2, 3 and 4 subjects were instructed to apply the solutions on an ‘as needed’ basis, but no more than six times daily and to fill in diaries the number of applications, along with daily scores for the main symptoms (congestion, rhinorrhoea, itching and sneezing), using a 6-grade scoring scale from 1 (no symptom) to 6 (full-blown expression). Side-effects were spontaneously reported by patients or specifically asked for by investigators at day 5 of both treatment periods. The study was approved by the Ethics Committee of Alexander's University Hospital.

Equipment

A rhinomanometer Rhinoscreen/Jaeger was used to measure nasal airflow resistance (NAR) expressed as Pa l⁻¹ s⁻¹.

TS and RS were kept in identically looking coded bottles. The application pipettes were calibrated to apply identical volumes of the solutions.

Statistical analysis

Basal NAR measurements were made using paired Student's t-test. Areas under the curve (AUC) were constructed for NAR and mean TS/RS ratio ±90% CI was calculated. Other results were presented as mean TS-RS differences ±95% CI. Wilcoxon's Signed Ranks Test was used to compare the incidence of side-effects. Correlation between objective and subjective measurements were performed using Pearson's correlation coefficient. A two-tailed level of significance of P < 0.05 was accepted.

Results

Nasal rhinomanometry

Comparison between initial morning NAR showed no significant difference between the solutions. On day 5 on TS the initial morning NAR was reduced by 34.2% compared with day 1 (P < 0.005), while on RS it slightly increased. TS and RS NAR measurements on day 1 expressed as NAR₀−NAR_i vs time were plotted (Figure 1). TS caused a stronger and longer lasting effect: after a mean of 258 min NAR with RS reached baseline (0) and further increased (NAR₀−NAR₃₆₀ =−0.16 Pa l⁻¹ s⁻¹), while with TS it remained above 0 after 360 min (the end-point of the measurements). The mean TS/RS ratio ± 90% CI of AUC was 3.56 ± 0.92.

Figure 1.

NAR change (NAR₀−NAR_i) over time (6 h) on day 1 after application of TS (•) and RS (○), both containing xylometazoline 0.1% as an active agent.

Nasal congestion

Nasal congestion was the main symptom bothering patients and was significantly reduced on day 5: the mean difference between the treatment arms was (−1.12 ± 0.59) (Figure 2).

Figure 2.

Patients assessment of their ‘nose stuffiness’ over a 5 day treatment period with the TS (•) and RS (○) (minimal discomfort=1; maximal discomfort=6).

Duration of effect

Subjects recorded a significantly longer-lasting effect of TS vs RS: mean difference 2.36 ± 0.10 h.

Need for medication

Patients applied TS less often than RS: mean difference −1.10 ± 0.20 times per day.

Symptom scores for other nasal symptoms

The effect of both solutions on rhinorrhoea, itching and sneezing was similar and rather inconspicuous.

Discomfort due to nasal symptoms appeared to be quite individual and did not correlate with NAR measurements and the duration of the effect of the applied preparation.

Side-effects

The main side-effects spontaneously reported by the subjects were bitter taste (TS/RS = 0/6, P = 0.014) and prickling (TS/RS = 2/6, P = 0.046)

No changes in the pulse rate and blood pressure values were detected with any of the medications.

Discussion

Nasal congestion is a most disturbing symptom for patients and is best relieved by decongestants (adrenergic agonists) [3]. Devising a drug carrier, which can ‘glue’ the agonist to the inflamed tissues and thus prolong the time of contact would potentially decrease the number of applications and the cumulative daily dose.

We developed a mucoadhesive solution and used it with a decongestant (xylometazoline) in volunteers with allergic rhinitis. Its clinical effect was significantly longer lasting than the commercial nonmucoadhesive product. This was supported by both the objective manometric measurements, and by the subjective symptom scores. This is in line with the initial expectations, based on the physicochemical properties of TS: it spreads over a larger surface due to its interpenetration with the mucus and the high affinity to the mucosa. Its adhesiveness allows the adrenergic agonist to stay longer at the site of application, resulting in prolonged and more pronounced effect.

We measured the initial morning NAR on days 1 and 5 to objectively assess eventual overnight effects of each treatment form on the nasal patency of our patients. Interestingly, there was a significant ‘left-over’ beneficial decrease of NAR after 5 days of treatment with TS, while a slight increase of NAR was noted with RS. This may be a reflection of the rebound-swelling phenomenon, described with adrenergic agonists [4]. This was distinctly demonstrated in our study within the 6 h follow-up after application: NAR increased over baseline level after RS, while after TS it remained below it. As both solutions contained the same active drug, we were led to believe that either the commercial solution contained a component accountable for the ‘in-excess-swelling’, or TS countered in some way the ‘rebound-swelling’ effect of the adrenergic agonist. Benzalkonium chloride is used as a preservative in RS, and was lacking in TS. It has been shown to possess irritating and swelling effects [4, 5]. On the other hand the mucoadhesive carrier in TS, while including a different preservative, may itself possess decongestant (healing?) properties, accounting for the much lower morning baseline NAR levels on day 5 of treatment with it. Actually two of the subjects, who were assigned to use TS after RS, made the unsolicited remark, that TS had a ‘healing’ effect on their chronic nasal congestion on top of the ‘just restoring of the nasal patency’ effect.

We did not find a meaningful correlation between the initial NAR measurements and the subjective symptoms in our cohort. This is supported by some authors [6, 7], but is in contrast with the findings of others [8]. However, we were the only ones to assess patients with perennial allergic rhinitis. They all indicated nasal congestion as their most bothersome complaint. Both TS and RS had a positive effect on objective NAR measurements and the patients’ sensation of ‘stuffy nose’, but quantitatively TS had a far superior effect.

Patients reported significantly less side-effects with TS. Bitter taste was reported only while on the RS. This may be attributed to the well-known fact that increasing the viscosity of a liquid weakens the sense of taste (a pharmaceutical technology for masking of unpleasant taste). Also, mucoadhesion of TS keeps the decongestant longer at the site of application, which is devoid of taste receptors.

The higher rate of prickling in the nose with RS may be related to the presence of benzalkonium chloride in it. Another explanation may be that the rheological properties of TS are closer to the characteristics of the body fluids in the nasal mucosa.

In conclusion a mucoadhesive solution carrying a decongestant has a significantly more pronounced and longer lasting effect on the nasal congestion in subjects with perennial allergic rhinitis than the commercially available decongestant solution. It had also fewer side-effects.