Pharmaceutical composition containing xylometazoline

Abstract

Pharmaceutical compositions are described comprising xylometazoline for use in a method for the treatment or the prevention, by intranasal administration, of insomnia or other sleep disorders, and more broadly to improve sleep quality in patients suffering from nasal congestion and / or an upper respiratory tract infection. Furthermore, pharmaceutical compositions are described comprising xylometazoline for use in methods of treatment to improve the vitality of a patient and / or for use in methods of treatment of fatigue or exhaustion in patients suffering from nasal congestion and / or an upper respiratory tract infection.

Description

[0001] PHARMACEUTICAL COMPOSITION CONTAINING XYLOMETAZOLINE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a novel use of pharmaceutical compositions containing xylometazoline for use in methods of treatment to improve the sleep quality of a patient and / or for use in methods of treatment or prevention of insomnia.

[0004] The present invention further relates to a novel use of pharmaceutical compositions containing xylometazoline for use in methods of treatment to improve the vitality of a patient and / or for use in methods of treatment of fatigue or exhaustion.

[0005] BACKGROUND TO THE INVENTION

[0006] Xylometazoline is an a-sympathomimetic which is employed for the local treatment of swellings of the nasal mucous membrane, for example in acute rhinitis and allergic rhinitis, a- Sympathomimetics stimulate a-receptors in the vessels and thus have a strong vasoconstrictory action. On local administration into the nose, a significant constriction of the vessels in the nasal mucous membrane occurs, which then results in a reduction in mucous secretion and decongestion of the mucous membranes. This improves the passage of air and eliminates the impedance to nasal breathing.

[0007] Surprisingly, it has been found that xylometazoline improves sleep quality in patients suffering from nasal congestion and / or upper respiratory tract infections, and can thus be employed for the prophylaxis and / or treatment of insomnia and other sleep-disorders. The invention therefore relates to the use of xylometazoline in methods of treatment to improve the quality of sleep of a patient and / or for use in methods of treatment or prevention of insomnia and other sleep disorders quality in patients suffering from nasal congestion and / or upper respiratory tract infections. It has also been found that xylometazoline improves vitality, namely by increasing alertness, energy levels, and motivation of patients suffering from nasal congestion and / or upper respiratory tract infections. The invention therefore also relates to the use of xylometazoline in methods of treatment to improve the vitality of a patient and / or for use in methods of treatment or prevention of insomnia and other sleep disorders. SUMMARY OF THE INVENTION

[0008] The present invention relates to a pharmaceutical composition comprising xlyometazoline for use in a method for the treatment or the prevention of insomnia or other sleep disorders in a patient, or to improve sleep quality more broadly.

[0009] Furthermore, the present invention also relates to a pharmaceutical composition comprising xylometazoline for use in a method for the treatment or the prevention of fatigue or exhaustion in a patient, or more broadly to improve vitality.

[0010] According to a preferred embodiment, the pharmaceutical composition is administered intranasally. Preferably, the composition is a nasal spray.

[0011] According to a preferred embodiment, a pharmaceutical composition according to embodiments described here is administered up to three times daily into each nostril of a patient, with one administration at night time before going to bed. The effect of the pharmaceutical composition can begin within 2 minutes and last for up to 12 hours, ie all night, which is why an administration at night will be particularly advantageous.

[0012] According to a preferred embodiment of the invention, the patient who is treated is suffering from upper respiratory tract infections (URTI) such as common cold. The common cold is an acute, mild upper respiratory disease and is considered the most frequent human disease (Heikkinen T and Jarvinen A. The common cold. Lancet (London, England) 2003; 361 : 51-59; Stein RA. Hopes and challenges for the common cold. Int J Clin Pract 2017; 71). Most adults experience at least one episode of the common cold per year (Blaiss MS, Dicpinigaitis PV, Eccles R, et al. Consumer attitudes on cough and cold: US (ACHOO) survey results. CurrMed Res Opin 2015; 31 : 1527-1538) with an average of four episodes yearly (Worrall G. Common cold. Can Fam Physician 2011; 57: 1289-1290), although frequency varies with age. It is usually a self-limiting illness caused predominately by a rhinovirus.

[0013] The common cold is easily self-diagnosed, and can last for 7 to 10 days. Symptoms typically include nasal congestion, cough, sore throat, sneezing, runny nose, and headaches. In addition, people with the common cold may also experience sleep disruption (Phillipson G, Aspley, S., Fietze, I. Perceptions of the importance of sleep in common cold - two online questionnairebased surveys. SN Comprehensive Clinical Medicine 2020; 2: 596-605) , fatigue (Eccles R. Understanding the symptoms of the common cold and influenza. Lancet Infect Dis 2005; 5: 718-725), cognitive impairment, and reduced alertness. Consequently, these symptoms impact individuals’ quality of life (QoL), such as the performance of daily activities, and individuals’ occupational functions.

[0014] Currently experts believe that the symptoms of URTIs are generated as a result of the host’s inflammatory immune response caused by a complex mix of cytokines and mediators, which amplify the inflammatory process. It has been reported that cytokines may induce the syndrome of “sickness behaviour” with anhedonia, cognitive dysfunction, anxiety / irritability, psychomotor slowing, anergia / fatigue, anorexia, sleep alterations, and increased sensitivity to pain (Eccles R. Understanding the symptoms of the common cold and influenza. Lancet Infect Dis 2005; 5: 718-725). The contribution of cytokines and the mechanism to these changes is poorly understood, but it is well established that patients suffering from URTIs such as common cold would benefit from any treatment treating or preventing fatigue and improving their vitality.

[0015] Furthermore, in upper respiratory tract infections (URTI) such as common cold a dry, unproductive cough can often cause loss of sleep and exhaustion. The unproductive cough may be caused by the inflammatory response in the upper airways spreading to the larynx. It is believed that the effects of inflammatory mediators on airway sensory nerve endings cause a hyper-reactivity of the cough reflex. In healthy condition, cough is generally induced by mechanical stimulation of the larynx, but during inflammation of the larynx, cough either may occur spontaneously or in response to stimuli that would not normally cause cough — eg, cold air (Eccles R. Understanding the symptoms of the common cold and influenza. Lancet Infect Dis 2005; 5: 718-725). Patients suffering from URTIs do thus frequently suffer from insomnia and other sleep disorders which are due to nasal congestion, coughing, and other symptoms.

[0016] Patients suffering from URTIs such as common cold are thus in particular in need of a treatment treating or preventing insomnia and other sleep disorders.

[0017] The inventors have shown that the administration of a pharmaceutical composition containing xylometazoline is particularly effective in patients suffering from UTRI, namely in common cold sufferers, to treat and prevent both insomnia and sleep disorders, and fatigue. Without being bound by theory, the inventors believe that this is due not only to the decongestant effect of the xylometazoline, but also to an additional effect of xylometazoline on cytokines.

[0018] Nitric oxide (NO) provides a first-line defense against infectious organisms in the nasal airway. During infections the NO concentration increases. The measurement of NO in the upper airway is a noninvasive diagnostic marker of airway pathologies.

[0019] The principal enzyme is the inducible isoform of nitric oxide synthase (iNOS), which is induced by proinflammatory mediators like cytokines and produces high-level sustained NO synthesis. (Bayarri M, Milara J, Estomut C et al. Nitric Oxide System and Bronchial Epithelium: More than a Barrier. Frontiers in Physiology 2021; 12: 1-20; Coleman JW. Nitric oxide in inflammation and immunity. International Immunopharmacology 2001; 1: 1397- 1406). These high concentrations of the reactive NO may contribute to aggravating airway inflammation after viral airway infection.

[0020] Studies (Westerveld GJ, Voss H-P, van der Hee RM, et al. Inhibition of nitric oxide synthase by nasal decongestants. Eur Respir J 2000; 16: 437-444; Serrano C, Valero A, Bartra J, et al. Effects on Nasal Nitric Oxide Production of 2 Mechanisms of Vasoconstriction. J Investig Aller gol Clin Immunol 2007; Vol. 17: 337-340) indicate that nitric oxide (NO) may be influenced by nasal decongestants like xylometazoline. It was observed that administration of a nasal decongestant significantly decreases nasal NO concentration. It seems that the nasal decongestant inhibits the induction of inducible nitric oxide synthase, which then mitigates the exacerbation of the inflammatory response. The mechanism by which xylomeatzoline reduces NO concentration is not understood, but it is speculated to be another one than vasoconstriction.

[0021] This hypothesis could be supported by in-vitro studies which have shown that a topical decongestant can have immunomodulating effects by e.g. partially inhibitation of pro- inflammatory cytokines (Beck-Speier I, Oswald B , Maier KL. Oxymetazoline Inhibits and Resolves Inflammatory Reactions in Human Neutrophils. J Pharmacol Sci 2009; 110: 276 - 284; Tuettenberg A , Koelsch S , Knop J et al. Oxymetazoline modulates proinflammatory cytokines and the T-cell stimulatory capacity of dendritic cells. Experimental Dermatology 2007; 16: 171-178). Both sleep disorders and fatigue are linked to cytokines as consequence of the immune response due to URTIs. Xylometazoline may play a role in the modulation of the cytokines which led to an improvement of sleep and vitality from day one in this trial.

[0022] According to a preferred embodiment, the pharmaceutical composition is an aqueous solution. Aqueous solutions are especially preferred because they are compatible with the spray mechanism and the materials of most kinds of commercially available nasal spray devices. Aqueous solutions are also preferred because of the low risk of side effects.

[0023] According to a preferred embodiment, the composition comprises 0.1% (w / w) xylometazoline hydrochloride, for example, a product under the brand name Otrivin® or Otrivine®.

[0024] According to a preferred embodiment, the pharmaceutical composition comprises a sodium chloride solution. Sodium chloride may be used as a tonicity agent. Adjusting the osmolality of pharmaceutical compositions for nasal administration is beneficial to preserve the integrity of the nasal epithelia . Sodium chloride is preferred as the ions of this salt are present ubiquitously in the human body and no adverse effects are associated with intranasal administration of sodium chloride solutions. Furthermore, sodium chloride solution is also safe for ingestion and has an acceptable taste and odour. This is important for compliance, as after nasal administration, especially nasal spray administration as discussed above, the applied dose of the composition may end up in the pharyngeal region of the patient and may contact the taste buds before being swallowed.

[0025] According to a preferred embodiment, the pharmaceutical composition is administered in a dose of 0.14 mg of xylometazoline hydrochloride into each nostril of a patient per administration.

[0026] According to a preferred embodiment, the composition further comprises menthol and / or cineol or eucalyptus oil. It is believed that in suitable concentrations, these ingredients can improve not only the sensory experience, but may potentially also have a positive impact on sleep quality, in particular help for falling asleep initially. According to another aspect of the present invention, a method for treatment or prevention of insomnia or other sleep disorders in a patient suffering from nasal congestion and / or upper respiratory tract infections is provided, comprising intranasally administering to a patient a pharmaceutical composition comprising xylometazoline.

[0027] According to another aspect of the present invention, a method for treatment or prevention of fatigue or exhaustion in a patient suffering from nasal congestion and / or upper respiratory tract infections is provided, comprising intranasally administering to a patient a pharmaceutical composition comprising xylometazoline.

[0028] It should be understood that in addition to the ingredients particularly mentioned above, the formulations described herein may include other agents conventional for nasal administration, such as preservatives, preferably benzalkonium chloride, pH-adjusting agents, viscosity modifiers, hydrating agents, solvents, solubilisers, and / or essential oils such as peppermint oil or lavender oil,

[0029] BRIEF DESCRIPTION OF THE DRAWINGS

[0030] FIG. 1 : WURSS-21 total score over time of treatment

[0031] FIG.2: WURSS-21 total symptom domain score over time of treatment

[0032] FIG 3: WURSS-21 total Quality of Life domain score over time of treatment

[0033] DETAILED DESCRIPTION OF THE INVENTION

[0034] EXAMPLES

[0035] Example 1

[0036] The inventors carried out a fully decentralised, longitudinal, open-label study to evaluate the effect on QoL factors in participants with the common cold using a nasal spray containing xylometazoline hydrochloride 0.1% (Otrivine ®, also referred to as “the study product” herein) in a real-world setting across the United Kingdom. No randomisation was carried out in this study. The study design ensured assessment of eligibility before and after the study product was provided to the participants. The first two steps of the study protocol were the prescreening stage, and the screening stage. At the pre-screening stage, eligible participants were invited via email to download the study app and participants completed an electronic informed consent form. Participants had an interview phone call with a medically qualified investigator to confirm personal details and medical history. At the screening stage, participants were asked to complete the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) and additional Quality of Life (QoL) questions as baseline assessments. Participants also confirmed their medical history and concomitant medication.

[0037] Enrolled participants were supplied with a xylometazoline hydrochloride 0.1% nasal spray with the composition provided in Table 1 within one day of completing screening, and confirmed receipt and usability of the product via the study app. Upon product receipt, participants were required to re-confirm their eligibility by reporting nasal congestion (described as ‘plugged nose’ in the WURSS-21) of at least moderate intensity (score 5) and at least one other common cold symptom of at least mild intensity (score 3) as per the WURSS- 21 questionnaire (Table 2). Participants started treatment on Day 0 of the study, which was expected to align with a very early stage of disease progression and peak symptom stage. This was considered a key period to start treatment of the common cold with xylometazoline hydrochloride 0.1% to relieve nasal congestion.

[0038] Every morning, participants’ QoL factors were assessed via completion of the WURSS-21 questionnaire and the additional QoL questions based on the effects of the study product used on the previous day. For example, the scores reported on Day 1 show the results from Day 0. As per leaflet instructions, xylometazoline hydrochloride 0.1% was used no more than three times a day for up to 7 days and participants had the option to stop treatment at their discretion based on their desire to treat nasal congestion. Opting out of the treatment before the completion of 7 days of treatment was possible if participants felt their symptoms did not warrant further treatment, or if their nasal congestion was resolved; both criteria were assessed daily. The last dose was the day of last treatment if before 7 days. On Day 7, or on the day after the last dose was used, participants completed an exit survey. Participants who did not satisfy the criteria for participation and treatment compliance were considered dropouts. Compositions

[0039] The composition used in example 1 is specified in Table 1 :

[0040] Table 1 : Composition used in example 1

[0041] (Otrivine Congestion Relief 0.1% Nasal Spray, commercially available in the UK)

[0042] Table 2: WURSS-21 QoL questionnaire and additional QoL questions answered by participants using a severity scale ranging from 0-7.

[0043] One objective of the study was to evaluate the over-time effects of the test composition on sleep quality and on vitality. Sleep quality was evaluated based on the QoL individual factors “Sleep well” (WURSS-21 QI 3), and “Snoring” (QoL QI).

[0044] Vitality was evaluated based on the QoL individual factors “Less energetic” (QoL Q7), “Less motivated” (QoL Q8)”, “Feel tired” (WURSS-21 QI 1) and “Alertness” (slow in response, QoL Q2). Statistical analysis

[0045] Sample size

[0046] A non-parametric Paired Wilcoxon test was performed to determine sample size, which was based on a significance level (a) of 0.05, 80% power (1 - P) and an estimated standardized effect size of 0.27. The modified intention-to-treat (mITT) analysis included all participants who received at least one dose of the study product and had data for at least one post-baseline QoL questionnaire.

[0047] Evaluation of impact on sleep quality and vitality

[0048] Analyses for QoL and data were summarized using the mITT population. Participants’ baseline scores were used to determine the effect of the test composition on additional QoL factors. The changes from baseline in mean additional QoL scores were analyzed each day using a Student’s paired t-test, and / ^-values were assessed to a significance level of a = 0.05. Median posttreatment scores were presented for each day of treatment through Day 7 or until data were no longer provided due to nasal symptom resolution, whichever came first.

[0049] The times to resolution of QoL factors were evaluated using Kaplan-Meier curves. Analyses were summarized using the mITT population.

[0050] Correlations and significance between the WURSS-21 ‘plugged nose’ symptom, the WURSS- 21 individual QoL domains (WURSS-21 questions 12 to 20), and the eight additional QoL factors were calculated using the Pearson Correlation Coefficient. The changes from baseline for the mean of each QoL category score were analyzed each day using a Student’ s paired t- test, and p-values were assessed to a significance level of a = 0.05.

[0051] Results

[0052] Study participants

[0053] A total of 172 adults were screened, of which 136 were enrolled in the study. Of the enrolled population, 102 participants were included in the mITT population as they used the study product at least once and completed at least one post-baseline QoL questionnaire. Two participants from the mITT population discontinued the study due to ‘early termination’ for non-compliance reasons after using the study product. Data up to the time of discontinuation were included in the mITT analysis. The number of participants decreased from Day 1 through Day 7 in the mITT population, with 39 participants remaining on day 6, and 30 participants remaining on day 7. A total of 100 participants completed the study, for which the scores of the last dose used were calculated.

[0054] WURSS-21 total score

[0055] Fig. 1 shows the total WURSS-21 score over time of treatment. Higher scores indicate more negative impact of symptoms and quality of life. The total score is a sum of questions 2 through 20 from the questionnaire in Table 2. The values in the chart are raw means ± standard error (SE). End of treatment includes all subjetcs’ last day of treatment regardless of the study day. WURSS-21 total score ranges from 0-133, in which higher scores indicate higher severity. At baseline, the mean (±standard error [SE]) of the WURSS-21 total score of the mITT population (n = 102) was 75.8 (±2.00), which represents mild (score = 57) to moderate (score = 95) severity level. Statistically significant decreases in the WURSS-21 total score were observed consistently from Day 2 to Day 7 of treatment with the study product (p < 0.0001 for all). At the last dose administered for all participants that completed the study (n = 100), a statistically significant difference in WURSS-21 total score indicated a significant improvement in symptoms and QoL factors (-51.09 [95%CI: -56.82, -45.36; p < 0.0001]) compared with baseline, with a 67.6% improvement from baseline to the last dose.

[0056] WURSS-21 total symptom domain score

[0057] Fig. 2 shows the WURSS-21 total symptom domain score over time of treatment.

[0058] WURSS-21 total symptom domain score ranges from 0-70, in which higher scores indicate higher severity. At baseline, the mean (±SE) of the WURSS-21 symptom domain score of the mITT population observed was 38.3 (±1.12), which represents a mild (score = 30) to moderate (score = 50) severity level (Figure 3). Statistically significant decreases in the WURSS-21 total symptom domain were observed consistently from Day 2 to Day 7 (p < 0.0001).

[0059] At the time of the last dose administered, the difference in WURSS-21 total symptom domain score was -24.7 (95% CI: -27.73, -21.67; p < 0.0001) compared with baseline, which represents a drop to a severity level between very mild and mild. A 64.8% improvement from baseline in WURSS-21 total symptom domain score was observed at the last dose of treatment needed for all participants completing the study (n = 100). WURSS-21 total QoL domain score

[0060] The WURSS-21 total QoL domain score ranges from 0-63, in which higher scores indicate higher severity. At baseline, the mean (±SE) of the WURSS-21 total QoL domain score of the mITT population observed was 37.5 (±1.15), which represents a mild (score = 27) to moderate (score = 45) severity level (Fig. 4). Statistically significant decreases in the WURSS-21 total QoL domain score were observed consistently from Day 1 (p = 0.0481) to Day 7 (p < 0.0001). By the last dose administered, the difference in WURSS-21 QoL domain score was -26.39 (95% CI: -29.75, -23.03; p < 0.0001) compared with baseline, representing a 70.4% improvement from baseline in WURSS-21 total QoL domain score at the last dose of the treatment needed for all participants who completed the study (n = 100).

[0061] Individual WURSS-21 symptom domain scores

[0062] The individual WURSS-21 symptom domain score ranges from 0-7 (Table 2), in which higher scores indicate higher severity. Of the 10 individual symptoms assessed using the WURSS-21 questionnaire, ‘plugged nose’, ‘runny nose’, ‘head congestion’, and ‘feeling tired’ scored a mean baseline score of at least 4, representing a mild (score=3) to moderate (score=5) severity level. These individual symptoms generally showed the greatest percentage improvement by the last day of dose administered. A statistically significant improvement in ‘plugged nose’ (p = 0.0023) was observed from Day 1 post-treatment. The mean ±SE score for ‘plugged nose’ at baseline was 5.5 (±0.09), which represents a moderate to severe level for this symptom. By the last dose of xylometazoline hydrochloride 0.1% was used, the ‘plugged nose’ symptom improved by 68.1% and dropped to a mean (±SE) score of 1.8 (±0.16), which represents a very mild-to-absent severity level. All 10 symptom scores improved by at least 50% from baseline at the last dose. Xylometazoline is well know for its decongestant effect, and improvement in ‘plugged nose’ was therefore expected. However, the inventors believe that the improvement in sleep quality which they have shown contributes also to the improvement of all symptoms, including the plugged nose, and that this improvement is not only due to the decongestant effect alone. The sleep improvement leads to a virtuous cycle where patients who sleep better will recover faster from a cold. Safety

[0063] There were no severe treatment-emergent adverse events, and no participants withdrew from the study due to adverse events. Participants who reported using the product more than three times a day did not report any safety issues.

[0064] QoL categories

[0065] The over-time effects of xylometazoline hydrochloride 0.1% on five QoL categories were evaluated. Each category grouped similar QoL factors from the WURSS-21 questionnaire and the additional QoL factors. Other QoL factors that were not included in a category were analyzed individually.

[0066] Sleep quality

[0067] The sleep quality category was defined by grouping the ‘sleep well’ factor from the WURSS- 21 questionnaire (Q13) and the ‘snoring’ factor from the additional QoL questions (QI). The severity scale for sleep quality was calculated by adding the two individual QoL scores included; the resulting range was 0-14, where 14 represented the highest severity. Because the ‘snoring’ factor could only be measured in participants who lived with a partner, the analyses for sleep quality category were assessed on an initial n of 80 participants, and not on the full mITT population (n = 102).

[0068] At baseline, the mean (±SE) score for ‘sleep quality’ was 9.7 (±0.30), which was considered a moderate severity level (score = 10). However, a significant improvement was seen on Day 1 of treatment (p = 0.0001), with a mean score of 7.3 (±0.37), which was closer to mild severity level (score =6). At the last dose administered sleep quality improved by 72.5% (Table 3)

[0069] ‘Sleep well’ and ‘snoring’ were found to be moderately affected at baseline with a mean score (±SE) of 4.9 (±0.16) and 4.7 (±0.19), respectively. Statistically significant improvements in the ‘sleep well’ factor (p = 0.0039) and ‘snoring’ factor (p < 0.0001) (Table 3) were observed by

[0070] Day 1 following the use of the test composition. Continued improvements were seen throughout the study for both factor scores (p < 0.0001). By the last dose of treatment, improvements of 66.3% and 80.0% were observed for the ‘sleep well’ and ‘snoring’ scores, respectively (Table 3). Table 3: Overview of changes observed in the sleep quality category

[0071] CI, confidence interval; n, number of patients in this category; Q, question; QoL, quality of life; SE, standard error; WURSS-21, Wisconsin Upper Respiratory Symptom Survey-21.aLast dose includes all patients’ last day of treatment regardless of study day.bNumber of participants who lived with partners and could score the snoring factor.

[0072] Vitality

[0073] QoL factors grouped in the vitality category correspond to ‘alertness’ (slow in responses, Q2), ‘energy’ (Q7), ‘motivation’ (Q8) factors of the additional QoL questionnaire and the ‘feeling tired’ symptom factor (QI 1) from the WURSS-21 questionnaire. The score range of the vitality category was calculated by adding the maximum score for each factor resulting in a range of 0-28; where higher scores indicate higher severity.

[0074] The vitality category mean score (±SE) at baseline was 19.1 (±0.50) and considered as moderate severity level (score = 20). The individual factors had mean scores within the range of 3.8-5.2, indicating a moderate severity level (score = 5) for each score at baseline (Table 4). The overall vitality category and its corresponding QoL factors showed a statistically significant improvement from Day 1 (p < 0.0001). ‘Feeling tired’, which is one of the WURSS-21 symptom factor, significantly improved by Day 2 (p = 0.0364). At the time of the observed significance, the scores had dropped from moderate severity to a mild severity level. By the last dose used for all participants, ‘motivation’ improved by 83.2%, ‘energy’ by 83.1%, ‘alertness’ by 85.9% and ‘feeling tired’ improved by 53.6%. By the last dose of treatment, the vitality category score improved by 76.1% (Table 4).

[0075] Table 4. Overview of changes observed in the vitality category.

[0076]

[0077] CI, confidence interval; n, number of patients in this category; Q, question; QoL, quality of life; SE, standard error.aLast dose includes all patients’ last day of treatment regardless of study day.bNumber of participants who answered the additional QoL questionnaire.cPost hoc analysis: QoL categories.dSecondary endpoint: additional QoL factors (Q2 [slow in response] and Q7-8).enumber of participants who answered the WURSS-21 questionnaire.fPost hoc analysis: WURSS-21 individual symptom factor (QI 1).

[0078] A positive correlation was found between the plugged nose symptom and all QoL factors; but for the QoL factors taken into account for sleep quality and vitality, the correlation was lower than for questions such as “breathe easily”, which suggests that the positive impact of the test composition on these QoL factors is not only due to the decongestant effect.

[0079] Temporary or chronic impairment of sleep quality results in fatigue, irritability, slowed responses and general daytime dysfunction. In this study, participants who experienced nasal congestion due to the common cold reported improvements in sleep quality from Day 1 after xylometazoline hydrochloride 0.1% usage, with similar findings for the associated QoL factors ‘sleep well’ and ‘snoring’.

[0080] Sleep has also been shown to impact QoL factors related to vitality, such as ‘energy’, ‘motivation’, and ‘alertness’ (being slow in response). In this study, all QoL factors for vitality had improved from Day 1, corroborating findings from the sleep quality category.

Claims

CLAIMS1. Pharmaceutical composition comprising xlyometazoline for use in a method for the treatment or the prevention of insomnia or other sleep disorders in a patient suffering from nasal congestion and / or an upper respiratory tract infection.

2. Pharmaceutical composition comprising xlyometazoline for use in a method for the treatment or the prevention of fatigue or exhaustion in a patient suffering from nasal congestion and / or an upper respiratory tract infection.

3. Pharmaceutical composition for use according to claim 1 or 2, wherein the composition is administered intranasally.

4. Pharmaceutical composition for use according to claim 3, wherein the pharmaceutical composition is administered up to three times daily into each nostril of a patient, preferably with one administration before going to bed.

5. Pharmaceutical composition for use according to any of the preceding claims, wherein the patient is suffering from an upper respiratory tract infection, namely from common cold.

6. Pharmaceutical composition for use according to any of the preceding claims, wherein the pharmaceutical composition is an aqueous solution.

7. Pharmaceutical composition for use according to any of the preceding claims, wherein the composition comprises 0.1% (w / w) xylometazoline hydrochloride.

8. Pharmaceutical composition according to claims 6 or 7, wherein the pharmaceutical composition comprises a sodium chloride solution.

9. Pharmaceutical composition for use according to any of the preceding claims, wherein the pharmaceutical composition is administered in a dose of 0.14 mg of xylometazoline hydrochloride into each nostril of a patient per administration.

10. Pharmaceutical composition for use according to any of the preceding claims, wherein the composition further comprises menthol and / or cineol.

11. A method for treatment or prevention of insomnia or other sleep disorders in a patient, comprising intranasally administering to a patient a pharmaceutical composition comprising xylometazoline.

12. A method for treatment or prevention of fatigue or exhaustion in a patient, comprising intranasally administering to a patient a pharmaceutical composition comprising xylometazoline.

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