Combination preparation for the treatment of acute and chronic rhinosinusitis and / or allergic rhinitis

Abstract

The present application provides a novel combination preparation for use in the treatment of acute, chronic and allergic rhinosinusitis and / or allergic rhinitis which does not cause dry nasal mucosa and is very effective in the treatment of the above diseases. The combination preparation comprises an active ingredient selected from mometasone and / or fluticasone or a pharmaceutically acceptable salt or solvate of any one of the foregoing, in combination with dexpanthenol or a pharmaceutically acceptable salt or solvate thereof, as well as a pharmaceutically acceptable excipient in the form of a nasal spray.

Description

COMBINATION PREPARATION FOR THE TREATMENT OF ACUTE AND CHRONIC RHINOSINUSITIS AND / OR ALLERGIC RHINITISFIELD OF INVENTION

[0001] The resent invention relates to a combination preparation for the treatment of acute and chronic rhinosinusitis and / or allergic rhinitis.BACKGROUND OF INVENTION

[0002] Chronic rhinosinusitis, including nasal polyps, is an inflammatory disease of the nose and sinuses. As disclosed in S.H. Cho et al. “Medical Management Strategies in Acute and Chronic Rhinosinusitis" , J. Allergy Clin. Immunol. Pract., 2020, 1159-1564 (doi: 10.1016 / j.jaip.2020.02.020), chronic rhinosinusitis, historically, has been considered to be caused by upper airway anatomical abnormalities. However, today that concept has changed, for it is now recognized as an inflammatory disorder of the nasal and sinus mucosa. Acute rhinosinusitis is usually caused by a viral infection, whereas chronic rhinosinusitis is a persistent and heterogeneous inflammatory disorder.

[0003] Common treatments of acute, chronic and also allergic rhinosinusitis include treatment with topical intranasal or oral corticosteroids. Long-term treatment with corticosteroid nasal spray reduces inflammation and nasal polyp size, and improves nasal symptoms such as nasal blockage, rhinorrea, and the loss of smell. Corticosteroid intranasal drops may be used when intranasal spray fails to demonstrate efficacy. Short courses of oral steroids are recommended in severe chronic rhinosinusitis with nasal polyps or when a rapid symptomatic improvement is needed. The mechanism of action of nasal corticosteroids involves the drug molecule binding the cytoplasmic CS receptor (CSR) which, after being transported into the nucleus, binds the GRE sequence which can be found in numerous gene promoters, thus affecting the expression of respective genes.

[0004] The corticosteroid budesonid, as an aqueous nasal spray, has been shown to have a positive impact for those with chronic rhinosinusitis and perennial allergic rhinitis. However, budesonid and other topical corticosteroids, that were initially launched on the market, led to the absorption of considerable amounts of the active ingredient in the bloodstream. This was likely the cause for a number of systemic sideeffects. The corticosteroids mometasone and fluticasone have also been suggested for the treatment of acute and chronic rhinosinusitis and show the effect of absorption into the bloodstream to a considerably lesser degree; less than 2% of the applied active ingredient is absorbed in the bloodstream. Thus, they have been preferably applied as a nasal spray for the treatment of acute and chronic rhinosinusitis.

[0005] Fluticasone is a manufactured glucocorticoid used to treat nasal symptoms. Both the esters, fluticasone propionate and fluticasone furoate, are also used as topical anti-inflammatories and inhaled corticosteroids.

[0006] Fluticasone propionate, sold under the brand names Flovent and Flonase among others, is described in GB 2 088 877. It is a corticosteroid known to exhibit topical anti-inflammatory activity. Fluticasone propionate is used by powder or aerosol inhalation for the prophylaxis of asthma. The nasal spray is used for prevention and treatment of allergic rhinitis. The use of Fluticasone furoate is

[0007] Fluticasone furoate, sold under the brand name Flonase Sensimist among others, is a corticosteroid for the treatment of non-allergic and allergic rhinitis administered by a nasal spray. It has been found to be effective to administer fluticasone propionate in the form of aerosols containing small particles of the medicament, conventionally prepared by micronization.

[0008] Conventionally, fluticasone propionate and fluticasone furoate aerosols have been administered by means of metered dose inhalers, which are designed to deliver a fixed unit dosage of medicament per actuation.

[0009] Generally, administration forms of fluticasone are designed so that each actuation of fluticasone delivers 50 pg of fluticasone propionate or fluticasone furoate in 100 mg of formulation through a nasal adapter. The recommended starting dosage of fluticasone propionate or fluticasone furoate in adults is 2 sprays (50 pg of fluticasone propionate each) in each nostril once daily (total daily dose, 200 pg).

[0010] Mometasone furoate is administered likewise in doses of 50 pg of mometasone furoate in 100 mg of formulation through a nasal adapter. Mometasone furoate is described in EP 0 057 401 , WO 2007 / 072704 A2, C.B. Small, “Efficacy and safety of mometasone furoate nasal spray in allergic rhinitis, acute rhinosinusitis and nasal polyposis”, Therapy, Vol. 6, No. 3, (2009), pages 393-406.

[0011] Generally, it takes days and weeks of topical corticosteroids to build up their strength, thus normally requiring the drug to be administered for a longer period of time. Topical corticosteroids therefore include preservatives. The anti-secretory effect, as well as the preservatives added often cause dry nasal mucosa to a greater or lesser extent. Acute or chronic inflammations cannot heal due to the dry mucousmembranes which delays healing and fastens new infections. The phenomenon of dry mucous membranes also occurs when using nasal sprays with vasoconstrictor compounds to reduce swelling.

[0012] It is therefore an object of the present invention to provide a combination preparation for the treatment of acute and chronic rhinosinusitis containing mometasone and / or fluticasone useful for topical administration which does not cause dry nasal mucosa.SUMMARY OF THE INVENTION

[0013] The object is solved with a combination preparation as claimed in claim 1 . Preferred embodiments are described in the appending claims.

[0014] In an embodiment, the present invention provides a combination preparation in the form of a nasal spray for the treatment of acute, chronic and allergic rhinosinusitis and / or allergic rhinitis, the nasal spray comprising(a) mometasone and / or fluticasone or a pharmaceutically acceptable salt or solvate of any one of the foregoing in a concentration ranging from about 0.02% (w / v) to about 0.10% (w / v), and(b) dexpanthenol or a pharmaceutically acceptable salt or solvate thereof as active pharmaceutical ingredients in a concentration of from about 1.00% (w / v) and about 10.00% (w / v),(c) as well as a pharmaceutically acceptable excipient.

[0015] It has shown that the combination preparation as described is effective in reducing the incidence of dry nasal mucosa and side effects associated therewith even after topical treatment thereof over an extended period of time. Furthermore, it has surprisingly shown that a faster onset of the pharmaceutical effect is achieved with the combination preparation according to the present invention than with mometasone and / or fluticasone alone. Finally, it has been shown that, surprisingly, the combination preparation in one single nasal spray as described showed a significant improvement in efficacy and a significantly lower side effect rate with regard to dry nasal mucous membranes compared to the application of the active ingredients in two separate sprays.

[0016] Fluticasone and / or mometasone are preferably be administered in the usual form, administering 20 pg to 100 pg, preferably about 40 pg to about 60 pg, mostpreferably about 50 pg of fluticasone propionate or fluticasone furoate or mometasone furoate per stroke. The concentration of fluticasone propionate or fluticasone furoate or mometasone furoate in the combination preparation according to the present invention is between about 0.02% (20 pg / 100mL) and about 0.10% (100 pg / 100 mL), preferably about 0.04% (40 pg / 100 mL) and about 0.06% (60 pg / 100 mL), most preferably about 0.05% (50 pg / 100 mL).

[0017] Dexpanthenol is the alcoholic analogue of pantothenic acid, and it is oxidized to this substance within the tissues.

[0018] The concentration of dexpanthenol in the combination preparation of the present invention is between about 1.00% (1 mg / mL) and about 10.00% (10 mg / mL), preferably between about 2.00% (2 mg / mL) and about 5.00 (5 mg / mL), most preferably about 3.50% (3.50 mg / mL).

[0019] It has shown that the combination preparation is particularly effective when mometasone and / or fluticasone or a pharmaceutically acceptable salt or solvate of any one of the foregoing in concentrations ranging from 20 pg / 100 mL to 100 pg / 100 mL is combined with 2.00% (2 mg / mL) to 10.00% (10 mg / mL) dexapanthenol.

[0020] Topical corticosteroids and in particular mometasone and fluticasone are hydrophobic, whereas dexpanthenol is hydrophilic. Therefore, the active agents cannot be combined directly in one solution. In an embodiment, the present invention therefore provides the combination preparation in form of a suspension, preferably in the form of an aqueous suspension, where dexapanthenol or a pharmaceutically acceptable salt thereof is present in the aqueous phase and mometasone and / or fluticasone or a pharmaceutically acceptable salt on any one of the foregoing being suspended therein.

[0021] Preferably fluticasone is administered in the form of fluticasone proprionate.

[0022] In an embodiment, the present application also relates to a suspension formulation suitable for nasal administration comprising (a) mometasone and / or fluticasone or a pharmaceutically acceptable salt or solvate of any one of the foregoing, and (b) dexpanthenol or a pharmaceutically acceptable salt or solvate thereof as active pharmaceutical ingredients.

[0023] In some cases, however, it is preferable that one or more of the ingredients of the combination preparation according to the present invention are present in microencapsulated form. In this form the hydrophilic and hydrophobic properties of the active ingredients addressed above can be combined in one medication.

[0024] In another embodiment, the present invention provides a method for treating acute, chronic and allergic rhinosinusitis in the form of a nasal spray with a combination preparation as described, wherein the combination preparation is administered one stroke for each nose hole, twice a day.EXAMPLE

[0025] 60 patients over 18 years of age who were to be treated for chronic rhinosinusitis with a nasal spray comprising 0.05% of the corticoid mometasone furoate (MF) for 10 weeks were randomly assigned to one of three groups. The first group was prescribed one stroke for each nose hole, twice a day without any other additives for application to both sides of the nose. The second group was prescribed to use MF in the same way as the first group and also apply another nasal spray with 3.50% dexpanthenol (DS) twice a day. In the third group, MF with DS in a single spray was prescribed twice daily for 10 weeks. The three groups were compared in terms of compliance, side effects and efficacy. The dosage in the dexpanthenol (DS) spray was 3.50%. The dosage in the mometasone furoate (MF) spray was 0.05%, corresponding to 50 pg mometasone for each stroke. In the combination preparation, the dosage was the same as in the individual sprays, i.e. 3.50% dexpanthenol and 0.05% mometasone furoate.

[0026] Of the 20 patients scheduled for group one, 16 presented for follow-up as agreed, the other 4 were not included in the study. Of the 16 patients, 11 reported having completed the therapy as prescribed. Compliance was therefore 69%. Seven of these 16 patients stated that the nasal mucosa had become dry during treatment (44%); three of these patients reported nose bleeding. No other side effects were reported.

[0027] An improvement in symptoms was reported by 10 of the patients in group one, i.e. 63%. No deterioration was reported by any of the patients, nor was any such deterioration found in the examination of the patients by the physician.

[0028] Of the 20 patients scheduled for group two, 15 presented for follow-up and were included in the study. All 15 patients stated that they had used MF as prescribed, but 8 of them reported that they had only used the dexpanthenol spray irregularly or not at all (compliance 47%). Of these 8 patients, 5 reported dry nose during treatment (33% of group two), 2 of these 5 patients also reported bloody secretions or slight nose bleeding. Of the 7 patients who used both MF and DS asprescribed, none reported a dry nose after treatment. No other side effects occurred in group two either.

[0029] An improvement in symptoms was reported by 9 of the 15 patients in group two, i.e. 60%, including 5 of the 7 patients who used the combination of the two nasal sprays as instructed. In 4 of the 8 patients who did not use the dexpanthenol spray or used it only irregularly, there was no improvement in symptoms.

[0030] Of the 20 patients scheduled for group three, in which MF and DS were to be applied in one spray, 12 presented for a follow-up examination and were included in the study. 10 patients had taken the spray for the prescribed period; compliance 83%. Two patients stated that they had stopped the treatment prematurely (after 5 and 7 weeks respectively) because they no longer noticed any symptoms. One patient (8%) reported a dry nose during treatment; however, he stated that this was only slightly pronounced. No other side effects were reported. In 10 of the 12 patients, both anamnestic and clinical findings showed an improvement, i.e. 83%.

[0031] The observations can be summarized as follows:1 . A combination of MF and DS reduced the side effect of dry nasal mucosa and even nosebleeds. This favorable effect was greater in the 3rdgroup, in which MF and DS were combined in one spray, than in the 2ndgroup, which applied MF and DS in 2 separate sprays; the occurrence of dry nasal mucosa under therapy in the 1stgroup was 44%, in the 2ndgroup 33%, and in the 3rdgroup 8%;2. Compliance was higher with the combined administration of MF and DS in one spray than with the administration of MF and DS separately in two sprays; 3rdgroup 83%, 2ndgroup 47%.3. The efficacy was not significantly different when MF and DS were administered in two separate sprays compared to the application of MS alone. In contrast, the effect was surprisingly improved better with the combination of MF and DS in one spray in comparison to separate application of MF and DS in two sprays; improvement in the 1stgroup 63%, in the 2ndgroup 60%, in the 3rdgroup 83%).

[0032] A statistical analysis of these results using the chi-square test allows the following conclusions to be drawn:

[0033] The combined administration of MF and DS in a single spray showed significantly improved compliance (83% vs. 47%; p= 0.0499) and a significantly lower side effect rate with regard to dry nasal mucous membranes (8% vs. 33%; p= 0.0401 ) compared to the application of MF and DS in 2 separate sprays. Even in the relativelysmall patient group, the combination spray tended to be more effective than MF alone (83% vs. 63%; p= 0.2272).

Claims

CLAIMS1 . A combination preparation in the form of a nasal spray for use in the treatment of acute, chronic and allergic rhinosinusitis and / or allergic rhinitis, the nasal spray comprising(a) mometasone and / or fluticasone or a pharmaceutically acceptable salt or solvate of any one of the foregoing in a concentration ranging from about 0.02% (w / v) to about 0.10% (w / v), and(b) dexpanthenol or a pharmaceutically acceptable salt or solvate thereof as active pharmaceutical ingredients in a concentration of from about 1.00% (w / v) and about 10.00% (w / v),(c) as well as a pharmaceutically acceptable excipient.

2. The combination preparation of claim 1 , wherein the concentration of fluticasone propionate or fluticasone furoate or mometasone furoate in the combination preparation between about 0.04% (40 pg / 100 mL) and about 0.06% (60 pg / 100 mL).

3. The combination preparation of claim 1 or of claim 2, wherein the concentration of dexpanthenol in the combination preparation is between about 2.00% (2 mg / mL) and about 5.00 (5 mg / mL).

4. The combination preparation of claim 1 , claim 2 or claim 3 wherein dexapanthenol or a pharmaceutically acceptable salt thereof is present in the aqueous phase and mometasone and / or fluticasone or a pharmaceutically acceptable salt on any one of the foregoing being suspended therein.

5. The combination preparation of any one of claims 1 to 4, wherein one or more of the ingredients of the combination preparation according to the present invention are present in microencapsulated form.

6. A combination preparation for use for use in the treatment of acute, chronic and allergic rhinosinusitis and / or allergic rhinitis according to any one of the foregoing claims, wherein mometasone and / or fluticasone or a pharmaceutically acceptable salt or solvate of any one of the foregoing is administered twice daily.

7. The combination preparation for use for use in the treatment of acute, chronic and allergic rhinosinusitis and / or allergic rhinitis according to clam 6, wherein combination preparation is administered one stroke for each nose hole, twice a day.

8. A method of treating method for treating acute, chronic and allergic rhinosinusitis and / or allergic rhinitis in the form of a nasal spray with a combination preparationaccording to any of claims 1 to 5, wherein the combination preparation is administered one stroke for each nose hole, twice a day.