COMPOSITIONS FOR THE TREATMENT OF A RESPIRATORY CONDITION

Abstract

The present disclosure relates to the administration of a composition comprising an interferon, azithromycin and chloroquine for the treatment of respiratory conditions.

Claims

1. A method for preventing or treating a respiratory condition, comprising: administering to a patient a composition comprising an interferon, azithromycin and chloroquine.

2. The method of claim 1, wherein the respiratory condition is a severe acute respiratory condition selected from the group consisting of of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).

3. The method of claim 1, wherein the respiratory condition is a mild respiratory condition selected from the group consisting of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).

4. The method of claim 1, wherein the composition is at least one of a dry powder formulation, a pressurised metered dose inhaler formulation and a nebulised formulation.

5. The method of claim 1, wherein the composition is administered by at least one of pulmonary administration, nasal administration and oropharyngeal administration.

6. The method of claim 1, wherein the interferon, azithromycin and chloroquine are administered to the patient simultaneously or sequentially.

7. The method of claim 4, wherein the composition has a bimodal particle size distribution as determined by laser diffraction.

8. The method of claim 4, wherein the composition has a trimodal particle size distribution as determined by laser diffraction.

9. The method of claim 7, wherein a lowest local maxima of the composition has a particle size of from 0.5 μm to 10 μm and a highest local maxima of the composition has a particle size from 30 μm to 120 μm, as determined by laser diffraction.

10. The method of claim 8, wherein an intermediate local maxima of the composition has a particle size between 10 μm and 30 μm, as determined by laser diffraction.

11. The method of claim 1, wherein the chloroquine is at least one of chloroquine phosphate or hydroxychloroquine or an acceptable salt thereof.

12. The method of claim 1, wherein the interferon is at least one of interferon-α and interferon β.

13. The method of claim 1, wherein the interferon is present in an amount of from 50 μg to 500 μg.

14. The method of claim 1, wherein the azithromycin is present in an amount of from 100 mg to 1000 mg.

15. The method of claim 16, wherein either the chloroquine phosphate or hydroxychloroquine sulfate is present in an amount of from 10 mg to 1000 mg.

16. The method of claim 1, wherein the hydroxychloroquine is hydroxychloroquine sulfate.

17. The method of claim 1, wherein the interferon is interferon-β 1a.

18. The method of claim 1, wherein the interferon is interferon-β 1b.

Description

FIGURES

[0103] FIG. 1 is a summary showing the percentage of patients with PCR-positive nasopharyngeal samples from inclusion to day 10 post-inclusion in COVID-19 patients treated with either inhaled chloroquine only (Group 2), inhaled interferon-β 1a (Group 3), inhaled hydroxychloroquine and azithromycin (Group 4) or inhaled interferon-β 1a, hydroxychloroquine and azithromycin (Group 5), compared with COVID-19 control patients (Group 1).

CLINICAL AND IN VITRO EVIDENCE PUBLISHED AFTER THE PRIORITY DATE OF THE APPLICATION

[0104] A study by Catteau et al. published on 24 Aug. 2020 in the International Journal of Antimicrobial Agents reported on a nationwide observational study of 8,075 participants and found there to be an effect of low-dose hydroxychloroquine therapy on mortality in hospitalised patients with COVID-19. Rather than use the extremely high doses of the RECOVERY TRIAL and SOLIDARITY TRIAL, this Belgium study administered 400 mg hydroxychloroquine sulphate in monotherapy and supportive care (hydroxychloroquine sulphate group) statim followed by 400 mg on Day 1, followed by 200 mg twice a day from Days 2 to 5, i.e. a total dose of 2400 mg. These patients were compared with a control group treated with supportive care only (no-hydroxychloroquine sulphate group). Of the 8,075 patients, 4,542 received hydroxychloroquine sulphate in monotherapy and 3,533 were in the no-hydroxychloroquine sulphate group. Hospital mortality was reported in 804/4,542 patients (17.7%) (hydroxychloroquine sulphate group) compared with 957/3,533 patients (27.1%) (no-hydroxychloroquine sulphate group). Using multivariate analysis, the authors report that mortality was lower in the hydroxychloroquine sulphate group compared with the no-hydroxychloroquine sulphate group [adjusted hazard ratio (aHR)=0.684, 95% confidence interval (CI) 0.617-0.758]. In other words, 1000 patients would survive in the hydroxychloroquine sulphate group, compared to only 684 surviving in the no-hydroxychloroquine sulphate group. Catteau et al. concluded that compared with supportive care only, low-dose hydroxychloroquine sulphate monotherapy was independently associated with lower mortality in hospitalised patients with COVID-19 diagnosed and treated early or later after symptom onset.

[0105] On 25 Apr. 2020, in the journal Microbial Pathogenesis, Andreani et al. reported that following in vitro testing of combined hydroxychloroquine and azithromycin on SARSCoV-2 showed a synergistic effect. In particular, the authors demonstrated that the combination of hydroxychloroquine and azithromycin has a synergistic effect in vitro on SARS-CoV-2 at concentrations compatible with that obtained in the human lung.

[0106] Finally, on 12 Nov. 2020, in the journal The Lancet Respiratory Medicine, Monk et al. reported the safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection during a phase 2 randomised, double-blind, placebo-controlled trial. The authors concluded that patients who received interferon-β 1a had greater odds of improvement and recovered more rapidly from SARS-CoV-2 infection than patients who received placebo only. Worth noting is that three patients died during the study; all deaths occurred in patients in the placebo group.

Example

[0107] Fifty patients, aged between 10-90 yrs, presenting with positive PCR documented SARS-CoV-2 carriage are included in this study and randomly assigned to the following groups.

[0108] Group 1: Ten patients are untreated patients.

[0109] Group 2: Ten patients are treated with inhaled chloroquine.

[0110] Group 3: Ten patients are treated with inhaled interferon-β 1a.

[0111] Group 4: Ten patients are treated with inhaled hydroxychloroquine and azithromycin.

[0112] Group 5: Ten patients are treated with inhaled interferon-β 1a, hydroxychloroquine and azithromycin.

[0113] Group 1: Untreated Patients

[0114] Viral clearance is determined each day by real-time reverse transcription-PCR of SARS-CoV-2 RNA from nasopharyngeal samples and the results reported in FIG. 1.

[0115] Group 2 Formulation: Inhaled Chloroquine Only

[0116] Unmicronised chloroquine (15 g, D.sub.10>20 μm, D.sub.50>100 μm, D.sub.90>200 μm is determined by Malvern Mastersizer 3000 wet analysis method) and is pre-stirred in a glass beaker using a metal spatula for 30 seconds before micronization in an AS-50 spiral jet mill (Inlet pressure=5 Bar, Grinding Pressure=3 Bar, Averaged Feed Rate=2

[0117] Micronised chloroquine is combined with lactose carrier to create a uniform blend. A portion of the blend is then filled into a capsule. The capsule is fitted into an inhaler and a dose of chloroquine is administered to the patient by an inhalation manoeuvre. The dosing is repeated as required.

[0118] Viral clearance is determined each day by real-time reverse transcription-PCR of SARS-CoV-2 RNA from nasopharyngeal samples and the results reported in FIG. 1.

[0119] Group 3 Formulation: Inhaled Interferon-β 1a Only

[0120] Unmicronised interferon-β 1a (15 g, D.sub.10>20 μm, D.sub.50>100 μm, D.sub.90>200 μm is determined by Malvern Mastersizer 3000 wet analysis method) and is pre-stirred in a glass beaker using a metal spatula for 30 seconds before micronization in an AS-50 spiral jet mill (Inlet pressure=5 Bar, Grinding Pressure=3 Bar, Averaged Feed Rate=2

[0121] Micronised interferon-β 1a is combined with lactose carrier to create a uniform blend. A portion of the blend is then filled into a capsule. The capsule is fitted into an inhaler and a dose of interferon-β 1a is administered to the patient by an inhalation manoeuvre. The dosing is repeated as required.

[0122] Viral clearance is determined each day by real-time reverse transcription-PCR of SARS-CoV-2 RNA from nasopharyngeal samples and the results reported in FIG. 1.

[0123] Group 4 Formulation: Inhaled Hydroxychloroquine and Azithromycin

[0124] Unmicronised hydroxychloroquine (15 g, D.sub.10>20 μm, D.sub.50>100 μm, D.sub.90>200 μm is determined by Malvern Mastersizer 3000 wet analysis method) and is pre-stirred in a glass beaker using a metal spatula for 30 seconds before micronization in an AS-50 spiral jet mill (Inlet pressure=5 Bar, Grinding Pressure=3 Bar, Averaged Feed Rate=2 g/min).

[0125] Micronised Hydroxychloroquine is Combined with Lactose Carrier.

[0126] Unmicronised azithromycin (15 g, D.sub.10>20 μm, D.sub.50>100 μm, D.sub.90>200 μm is determined by Malvern Mastersizer 3000 wet analysis method) and is pre-stirred in a glass beaker using a metal spatula for 30 seconds before micronization in an AS-50 spiral jet mill (Inlet pressure=5 Bar, Grinding Pressure=3 Bar, Averaged Feed Rate=2

[0127] Micronised azithromycin is combined with lactose carrier.

[0128] The two blends are combined to create a uniform blend. A portion of the combined blend is then filled into a capsule. The capsule is fitted into an inhaler and a dose of hydroxychloroquine and azithromycin is administered to the patient by an inhalation manoeuvre. The dosing is repeated as required.

[0129] Viral clearance is determined each day by real-time reverse transcription-PCR of SARS-CoV-2 RNA from nasopharyngeal samples and the results reported in FIG. 1.

[0130] Group 5 Formulation: Inhaled Hydroxychloroquine, Azithromycin and Interferon-β 1a

[0131] Unmicronised hydroxychloroquine sulfate (15 g, D.sub.10>20 μm, D.sub.50>100 μm, D.sub.90>200 μm determined by Malvern Mastersizer 3000 wet analysis method) is pre-stirred in a glass beaker using a metal spatula for 30 seconds before micronization in an AS-50 spiral jet mill (Inlet pressure=5 Bar, Grinding Pressure=3 Bar, Averaged Feed Rate=2 g/min).

[0132] Micronised Hydroxychloroquine Sulfate is Combined with Lactose Carrier.

[0133] Unmicronised azithromycin (15 g, D.sub.10>20 μm, D.sub.50>100 μm, D.sub.90>200 μm determined by Malvern Mastersizer 3000 wet analysis method) is pre-stirred in a glass beaker using a metal spatula for 30 seconds before micronization in an AS-50 spiral jet mill (Inlet pressure=5 Bar, Grinding Pressure=3 Bar, Averaged Feed Rate=2 g/min).

[0134] Micronised Azithromycin is Combined with Lactose Carrier.

[0135] The two blends are combined to create a uniform blend. A portion of the combined blend is then filled into a capsule to create a nominal dose. The capsule is fitted into an inhaler and a dose of hydroxychloroquine sulfate (200 mg per nominal dose) and azithromycin (500 mg per nominal dose) is administered to the patient by an inhalation manoeuvre. The dosing is repeated as required.

[0136] The interferon-β 1a (250 μg per nominal dose) is in solution to be administered sequentially by nebuliser. The dosing is repeated as required.

[0137] Alternatively, the interferon-β 1a (250 μg per nominal dose) is administered simultaneously as a dry powder with the hydroxychloroquine sulfate and azithromycin. The dosing is repeated as required.

[0138] The formulations are assessed by laser diffraction prior to blending with carrier and the APIs are found to exhibit a trimodal distribution having a lowest local maxima with a particle size of from 0.5 μm to 10 μm, an intermediate local maxima having a particle size between 10 μm and 30 μm and a highest local maxima with a particle size from 30 μm to 120 μm. The three distributions being eminently suitable for simultaneously targeting the pulmonary, nasal and oropharyngeal epithelium.

[0139] Viral clearance is determined each day by real-time reverse transcription-PCR of SARS-CoV-2 RNA from nasopharyngeal samples and the results reported in FIG. 1.

[0140] FIG. 1 demonstrates that inhaled hydroxychloroquine, azithromycin and interferon-β 1a (Group 5) yields the quickest reduction in viral loading compared with other formulations (Group 1-4).