WO2023203306A1 - Compositions and applications thereof - Google Patents

Compositions and applications thereof Download PDF

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Publication number
WO2023203306A1
WO2023203306A1 PCT/GB2023/000021 GB2023000021W WO2023203306A1 WO 2023203306 A1 WO2023203306 A1 WO 2023203306A1 GB 2023000021 W GB2023000021 W GB 2023000021W WO 2023203306 A1 WO2023203306 A1 WO 2023203306A1
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Prior art keywords
composition
asthma
treatment
hpmc
powder
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PCT/GB2023/000021
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French (fr)
Inventor
Todor POPOV
Peter David Josling
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Nasaleze Patents Limited
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Publication of WO2023203306A1 publication Critical patent/WO2023203306A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/717—Celluloses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • compositions of use in the present invention comprise powdered hydroxypropyl methylcellulose (pHPMC) particles of a defined mean particle size, and a signalling agent.
  • pHPMC powdered hydroxypropyl methylcellulose
  • Asthma is a major non-communicable disease (NCD), affecting both children and adults. It is the most common chronic non-communicable disease which can lead to disability and death.
  • NBD non-communicable disease
  • the air passages in the lungs become narrow due to inflammation and tightening of the muscles around the airways. This causes asthma symptoms: wheezing, shortness of breath, chest tightness and coughing. These symptoms are intermittent and are often worse at night or during exercise.
  • Other common “triggers” can make asthma symptoms worse. Triggers vary from person to person, but can include viral infections (colds), grass and tree pollen, house dust mites, animal dander, smoke, fumes, changes in the weather, and strong scents.
  • Medicaments rendered through bronchodilator and steroid inhalers such as. salbutamol and beclomethasone, respectively, are used to control asthma symptoms and allow asthma sufferers to lead more or less normal, active lives.
  • an estimated 262 million people were affected by asthma in 2019 and asthma caused 461 ,000 deaths (Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258): 1204-22).
  • access to inhalers is a problem in many countries.
  • the nose is the filter of the incoming air and both allergic and infectious (viral) noxae attack the nasal mucosa and evoke inflammation, which then may spread to the lower airways (asthma, pneumonia), inner ears (otitis), or the eyes (conjunctivitis). Inflammation of any kind presents itself among other things with increased temperature of the inflamed tissues.
  • Allergic rhinitis is a global health problem which affects up to 25% of the adult population in industrialised countries and more than 40% of children and is thought to be responsible for economic losses amounting to some $2 to $5 billion per annum in the USA alone 1 .
  • HPMC powdered compositions for treating allergic rhinitis (AR) and other respiratory diseases but includes no data on being used in lower airway disease like asthma.
  • compositions for use in the treatment of asthma in a patient in the form of a dry homogenised powder consisting of, or comprising: i) hydroxypropyl methylcellulose (pHPMC) particles; and ii) at least one chemical agent selected from signalling agents, wherein the HPMC particles have a mean particle size diameter of > 20 pm to ⁇ 500 pm.
  • pHPMC hydroxypropyl methylcellulose
  • compositions of the invention for use in the treatment of asthma are made up of HPMC particles that make up from 89% to 99.5% of the total weight of the said composition and the signalling agent makes up from 0.5% to 10% of the total weight of the said composition.
  • Compositions of the invention for use in the treatment of asthma are shown to reduce or alleviates lower airway inflammation in the lungs, for example as shown by differences in exhaled breath temperature (EBT). Typically, decreases in EBT are indicative of decreased lower airway inflammation in the lungs (Popov TA, et al. The added value of exhaled breath temperature in respiratory medicine. J Breath Res. 2017; 11 (3): 034001 ). Where compositions of use in the invention are applied in conjunction with nasally applied drugs used in the treatment of asthma, the effect of such drugs is enhanced. In addition, compositions of the invention also protect against viral exacerbations of asthma.
  • compositions for use in the treatment of asthma comprise or consist of homogenised dry powder particles having a mean particle size diameter of > 20 pm to ⁇ 500 pm.
  • the mean particle size diameter is in the range >60 to ⁇ 150 pm, preferably in the range >80 to ⁇ 125 pm, and typically is about 86 pm +/- 15 pm.
  • the person skilled in the art will appreciate that the mean particle size diameter will in some degree depend on how much powdered signalling agent is added to the HPMC particles.
  • compositions for use in the treatment of asthma of the present invention include at least a signalling agent is selected from menthol, strawberry, mint, spearmint, peppermint, eucalyptus, lavender, citrus, and any combination thereof.
  • the signalling agent makes up >0.25% to ⁇ 10% of the total weight of the composition, for example, 1 .5% of the total weight of the composition with powdered HPMC making up 98.5% of the total weight of the composition.
  • compositions consisting of or comprised of powdered HPMC particles and a powdered signalling agent as herein described and defined for use in the treatment of asthma are dry homogenised powders having a mean viscosity within the range 26000 mPa.s +/- 2000 mPa.S to 40000 mPa.s. +/-5000mPa.S at 20°C in a 3.6% aqueous solution.
  • the mean viscosity of the dry homogenised powder of the invention lies within the range 29000 +/- 5000 mPa.S to 38000 +/-.5000 mPa.S at 20°C in a 3.6% aqueous solution.
  • the mean viscosity is 32900 mPa.S +/- 5500 mPa.S 37453 +/-1100 mPa.S at 20°C in a 3.6% aqueous solution and the signalling agent is peppermint powder making up 1.5% of the total weight of the composition.
  • the viscosities of compositions of the invention are measured using standard procedures as taught in the European Pharmacopeia Chapter 2.2.10 on Rheology Analysis and may be performed on a TA Discovery Hybrid Rheometer 1 (TA DHR1 ) from TA Instruments Inc., Wilmington, USA), or comparable Rheometer, and the mean viscosity of several samples calculated therefrom.
  • compositions for use in the treatment of asthma as defined herein find use in the prophylaxis of viral exacerbations of asthma. Also included within the present invention is the use of a composition in the treatment of asthma, as defined herein.
  • compositions of the invention are designed for application to the nasal mucosa through insufflation via the nose.
  • compositions of the invention must be able to form gels on contact with moisture in the nasal cavity.
  • the compositions of the invention should not contain additives that may or could substantially interfere with their ability to form gels on contact with moisture, such as additives that can significantly lower the pH of the nasal mucosa.
  • the dry powder particles of the invention absorb moisture and thereby form a gel matrix on the surface thereof.
  • the function of the gel is considered to be at least twofold: firstly, it acts as a physical barrier to the uptake of small particulates such as aerial borne allergens and viruses through the nasal mucosa and secondly, if anti-asthmatic drugs are co-administered or administered sequentially, it permits the diffusion of such drugs of choice across the nasal mucosal cells and into the bloodstream. It is thought that during the hydration of dry powdered compositions of the invention a gel matrix is formed through contact with moisture in which larger particles and smaller particles combine to form a molecular net or molecular matrix wherein the smaller particles occupy spaces or gaps between larger particles and so contribute to gel formation, helping the larger particles to subsume together more easily. Particulate matter becomes trapped in the gel and is largely unable to pass over the mucosal membrane.
  • Compositions according to the invention may contain powder HPMC and a signalling agent in dry powder form selected from menthol, strawberry, mint, spearmint, peppermint, eucalyptus, lavender, and citrus, or any combination thereof.
  • a signalling agent in dry powder form selected from menthol, strawberry, mint, spearmint, peppermint, eucalyptus, lavender, and citrus, or any combination thereof.
  • citrus may include lemon, lime, and cumquat (aka kumquat).
  • the signalling agent is one that is not known to be or implicated as being an irritant to the nasal mucosa, such as those selected from lemon, lime, cumquat (aka kumquat), and strawberry.
  • a signalling agent is one that can provide the patient with a pleasant olfactory feedback upon use
  • a flavouring agent is one that can provide the patient with a pleasant sensory (taste) feedback upon use.
  • the signalling agent may be present at >0.25% w/w to ⁇ 10% w/w, from 0.50% w/w to 5% w/w of the total weight of the composition, for example from >0.25% w/w to ⁇ 2% w/w, preferably from >0.50% w/w to ⁇ 2% w/w of the total weight of the composition, such as 1.5% w/w of the total weight of the composition.
  • Homogenised dry powder compositions of the invention consist of or comprise HPMC particles as herein defined at >89%, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 98.5%, 99%, ⁇ 99.75% or any % w/w therein between of the composition, again depending on design.
  • Compositions of the invention are able to physically contain and/or disrupt the physiology of viruses such as those selected from influenza viruses including type A, H1 N1 , H5N1 and H3N2; coronaviruses, such as MERS-CoV, SARS-CoV, HCoV- 229E, HCov-NL63, HCoV-OC43, CoV-HKLH , and SARS-COV-2; and from bacteria such as Staphylococcus aureus, methicillin resistant Staphylococcus aureus, Haemophilus influenzae, Mycobacterium tuberculosis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterococcus faecium, Candida albicans, Candida tropicalis and Enterobacter species.
  • viruses such as those selected from influenza viruses including type A, H1 N1 , H5N1 and H3N2; coronaviruses
  • the signalling agents may have other beneficial effects on the subject. Without the intention of being bound by theory certain formulations according to the present invention which include mint may have the effect of helping to dilate airways. This may be particularly beneficial when the formulations are used to treat patients suffering from asthma.
  • the administration of HPMC formulations including agents such as mint may also provide a feel-good factor which may be of help in restoring normal breathing patterns.
  • the combination of the HPMC and signalling agent is provided for sequential or simultaneous administration.
  • the HPMC and signalling agent may be included together in a single preparation. Alternatively, the HPMC and signalling agent may be provided in separate preparations, for sequential administration.
  • the preparation is in the form of a powder.
  • the preparation may be in any form suitable for intranasal administration. Suitable physical forms of the HPMC include as a powder, or as a liquid. An especially useful form is as a powder.
  • powder compositions of the invention do not include any other additives or molecular components because such additives may interfere with the ability of inventive compositions to form gels on application to the nasal mucosa.
  • additives deleterious to the formation of gels in the nasal passages include citric acid in combination with sodium citrate and benzalkonium chloride.
  • other additives or components which are often used in intranasal compositions such as other dry powders or solutions can cause irritation or affect ciliary movement, for example, solvents, such as propylene glycol, absorption enhancers, such as cyclodextrins or glycosides, or muco-adhesives such as chitosan.
  • solvents such as propylene glycol
  • absorption enhancers such as cyclodextrins or glycosides
  • muco-adhesives such as chitosan.
  • the use of such additives can be undesirable, as they can cause discomfort and interfere with the normal functioning of the nose, which can adversely affect breathing
  • Powder ingredients may be blended together using a ribbon blender, or similar type of blender for approximately 15 to 20 minutes. The time of mixing is dependent upon the moisture content and compatibility of the powders. Ingredients preferably have a moisture content of less than 5% immediately after blending as checked with the United States Pharmacopeia and National Formulary (USP/NF) loss on drying method.
  • USP/NF United States Pharmacopeia and National Formulary
  • compositions according to the present invention are preferably administered in amounts of between about 1 mg and about 10 mg per nostril.
  • the dose is between about 2.5 mg to about 7.5 mg, between 3 mg and about 7 mg, between about 4 mg and about 6 mg, or about 5 mg.
  • the dry, free-flowing powder HPMC particles per se for use in the invention possess a mean particle size diameter of > 20 pm to ⁇ 500 pm.
  • the mean particle size diameter is in the range >60 to ⁇ 150 pm, preferably in the range >70 to ⁇ 140 pm, such as >110 to ⁇ 140 pm or >115 to ⁇ 135 pm, or >118 to ⁇ 134 pm for example 118pm and typically is about 86 pm +/- 15 pm.
  • the person skilled in the art will appreciate that the mean particle size diameter will in some degree vary with the ambient moisture content and storage conditions.
  • particles of HPMC perse may have a mean particle size of from about 110pm to 140pm, such as 115pm to about 135pm, for example 118pm to 134pm depending on moisture uptake.
  • a composition of this embodiment of the invention preferably consists of powdered HPMC particles wherein the mean particle diameter size of the particles is in the range of >60 to ⁇ 150 pm, preferably from >80 to ⁇ 125 pm. more preferably 86 pm +/- 15 pm; a signalling agent selected from the group: mint, spearmint, peppermint, eucalyptus, lavender, citrus, or any combination thereof.
  • the signalling agent is selected from strawberry, citrus, such as lemon, lime, cumquat (aka kumquat), mint, or any combination thereof.
  • the signalling agent makes up from >0.25% to ⁇ 10% of the total weight of the composition.
  • compositions for use in the treatment of asthma as herein defined wherein the said composition is for use as a nasally administered medicament.
  • compositions for use in the treatment of asthma as herein defined wherein the said composition is for use in the prophylaxis of viral exacerbations of asthma.
  • compositions of the invention shall comprise or consist of HPMC particles that make up >89% to ⁇ 99.5% of the total weight of the said composition and a signalling agent making up from >0.5% to ⁇ 10% of the total weight of the said composition.
  • the viscosity of HPMC powders of use in the invention have a viscosity of 10-20 Pa.S in a 2% aqueous solution at 20°C, or wherein the powder has a viscosity of 13-17 Pa.S, or 14-16 Pa.S, or 15Pa.S in a 2% aqueous solution at 20°C.
  • powder compositions of use in this aspect of the invention may also include one or more ingredients selected from the group consisting of kali bichromicum, a thickening agent, gum, starch, a disintegrant, sodium glycolate, a cross linked povidone, a release agent, magnesium stearate, an emulsifying agent, a surfactant, anticaking agents, granulating agents, preservative, and a colorant, provided that such ingredients, if present, do not interfere deleteriously with the alleviation of symptoms of asthma.
  • ingredients if present, do not interfere deleteriously with the alleviation of symptoms of asthma.
  • all compositional embodiments of the invention detailed herein are for delivery to the nasal mucosa via insufflation through the nose.
  • compositions of the invention as described and defined herein may be administered with or co-administered alongside drugs of choice known for treating asthma.
  • Such drugs of choice may be selected from inhaled corticosteroids, such as Fluticasone (Flovent HFA, Arnuity Ellipta), Budesonide (Pulmicort Flexhaler), Mometasone (Asmanex Twisthaler), Beclomethasone (Qvar RediHaler) and Ciclesonide (Alvesco); oral corticosteroids such as Prednisone and Methylprednisolone; bronchodilators, such as long-acting and short-acting beta agonists (LABAs and SABAs) for example the LABAs formoterol and salmeterol and SABAs such as albuterol, levalbuterol, and theophylline; leukotriene modifiers/inhibitors, such as Montelukast (Singulair), Zafirlukast (Accolate) and Zileuton (Zyflo); long-acting muscarinic antagonists (LAMAs) such as
  • a two-part composition for use in the treatment of asthma comprising or consisting of a first part as defined in any one of claims 1 to 13 and a second part selected from inhaled corticosteroids, oral corticosteroids, bronchodilators, such as LABAs and SABAs, leukotriene inhibitors/modifiers, LAMAs, and biologies such as monoclonal antibodies.
  • the second part of the two-part composition for use in the treatment of asthma as defined herein is selected from Fluticasone (Flovent HFA, Arnuity Ellipta), Budesonide (Pulmicort Flexhaler), Mometasone (Asmanex Twisthaler), Beclomethasone (Qvar RediHaler) and Ciclesonide (Alvesco); oral corticosteroids such as Prednisone and Methylprednisolone; the LABAs formoterol and salmeterol and SABAs such as albuterol, levalbuterol, and theophylline; leukotriene modifiers/inhibitors selected from Montelukast (Singulair), Zafirlukast (Accolate) and Zileuton (Zyflo); long-acting muscarinic antagonists (LAMAs) such as tiotropium (Spiriva Respimat) or any therapeutic combination thereof.
  • LAMAs long-acting mus
  • the invention is compatible and supportive of the application of biologies selected from Benralizumab (Fasenra), Dupilumab (Dupixent), Mepolizumab (Nucala), Omalizumab (Xolair), Reslizumab (Cinqair) and Tezepelumab-ekko (Tezspire).
  • a two-part composition comprising or consisting of a first part as defined in any one of claims 1 to 13 and a second part selected from inhaled corticosteroids, oral corticosteroids, bronchodilators, such as LABAs and SABAs, leukotriene inhibitors/modifiers, LAMAs, and biologies such as monoclonal antibodies or any therapeutic combination thereof.
  • the two-part composition in this aspect of the invention comprises or consists of a first part as defined in any one of claims 1 to 13 and a second part selected from Fluticasone (Flovent HFA, Arnuity Ellipta), Budesonide (Pulmicort Flexhaler), Mometasone (Asmanex Twisthaler), Beclomethasone (Qvar RediHaler) and Ciclesonide (Alvesco); oral corticosteroids such as Prednisone and Methylprednisolone; the LABAs formoterol and salmeterol and SABAs such as albuterol, levalbuterol, and theophylline; leukotriene modifiers/inhibitors selected from Montelukast (Singulair), Zafirlukast (Accolate) and Zileuton (Zyflo); long-acting muscarinic antagonists (LAMAs) such as tiotropium (Spiriva Respimat)
  • the invention is compatible and supportive of the application of biologies selected from Benralizumab (Fasenra), Dupilumab (Dupixent), Mepolizumab (Nucala), Omalizumab (Xolair), Reslizumab (Cinqair) and Tezepelumab-ekko (Tezspire).
  • composition for use in the treatment of asthma as described and defined herein, wherein the composition reduces or alleviates lower airway inflammation in the lungs as shown by differences in exhaled breath temperature.
  • composition for use in the treatment of asthma as described and defined herein, wherein the composition enhances the effect of nasally applied drugs used in the treatment of asthma.
  • pHPMC used continuously in patients with A+ChrRhS as a physical barrier against inhaled noxious agents and for enhancement of the effect of nasally applied drugs by sealing these to the nasal mucosa, offers further protection against viral/SARS-COV-2 exacerbations of asthma.
  • Allergic rhinitis is the most common co-morbidity of asthma and the underlying mechanism in both diseases is airway inflammation. There is a continuous crosstalk and interplay between the upper and lower airways.
  • pHPMC powder hydroxypropylmethyl-cellulose
  • EBT exhaled breath temperature

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Abstract

Compositions for use in the treatment of asthma patients in the form of a dry homogenised powder consisting of or comprising hydroxypropyl methylcellulose (HPMC) particles and signalling agents of a given viscosity, uses therefor, and methods of manufacture.

Description

Compositions and Applications Thereof
The present invention relates to dry powder compositions for use in patients suffering from asthma (‘asthmatics’ hereinafter), uses, and method of manufacture. In particular, compositions of use in the present invention comprise powdered hydroxypropyl methylcellulose (pHPMC) particles of a defined mean particle size, and a signalling agent.
Asthma is a major non-communicable disease (NCD), affecting both children and adults. It is the most common chronic non-communicable disease which can lead to disability and death. The air passages in the lungs become narrow due to inflammation and tightening of the muscles around the airways. This causes asthma symptoms: wheezing, shortness of breath, chest tightness and coughing. These symptoms are intermittent and are often worse at night or during exercise. Other common “triggers” can make asthma symptoms worse. Triggers vary from person to person, but can include viral infections (colds), grass and tree pollen, house dust mites, animal dander, smoke, fumes, changes in the weather, and strong scents.
Medicaments rendered through bronchodilator and steroid inhalers such as. salbutamol and beclomethasone, respectively, are used to control asthma symptoms and allow asthma sufferers to lead more or less normal, active lives. However, an estimated 262 million people were affected by asthma in 2019 and asthma caused 461 ,000 deaths (Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258): 1204-22). However, access to inhalers is a problem in many countries. In 2019, only half of people with asthma had access to a bronchodilator and less than one in five had access to a steroid inhaler in public primary health-care facilities in low-income countries (Assessing national capacity for the prevention and control of noncommunicable diseases: report of the 2019 global survey. Geneva: World Health Organization; 2020. Licence: CO BY-NC-SA 3.0 IGO). It is a concerning fact that most asthma-related deaths still occur in low- and lower-middle income countries, where under-diagnosis and under-treatment is commonplace. Allergic rhinitis/rhinosinusitis are the most widespread chronic non-communicable disease and they are a risk factor for the development of asthma, the most expensive chronic non-communicable disease. The nose is the filter of the incoming air and both allergic and infectious (viral) noxae attack the nasal mucosa and evoke inflammation, which then may spread to the lower airways (asthma, pneumonia), inner ears (otitis), or the eyes (conjunctivitis). Inflammation of any kind presents itself among other things with increased temperature of the inflamed tissues.
Allergic rhinitis (AR) is a global health problem which affects up to 25% of the adult population in industrialised countries and more than 40% of children and is thought to be responsible for economic losses amounting to some $2 to $5 billion per annum in the USA alone1.
The prior art teaches or alludes to the use of HPMC powdered compositions for treating allergic rhinitis (AR) and other respiratory diseases but includes no data on being used in lower airway disease like asthma.
Diethart B. et al Nat. Sci. 2010; Vol. 2 No.2:79-84 teaches the diffusion of a house dust mite allergen through HPMC and agar gels, and thus the potential of using HPMC to block uptake of the allergen. There is no reference to HPMC being used in asthmatic respiratory disease.
A study in Russia by M.K. Erofeeva et al (https://medi.ru/info/7023/) points to HPMC being useful in preventing influenza in children. However, there was no teaching of using dry powder HPMC being used to treat asthmatic respiratory disease.
Defective nasal barrier function is implicated in allergic rhinitis which results in persistent inflammation and clinical symptoms, among which congestion plays a prominent role. In a recent study by Valerieva, A. et al Allergy Asthma Proc 36:1 -6, 2015; doi: 10.2500/aap.2015.36.3879, it was shown that administering HPMC after administration of oxymetazoline provided enhanced relief of nasal symptoms for a sample of patients who were known to be sensitive to at least one of a panel of perennial allergens. However, there was no reference to HPMC being used to treat asthmatic respiratory disease.
An overview by Popov T.A. et al on HPMC powder for the prevention and management of nasal symptoms (Popov T.A. et al Expert Review of Respiratory Medicine, 2017 Vol. 11. No. 11. 885-892 (https://doi.org/10.1080/17476348.2017.1375408) reported that HPMC provided a natural barrier to pollen allergens and noxious agents. The article itself and a number of studies cited therein involved various plant pollens and house dust mite allergens but did not refer to the mean particle size of the powdered formulations employed. There is no reference to HPMC being used to treat asthmatic respiratory disease.
In summary, the prior art does not teach that asthmatics can benefit from taking HPMC-containing powders (pHPMC) of the present invention intranasally in addition to their usual asthma medications as shown herein.
In the experimental section as presented herein, it is proven that subjects with asthma and rhinitis who have been using pHPMC to treat/prevent their nasal symptoms reduce their exhaled breath temperature (EBT), meaning their asthma improves. Furthermore, the experimental section also shows that in some of the patients with asthma and chronic rhinosinusitis which were prescribed regular use of pHPMC, fewer asthma exacerbations due to viral infections (the most common cause of exacerbations in asthma and chronic obstructive lung disease) and fewer COVID-19 infections were documented.
The advantages alluded to above and other advantages of the present invention will become apparent from the following description.
According to the present invention, there is provided a composition for use in the treatment of asthma in a patient, in the form of a dry homogenised powder consisting of, or comprising: i) hydroxypropyl methylcellulose (pHPMC) particles; and ii) at least one chemical agent selected from signalling agents, wherein the HPMC particles have a mean particle size diameter of > 20 pm to < 500 pm.
In a preferment, compositions of the invention for use in the treatment of asthma are made up of HPMC particles that make up from 89% to 99.5% of the total weight of the said composition and the signalling agent makes up from 0.5% to 10% of the total weight of the said composition. Compositions of the invention for use in the treatment of asthma are shown to reduce or alleviates lower airway inflammation in the lungs, for example as shown by differences in exhaled breath temperature (EBT). Typically, decreases in EBT are indicative of decreased lower airway inflammation in the lungs (Popov TA, et al. The added value of exhaled breath temperature in respiratory medicine. J Breath Res. 2017; 11 (3): 034001 ). Where compositions of use in the invention are applied in conjunction with nasally applied drugs used in the treatment of asthma, the effect of such drugs is enhanced. In addition, compositions of the invention also protect against viral exacerbations of asthma.
Compositions for use in the treatment of asthma according to the present invention comprise or consist of homogenised dry powder particles having a mean particle size diameter of > 20 pm to < 500 pm. In a preferment, the mean particle size diameter is in the range >60 to <150 pm, preferably in the range >80 to <125 pm, and typically is about 86 pm +/- 15 pm. The person skilled in the art will appreciate that the mean particle size diameter will in some degree depend on how much powdered signalling agent is added to the HPMC particles.
Compositions for use in the treatment of asthma of the present invention include at least a signalling agent is selected from menthol, strawberry, mint, spearmint, peppermint, eucalyptus, lavender, citrus, and any combination thereof. The signalling agent makes up >0.25% to <10% of the total weight of the composition, for example, 1 .5% of the total weight of the composition with powdered HPMC making up 98.5% of the total weight of the composition.
Whole or mixed compositions consisting of or comprised of powdered HPMC particles and a powdered signalling agent as herein described and defined for use in the treatment of asthma are dry homogenised powders having a mean viscosity within the range 26000 mPa.s +/- 2000 mPa.S to 40000 mPa.s. +/-5000mPa.S at 20°C in a 3.6% aqueous solution. In a preferment, the mean viscosity of the dry homogenised powder of the invention lies within the range 29000 +/- 5000 mPa.S to 38000 +/-.5000 mPa.S at 20°C in a 3.6% aqueous solution. In a further preferment the mean viscosity is 32900 mPa.S +/- 5500 mPa.S 37453 +/-1100 mPa.S at 20°C in a 3.6% aqueous solution and the signalling agent is peppermint powder making up 1.5% of the total weight of the composition. The viscosities of compositions of the invention are measured using standard procedures as taught in the European Pharmacopeia Chapter 2.2.10 on Rheology Analysis and may be performed on a TA Discovery Hybrid Rheometer 1 (TA DHR1 ) from TA Instruments Inc., Wilmington, USA), or comparable Rheometer, and the mean viscosity of several samples calculated therefrom.
In a further embodiment of the invention compositions for use in the treatment of asthma as defined herein, find use in the prophylaxis of viral exacerbations of asthma. Also included within the present invention is the use of a composition in the treatment of asthma, as defined herein.
The compositions of the invention are designed for application to the nasal mucosa through insufflation via the nose.
Compositions of the invention must be able to form gels on contact with moisture in the nasal cavity. The compositions of the invention should not contain additives that may or could substantially interfere with their ability to form gels on contact with moisture, such as additives that can significantly lower the pH of the nasal mucosa. On contact with the nasal mucosa, the dry powder particles of the invention absorb moisture and thereby form a gel matrix on the surface thereof. The function of the gel is considered to be at least twofold: firstly, it acts as a physical barrier to the uptake of small particulates such as aerial borne allergens and viruses through the nasal mucosa and secondly, if anti-asthmatic drugs are co-administered or administered sequentially, it permits the diffusion of such drugs of choice across the nasal mucosal cells and into the bloodstream. It is thought that during the hydration of dry powdered compositions of the invention a gel matrix is formed through contact with moisture in which larger particles and smaller particles combine to form a molecular net or molecular matrix wherein the smaller particles occupy spaces or gaps between larger particles and so contribute to gel formation, helping the larger particles to subsume together more easily. Particulate matter becomes trapped in the gel and is largely unable to pass over the mucosal membrane.
Compositions according to the invention may contain powder HPMC and a signalling agent in dry powder form selected from menthol, strawberry, mint, spearmint, peppermint, eucalyptus, lavender, and citrus, or any combination thereof. Examples of citrus may include lemon, lime, and cumquat (aka kumquat). Preferably, the signalling agent is one that is not known to be or implicated as being an irritant to the nasal mucosa, such as those selected from lemon, lime, cumquat (aka kumquat), and strawberry. As alluded to herein, and for the benefit of the person skilled in the art, a signalling agent is one that can provide the patient with a pleasant olfactory feedback upon use, and a flavouring agent is one that can provide the patient with a pleasant sensory (taste) feedback upon use.
The signalling agent may be present at >0.25% w/w to <10% w/w, from 0.50% w/w to 5% w/w of the total weight of the composition, for example from >0.25% w/w to <2% w/w, preferably from >0.50% w/w to <2% w/w of the total weight of the composition, such as 1.5% w/w of the total weight of the composition. Homogenised dry powder compositions of the invention consist of or comprise HPMC particles as herein defined at >89%, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 98.5%, 99%, <99.75% or any % w/w therein between of the composition, again depending on design.
Compositions of the invention are able to physically contain and/or disrupt the physiology of viruses such as those selected from influenza viruses including type A, H1 N1 , H5N1 and H3N2; coronaviruses, such as MERS-CoV, SARS-CoV, HCoV- 229E, HCov-NL63, HCoV-OC43, CoV-HKLH , and SARS-COV-2; and from bacteria such as Staphylococcus aureus, methicillin resistant Staphylococcus aureus, Haemophilus influenzae, Mycobacterium tuberculosis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterococcus faecium, Candida albicans, Candida tropicalis and Enterobacter species.
The signalling agents may have other beneficial effects on the subject. Without the intention of being bound by theory certain formulations according to the present invention which include mint may have the effect of helping to dilate airways. This may be particularly beneficial when the formulations are used to treat patients suffering from asthma. The administration of HPMC formulations including agents such as mint may also provide a feel-good factor which may be of help in restoring normal breathing patterns. In certain embodiments of the present invention, the combination of the HPMC and signalling agent is provided for sequential or simultaneous administration. The HPMC and signalling agent may be included together in a single preparation. Alternatively, the HPMC and signalling agent may be provided in separate preparations, for sequential administration.
Where the powdered HPMC and signalling agent are included in the same preparation, the preparation is in the form of a powder. Where the HPMC and the signalling agent are included in separate preparations, the preparation may be in any form suitable for intranasal administration. Suitable physical forms of the HPMC include as a powder, or as a liquid. An especially useful form is as a powder.
Preferably, powder compositions of the invention do not include any other additives or molecular components because such additives may interfere with the ability of inventive compositions to form gels on application to the nasal mucosa. Such additives deleterious to the formation of gels in the nasal passages include citric acid in combination with sodium citrate and benzalkonium chloride. Furthermore, other additives or components which are often used in intranasal compositions, such as other dry powders or solutions can cause irritation or affect ciliary movement, for example, solvents, such as propylene glycol, absorption enhancers, such as cyclodextrins or glycosides, or muco-adhesives such as chitosan. The use of such additives can be undesirable, as they can cause discomfort and interfere with the normal functioning of the nose, which can adversely affect breathing I gaseous exchange in the lungs.
Powder ingredients may be blended together using a ribbon blender, or similar type of blender for approximately 15 to 20 minutes. The time of mixing is dependent upon the moisture content and compatibility of the powders. Ingredients preferably have a moisture content of less than 5% immediately after blending as checked with the United States Pharmacopeia and National Formulary (USP/NF) loss on drying method.
Devices which are suitable for dispensing the compositions according to the present invention are disclosed in, for example, EP1368090B1 and EP3183022B1 , the teaching of which is incorporated herein in its entirety. The bottles disclosed therein use a very simple mechanism for restricting the amount of powder which is dispensed. Whilst the amount of powdered cellulose delivered to the nasal tract in order to enhance natural mucus does not have to be precisely controlled, the administration of too much powder could potentially cause an uncomfortable blockage of the nasal tract and may even result in difficulty in breathing through the nose. The use of devices described in EP1368090B1 and EP3183022B1 minimises the risk of blockages occurring in the nasal tract.
The compositions according to the present invention are preferably administered in amounts of between about 1 mg and about 10 mg per nostril. Preferably, the dose is between about 2.5 mg to about 7.5 mg, between 3 mg and about 7 mg, between about 4 mg and about 6 mg, or about 5 mg.
The dry, free-flowing powder HPMC particles per se (that is, before addition of other dry powder components forming compositions of the invention) for use in the invention possess a mean particle size diameter of > 20 pm to < 500 pm. In a preferment, the mean particle size diameter is in the range >60 to <150 pm, preferably in the range >70 to <140 pm, such as >110 to <140 pm or >115 to <135 pm, or >118 to <134 pm for example 118pm and typically is about 86 pm +/- 15 pm. The person skilled in the art will appreciate that the mean particle size diameter will in some degree vary with the ambient moisture content and storage conditions. Under storage conditions, moisture from the air may be absorbed by the particles causing them to swell by up to 14% but still remain in free-flowing powder form. Particles that have been stored may assume a mean particle size diameter of up to about 134pm. Thus particles of HPMC perse may have a mean particle size of from about 110pm to 140pm, such as 115pm to about 135pm, for example 118pm to 134pm depending on moisture uptake.
A composition of this embodiment of the invention preferably consists of powdered HPMC particles wherein the mean particle diameter size of the particles is in the range of >60 to <150 pm, preferably from >80 to <125 pm. more preferably 86 pm +/- 15 pm; a signalling agent selected from the group: mint, spearmint, peppermint, eucalyptus, lavender, citrus, or any combination thereof. Preferably, the signalling agent is selected from strawberry, citrus, such as lemon, lime, cumquat (aka kumquat), mint, or any combination thereof. The signalling agent makes up from >0.25% to <10% of the total weight of the composition.
As a further embodiment of the invention there is provided a composition for use in the treatment of asthma as herein defined, wherein the said composition is for use as a nasally administered medicament.
As a still further embodiment of the invention there is provided a composition for use in the treatment of asthma as herein defined, wherein the said composition is for use in the prophylaxis of viral exacerbations of asthma.
As a still further embodiment of the invention there is provided a method of treating a patient with asthma, comprising administering intranasally to a patient a composition for use in the treatment of asthma as defined herein twice a day over a sustained time period such as a period of two months. The composition for use in the treatment of asthma as defined herein may be administered as a single puff or squirt. Naturally, the person skilled in the art will appreciate that compositions of the invention shall comprise or consist of HPMC particles that make up >89% to <99.5% of the total weight of the said composition and a signalling agent making up from >0.5% to <10% of the total weight of the said composition. Furthermore, the viscosity of HPMC powders of use in the invention have a viscosity of 10-20 Pa.S in a 2% aqueous solution at 20°C, or wherein the powder has a viscosity of 13-17 Pa.S, or 14-16 Pa.S, or 15Pa.S in a 2% aqueous solution at 20°C.
The skilled addressee will also appreciate that powder compositions of use in this aspect of the invention may also include one or more ingredients selected from the group consisting of kali bichromicum, a thickening agent, gum, starch, a disintegrant, sodium glycolate, a cross linked povidone, a release agent, magnesium stearate, an emulsifying agent, a surfactant, anticaking agents, granulating agents, preservative, and a colorant, provided that such ingredients, if present, do not interfere deleteriously with the alleviation of symptoms of asthma. Naturally, the skilled artisan will appreciate that all compositional embodiments of the invention detailed herein are for delivery to the nasal mucosa via insufflation through the nose.
There is also provided a method of making a powdered composition for use in the treatment of asthma as described and defined herein comprising:
1 ) adding signalling agent powder to hydroxypropyl methylcellulose powder;
2) diffusively blending the two ingredients of 1 ) in a blending machine.
Naturally, the skilled artisan will appreciate that compositions of the invention as described and defined herein may be administered with or co-administered alongside drugs of choice known for treating asthma.
(https://www.mayoclinic.org/diseases-conditions/asthma/in-depth/asthma- medications/art-20045557. Asthma medications: Know your options - Mayo Clinic, August, 2022)
Such drugs of choice may be selected from inhaled corticosteroids, such as Fluticasone (Flovent HFA, Arnuity Ellipta), Budesonide (Pulmicort Flexhaler), Mometasone (Asmanex Twisthaler), Beclomethasone (Qvar RediHaler) and Ciclesonide (Alvesco); oral corticosteroids such as Prednisone and Methylprednisolone; bronchodilators, such as long-acting and short-acting beta agonists (LABAs and SABAs) for example the LABAs formoterol and salmeterol and SABAs such as albuterol, levalbuterol, and theophylline; leukotriene modifiers/inhibitors, such as Montelukast (Singulair), Zafirlukast (Accolate) and Zileuton (Zyflo); long-acting muscarinic antagonists (LAMAs) such as tiotropium (Spiriva Respimat); and biologies such as Benralizumab (Fasenra), Dupilumab (Dupixent), Mepolizumab (Nucala), Omalizumab (Xolair), Reslizumab (Cinqair) and Tezepelumab-ekko (Tezspire). Naturally, the skilled artisan will know that certain combinations of the forementioned drugs may be taken together in any one treatment regime depending on the severity of or exacerbation of asthmatic disease presenting in a patient in need thereof. Thus, as further aspect of the invention there is provided a two-part composition for use in the treatment of asthma comprising or consisting of a first part as defined in any one of claims 1 to 13 and a second part selected from inhaled corticosteroids, oral corticosteroids, bronchodilators, such as LABAs and SABAs, leukotriene inhibitors/modifiers, LAMAs, and biologies such as monoclonal antibodies. Preferably, the second part of the two-part composition for use in the treatment of asthma as defined herein is selected from Fluticasone (Flovent HFA, Arnuity Ellipta), Budesonide (Pulmicort Flexhaler), Mometasone (Asmanex Twisthaler), Beclomethasone (Qvar RediHaler) and Ciclesonide (Alvesco); oral corticosteroids such as Prednisone and Methylprednisolone; the LABAs formoterol and salmeterol and SABAs such as albuterol, levalbuterol, and theophylline; leukotriene modifiers/inhibitors selected from Montelukast (Singulair), Zafirlukast (Accolate) and Zileuton (Zyflo); long-acting muscarinic antagonists (LAMAs) such as tiotropium (Spiriva Respimat) or any therapeutic combination thereof.. The invention is compatible and supportive of the application of biologies selected from Benralizumab (Fasenra), Dupilumab (Dupixent), Mepolizumab (Nucala), Omalizumab (Xolair), Reslizumab (Cinqair) and Tezepelumab-ekko (Tezspire).
As a yet further aspect of the invention there is provided a two-part composition comprising or consisting of a first part as defined in any one of claims 1 to 13 and a second part selected from inhaled corticosteroids, oral corticosteroids, bronchodilators, such as LABAs and SABAs, leukotriene inhibitors/modifiers, LAMAs, and biologies such as monoclonal antibodies or any therapeutic combination thereof. Preferably, the two-part composition in this aspect of the invention comprises or consists of a first part as defined in any one of claims 1 to 13 and a second part selected from Fluticasone (Flovent HFA, Arnuity Ellipta), Budesonide (Pulmicort Flexhaler), Mometasone (Asmanex Twisthaler), Beclomethasone (Qvar RediHaler) and Ciclesonide (Alvesco); oral corticosteroids such as Prednisone and Methylprednisolone; the LABAs formoterol and salmeterol and SABAs such as albuterol, levalbuterol, and theophylline; leukotriene modifiers/inhibitors selected from Montelukast (Singulair), Zafirlukast (Accolate) and Zileuton (Zyflo); long-acting muscarinic antagonists (LAMAs) such as tiotropium (Spiriva Respimat) or any therapeutic combination thereof. The invention is compatible and supportive of the application of biologies selected from Benralizumab (Fasenra), Dupilumab (Dupixent), Mepolizumab (Nucala), Omalizumab (Xolair), Reslizumab (Cinqair) and Tezepelumab-ekko (Tezspire).
There is also provided a method of making a powdered composition for use in the treatment of asthma as described and defined herein, wherein the composition reduces or alleviates lower airway inflammation in the lungs as shown by differences in exhaled breath temperature.
There is also provided a method of making a powdered composition for use in the treatment of asthma as described and defined herein, wherein the composition enhances the effect of nasally applied drugs used in the treatment of asthma.
There is also provided a method of making a powdered composition for use in the treatment of asthma as described and defined herein, wherein the composition protects against viral exacerbations of asthma.
There now follow examples illustrating the invention. It is to be understood that the teaching of the examples is not to be construed as limiting the invention in any way.
Experimental Section
Study 1
Long term use of nasal powder hydroxypropylmethyl-cellulose as add-on treatment of chronic rhinosinusitis in asthmatics protects against viral exacerbations
Introduction: The aim of this study was to find out whether regular use of powder HPMC (pHPMC) in asthmatic patients with chronic rhinosinusitis (A+ChrRhS) requiring continuous intranasal drug treatment involving pHPMC insufflation would also be protective against viral infections, SARS-CoV-2 infection in particular.
Methods: This is a real life longitudinal study following up a cohort of patients with perennial A+ChrRhS with or without polyps: 29 subjects (19 women), median age 51 years (range 25-73 years). On top of their regular asthma treatment they all inhaled corticosteroid daily, followed by pHPMC (Nasaleze Allergy Blocker, Nasaleze Ltd, UK). Gender matched asthmatics (29, 19 women, median age 51 years (range 20-65 years) not needing continuous therapy for nasal symptoms served as control (A- RhTh). All patients were at least on inhaled corticosteroids, their asthma being mostly well controlled. Subjects were followed up from March 2020, when the first cases of COVID-19 were registered in Bulgaria, up to the end of 2021 . Episodes characterized by sudden increase of body temperature and general malaise with surge in upper airway symptoms, followed by worsening of asthma symptoms requiring increase of the maintenance therapy were considered as asthma exacerbations due to viral infection. Subjects were asked to report episodes of “common cold” and referred to perform antigen or PCR tests for SAR-CoV-2 on such occasions.
Figure imgf000014_0001
pMC - Powdered hydroxypropylmethyl cellulose
A+ChrRhs - Asthma plus chronic rhinosinusitis
A-RhTh - Asthma not requiring continuous therapy
SARS Cov 2 - SARS Covid 19 infection
Results: There was no significant difference between the baseline characteristics of subjects with A+ChrRhS and A-RhTh. Data on the control of their asthma and occurrence of viral infections in A+ChrRhS patients revealed 5 episodes of viral asthma exacerbations compared with 13 exacerbations in the A-RhTh group in which no pHPMC was administered (P=0.02, Chi-square analysis). During the observation period there were 4 waves of the COVID-19 epidemic sweeping across the country: 5 cases of SARS-CoV-2 infections were registered among the A-RhTh patients, while no SARS-CoV-2 infections occurred in the A+ChrRhS group using pMC continuously (P=0.05, Chi-square analysis). Conclusions: pHPMC used continuously in patients with A+ChrRhS as a physical barrier against inhaled noxious agents and for enhancement of the effect of nasally applied drugs by sealing these to the nasal mucosa, offers further protection against viral/SARS-COV-2 exacerbations of asthma.
Study 2
Regular use of nasal powder hydroxypropylmethyl-cellulose in asthmatics with accompanying rhinitis reduces the temperature of the lower airways
Introduction: Allergic rhinitis is the most common co-morbidity of asthma and the underlying mechanism in both diseases is airway inflammation. There is a continuous crosstalk and interplay between the upper and lower airways. We hypothesized that applying powder hydroxypropylmethyl-cellulose (pHPMC) as a non-pharmacological approach to enhance the barrier function of the nasal mucosa against allergens and airborne noxious agents may also reduce level of airway inflammation in the lungs.
Methods: In this real-life open label study we followed up 23 subjects (14 women, median age 51 years, range [25-73 years]) with perennial mild or moderate asthma with continuous rhinitis symptoms (A+Rh) and 23 subjects with asthma (16 women, median age 51 [28-63 years]) but without nasal symptoms (A-Rh) for 2 months during the fall and winter season. Subjects in the A+Rh group were provided with pHPMC (Nasaleze Cold & Flu, Nasaleze Ltd, UK) and instructed to administer twice day in each nostril throughout the study. Both A+Rh and A-Rh subjects received their regular asthma therapy. We assessed the exhaled breath temperature (EBT) of all subjects using a device as described and defined in EP1906829 B1 as a surrogate measure of lower airway inflammation before and at the end of the study period and compared the EBT values and the before and after EBT residual between the two groups.
Results: There were no significant differences between the asthma characteristics of the A+Rh group and the A-Rh controls, including the baseline EBT: mean 33,21 ± s.e.m. 0,25 vs. 33,56±0.23, P=0.29. At the end of the study period EBT of the pHPMC treated A+Rh patients was significantly lower than in the A-Rh controls: 33,23±0,26 vs. 33,94+0.23, P=0.049. This result was also confirmed by the comparison of the before and after EBT residuals with a still higher statistical significance. Conclusions: pHPMC applied intranasally by patients with perennial A+Rh during the fall and winter season also reduces lower airway inflammation as judged by the changes in EBT.

Claims

1 . A composition for use in the treatment of asthma in a patient, in the form of a dry homogenised powder consisting of, or comprising: i) hydroxypropyl methylcellulose (HPMC) particles; and ii) at least one chemical agent selected from signalling agents, wherein the HPMC particles have a mean particle size diameter of > 20 pm to < 500 pm.
2. A composition for use in the treatment of asthma in a patient according to claiml , wherein the HPMC particles make up from 89% to 99.5% of the total weight of the said composition and the signalling agent makes up from 0.5% to 10% of the total weight of the said composition.
3. A composition for use in the treatment of asthma in a patient according to claim 1 or claim 2, wherein the composition reduces or alleviates lower airway inflammation in the lungs as shown by differences in exhaled breath temperature.
4. A composition for use in the treatment of asthma according to any one of claims 1 to 3, wherein the composition enhances the effect of nasally applied drugs selected from the group comprising or consisting of inhaled corticosteroids, oral corticosteroids, bronchodilators, such as LABAs and SABAs, leukotriene inhibitors/modifiers, LAMAs, or any therapeutic combination thereof; and biologies such as monoclonal antibodies used in the treatment or control of asthma.
5. A composition for use in the treatment of asthma according to any one of claims 1 to 4, wherein the composition further protects against viral exacerbations of asthma.
6. A composition for use in the treatment of asthma according to any one of claims 1 to 5, wherein the mean particle size diameter is in the range 60 to 150 pm.
7. A composition for use in the treatment of asthma according to any one of claims 1 to 6, wherein the mean particle size diameter is in the range 70 to 140 pm.
8. A composition for use in the treatment of asthma according to any one of claims 1 to 7, wherein the mean particle size diameter is 86 pm +/- 15 pm.
9. A composition for use in the treatment of asthma according to any one of claims 1 to 8, wherein the dry homogenised powder has a mean viscosity within the range 26000 mPa.s +/- 2000 mPa.S to 40000 mPa.s. +/-5000mPa.S at 20°C in a 3.6% aqueous solution.
10. A composition for use in the treatment of asthma according to any one of claims 1 to 9, wherein the signalling agent is selected from menthol, strawberry, mint, spearmint, peppermint, eucalyptus, lavender, citrus, and any combination thereof.
11. A composition for use in the treatment of asthma according to any one of claims 1 to 10, wherein the signalling agent makes up from 0.25% to <10% of the total weight of the composition.
12. A composition for use in the treatment of asthma according to any one of claims 1 to 11 , wherein the signalling agent makes up 1 .5% of the total weight of the composition and the HPMC makes up 98.5% of the total weight of the composition.
13. A composition for use in the treatment of asthma according to any one of claims 1 to 12, wherein the said composition is for use in the prophylaxis of viral exacerbations of asthma.
14. A two-part composition for use in the treatment of asthma comprising or consisting of a first part as defined in any one of claims 1 to 13 and a second part selected from inhaled corticosteroids, oral corticosteroids, bronchodilators, such as LABAs and SABAs, leukotriene inhibitors/modifiers, LAMAs, or any therapeutic combination thereof; and biologies such as monoclonal antibodies.
15. A two-part composition for use in the treatment of asthma according to claim 14, wherein the second part is selected from Fluticasone (Flovent HFA, Arnuity Ellipta), Budesonide (Pulmicort Flexhaler), Mometasone (Asmanex Twisthaler), Beclomethasone (Qvar RediHaler) and Ciclesonide (Alvesco); oral corticosteroids such as Prednisone and Methylprednisolone; the LABAs formoterol and salmeterol and SABAs such as albuterol, levalbuterol, and theophylline; leukotriene modifiers/inhibitors selected from Montelukast (Singulair), Zafirlukast (Accolate) and Zileuton (Zyflo); long-acting muscarinic antagonists (LAMAs) such as tiotropium (Spiriva Respimat) or any therapeutic combination thereof; and biologies selected from Benralizumab (Fasenra), Dupilumab (Dupixent), Mepolizumab (Nucala), Omalizumab (Xolair), Reslizumab (Cinqair) and Tezepelumab-ekko (Tezspire).
16. A two-part composition for treating asthma comprising or consisting of a first part as defined in any one of claims 1 to 13 and a second part selected from inhaled corticosteroids, oral corticosteroids, bronchodilators, such as LABAs and SABAs, leukotriene inhibitors/modifiers, LAMAs, or any therapeutic combination thereof; and biologies such as monoclonal antibodies.
17. A two-part composition according to claim 16, wherein the second part is selected from Fluticasone (Flovent HFA, Arnuity Ellipta), Budesonide (Pulmicort Flexhaler), Mometasone (Asmanex Twisthaler), Beclomethasone (Qvar RediHaler) and Ciclesonide (Alvesco); oral corticosteroids such as Prednisone and Methylprednisolone; the LABAs formoterol and salmeterol and SABAs such as albuterol, levalbuterol, and theophylline; leukotriene modifiers/inhibitors selected from Montelukast (Singulair), Zafirlukast (Accolate) and Zileuton (Zyflo); long-acting muscarinic antagonists (LAMAs) such as tiotropium (Spiriva Respimat) or any combination thereof; and biologies selected from Benralizumab (Fasenra), Dupilumab (Dupixent), Mepolizumab (Nucala), Omalizumab (Xolair), Reslizumab (Cinqair) and Tezepelumab-ekko (Tezspire).
18. A method of making a powdered composition for use in the treatment of asthma as defined in any one of claims 1 to 13 comprising:
1 ) adding signalling agent powder to hydroxypropyl methylcellulose powder;
2) diffusively blending the two ingredients of 1 ) in a blending machine.
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