EP4099983A1

EP4099983A1 - Composition in the form of powder containing an extract of cannabis sativa for the treatment of inflammations or infections or allergies of the respiratory system and /or hypersecretion of the mucus, and device for its dosage

Info

Publication number: EP4099983A1
Application number: EP21710048.6A
Authority: EP
Inventors: Andrea BIFFI; Walter FIORE
Original assignee: Sofar SpA
Current assignee: Sofar SpA
Priority date: 2020-02-06
Filing date: 2021-02-08
Publication date: 2022-12-14
Also published as: WO2021156839A1; IT202000002368A1

Abstract

The present invention relates to a composition in the form of powder for oral inhalation, preferably for oral aspiration, comprising an active agent, preferably said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L. Furthermore, the present invention relates to said composition for use in a method for the treatment of mucus hypersecretion and/or inflammations or infections or allergies of the respiratory system, preferably diseases, symptoms or disorders associated with mucus hypersecretion, in a subject in need. Lastly, the present invention regards a device for administration to said subject in need through the inhalation route for oral aspiration.

Description

DESCRIPTION of the invention having the title:

COMPOSITION IN THE FORM OF POWDER CONTAINING AN EXTRACT OF CANNABIS SATIVA FOR THE TREATMENT OF INFLAMMATIONS OR INFECTIONS OR ALLERGIES OF THE RESPIRATORY SYSTEM AND /OR HYPERSECRECTION OF THE MUCUS, AND DEVICE FOR ITS DOSAGE

The present invention relates to a composition in the form of powder (dry powder) for oral inhalation, preferably for oral aspiration, comprising an active agent, preferably said active agent being an extract of a plant of the genus Cannabis, preferably an extract of Cannabis sativa L

Furthermore, the present invention relates to said composition for use in a method for the treatment of 5 mucus hypersecretion (or bronchial mucus) and preferably of diseases, symptoms or disorders associated therewith, in a subject in need.

Furthermore, the present invention relates to said composition for use in a method for the treatment of inflammations or infections or allergies of the respiratory system, preferably associated with mucus hypersecretion in a subject in need.

10 Lastly, the present invention relates to a dispensing device for the administration, through the inhalation route, for oral aspiration, of said composition in the form of dry powder to said subject in need.

In addition, the present invention relates to a kit comprising said dispensing device for the administration through the inhalation route, for oral aspiration, and said composition in the form of dry powder.

15 The respiratory tracts and the lungs (respiratory system) are affected by serious diseases caused by bacteria, viruses and toxic substances that can easily penetrate into the respiratory system along with the inspired air. Inflammations, infections or allergies of the respiratory system are generally associated with mucus hypersecretion. In physiological situations the mucus of the respiratory system (or bronchial mucus), a fluid and stringy substance, serves for moistening the respiratory tract and for trapping any 20 possible foreign particles and microorganisms. In case of inflammations or infection or allergy of the respiratory system, the production of mucus increases starting off mucus hypersecretion (or formation of phlegm) with increased consistency (viscosity). Said mucus hypersecretion has the purpose of capturing and eliminating, by coughing, the pathogen microorganisms that triggered the aforementioned inflammation or infection or allergy.

25 The alterations of production of mucus and the mucociliary clearance are generally treated using mucolytic/mucoregulatory drugs and with expectorant drugs. Mucolytic/mucoregulatory drugs act on mucus hypersecretion and on the characteristics of the mucus produced and they are used as symptomatic and adjuvant drugs when treating inflammatory diseases, infections or allergies regarding the respiratory tract. Mucolytic/mucoregulatory agents are capable of modifying the chemical/physical properties of the bronchial secretions facilitating the expectoration thereof and reducing the production thereof. Given that the hyperproduction of mucus and the modification of the characteristics thereof (e.g. increased viscosity) can generate symptoms of the obstructive type, which force the system to utilise the cough reflex to clear the airways, the drugs active on the mucosal secretion take an active part in controlling the cough too.

There are two types of mucolytic/mucoregulatory drugs, depending on their action mechanism: direct action, or fluidifying mucolytic/mucoregulatory drugs which are drugs capable of acting on the mucus already formed or present in the respiratory airways, for example compounds that split the mucus polymers (e.g. N-acetylcysteine); indirect action mucolytic/mucoregulatory drugs, capable of acting on the production of mucus by the mucus-secretory cells. These modify the secretion and characteristics of the mucus (e.g. sobrerol and carbocisteine) or the adhesiveness of the mucus (e.g. ambroxol and bromhexine).

Drugs or other remedies currently available on the market for the treatment of mucus hypersecretion and/or inflammation or infection or allergies of the respiratory system, preferably of diseases, symptoms or disorders associated with mucus hypersecretions, are often ineffective or only partially effective. Furthermore, some of the prior art products may cause side effects such as taste disorders, intestinal disorders, nausea, dyspepsia, vomit, dry mouth, abdominal pain, at times urticaria, skin rash, erythema, dermatitis, vertigo, dyspnoea, angioedema.

Furthermore, most of the drugs and other remedies currently available on the market for the treatment of mucus hypersecretion and/or inflammations or infections or allergies of the respiratory system are in the form of solutions or suspensions. When said solutions or suspensions are to be administered to the lungs through inhalation, this occurs using nebulisers. These devices dispense solutions and suspensions in the form of thin spray and they generally have a face mask attached, so that the subject can inhale the thin spray through the mouth or nose. However, nebulisers tend to be large and generally non-portable devices, hence inappropriate for an easy, quick and convenient administration of a medicinal product, like in the case of the present invention.

A further problem associated with the use of nebulisers lies in the difficulty of obtaining accurate information on the dose actually dispensed to the subject. Using nebulisers also entails a general lack of precision, reproducibility and efficiency when it comes to administering the medicinal product, which leads to the need to increase the administered dose so as to guarantee the achievement of the desired therapeutic effect, with ensuing waste of the drug and higher risk of adverse effects. When said drugs are in the form thin powder for administration through the inhalation route, they must be administered using a dispensing device. The dispensing devices currently available on the market do not always guarantee an effective administration of the drug and they are often difficult to handle and activate. In addition, it is known that delivery of compositions in the form dry powder to the respiratory tract reveals some drawbacks. The dispensing device (or inhaler device) should provide the maximum possible proportion of the active particles delivered into the lungs, including a significant proportion in the deepest part of the lungs. Thus, dry powder compositions capable of increasing the proportion of the active particles that are delivered to the lower respiratory tract or to the deep part of the lungs.

The type of dry powder inhaler device used may impact the efficiency of release of the active particles to the respiratory tract. Furthermore, the chemical/physical properties of the powder affect both the efficiency and the reproducibility of the release of active particles and on the deposition site in the respiratory tract.

Thus, there is high demand from the society for appropriate treatments of mucus hypersecretion (or bronchial mucus) and/or of the inflammations or infections or allergies of the respiratory system, preferably of diseases, symptoms or disorders associated with mucus hypersecretion.

The technical problem addressed and solved by the present invention lies in providing a valid solution for the effective therapeutic and non-therapeutic treatment of mucus hypersecretions and/or of the inflammations or infections (bacterial or viral) or allergies of the respiratory system, preferably of diseases, symptoms and/or disorders associated with said mucus hypersecretions capable of overcoming the currently unresolved drawbacks of the prior art, in particular, as regards the ineffectiveness and/or presence of side effects and/or administration challenges.

Furthermore, the technical problem addressed and solved by the present invention lies in providing novel compositions comprising an active agent, in particular a mucolytic agent and/or anti-inflammatory agent, in the form of dry powder, suitable for inhalation administration having a good flowability, a good uniformity of distribution of the active agent, an appropriate chemical and physical stability prior to use and that do not tend to agglomerate, hence, that are easy to handle and administer.

In addition, the technical problem addressed and solved by the present invention lies in providing both novel compositions in the form of dry powder and a device for the inhalation administration thereof (for example a kit) capable of creating a good breathable fraction and providing an accurate therapeutically active dose of the active ingredient comprised in said composition.

In order to overcome these technical problems, the present invention provides a composition in the form of powder, preferably dry powder, suitable for inhalation administration by means of oral aspiration comprising an active agent, in particular a mucolytic agent and/or an anti-inflammatory agent, preferably an extract of a plant of the genus Cannabis, more preferably of Cannabis sativa L, and optionally other components (for example first and/or second support agent) which facilitate the administration of said composition in the form of powder, preferably dry powder, through the inhalation route by means of oral aspiration. Such composition is capable of effectively and quickly treating mucus hypersecretion and/or inflammations or infections or allergies of the respiratory system, preferably diseases, symptoms or disorders associated with said mucus hypersecretion, both in pathological subjects and in healthy subjects (not yet defined pathological). In addition, said composition is without the adverse effects present in the treatments of the prior art, it is easy to administer through the inhalation route, it is easy to prepare and it is cost-effective.

Furthermore, the present invention provides a device for administering the composition of the invention in the form of powder for inhalation, preferably inhalation actuated through oral aspiration, that is easy to use, that allows to enhance the adherence of the subject to the therapy and having optimal capacity of administration of the composition of the invention and, thus, of the active agent comprised therein.

Lastly, in order to overcome said technical problems, the present invention provides a kit comprising said composition in the form of dry powder and a device for the administration thereof through oral inhalation actuated by the aspiration of the subject to be treated.

These and other objects, which will be clear from the detailed description that follows, are achieved by the composition and by the device of the present invention, as well as by the use thereof and by the method of administration thereof, thanks to the technical characteristics claimed in the attached claims and reported in the present description

Following an intensive research and development step, the Applicant found out that the inhalation administration by means of oral inhalation, preferably by means of oral aspiration - of the composition according to the present invention is capable of effectively and quickly treating mucus hypersecretion and/or inflammations or infections or allergies of the respiratory system, preferably diseases, symptoms and/or disorders associated with said mucus hypersecretion.

Furthermore, following an intensive research and development, the Applicant found out that the use of a dispensing device of the invention for the administration - through oral inhalation, preferably by means of oral aspiration - of the composition of the invention in the form of powder improves the administration of the composition of the invention and, thus, of the active ingredient comprised therein. Furthermore, said device is easy to use, hence, it improves the adherence of the subject to the therapy.

Said therapeutic or non-therapeutic pharmacological treatment activity of the composition is due to the active agent present in the composition, such as for example an extract of the plant of the genus Cannabis, preferably of Cannabis sativa L, which can act as mucolytic and/or anti-inflammatory agent, due to the additional components, if present in the composition of the invention besides the active agent, which allow to obtain an optimal powder for the administration thereof through the inhalation route and due to the dispensing device by means of which the composition of the invention in the form of powder is administered in the respiratory system (upper and/or lower airways) through oral aspiration.

Furthermore, when the device of the invention is of the disposable type, it is free from bacterial sterility- related problems. Lastly, if the blister comprising the mixture or composition of the invention is inserted into the inhaler of the invention by the manufacturer of the kit of the present invention, instead of by the user, the use of the device of the invention is even simpler and intuitive for the subject in need.

FIGURES AND DEFINITIONS

Figure 1 relates to an upper perspective view of the inhaler seen from the distal end thereof;

Figure 2 relates to a lower perspective view of the inhaler seen from the distal end thereof;

Figure 3 relates to a top plan view of the inhaler;

Figure 4 relates to a view similar to the preceding one with the cartridge mounted on the inhaler;

Figure 5 relates to a sectional view of the inhaler along the longitudinal centreline plane thereof, with the blister (or cartridge) mounted thereon;

Figure 6 relates to a view similar to the preceding one with the blister open for dispensing the mixture or composition of the invention;

Figure 7 relates to a schematic representation of a Next Generation Impactor (NGI) as indicated by the EU. Pharm. 8.0, 2.9.18;

Figure 8 relates to a schematic representation of the ramifications present at the bronchial tree.

In the context of the present invention the terms "upper airways” and “upper respiratory airways” are synonyms used interchangeably and they mainly represent nose (or nasal cavities), pharynx, larynx, trachea and upper part of the bronchi.

In the context of the present invention the terms “lower airways” and “lower respiratory airways" and “deep airways” are synonyms used interchangeably and they mainly represent the lower part of the bronchi, lungs, bronchioles, alveoli.

In the context of the present invention, the terms “blister” or “single-dose blister” are used to indicate a closed and sealed container having a volume suitable to house a mixture or a composition of the present invention, said blister being pierceable by applying a pressure exerted manually by a subject, for example, a plastic and/or aluminium container or cartridge comprising a pierceable aluminium sheet on one side. DETAILED DESCRIPTION OF THE INVENTION

Forming an object of the present invention is a composition in the form of powder (dry powder) suitable for administration through oral inhalation (in short composition of the invention or composition) comprising (i) a mixture M (in short mixture of the invention or mixture) comprising, or alternatively, consisting of an active agent (or active ingredient of the composition of the invention) and, optionally, (ii) at least one acceptable pharmaceutical or food grade additive and/or excipient.

Preferably, said composition in the form of powder (dry powder) is soluble in water at a temperature of 25°C and at atmospheric pressure.

Said active agent, preferably the extract of a plant of the genus Cannabis, preferably of Cannabis sativa L, may act as a mucolytic agent in subjects suffering from mucus hypersecretion in the absence of inflammations or infections or allergies of the respiratory system, as an anti-inflammatory agent in subjects suffering from inflammations or infections or allergies of the respiratory system in the absence of mucus hypersecretion, as is a mucolytic and anti-inflammatory agent in subjects suffering from inflammations or infections or allergies of the respiratory system in the presence of mucus hypersecretion.

In a preferred embodiment, said active agent is an extract of a plant of the genus Cannabis, preferably a plant of the species Cannabis sativa L.

The Cannabis sativa L. (or cannabis sativa) is cultivated mainly for use in the textile or construction industry and for paper production, although some psychoactive substances are present therein in percentages varying depending on the variety

Said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L. comprises one or more compounds selected from the group comprising or, alternatively, consisting of: tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), tetrahydrocannabivarin (THCV), cannabinol (CBN), cannabichromene (CBN), cannabicyclol (CBL), cannabielsoin (CBE), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabinidiol (CBND), cannabitriol (CBT), cannabivarin (CBV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monoethylether (CBGM), or acceptable pharmaceutical of food grade salts thereof, and mixtures thereof;

More preferably, said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L, comprises or, alternatively, consists of CBD, CBDV, THCV, CBG, CBDA or acceptable pharmaceutical or food grade salts thereof, and optionally “traces" (preferably in an amount < 0.3% by weight with respect to the total weight of said extract, for example from 0.01% or 0.1% to 0.3%) of other compounds selected from the aforementioned group.

Even more preferably, said extract of a plant of the genus Cannabis, preferably said extract of Cannabis sativa L, comprises or, alternatively, consists of: table 1 or table 2.

Table 1 Table 2

Preferably, said extract of a plant of the genus Cannabis, preferably said extract of Cannabis sativa L, comprises cannabidiol (CBD) or an acceptable pharmaceutical or food grade salt thereof. More preferably, cannabidiol (CBD) or a salt thereof is the most abundant active component of said extract.

Even more preferably, said extract of a plant of the genus Cannabis, preferably said extract of Cannabis sativa L, comprises or, alternatively, consists of cannabidiol (CBD) and tetrahydrocannabinol (THC) or acceptable pharmaceutical or food grade salts thereof. An amount of said THC is preferably equal to or less than 0.5% by weight with respect to the total weight of said extract (for example from 0.001% or 0.01% or 0.1% to 0.5%), preferably equal to or less than 0.2% by weight (for example from 0.001% or 0.01% or 0.1% to 0.2%), more preferably equal to or less than 0.1% by weight (for example from 0.001% or 0.01% to 0.1%), even more preferably equal to or less than 0.05% by weight (for example from 0.001% or 0.01% to 0.05%).

Mucolytics are substances that make the mucus secreted by the respiratory system more fluid and facilitate the work of ejecting the mucus by the bronchi and trachea. It is known that the major determinants of viscosity and elasticity of the secretions of the respiratory system are fucomucins and IgG immunoglobulins. The extract of Cannabis sativa L, in particular, is characterised by the capacity to split the sulphur bridges in proteins: in the case of mucus, extract depolymerises the mucoprotein complexes (glycoprotein agglomerates) into smaller units, provided with lower viscosity, and it exercises an important mucolytic and fluidifying effect on the mucosal and mucopurulent secretions effect

Furthermore, the cannabidiol (CBD) contained in said extract offers many benefits thanks to the mainly anti-inflammatory, immunosuppressive and broncho-dilating qualities thereof. Further benefits include: improved sleep patterns and increased immune system functionality, pain relief as regards chest and lung regions, and decrease in the production of mucus and catarrh. It should be pointed out that said broncho- dilating properties could be related to a relaxant action at the level of the lung muscles by means of the cannabinoid receptor type 1 (CBi in abbreviated form). THC also performs a similar muscle-relaxant function.

Anti-inflammatory drugs are part of the antalgic drugs that relieve pain by reducing inflammation. Cannabidiol (CBD) specifically enhances activation of the cannabinoid receptor type 2 (CB2 in abbreviated form), a G protein-coupled receptor. The activation of the CB2 receptor on mast cells has direct anti inflammatory effects, in that it is capable of reducing the release of the pro-inflammatory mediators of such cells. CBD and THC have both been shown to enhance apoptosis and combat angiogenesis. Other components of the extract of a plant of the genus Cannabis, preferably of a plant of the species Cannabis sativa L, may be involved in similar mechanisms.

Cannabidiol (CBD; lUPAC name: 2-[(1R,6R)-3-methyl-6-prop-1-en-2-yl)-cyclohex-2-en-1-yl]-5- pentylbenzene-1 ,3-diol; CAS No. 13956-29-1) is the second most abundant metabolite of Cannabis sativa L. Unlike THC (del ta-9-tetrahyd rocan n abi n ol , the first metabolite by quantity), CBD is not psychoactive and it does not create addiction.

In the present mixture M, said extract of a plant of the genus Cannabis is preferably in the form of dry extract. More preferably, said dry extract is obtained through an extraction process with CO2, or with an organic solvent, preferably alcoholic or hydroalcoholic, for example ethanol.

In an embodiment, besides the active agent, said (i) mixture M preferably comprises said extract of a plant of the genus Cannabis ; furthermore, it comprises a first support agent selected from the group comprising or, alternatively, consisting of lactose, a dextran, mannitol and the mixtures thereof; more preferably lactose.

Preferably, said (i) mixture M comprises said extract of a plant of the genus Cannabis and lactose.

Lactose (lUPAC name b-D-galactopyranosyl (1 4) D-glucopyranose, CAS 63- 42- 3) is a disaccharide and a dextrorotatory reducing sugar. The lactose molecule consists of a D-galactose and of a D-glucose molecule linked by a glyosidic bond (acetal) b(1 - 4). The aldehyde group of the glucose unit is responsible for the reducing properties of lactose. Lactose is added to the inhalation powders of the present invention to improve the efficiency at which the blister empties after respiratory activation, the turbulence and the dispersion of the drug in the small airways.

Mannitol (or D(-)mannitol, or E421 according to European regulation), alternatively referred to as mannite, is a chiral alditol (lUPAC name (2R,3R,4R,5R)hexan-1 ,2,3,4,5,6-hexol, brute formula C6H1406, molecular weight (u) 182.17, example of CAS No. 69-65-8).

The lactose and/or mannitol particles have a particle size distribution (> 50 pm, for example from 50 pm to 100 pm) such that they cannot penetrate into the deep parts of the respiratory system. Hence, most of the lactose settles in the oropharynx before moving on to the stomach after being swallowed.

Both lactose and mannitol may be comprised/contained in the mixture M or composition of the present invention in the form of dry inhalation powders. Their presence (individually or combined) helps for example to: (i) improve the efficiency with which the volume in the blister of the dry powder inhaler of the invention is emptied after respiratory activation (inhalation by the user who - by exerting pressure with the fingers thereof - pierces the walls of the blister), (ii) improve the turbulence and the dispersion of the active agent in the small airways, (iii) avoid aggregation of the particles of the active agent powder to be inhaled. In an embodiment, besides the active agent, said (i) mixture M preferably comprises said extract of a plant of the genus Cannabis and, optionally, said first support agent selected from the group comprising or, alternatively, consisting of lactose, a dextran, mannitol and mixtures thereof; furthermore, it comprises a second support agent, wherein said second agent is a stearate metal or a derivative thereof selected from the group comprising or, alternatively, consisting of: magnesium stearate, zinc stearate, calcium stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and mixtures thereof; more preferably magnesium stearate.

Thus, the (i) mixture M may comprise said second support agent as an alternative to said first support agent or in presence of said first support agent.

In an embodiment, besides the active agent, said (i) mixture M preferably comprises said extract of a plant of the genus Cannabis , and lactose; furthermore, it comprises magnesium stearate.

Preferably, said (i) mixture M comprises said extract of a plant of the genus Cannabis, lactose and magnesium stearate.

Alternatively, said (i) mixture M comprises said extract of a plant of the genus Cannabis and magnesium stearate, in the absence of lactose.

Magnesium stearate (IUPAC name magnesium octadecanoate, CAS 557- 04-0) is used in the pharmaceutical industry as a lubricant in the preparation of solid compositions, preferably tablets, for facilitating the detachment between the powder or granulate and the metallic walls of the processing equipment.

In a preferred embodiment, besides said active agent, said (i) mixture M preferably comprises said extract of a plant of the genus Cannabis ; furthermore, it comprises a hyaluronic acid or an acceptable pharmaceutical or food grade salt thereof.

In an embodiment, said (i) mixture M comprises said active agent, preferably said extract of a plant of the genus Cannabis, hyaluronic acid or a salt thereof and said first support agent, preferably lactose.

In an embodiment, said (i) mixture M comprises said active agent. Preferably said extract of a plant of the genus Cannabis, hyaluronic acid or a salt thereof and said second support agent, preferably magnesium stearate.

In an embodiment, said (i) mixture M comprises said active agent, preferably said extract of a plant of the genus Cannabis, hyaluronic acid or a salt thereof, said first support agent, preferably lactose, and said second support agent, preferably magnesium stearate. In a preferred embodiment, besides said active agent, said (i) mixture M preferably comprises said extract of a plant of the genus Cannabis, lactose and/or magnesium stearate; furthermore, it comprises a hyaluronic acid or an acceptable pharmaceutical or food grade salt thereof.

The presence of hyaluronic acid in the composition of the invention combined with said active agent, said extract of a plant of the genus Cannabis, enhances the mucolytic and/or anti-inflammatory effectiveness of the active agent (decrease in inflammation symptoms and/or decrease in mucus viscosity and ease of expectoration/elimination of the mucus for the subject suffering from mucus hyper-production). Therefore, in the compositions of the invention it is possible to use a low percentage of active agent, preferably said extract of a plant of the genus Cannabis.

In the context of the present invention, the expression hyaluronic acid salt is preferably used to indicate a salt of an alkaline metal or of an alkaline earth metal, such as for example sodium, potassium, magnesium or calcium; preferably the hyaluronic acid salt is the sodium salt (sodium hyaluronate).

Hyaluronic acid (CAS 9004- 61- 9) is a non-sulfated glycosaminoglycan and devoid of protein core. Hyaluronic acid and the salts thereof are macromolecules. In particular, in the context of the present invention hyaluronic acid or the salt thereof, preferably sodium hyaluronate preferably has an average molecular weight comprised from 20 kDa to 4000 kDa (for example, 100 kDa, 200 kDa, 300 kDa, 400 kDa, 500 kDa, 600 kDa, 700 kDa, 800 kDa, 900 kDa, 1000 KDa, 1200 kDa, 1400 kDa, 1600 kDa, 1800 kDa, 2000 kDa, 2500 kDa o 3000 kDa; kDa=kiloDalton= 1000 Dalton), preferably comprised from 50 kDa to 1500 kDa, even more preferably comprised from 150 kDa to 1000 kDa.

The hyaluronic acid used in the context of the present invention together with an extract of Cannabis sativa, (preferably CBD) can be of animal origin or of plant origin. Hyaluronic acid of plant origin can be obtained through microbial fermentation of a plant substrate (for example soy), a biotechnology process consisting in allowing particular yeasts or bacteria that produce it spontaneously to ferment.

An example of powdered sodium hyaluronate that can be used in the context of the present invention (comprised in the mixture or composition of the invention together with an extract of Cannabis sativa) is a sodium hyaluronate (for example CAS No. 9067-32-7) having the following characteristics (European reference method or European Pharmacopoeia, in short EU. Pharm.): appearance (EP <1472>): white or almost white powder, very hygroscopic; solubility (EP <1472>): poorly soluble or soluble in water, practically insoluble in acetone and anhydrous ethanol; IR spectrum identification (EU. Pharm.:2.2.24); sodium identification (EU. Pharm. :2.3.1): sodium reaction; appearance in S solution (EU. Pharm.:2.2.1); absorbance at 600 nm of solution S (EU. Pharm.:2.2.25) (0.33% solution, on dry product): £ 0.01; pH (Eu. Pharm.: 2.2.3) (0.5% in water, on dry product) 5.0 ÷ 8.5; intrinsic viscosity at 25°C (EU. Pharm.:2.2.9) 1.35-1.60 m³/kg; loss on drying (LOD) (0.500 g at 100°C-110°C on diphosphorus pentoxide R for 6 hours; EU. Pharm. :2.2.32) £ 15.0% (6.0%-8.0%); sodium hyaluronate content (EU. Pharm. :2.2.25): 95.0%- 105,0%; compressibility index 16.66-21.46; Hauser ratio 1.20-1,27; average molecular weight from 700 kDa to 1000 kDa ( Size Exclusion Chromatography Method SEC TDA).

A further example of sodium hyaluronate that can be used in the context of the present invention (comprised in the mixture or composition of the invention together with an extract of Cannabis sativa) is a sodium hyaluronate (for example CAS No. 9067-32-7) obtained through food grade fermentation (or biotechnological process) and having the following characteristics: average molecular weight from 600 kDa to 800 kDa (chromatographic method), powder, minimum amount 90%-91% (w/w), glucuronic acid not less than 42% (w/w), loss on drying not higher than 10% (w/w), preferably pH 6.0-7.5 or 5.0-8.0 (5% aqueous solution).

In an embodiment, the composition of the invention comprises said (i) mixture M comprising or, alternatively, consisting of: a concentration (%) by weight of the active agent, preferably said extract of a plant of the gemsCannabis, preferably of Cannabis sativa L, comprised in the range from 50% to 95% with respect to the total weight of the mixture M (for example 60%, 70%, 80% or 90%), preferably from 55% to 90%, more preferably from 60% to 85%; and, if present, a concentration (%) by weight of lactose, comprised in the range from 5% (or 4.9% if present magnesium stearate) at 40% with respect to the total weight of the mixture M (for example 10%, 20% or 30%), preferably from 10% to 35%, more preferably from 15% to 30%; and, if present, a concentration (%) by weight of magnesium stearate, comprised in the range from 0 1% to 20% with respect to the total weight of the mixture M (for example 1%, 5%, 10% or 15%), preferably from 0.5% to 15%, more preferably from 1% to 10%.

In an alternative embodiment, the composition of the invention comprises said (i) mixture M comprising or, alternatively, consisting of: a percentage by weight of said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L, comprised in the range from 0.1% to 60% with respect to the total weight of the mixture M (for example 1%, 10%, 20%, 30%, 40% or 50%), preferably from 5% to 50%, more preferably from 10% to 40%.

In an alternative embodiment, the composition of the invention comprises said (i) mixture M comprising or, alternatively, consisting of: a percentage by weight of said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L, comprised in the range from 0.1% to 60% with respect to the total weight of the mixture M (for example 1%, 10%, 20%, 30%, 40% or 50%), preferably from 5% to 50%, more preferably from 10% to 40%; and a percentage by weight of hyaluronic acid (present as such or in the form of salt) comprised in the range from 40% to 90% with respect to the total weight of the mixture M (for example 50%, 60%, 70%, or 80%), preferably from 50% to 80%, more preferably from 60% to 80%. In a further preferred embodiment, the composition of the invention comprises said (i) mixture M comprising or, alternatively, consisting of: a percentage by weight of said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L, comprised in the range from 0.1% to 58% with respect to the total weight of the mixture M (for example 1%, 10%, 20%, 30%, 40% or 50%), preferably from 5% to 50%, more preferably from 10% to 40%; and a percentage by weight of hyaluronic acid (present as such or in the form of salt) comprised in the range from 40% to 90% with respect to the total weight of the mixture M (for example 50%, 60%, 70%, or 80%), preferably from 50% to 80%, more preferably from 60% to 80%; and, if present, a percentage by weight of a first support agent, preferably lactose, and/or of a second support agent, preferably magnesium stearate, comprised in the range from 2% to 35% with respect to the total weight of the mixture M (for example 5%, 10%, 20%, or 30%), preferably between 10% and 30%, more preferably between 15% and 25%.

In a further preferred embodiment, the composition of the invention comprises said (i) mixture M comprising or, alternatively, consisting of: a percentage by weight of said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L, comprised in the range from 0.1% to 50% with respect to the total weight of the mixture M (for example 1%, 10%, 20%, 30%, 40% o 50%), preferably from 5% to 50%, more preferably from 10% to 40%; and a percentage by weight of hyaluronic acid (present as such or in the form of salt) comprised in the range from 40% to 90% with respect to the total weight of the mixture M (for example 50%, 60%, 70%, or 80%), preferably from 50% to 80%, more preferably from 60% to 80%; and, if present, a percentage by weight of a first support agent, preferably lactose, and of a second support agent, preferably magnesium stearate, comprised in the range from 10% to 40% with respect to the total weight of the mixture M, preferably between 15% and 35%, more preferably between 20% and 30%.

The composition of the invention is in the form of powder, preferably a dry powder, said composition in the form of powder having a particle size distribution (average particle size distribution) such to make the composition suitable to be administered through the oral inhalation route. Preferably, the composition of the invention in the form of powder (dry powder) has a particle size distribution (average particle size distribution) comprised in the range from 0.1 pm or 1 pm to 200 pm (for example 0.5 pm, 1 pm, 1.5 pm, 2 pm, 2.5 pm, 3 pm, 3.5 pm, 4 pm, 4.5 pm, 5 pm, 6 pm, 8 pm, 10 pm, 20 pm, 30 pm, 40 pm, 50 pm, or 100 pm), preferably from 1 pm to 100 pm, more preferably from 1 pm to 50 pm. For example, said composition of the invention in the form of powder could have an average particle diameter of about 85 pm ± 3.9 pm.

In a preferred embodiment of the composition of the invention in the form of dry powder comprising CBD and, optionally, said first support agent and/or second support agent and/or hyaluronic acid, or salts thereof, the average particle diameter comprised in the range from 0.1 pm to 10 pm (for example 0.5 pm, 1 mhi, 1.5 mpi, 2 mhi, 2.5 mhi, 3 mih, 3.5 mhh, 4 mih, 4.5 mhi, 5 mhh, 5.5 mhh, 6 mhh, 6.5 mhi, 7 mhh, 7.5 mih, 8 mhi, 8.5 mph, 9 miti, or 9.5 mih), preferably from 0.5 pm to 5 pm, more preferably from 1 pm to 5 pm.

In the context of the present invention, the definition “average particle diameter¹' refers to the size of a particle comprising all the components of the composition, for example, depending on the embodiment of the invention, of a particle comprising said extract of a plant of the genus Cannabis , preferably of Cannabis sativa L, or said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L, and HA, or said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L, and HA and lactose, or said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L, and HA and magnesium stearate.

The powder particles may mainly be classified into inhalable and breathable. The inhalable fraction is represented by a suspension of particles of various diameters (generally comprised between 10 pm to 100 pm) whose dimensions are such to determine the interaction with the human respiratory system.

The inhalable fraction is represented by a suspension of particles with grain size class (generally < 4 pm, for example from 0.5 pm to 1 pm or 1 .5 pm or 2 pm or 2.5 pm or 3 pm or 3.5 pm) such to reach, due to the breathing motions, the non-ciliated part of the lung (alveolar area).

Alternatively, the dry powder particle size distribution of the composition or mixture M of the present invention may be indicated as the mass median aerodynamic diameter (in short, MMAD). Said mass median aerodynamic diameter (MMAD) of the powder (or dry powder) of the mixture M or composition of the present invention or, alternatively, of the individual components of the mixture (such as extract of Cannabis and/or hyaluronic acid and/or first supporting agent and/or second supporting agent) is measured according to standard methods and equipment known to the man skilled the art of inhalation powders (for example, using a Next Generation Impactor (NGI) as indicated by the EU. Pharm. 8.0, 2.9.18, and represented in figure 7).

The composition or mixture of the present invention (or the individual components thereof) may have a mass median aerodynamic diameter (in short, MMAD) comprised in the range from 0.5 pm to 50 pm (for example about 1 pm, 2 pm, 3 pm, 4 pm, 5 pm, 6 pm, 7 pm, 8pm, 9 pm, 10 pm, 11 pm, 12 pm, 13 pm, 14 pm, 15 pm, 16 pm, 18 pm, 20 pm, 22 pm, 24 pm, 26 pm, 28 pm, 30 pm, 35 pm, 40 pm, (all+0.5 pm)), preferably from 1 pm to 15 pm.

The mixture of the invention or, alternatively, the individual components of the mixture have a heterogeneity of the particle size distribution with values of geometric standard deviation (GSD) >1.22. Geometric standard deviation (GSD) measures the variability of the particle size distribution of an aerosol; it provides an indication of the distribution of inhalable particle diameters and differentiates aerosols in two classes: monodisperse, with GSD values < 1.22 and polydisperse with GSD values >1.22. Usually the aerosolised formulations are polydisperse formulations, i.e. consisting of particles of different sizes. For example, the geometric standard deviation for a mixture of the invention may be comprised in the range from 1.3 to 2.8, preferably from 1.8 to 2.1, confirming the heterogeneity of the particle size distribution that will be distributed both at the level of the upper airways (in a high percentage) and at the level of the first lower airways (in minimum percentage).

The particle size distribution (volume median diameter (DX(50)) of the powders of the mixture or composition of the invention (or of the individual components thereof) may be determined with a laser refractometer after dispersion of the powder in an organic solvent. The value of DX(50) of the mixtures or compositions of the present invention (or of the individual components thereof, such as extract of Cannabis and/or hyaluronic acid) may be comprised from 1 m to 100 pm (for example, 5 pm, 10 pm, 15 pm, 20 pm, 35 pm, 45 pm, 55 pm, or 80 pm), preferably from 1 pm to 20 pm. Said volume median diameter (DX(50)) may be understood as the diameter of each component of the mixture or, alternatively, as the diameter of the mixture or composition.

The particle size distribution of the powder of the mixture or composition of the present invention (or of the individual components thereof) may be determined with a particle sizer (for example, AccuSizer™ Particle Sizer Model 770; particle sizing system , Santa Barbara California, USA). The volume median diameter (VMD) of the powder of the mixture or composition of the present invention (or of the individual components thereof, such as extract of Cannabis and/or hyaluronic acid) may be comprised from 1 pm to 100 pm (for example, 5 pm, 10 pm, 15 pm, 20 pm, 30 pm, 35 pm, 45 pm, 55 pm, or 80 pm), preferably from 1 pm to 20 pm.

The volume median diameter (VMD) of a first or second support agent (for example, lactose or mannitol) present in the mixtures M or compositions of the present invention may be comprised from 1 pm to 150 pm (for example, 5 pm, 10 pm, 15 pm, 20 pm, 30 pm, 40 pm, 50 pm, 60 pm, 70 pm, 80 pm, 90 pm, 100 pm, 110 pm, 120 pm, 130 pm, or 140 pm).

In the context of the present invention, the expression “dry powder" is used to indicate a powder having a low moisture content (water), for example a powder having a moisture content comprised in the range from 0.01% to10% or 30% by weight with respect to the total weight of the powder (for example, 0.5%, 1%, 2%, 4%, 6%, 8%, 15%, or 20%), preferably from 0.1% to 5%, more preferably from 0.1% to 3%. Said water content is determined by means of methods and equipment known to the man skilled in the art, for example by means of thermogravimetric analysis (TGA). The mixture or composition of the invention in the form of dry powder may be in the solid form of micronized dry powder.

The composition of the present invention may comprise - optionally in addition to said first support agent (preferably lactose) and, if present, to said second support agent (preferably magnesium stearate) and/or hyaluronic acid or a salt thereof - further (ii) pharmaceutical or food grade additives and/or excipients, i.e. a substance devoid of therapeutic activity suitable for pharmaceutical or food use. In the context of the present invention the acceptable ingredients for pharmaceutical or food use comprise all ancillary substances known to the man skilled in the art such as, by way of non-limiting example, diluents, solvents (including water, glycerine, ethyl alcohol), solubilisers, thickeners, sweeteners, flavour-enhancement agents, colorants, lubricants, surfactants, antimicrobials, antioxidants, preservatives, pH stabilisation buffers and the mixtures thereof.

Besides the components of the (i) mixture M mentioned above (such as an active agent (i.e. said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L), and, optionally, a first and a second support agent and/or hyaluronic acid or a salt thereof) and, optionally, besides further (ii) additives and/or excipients, the composition according to the present invention may further comprise further active ingredients such as, by way of non-limiting example, anti-inflammatories, antioxidants, antibacterial agents, disinfectants, vasoconstrictors, probiotics, extracts of medicinal plants, vitamins, mineral salts, further mucolytics and generally products for the treatment of inflammations or infections or allergies of the respiratory system.

The mixture or composition of the invention may be produced in the form of dry powder for inhalation by means of processes and equipment known to the man skilled in the art of inhal able drugs or products. In a preferred embodiment, the composition of the invention is prepared using the process for the mechanical mixing of the single components. In an alternative embodiment, the composition of the invention is prepared by means of a spray-drying process.

The composition of the invention may be a pharmaceutical composition, nutraceutical composition, dietary supplement or food for special medical purposes (FSMP) or a medical device composition.

The expression "medical device” in the context of the present invention is used according to the meaning laid down by the Italian Legislative Decree n° 46, dated 24 February 1997 or according to the new Medical Devices Regulation (UE) 2017/745 (MDR), i.e. it indicates a substance or another product, used alone or in combination, designated by the manufacturer to be used in humans for the diagnosis, prevention, control, therapy or attenuation of a disease, the product not exercising the main action, in or on the human body, for which it is designated, neither using pharmacological or immunology means nor by means of a metabolic process but the function thereof can be coadjuvated by such means. Forming an object of the present invention is the composition of the invention as defined above (such as, comprising an active agent, preferably said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L, and, optionally, a first and/or a second support agent such as lactose and magnesium stearate, and/or hyaluronic acid or a salt thereof) for use as medicament.

Furthermore, forming an object of the present invention is the composition of the invention as defined above (such as, comprising an active agent, preferably said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L., and, optionally, a first and/or a second support agent, such as lactose and magnesium stearate, and/or hyaluronic acid or a salt thereof) for use in a method for the preventive and/or curative treatment of mucus hypersecretion and, preferably, of a disease, symptom and/or disorder associated with said mucus hypersecretion, in a subject in need, preferably wherein said composition for use is administered through the oral inhalation actuated by an aspiration action by the subject.

Furthermore, forming an object of the present invention is the composition of the invention as defined above (such as, comprising an active agent, preferably said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L, and, optionally, a first and/or a second support agent, such as lactose and magnesium stearate, and/or hyaluronic acid or a salt thereof) for use in a method for the preventive and/or curative treatment of inflammations or infections (bacterial or viral) or allergies of the respiratory system (upper and/or lower airways), preferably associated with mucus hypersecretion. Preferably, said inflammations or infections or allergies of the respiratory system are selected from the group comprising or, alternatively, consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis, pertussis, pneumonia, pleuritis, bronchiolitis, cold, sinusitis, rhinitis, tracheitis, pharyngitis, laryngitis, epiglottitis, bronchiectasis, acute laryngotracheobronchitis, respiratory complications and COVID-19 disease (coronavirus disease 2019) caused by SARS-CoV2 virus.

Furthermore, forming an object of the present invention is a dispensing device (in short device of the invention or, simply, device) for the administration - through the oral inhalation route - of the composition of the invention in form of powder, preferably dry powder, to a subject in need, wherein said device releases an effective dose (predetermined effective dose) of the composition of the invention when actuated by the subject through oral aspiration (in short device of the invention or dispensing device of the invention).

In the context of the present invention, the terms "dispensing device" or "dry powder inhaler" or "dry powder inhaler that can be actuated through oral aspiration by a subject” are synonyms that can be used interchangeably.

The dispensing device of the invention is a state of the art inhaler, without propellant, which releases an effective dose of the composition of the invention when actuated by the subject through oral aspiration. In the context of the present invention, the expression "oral aspiration" or "oral aspiration action” is used to indicate that the subject inhales or exhales using the mouth in a single action (one-time aspiration action) at a force intensity such to allow the device of the invention to dispense a predetermined dose of the composition of the invention in the form of powder in the dispensing device in question.

Said predetermined dose of the composition of the invention that can be dispensed by the device of the invention by means of the oral aspiration action by the subject may vary according to the variation of the age of the subject, the physical size of the subject (number of Kg) and the type of disease or disorder being treated.

Preferably, the device of the invention allows, by means of only one oral aspiration action, the dispensing of a dose of composition of the invention in dry powder form comprised in the range from 10 mg to 70 mg, preferably from 20 mg to 50 mg, more preferably from 35 mg to 40 mg.

Alternatively, said dose of composition of the invention in the form of dry powder comprised in the range from 10 mg to 70 mg, preferably from 20 mg to 50 mg, more preferably from 35 mg to 40 mg, may be dispensed by the device of the invention by means of an “n” number of oral aspirations, wherein “n” is a number variable from 2 to 4, preferably 2.

Furthermore, in order to reach the daily dose of the composition of the invention required for said subject, the administration of said predetermined dose, dispensed by the device of the invention through one or more oral aspiration actions of the subject, can be carried out only 1 time per day or repeated 2 or 3 or 4 or 5 or 6 times per day.

The dispensing device of the invention can be of the single-use (disposable) or refillable type. In a preferred embodiment, the device of the invention is refillable with the possibility of having single-dose or multi-dose.

The dispensing device of the invention, when refillable, can be of the single-dose or multi-dose type; when the dispensing device is of the multi-dose type it may contain a dosing indicator. In a preferred embodiment, the dispensing device of the invention is of the single-use (disposable) single-dose type (for example, Figures 1-6).

The dispensing device of the invention for the administration of a dry powder through the oral inhalation route comprises;

- a compartment for containing the powder comprising the composition in the form of dry powder according to any one of the embodiments of the invention;

- an aspiration channel, wherein a first end is directly or indirectly connected to the powder containment compartment and a second end allows the subject to carry out the oral aspiration action; and, optionally,

- a compartment for containing the loader, wherein said loader, single-dose or multi-dose, contains the composition of the invention in the form of powder; and wherein said dispensing device of the invention is structured so as to dispense a dose of said composition following an oral aspiration action by the subject in need of said administration.

When the device of the invention is "refillable”, the composition of the invention is loaded into the powder containment compartment using said loader comprising the composition of the invention; said container may be a single-dose container (for example a capsule or a sachet) or a multi-dose container, preferably a single-dose loader. Furthermore, the loader may be inside the device of the invention (internal loader) or outside the device of the invention (external loader).

In an embodiment of the refillable device, said loader is an external loader not housed in the device and the device is structured so as to allow the direct transfer of a single-dose of said composition from the external loader (single-dose or multi-dose) to the powder containment compartment (direct loading refillable device). For example, said single-dose external loader is a sachet containing the composition of the invention in the form of dry powder.

In an alternative embodiment of the refillable device, said loader is an internal loader housed in the device in a loader containment compartment and the device is structured so as to allow the indirect transfer of a single-dose of said composition from the internal loader (single-dose or multi-dose) to the powder containment compartment by actuating a pressure on the device which causes the opening of the internal loader (indirect loading refillable device) or, alternatively, by actuating a pressure on the internal loader (for example Figures 1-6). For example, said single-dose internal loader is a capsule containing the composition of the invention in the form of dry powder, for example, a capsule made of flexible material, such as an aluminium capsule.

The expression "refillable", “single-dose” dispensing device is used in the context of the present invention to indicate that a single-dose of the composition of the invention is contained in a single-dose container separated or separable from the dispensing device (for example a sachet or a capsule). Said single-dose of the composition of the invention is transferred from the single-dose container in the dispensing device in the powder containment compartment and, lastly, said single-dose of the composition of the invention is dispensed by the dispensing device to the subject through oral aspiration by the subject (for example by means of one or more aspiration actions). The advantage of the “single-dose” dispensing device lies in the fact that the subject does not risk taking more than one dose, thus guaranteeing maximum safety.

The expression “refillable”, “multi-dose” dispensing device is used in the context of the present invention to indicate that a multi dose of the composition of the invention in the form of powder is contained in a multi dose container separated or separable from the dispensing device. Such multi-dose container, containing a defined number of doses of the composition of the invention, is inserted into the dispensing device of the invention (in the loader containment compartment) before the dispensing of said defined number of doses. Subsequently, a single-dose of the composition of the invention is transferred from said multi-dose container into the dispensing device in the powder containment compartment, for example by means of pressure on the device or on the multi-dose container inserted into the device by a subject (for example pressure exerted by the hand of the subject on a part of the device or on the multi-dose container to load the single-dose of composition to be dispensed into the special powder containment compartment; indirect multi-dose refillable dispensing device). Lastly, the single-dose of the composition of the invention loaded into the dispensing device (in the loader containment compartment) is dispensed by the dispensing device to the subject through oral aspiration by the subject (for example by means of one or more aspiration actions).

The dispensing device of the invention, when of the single-dose refillable type, can be of the "direct loading” type (with external loader) or of the “indirect loading type” (with internal loader).

In an embodiment, the dispensing device of the invention is of the indirect loading single-dose refillable type in that the powder (dry powder) is contained in the device (internal container) and it is released into the dispensing device (in the powder containment compartment) upon pressing by the subject.

In an alternative embodiment, the dispensing device of the invention is of the direct loading single-dose refillable type

The expression “direct loading'¹ “refillable'¹, “single-dose” device is used in the context of the present invention to indicate that the single-dose of the composition of the invention is contained in a single-dose container separated from the device (external container), for example a sachet. The single-dose of the composition of the invention is directly transferred from the single-dose container to the dispensing device of the invention (in the powder containment compartment) before dispensing, for example by means of the opening of the single-dose container (e.g. a sachet) by a subject and direct transfer of the composition of the invention in the form of powder from the single-dose container to the dispensing device, more precisely to the powder containment compartment. Lastly, the composition of the invention is dispensed by the dispensing device to the subject through oral aspiration by the subject (for example by means of one or more aspiration actions).

The expression “indirect loading” “refillable”, “single-dose" device is used in the context of the present invention to indicate that the single-dose of the composition of the invention is contained in a single-dose container separated from the device, for example a capsule. Such container, containing the composition of the invention is inserted into the dispensing device (in the loader containment compartment) before dispensing. An opening is subsequently created in said single-dose container, for example by exerting pressure on the dispensing device by a subject, so that the composition is released into the dispensing device, more precisely into the powder containment compartment. Lastly, the single-dose of the composition of the invention is dispensed by the dispensing device to the subject through oral aspiration by the subject (for example by means of one or more aspiration actions).

The dispensing device of the invention allows the dispensing of the composition of the invention in the form a powder cloud which is durable over time and guarantees a more effective inhalation as well as a uniform and optimal distribution of the active ingredient or active ingredients comprised in the composition in the respiratory system, leading to benefits in terms of therapeutic results.

According to a preferred embodiment, a dry powder inhaler that can be actuated through oral aspiration by a subject according to the present invention (for example represented in Figures 1-6) comprises a substantially pipe-shaped hollow body comprising a first portion (1) for housing said blister (C), and a second portion (2) connected to said first portion (1) for dispensing said mixture or composition in the form of dry powder by means of a primary air flow (FP) which carries the powder from an inner drop region (5), located on the bottom of said first portion (1), along a dispensing duct (3) whose end is suitable to be arranged in the mouth of said subject, said dispensing duct (3) being divided horizontally by a separator septum (4) into an upper duct (3a) which dispenses said primary air flow (FP) and a lower duct (3b) which dispenses a secondary air flow (FS) devoid of powder, the aspiration of the air forming the primary flow (FP) being obtained by means of at least three air intakes (7) formed in the first portion (1) which are preferably arranged symmetrically with respect to the longitudinal centreline plane of the inhaler, the aspiration of the air forming the secondary flow (FS) being provided by means of an air intake (8) obtained at the distal end of said lower duct (3b), the inhaler being characterised in that said base for supporting the blister (C) includes a plurality of horizontal support surfaces (9) projecting into the first portion (1), and oriented flow channels (11) formed in the support base extending between said at least three air intakes (7) and the internal region where the powder (5) drops.

The term “blister” is used to indicate a closed, sealed and openable container.

Forming an object of the present invention is method for the treatment of mucus hypersecretion and/or of an inflammation or infection or allergy of the respiratory system, preferably of diseases, symptoms or disorders associated with mucus hypersecretion, in a subject in need, wherein said treatment method provides for the administration of the composition of the invention as defined above through the inhalation route by means of oral aspiration by the subject using the dispensing device of the present invention (or treatment method using the kit of the invention).

Forming an object of the present invention is the non-therapeutic use of the composition of the invention as defined above or the kit of the present invention for the non-therapeutic treatment of mucus hypersecretion and of a disorder associated with said mucus hypersecretion in a subject in need (healthy or non-pathological subject), wherein said non-therapeutic use provides for the administration of said composition through the inhalation route by means of oral aspiration using the dispensing device of the present invention.

In a preferred embodiment, the non-therapeutic use of the composition or kit according to the invention is for the non-therapeutic treatment of a disorder associated with said mucus hypersecretion such as an inflammation or infection or allergy of the respiratory system.

Preferably, said inflammation or infection (bacterial or non-bacterial or viral) or allergy of the respiratory system is selected from the group comprising or, alternatively, consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis, pertussis, pneumonia, pleuritis, bronchiolitis, cold, sinusitis, rhinitis, tracheitis, pharyngitis, laryngitis, epiglottitis, bronchiectasis, acute laryngotracheobronchitis and respiratory complications.

Furthermore, forming an object of the present invention is the use of said dispensing device (in short device of the invention of, simply, device) for the administration - through the oral inhalation route - of the composition of the invention in the form of powder, preferably dry powder, to a subject in need subject, wherein said device releases an effective dose (predetermined effective dose) of the composition of the invention when actuated by the subject through oral aspiration (in short device of the invention or dispensing device of the invention).

Lastly, forming an object of the present invention is a kit comprising (a) the composition of the invention, according to any one of the embodiments of the invention, (b) the dispensing device according to the invention for administering the composition of the invention to a subject in need; (c) instructions for administering the composition of the invention by means of the (b) dispensing device; and, optionally, (d) an additional active ingredient, that can be in a dosing form equal to and/or different from the composition of the invention (in short kit of the invention).

According to an aspect of the present invention, said kit for the administration - through the inhalation route - of the mixture or composition of the invention (in short, kit of the present invention) comprises:

- a dry-powder single-dose inhaler (in short, inhaler of the present invention) having the characteristics reported hereinafter and in the patent document EP 3386575 B1 incorporated in the present description in the parts describing the inhaler for reference, such as from [0024] to [0041] and from Figure 1 to Figure 8 of EP 3386575 B1; and

- at least one blister (or cartridge) comprising the composition in the form of dry powder of the invention according to any one of the aspects or embodiments described in the present invention (mixture comprising an extract of Cannabis sativa and, optionally, hyaluronic acid), wherein said blister is housed in a housing present in said inhaler in order to administer said composition for inhalation through oral aspiration, aspiration exerted by a subject in need of a treatment. In the present description the terms “blister” and “cartridge" (or cartridge (C)) are synonyms and used interchangeably.

In a first aspect of the kit of the present invention, said at least one blister (comprising a mixture or composition of the invention therein) may be prepared and sold separately from the inhaler of the invention. In this case, the user houses/places the blister in the housing present in said inhaler when using the inhaler.

According to said first aspect, the inhaler present in the kit may be of the single-use (disposable) or multi use type; in the case of multi-use inhaler, the kit will for example contain one inhaler and a determined number of blisters to be inserted into the inhaler from whenever required; in the case of a single-use (disposable) inhaler, the kit will for example contain “n” inhalers and “n” blisters.

In a second aspect of the kit of the present invention, said blister (comprising a mixture or composition of the invention therein) is fixedly inserted into said inhaler of the present invention at the time of production thereof (for example by the manufacturer). According to said second aspect the kit is disposable.

According to a preferred embodiment, said kit of the invention (for example represented in Figures 4-6), for the administration - through the inhalation route - of a composition in the form of dry powder according to the present invention, comprises:

(I) at least one blister (C) comprising the composition of the present invention in the form of dry powder for inhalation comprising an extract of Cannabis sativa (according to any one of the described embodiments), and

(II) a dry powder inhaler that can be actuated through oral aspiration by a subject (for example represented in Figures 1-6), wherein said inhaler comprises a substantially pipe-shaped hollow body comprising a first portion (1) for housing said blister (C), and a second portion (2) connected to said first portion (1) for dispensing said mixture or composition in the form of dry powder by means of a primary air flow (FP) which carries the powder from an inner drop region (5), located on the bottom of said first portion (1), along a dispensing duct (3) whose end is suitable to be arranged in the mouth of said subject, said dispensing duct (3) being divided horizontally by a separator septum (4) into an upper duct (3a) which dispenses said primary air flow (FP) and a lower duct (3b) which dispenses a secondary air flow (FS) devoid of powder, the aspiration of the air forming the primary flow (FP) being obtained by means of at least three air intakes (7) formed in the first portion (1) which are preferably arranged symmetrically with respect to the longitudinal centreline plane of the inhaler, the aspiration of the air forming the secondary flow (FS) being provided by means of an air intake (8) obtained at the distal end of said lower duct (3b), the inhaler being characterised in that said base for supporting the blister (C) includes a plurality of horizontal support surfaces (9) projecting into the first portion (1), and oriented flow channels (11) formed in the support base extending between said at least three air intakes (7) and the internal region where the powder (5) drops.

Said kit of the present invention is for use as medicament, for example 1 for use in a method for the preventive and/or curative treatment of mucus hypersecretion and/or bacterial inflammations or infections or viral infections or allergies of the respiratory system (upper and/or lower airways) in a subject in need. Preferably, said inflammations or infections (bacterial or non-bacterial or viral) or allergies of the respiratory system is selected from the group comprising or, alternatively, consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis, pertussis, pneumonia, pleuritis, bronchiolitis, cold, sinusitis, rhinitis, tracheitis, pharyngitis, laryngitis, epiglottitis, bronchiectasis, acute laryngotracheobronchitis and respiratory complications.

According to an aspect, the composition or kit according to the present invention (according to any one of the described embodiments) may be for use in a method for the treatment of the COVID-19 disease (coronavirus disease 2019) caused by SARS-CoV2 virus.

Cannabidiol (CBD) has a potential to limit the severity and progression of the disease for several reasons: (a) the extracts of Cannabis sativa with a high content of cannabidiol showed to down-regulate the expression of the two key SARS-CoV2 receptors (angiotensin converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2)) in human epithelia models, (b) cannabidiol exerts a wide range of immunomodulatory and anti-inflammatory effects and it can mitigate uncontrolled production of cytokines responsible for acute lung damage, (c) PPARy agonist, cannabidiol may exhibit direct antiviral activity and (d) PPARy agonists are regulators of fibroblast/myofibroblast activation and they can inhibit the development of pulmonary fibrosis, thus improving lung function in healed patients.

Furthermore, SARS-CoV-2 infection causes inflammation due to the immune response and the triggering of a cytokine "storm", which cannabinoids can combat, given that they are effective in suppressing immune and inflammatory functions.

Examples of bacteria or viruses responsible for said infections/inflammations of the upper and/or lower airways can be: strains of the group A Streptococcus (GAS, responsible for pharyngitis and infections of the throat, for example the species Steptococcus pyogenes ), Coxsackievirus B5, Herpes Simplex Virus-1, Mumps Virus, Adenovirus-5, Influenza Virus (for example Influenza Virus A/H1N1), Human Herpesvirus-6, Porcine Parvovirus, Porcine Reproductive and Respiratory Syndrome Virus, RNA virus (for example Coronavirus), DNA virus.

The expression "treatment method” in the context of the present invention is used to indicate an action, comprising the administration of a therapeutically effective amount of a substance, or mixture of substances or combination thereof, with the aim of eliminating, reducing/decreasing or preventing a pathology or disease and its symptoms or disorders.

Unless specified otherwise, the indication that a composition "comprises” one or more components or substances means that other components or substances can be present besides the one, or the ones, indicated specifically.

The compositions of the present invention comprising said extract of a plant of the genus Cannabis , preferably of Cannabis sativa L. alone or combined with hyaluronic acid and/or lactose and/or magnesium stearate, in powder form, preferably dry powder, for inhalation by means of oral aspiration, are effective for the therapeutic and non-therapeutic treatment of mucus hypersecretion (or bronchial mucus) and/or of the inflammations or infections or allergies of the respiratory system, preferably of the various diseases, symptoms or disorders of the respiratory system associated with said bronchial mucus hypersecretion.

In addition, the administration of the compositions of the invention by means of the dispensing device of the invention, actuated by the aspiration of the subject undergoing the administration is such make the administration of the effective dose effective and optimise the inherent effectiveness of the compositions of the invention to the maximum.

The composition of the invention, according to any one of the embodiments defined in the present invention, shows a good flowability, a good uniformity of distribution of the active ingredient (mucolytic agent and/or anti-inflammatory agent, preferably said extract of a plant of the genus Cannabis , preferably of Cannabis sativa L) and an appropriate chemical and physical stability prior to use

Furthermore, the composition of the invention, when inhaled using the inhalation device of the invention actuated by means of a single aspiration action by the subject to whom the composition is administered, gives forth a good inhalable fraction and an accurate therapeutically active dose of the active ingredient (mucolytic and/or anti-inflammatory agent, preferably said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L.).

The expression "good flowability'¹ refers to a composition that can be easily handled during the preparation process and it is capable of guaranteeing an accurate and reproducible administration of the therapeutically effective dose when administered using the device of the invention by means of the aspiration action of the subject. The flow characteristics can be evaluated by measuring the Carr index; a Carr index lower than 25 is usually used to indicate good flow characteristics.

The expression "distribution uniformity” refers to a composition in which, at the time of mixing, the uniformity of the content of the active ingredient, expressed as the relative standard deviation (RSD), is lower than 5%.

The expression "chemically stable" refers to a formulation that meets the ICH Q1A guidelines referring to "Stability testing of novel active substances (and medicinal products)". The expression "physically stable” refers to a formulation in which if several components of the dry powder particles of the composition of the invention are present, these components substantially do not separate during the process for preparing the dry powder and/or over the time comprised between the preparation and the use of the composition.

The tendency to separate can be evaluated according to Staniforth et at, J. Pharm. Pharmacol., 34.700- 706, 1982, which is wholly incorporated herein for reference, and it is considered acceptable if the distribution of the active ingredient in the dry powder composition after the test, expressed as the relative standard deviation (RSD), does not change significantly with respect to that of the composition prior to the test.

The expression "inhalable fraction" refers to an index of the particle percentage of active ingredient (mucolytic and/or anti-inflammatory agent, preferably said extract of a plant of the genus Cannabis , preferably of Cannabis sativa L.) which reach the lungs (deep area) in a subject. The inhalable fraction, also referred to as the fine particle fraction (FPF), is evaluated using appropriate in vitro apparatus such as Multistage Cascade Impactor or Multi Stage Liquid Impinger (MSLI) according to the procedures indicated in common pharmacopeia. FPF is calculated from the ratio between the dispensed dose and the fine particle mass (of fine particle dose, in short FPD). An inhalable fraction greater than 30% is an index of good inhalation performance.

The expression "accurate therapeutically active dose of the active ingredient" refers to a composition in which the variation between the average dispensed daily dose and the average emitted dose is equal to or lower than 15%, preferably lower than 10%.

In the context of the present invention, the expressions “active agent” and “active ingredient” are synonyms and they refer to the active agent, preferably said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L..

Embodiments (FRnr) of the present invention are reported below:

FR1. A composition in a dry powder form for oral inhalation, preferably for oral aspiration, comprising:

(i) a mixture M comprising, or alternatively, consisting of an active agent and, optionally,

(ii) at least one acceptable pharmaceutical or food grade additive and/or excipient.

FR2. A composition according to FR1, wherein said active agent, mucolytic and/or anti-inflammatory, is said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L.

FR3. A composition according to FR1 or FR2, wherein said (i) mixture M further comprises lactose.

FR4. A composition according to any one of FR1 to FR3, wherein said (i) mixture M further comprises magnesium stearate.

FR5. A composition according to any one of FR1 to FR4, wherein said (i) mixture M further comprises a hyaluronic acid or an acceptable pharmaceutical or food grade salt thereof. FR6. The composition according to any one of FR1 to FR5, wherein the (i) mixture M comprises or, alternatively, consists of: a concentration by weight of the active agent, mucolytic and/or anti-inflammatory, preferably said extract of a plant of the genus Cannabis, preferably of Cannabis sativa L, comprised in the range from 50% to 95% with respect to the total weight of the mixture, preferably from 55% to 90%, more preferably from 60% to 85%; of a concentration by weight of lactose, comprised in the range from 5% to 40% with respect to the total weight of the mixture, preferably from 10% to 35%, more preferably from 15% to 30%; and, if present, of a concentration by weight of magnesium stearate, comprised in the range from 0.1% to 20% with respect to the total weight of the mixture, preferably from 0.5% to 15%, more preferably from 1% to 10%.

FR7. The composition according to any one of FR1 to FR6, wherein said composition is for use in a method for the preventive and/or curative treatment of mucus hypersecretion and/or inflammations or infections or allergies of the respiratory system, preferably of a disease, symptom and/or disorder associated with said mucus hypersecretion, in a subject in need.

FR8. The composition for use according to FR7, wherein said disease, symptom and/or disorder associated with said mucus hypersecretion is an inflammation or infection or allergy of the respiratory system, preferably wherein said inflammation or infection or allergy of the respiratory system is selected from the group comprising or, alternatively, consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis, pertussis, pneumonia, pleuritis, bronchiolitis, cold, sinusitis, rhinitis, tracheitis, pharyngitis, laryngitis, epiglottitis, bronchiectasis, acute laryngotracheobronchitis and respiratory complications.

FR9. Dispensing device for the administration - through the oral inhalation route - of the composition in the form of powder according to any one of FR1 to FR8 to said subject in need (pathological or healthy), wherein said device releases an effective dose of said composition when actuated by the subject by means of oral aspiration.

FR10. Kit comprising:

(a) the composition according to any one of FR1 to FR8, preferably wherein said composition is contained in a container;

(B) the device according to FR9; and

(c) instructions on the method of use of said (a) composition and of said (b) device.

FR11. Non-therapeutic use of the composition according to any one of FR1 to FR10, wherein said use is for the non-therapeutic treatment of mucus hypersecretion and of a disorder associated with said mucus hypersecretion in a subject in need (healthy subject), wherein said non-therapeutic use provides for the administration of said composition through the inhalation route by means of oral aspiration using the dispensing device according to FR9 and FR10.

Claims

1. A kit for the administration of a composition in the form of dry powder through the inhalation route, wherein said kit comprises:

(I) at least one blister (C) comprising the composition in the form of dry powder for oral inhalation, wherein said composition comprises:

(ii) at least one acceptable pharmaceutical or food grade additive and/or excipient, wherein said active agent is an extract of Cannabis sativa L and

(II) a dry-powder inhaler operable through oral aspiration by a subject, wherein said inhaler comprises a substantially pipe-shaped hollow body comprising a first portion (1) for housing said blister (C), and a second portion (2) connected to said first portion (1) for dispensing said mixture or composition in the form of dry powder by means of a primary air flow (FP) which carries the powder from an inner drop region (5), located on the bottom of said first portion (1), along a dispensing duct (3) whose end is suitable to be arranged in the mouth of said subject, said dispensing duct (3) being divided horizontally by a separator septum (4) into an upper duct (3a) which dispenses said primary air flow (FP) and a lower duct (3b) which dispenses a secondary air flow (FS) devoid of powder, the aspiration of the air forming the primary flow (FP) being provided by means of at least three air intakes (7) formed in the first portion (1) which are preferably arranged symmetrically with respect to the longitudinal centreline plane of the inhaler, the aspiration of the air forming the secondary flow (FS) being provided by means of an air intake (8) obtained at the distal end of said lower duct (3b), the inhaler being characterised in that said support base for the blister (C) includes a plurality of horizontal support surfaces (9) projecting into the first portion (1), and oriented flow channels (11) formed in the support base extending between said at least three air intakes (7) and the inner drop region (5).

2. The kit according to claim 1 for use as medicament.

3. The kit according to claim 1 or 2 for use in a method for the preventive and/or curative treatment of mucus hypersecretion and/or bacterial inflammations or infections or viral infections or allergies of the respiratory system in a subject in need.

4. The composition in the form of dry powder for oral inhalation according to claim 1 for use in a method for the preventive and/or curative treatment of mucus hypersecretion and/or bacterial inflammations or infections or viral infections of the respiratory system in a subject in need, and wherein said composition for use is administered through the oral inhalation actuated by an aspiration action by the subject, provided that said composition is not for use in the treatment of a cold, and wherein said composition comprises:

(ii) at least one acceptable pharmaceutical or food grade additive and/or excipient, wherein said active agent is an extract of Cannabis sativa L.

5. The composition for use according to claim 4, wherein said extract of Cannabis sativa L. comprises at least one compound selected from the group comprising or, alternatively, consisting of: tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), tetrahydrocannabivarin (THCV), cannabinol (CBN), cannabichromene(CBN), cannabicyclol (CBL), cannabielsoin (CBE), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabinidiol (CBND), cannabitriol (CBT), cannabivarin (CBV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monoethylether (CBGM), or acceptable pharmaceutical or food grade salts thereof, and mixtures thereof; preferably wherein said extract of Cannabis sativa L. comprises or, alternatively, consists of CBD, CBDV, THCV, CBG, CBDA or acceptable pharmaceutical or food grade salts thereof, and optionally traces of other compounds selected from said group;

6. The composition for use according to claim 4 or 5, wherein said extract of Cannabis sativa L. comprises or, alternatively, consists of:

7. The composition for use according to any one of claims 4-6, wherein said extract of Cannabis sativa L. comprises or, alternatively, consists of cannabidiol (CBD) and tetrahydrocannabinol (THC) or acceptable pharmaceutical or food grade salts thereof, wherein an amount of THC is equal to or less than 0.5% by weight with respect to the total weight of said extract, preferably equal to or less than 0.2% by weight, more preferably equal to or less than 0.1% by weight, even more preferably equal to or less than 0.05% by weight.

8. The composition for use according to any one of claims 4- 7, wherein said (i) mixture M further comprises a hyaluronic acid or an acceptable pharmaceutical or food grade salt thereof.

9 The composition for use according to any one of claims 4-8, wherein said (i) mixture M further comprises: - a first support agent selected from the group comprising or, alternatively, consisting of lactose, a dextran, mannitol and mixtures thereof; more preferably lactose; and/or

- a second support agent, wherein said second agent is a stearate metal or a derivative thereof selected from the group comprising or, alternatively, consisting of: magnesium stearate, zinc stearate, calcium stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and mixtures thereof; preferably magnesium stearate.

10. The composition for use according to claim 9, wherein the (i) mixture M comprises or, alternatively, consists of said extract of Cannabis sativa L. and hyaluronic acid, or salts thereof, and, furthermore, lactose and/or magnesium stearate.

11. The composition for use according to any one of claims 4-10, wherein the (i) mixture M comprises or, alternatively, consists of a percentage by weight of extract of Cannabis sativa L comprised in the range from 0.1% to 60% with respect to the total weight of the mixture M, preferably from 5% to 50%, more preferably from 10% to 40% and, optionally, a percentage by weight of hyaluronic acid, or a salt thereof, comprised in the range from 40% to 90% with respect to the total weight of the mixture M, preferably from 50% to 80%, more preferably from 60% to 80%.

12 The composition for use according to claim 9 or 10, wherein the (i) mixture M comprises or, alternatively, consists of: a percentage by weight of extract of Cannabis sativa L. comprised in the range from 0.1% to 58% with respect to the total weight of the mixture M, preferably from 5% to 50%, more preferably from 10% to 40%; and a percentage by weight of hyaluronic acid, or a salt thereof, comprised in the range from 40% to 90% with respect to the total weight of the mixture M, preferably from 50% to 80%, more preferably from 60% to 80%; and a percentage by weight of a first support agent, preferably lactose and/or of a second support agent, magnesium stearate, comprised in the range from 2% to 35% with respect to the total weight of the mixture M, preferably from 10% to 30%, more preferably from 15% to 25%.

13. The composition for use according to any one of claims 4-12, wherein said disease, symptom and/or disorder associated with said mucus hypersecretion is caused by or related with a bacterial inflammation or infection or viral infection of the respiratory system.

14. The composition for use according to any one of claims 4-13, wherein said inflammation or infection of the respiratory system is selected from the group comprising or, alternatively, consisting of: chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis, pertussis, pneumonia, pleuritis, bronchiolitis, sinusitis, non-allergic rhinitis, tracheitis, pharyngitis, laryngitis, epiglottitis, bronchiectasis, acute laryngotracheobronchitis, respiratory complications and SARS-CoV2 (COVID-19) virus infection.

15. The kit according to claim 1, wherein said at least one blister (C) comprising the composition in the form of dry powder according to any one of claims 4-12.

16. The kit for use according to claim 23, wherein said at least one blister (C) comprising the composition in the form of dry powder according to any one of claims 4-12.

17. The kit for use according to any one of claims 2, 3 and 16 wherein said disease, symptom and/or disorder associated with said mucus hypersecretion is caused by or related with a bacterial inflammation or infection or viral infection of the respiratory system.

18. The kit for use according to any one of claims 2, 3, 16 and 17, wherein said bacterial inflammation or infection or viral infection or allergy of the respiratory system is selected from the group comprising or, alternatively, consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis, pertussis, pneumonia, pleuritis, bronchiolitis, cold, sinusitis, rhinitis, tracheitis, pharyngitis, laryngitis, epiglottitis, bronchiectasis, acute laryngotracheobronchitis, respiratory complications and SARS-CoV2 (COVID-19) virus infection.