IT202100001349A1 - COMPOSITION IN THE FORM OF DRY POWDER FOR INHALATION COMPRISING A HYALURONIC ACID AND A CHONDROITIN SULPHATE, USE OF THE COMPOSITION AND INHALER DEVICE CONTAINING THE COMPOSITION - Google Patents

Description

DESCRIPTION of the invention entitled:

?COMPOSITION IN THE FORM OF DRY POWDER FOR INHALATION COMPRISING A HYALURONIC ACID AND A CHONDROITIN SULPHATE, USE OF THE COMPOSITION AND INHALER DEVICE CONTAINING THE COMPOSITION?

The present invention relates to a mixture or composition in the form of dry powder for oral inhalation comprising hyaluronic acid and chondroitin sulfate, or their salts. The present invention also relates to a kit comprising an inhaler for dry powders and a blister pack, wherein said blister pack contains said mixture or composition in the form of a dry powder comprising hyaluronic acid and chondroitin sulfate, or their salts. Finally, the present invention refers to said mixture or composition or kit for use in the preventive and/or curative treatment of pathologies and/or symptoms mainly affecting the mucous membranes and tissues of the oral cavity, upper and lower respiratory tracts and of the oesophagus, such as ulcers, lacerations and/or inflammation. These pathologies and/or symptoms affecting the mucous membranes and tissues of the oral cavity, the upper and lower respiratory tracts and the esophagus can be caused by gastric or biliary or mixed reflux in esophageal and/or extraesophageal areas or by infections bacterial or non-bacterial or from irritating factors, such as cigarette smoke, dust, pollution and various allergens.

The damage or inflammation of the mucous membranes and tissues of the oral tract, of the upper and lower respiratory tracts and/or of the esophagus are widespread problems in the population which, in addition to causing a deterioration in the quality of of life and a difficulty? in the intake of food and drink, they can cause permanent and highly serious damage.

The parietal cells, located in the gastric mucosa, are responsible for the secretion of hydrochloric acid in the stomach. Chemical and physical stimuli induce the release of numerous mediators which finely regulate this secretion. In some cases, however, there is an imbalance of these regulations resulting in acid hypersecretion. Furthermore, a malfunction of the lower esophageal sphincter leads to the ascent of gastric acid secretion and/or biliary and/or mixed secretion from the stomach to the esophagus and/or to extraesophageal regions. Said acid hypersecretion and/or acid gastric secretion and/or biliary and/or mixed secretion can? lead to pathological conditions such as gastroesophageal reflux disease, pharyngolaryngeal (or extra-esophageal) reflux disease and/or the formation of ulcers on the mucosa of the upper digestive tract up to the oral cavity, including the upper respiratory tract .

Gastroesophageal reflux disease (GERD or GERD, gastroesophageal reflux disease) ? a clinical condition characterized by massive ascent of gastro-duodenal contents into the esophagus. The strongly acidic gastric contents and the bile contained therein in contact with the esophageal mucosa lead to inflammatory states that can result in heartburn or esophageal ulcers. The characteristic symptoms of this disorder can be divided into typical (e.g. acid regurgitation, heartburn), atypical (e.g. feeling of gastric fullness, epigastric pain, dyspepsia, nausea) and extra-oesophageal (e.g. chronic cough, bronchospasm, laryngospasm, hoarseness throat, dysphonia, dysphagia, excessive throat clearing, throat pain or burning, sore throat, postnasal drip, laryngitis, pharyngitis, and/or other upper respiratory symptoms).

Pharyngolaryngeal reflux disease (RFL or LPR from English LaryngoPharyngeal Reflux) or extraesophageal reflux? a clinical condition characterized by the ascent of the gastro-duodenal contents from the stomach to the extra-oesophageal regions such as the upper respiratory tract (the nasal cavity, the paranasal sinuses, the oral cavity, the pharynx, the epiglottis and the larynx).

Acid hypersecretion, gastroesophageal, pharyngolaryngeal or extra-oesophageal reflux, ulcers in the gastric and oesophageal mucosa and throat, and other related symptoms can be treated with drug therapy (for example, H2 blockers, of the proton pump (PPI), etc.), or through compounds that exert a mainly mechanical action (for example, floating raft or the formation of film coating of the mucous membranes), or through the use of solutions and/or sprays based on hyaluronic acid, inactivated bacteria, and/or botanicals.

Furthermore, the mucous membranes and tissues of the upper and lower respiratory tracts are constantly subject to inflammation caused by infections of a bacterial or non-bacterial nature (for example virus infections) or by irritating factors, such as cigarette smoke, dust, pollution and various allergens.

Despite the presence on the market of various products for the treatment of diseases of the mucous membranes and tissues of the oral cavity, of the upper and lower respiratory tracts and of the esophagus connected to gastric and/or biliary reflux or to bacterial or non-bacterial infections, the demand for effective products, free of side effects, easy to use and inexpensive for the preventive and/or curative treatment of inflammation, ulcers and/or lesions of the mucous membranes and tissues of the oral tract, upper and lower respiratory tract and oesophagus .

Compositions comprising chondroitin sulfate and hyaluronic acid are known in the art for the treatment of disorders caused by gastric reflux to the tissues of the oral tract, the upper and lower respiratory tracts, the pharyngolaryngeal tract and/or the gastroesophageal tract, in which said compounds are in the form of syrups or tablets (tablets as they are, to be chewed or dissolved in the mouth).

The technical problem that the present invention faces and solves? that of providing new formulations of mixtures or compositions comprising chondroitin sulphate and hyaluronic acid (or their salts) and new ways of administering said new formulations which are highly effective, free of side effects and easy to administer to any category of subjects for use in a method of treatment, preventive and/or curative, of pathologies and/or symptoms affecting the mucous membrane and tissues of the oral cavity, the upper and lower respiratory tract and the esophagus, such as, for example, ulcers, lacerations or inflammations, mainly caused , but not exclusively, from gastric reflux in an esophageal and/or extra-esophageal area or from infections of a bacterial or non-bacterial nature (for example from viruses) or from irritating factors, such as for example cigarette smoke, dust, pollution and various allergens.

The Applicant tackles and solves said technical problem, and others resulting from the present description, by providing mixtures or compositions in the form of dry powders for inhalation (by mouth) comprising chondroitin sulfate and hyaluronic acid, or their salts (in short, mixtures or compositions of ?invention).

Furthermore, the Applicant faces and solves said technical problem, and others which result from the present description, by providing a kit (in short, kit of the invention) comprising a specific single-dose dry powder inhaler (DPI, dry powder inhaler) (in short, inhaler of the invention), and a single-dose blister (or similar) comprising said mixture or composition of the invention, wherein said kit is effective for the inhaled administration of chondroitin sulfate and hyaluronic acid (or their salts) to a subject having need.

The administration of active substances in the form of dry powder by inhalation can cause problems, such as: cause cough in the subject to whom the powder is administered, difficulty? to dose low dosages that are constant and repeatable throughout the treatment due to the limited ability? emission of inhalers, powder packing problems, difficulty? by the subject to use the inhalers, difficulty? to adjust the dosage by the subject in case of multi-dose inhalers, sterility problems? bacterial in case of multi-use inhalers.

Therefore, ? felt the need? to be able to have both a dry powder having optimal characteristics for being inhaled orally, and a kit comprising, in addition to said dry powder, an administration device by inhalation (of said dry powder) which is free from the limitations and drawbacks present in current devices on the market.

Said mixtures or compositions of the invention comprising a chondroitin sulphate and hyaluronic acid (or salts thereof), when administered to a subject in need, are capable of exerting in a lasting and effective manner both a mechanical protection of the lining of the mucous membranes or tissues present in the oral cavity, in the upper and lower respiratory tract and/or in the esophagus, and an anti-inflammatory and re-epithelialisation and/or cicatrisation action of said mucous membranes or tissues.

The mixtures or compositions of the invention based on chondroitin sulphate and hyaluronic acid (or their salts) do not have relevant side effects and can be administered to all categories of subjects in need, including the elderly, pregnant or breastfeeding women, pediatric subjects ( 0-12 years), subjects with respiratory complications or other comorbidities.

Furthermore, the mixtures or compositions of the invention based on chondroitin sulphate and hyaluronic acid (or salts thereof) are easy to prepare and economically advantageous, thus such as the kit or the dry powder inhaler of the invention are simple to construct and cheap. Furthermore, both the kit of the invention and the dry powder inhaler of the invention are easy to use by any type of subject, including subjects with difficulty breathing. respiratory, for example asthmatics, children and the elderly. The easy use of the device of the invention allows to improve the adherence of the subject to the therapy. Furthermore, when is the device of the invention? disposable is free from problems of sterility? bacterial. Finally, if the insertion of the blister comprising the mixture or composition of the invention into the inhaler of the invention takes place by the manufacturer of the kit of the present invention, instead of by the user, the use of the device of the The invention is even more simple and immediate for the subject in need.

A diagram of the respiratory tract of a human subject? shown in Figure 8.

In the context of the present invention the terms ?upper respiratory tract? and ?upper respiratory tract? are synonyms used interchangeably and mainly represent nose (or nasal cavity), pharynx, larynx, trachea, and upper part of the bronchi.

In the context of the present invention the terms ?lower respiratory tract? and ?lower respiratory tract? and ?deep respiratory tract? are synonyms used interchangeably and mainly represent lower part of the bronchi, lungs, bronchioles, alveoli.

In the context of the present invention the terms ?blister? or ?single-dose blister? indicates a closed and sealed container having a volume suitable for housing a mixture or a composition of the present invention, said blister being perforable by the application of a pressure exerted manually by a subject, for example a plastic container or cartridge and/ or aluminum comprising on one side a pierceable aluminum sheet.

These aims and others which will become clear from the detailed description which follows are achieved by the mixtures, compositions and kits of the present invention thanks to the technical characteristics present in the description and claimed in the attached claims.

SUMMARY OF THE INVENTION

A first aspect of the present invention relates to a mixture, in the form of a powder or dry powder for oral inhalation, (in short, a mixture of the invention) which comprises or, alternatively, consists of: (a) a chondroitin sulfate (of animal origin or vegetable) and (b) a hyaluronic acid (of animal or vegetable origin), or salts thereof of acceptable pharmaceutical or food grade (for example of sodium), wherein said chondroitin sulfate and hyaluronic acid can be of animal or vegetable origin.

A second aspect of the present invention relates to a composition in the form of dry powder for oral inhalation (in short, composition of the invention) which comprises said mixture of chondroitin sulfate and hyaluronic acid of the present invention and at least one pharmacological grade additive and/or excipient or acceptable food.

A third aspect of the present invention relates to a kit comprising an inhaler for dry powders and a blister pack, wherein said blister pack contains said mixture or composition of the invention in the form of dry powder for inhalation.

A fourth aspect of the present invention relates to said mixture or composition of the invention or said kit of the invention for use as a medicament, preferably for use in a method of treatment, preventive and/or curative, of pathologies and/or symptoms, such as for example ulcers, lacerations and/or inflammation of the mucous membranes and tissues of the oral cavity, upper and lower respiratory tract and esophagus, caused by gastric reflux in an esophageal and/or extra-esophageal area or caused by a bacterial infection or nonbacterial (for example viral) or by irritating factors, such as for example cigarette smoke, dust, pollution and various allergens, as defined in the context of the present description.

A fifth aspect of the present invention relates to a method of preventive and/or curative treatment of pathologies and/or symptoms, such as for example ulcers, lacerations and/or inflammations, affecting the mucous membranes and tissues of the oral cavity, the upper and lower respiratory tract and oesophagus, caused by gastric reflux in an oesophageal and/or extra-oesophageal area or caused by a bacterial or non-bacterial (e.g. viral) infection or by irritating factors, such as cigarette smoke, dust , pollution and various allergens, in which this method provides for the administration of a quantity therapeutically effective of said mixture or said composition of the invention, for example by means of the kit of the present invention, to a subject in need.

A sixth aspect of the present invention relates to the non-therapeutic use of said mixture or composition of the invention or said kit of the invention.

FIGURES

Figure 1 is a top perspective view of the inhaler as seen from the end of the inhaler. distal;

Figure 2 refers to a lower perspective view of the inhaler seen from its end. distal;

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

Figure 4 refers to a view similar to the previous one with the cartridge mounted on the inhaler;

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

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

Figure 7 refers to a schematic representation of a cascade impactor (NGI, Next Generation Impactor) as indicated by Eu. Pharm. 8.0, 2.9.18;

Figure 8 refers to a schematic representation of the ramifications present at the level of the respiratory tree.

DETAILED DESCRIPTION OF THE INVENTION

The mixture of the invention in the form of a powder or dry powder for oral inhalation comprises or alternatively consists of (a) a chondroitin sulfate (of animal origin or of vegetable origin or its analogue of vegetable origin) and (b) an acid hyaluronic acid (of animal or vegetable origin), or their salts of acceptable pharmaceutical or food grade (in short, mixture of the invention).

Chondroitin sulfate (or chondroitin sulfate) ? a glycosaminoglycan (GAG) sulfate, which is a polysaccharide of variable length containing two alternating monosaccharides: N-acetyl-D-galactosamine and D-glucuronic acid.

In the context of the present invention, unless otherwise specified, the term ?chondroitin sulfate? means both chondroitin sulfate as such and an acceptable pharmaceutical or food grade salt thereof. Said chondroitin sulfate salt? preferably a salt of an alkali metal or an alkaline earth metal, for example selected from the group comprising or alternatively consisting of sodium chondroitin sulphate, potassium chondroitin sulphate, calcium chondroitin sulphate and magnesium chondroitin sulphate, or a salt of a metal, for example chondroitin aluminum sulfate; more preferably, the mixture of the present invention comprises a sodium (mono- or disodium) chondroitin sulfate.

In the context of the present invention the terms ?chondroitin sulfate? and ?chondroitin? can be used synonymously interchangeably.

Chondroitin sulfate (a), included in the mixture comprising (a) and (b), comprises the SO3H or SO3 group - mainly in the 4-CS and/or 6-CS position and to a lesser extent in the 4,6-CS position and /or 2,6-CS and/or 2,4-CS. For example, the chondroitin sulfate included in the blend of the present invention comprises a 4-chondroitin sulfate in a weight percent of 0.1% to 99.5% (e.g., about 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 98%), and 6-chondroitin sulfate in the range of 0.1% to 99.5% by weight (e.g., about 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 98%), with respect to the total disaccharides contained in chondroitin sulfate; % determined, for example, by HPLC.

According to one embodiment, said chondroitin sulfate (a), included in the mixture comprising (a) and (b), can be a chondroitin sulphate of animal origin (in short, (a.1)) obtained by extraction from animal cartilage, such as for example cartilage of cattle, pigs, chicken, sharks, fish or crustaceans; preferably chondroitin sulphate derived from chicken. Said chondroitin sulphate of animal origin (a.1) can? have an average molecular weight in the range greater than 50 kDa to 2000 kDa (e.g., 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, or 1800 kDa).

An example of chicken-derived sodium chondroitin sulfate (CS-Na) powder usable in the context of the present invention (included in the mixture or composition of the invention, together with (b)) has the following characteristics: it comprises at least 90% in weight of chondroitin sulphate (purity on a dry basis, ups method), a protein content not exceeding 6% by weight, a pH between 5.5 and 7.5, a loss on drying not exceeding 10%, a specific rotation between -20? at -30? (for example determined through the methods of the European Pharmacopoeia 7.0), a viscosity? intrinsic from 0.01 m?/kg to 0.15 m?/kg, where the percentages are with respect to the total weight of sodium chondroitin sulphate.

According to a further embodiment, said chondroitin sulphate (a), included in the mixture comprising (a) and (b), can be a chondroitin sulfate of plant origin (in short, (a.2)) obtained by extraction and/or fermentation from a plant source (e.g., at least one plant and/or a fungus and/or an alga) having a low weight medium molecular weight, a homogeneous profile and a low polydispersion, as described in the present invention.

Said (a.2) vegetable chondroitin sulfate or a salt thereof (e.g. sodium chondroitin sulfate) used in the context of the present invention have an average molecular weight ranging from about 1 kDa to 250 kDa (e.g., 100 kDa, 150 kDa or 200 kDa), preferably from about 1 kDa to less than or equal to about 50 kDa (e.g., 2 kDa, 3 kDa, 4 kDa, 5 kDa, 6 kDa, 7 kDa, 8 kDa, 9 kDa, 10 kDa, 11 kDa , 12 kDa, 13 kDa, 14 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa or 50 kDa), preferably from about 1 kDa to about 20 kDa, more? preferably from about 5 kDa to about 15 kDa (1000 Da = 1 kDa, Da = Dalton). Said (a.2) low molecular weight vegetable chondroitin sulphate (for example, about 1-50 KDa or about 1-20 KDa) has properties high intestinal permeation and high bioavailability? blood when administered to a subject.

Preferably, the chondroitin sulphate of vegetable origin or a salt thereof (for example sodium chondroitin sulphate) used in the context of the present invention have a density charge ranging from about 0.70 to about 1.50 (e.g., 0.80, 0.85, 0.87, 0.90, 0.92, 0.94, 0.96, 1.10, 1, 30 or 1.40), preferably ranging from about 0.75 to about 1.20, plus? preferably ranging from about 0.80 to about 0.99.

The vegetable chondroitin sulfate or a salt thereof (e.g., sodium chondroitin sulfate) used in the context of the present invention preferably comprises a weight percent of 6-chondroitin sulfate ranging from 50% to 99.5% (e.g. about 55%, 60 %, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98%), preferably from 75% to 90% or 95%, and a percentage by weight of 4-chondroitin sulfate ranging from about 0.01% to about 10% (for example, about 0.05%, 0.1%, 0.2%, 0.3%, 0.4% 0.5%, 1%, 2%, 3 %, 4%, 5%, 6%, 7%, 8%, or 9%), preferably from 0.1% to 5% or 10%, with respect to the total disaccharides contained in the chondroitin sulfate; % determined, for example, by HPLC.

Said vegetable chondroitin sulphate or a salt thereof also comprise low percentages by weight of chondroitin sulphate in which the SO3H or SO3<- >? in position 4,6-CS and/or 2,6-CS and/or 2,4-CS, wherein for example said low percentages are between 0.01% and 20% (for example, about 0.1% , 0.5%, 1%, 2%, 4%, 5%, 8%, 10% or 15%), with respect to the total disaccharides contained in said vegetable chondroitin sulphate.

A realization of said (a.2) plant-derived chondroitin sulfate ? sodium chondroitin sulfate having an average molecular weight of about 7 kDa to about 12 kDa (about 9 kDa), a protein content of about 0.5% (about 0.1%), a 6-chondroitin sulfate content of about 75% to about 90% and of 4-chondroitin sulphate in a percentage by weight ranging from about 0.1% to about 5% (% by weight with respect to the total disaccharides contained in the chondroitin sulphate).

According to a further embodiment, said chondroitin sulphate (a), included in the mixture comprising (a) and (b), can be an analogue of a chondroitin sulfate of plant origin (in short, (a.3)), such as a compound comprising a mixture comprising or, alternatively, consisting of an extract of at least one alga belonging to the species Ulva Lactuca (L. ) and/or an alga belonging to the genus Fucus (L.) (preferably belonging to the species Fucus Vesiculosus). Preferably said analogue of a chondroitin sulphate of vegetable origin (a.3) comprises or, alternatively, consists of an extract of Ulva Lactuca (L.) and Fucus Vesiculosus.

Said (a.3), comprising an extract of Ulva Lactuca and/or Fucus (preferably, an extract of Ulva Lactuca and Fucus Vesiculosus), can? further comprise a hyaluronic acid or a salt thereof (e.g. sodium) having an average molecular weight of from about 1 kDa to about 2000 kDa (e.g., about 100 kDa, 200 kDa, 300, kDa, 400 kDa, 500 kDa, 600 kDa , 700 kDa, 800 kDa, 900 kDa, 1000 kDa, 1200 kDa, or 1500 kDa, kDa= kilodalton). Furthermore, said (a.3) pu? comprising at least one pharmaceutical or food grade additive and/or excipient (e.g. maltodextrin or wheat maltodextrin).

Said (a.3) is defined as an ?analogue of a vegetable chondroitin sulphate? how much? a composition or a mixture which mimics a chondroitin sulphate thanks to the presence in said (a.3) of mucopolysaccharides, of which the algae Ulva Lactuca and/or Fucus are rich, comprising glucoronic acid and N-acetylglucosamine. For example, said Ulva Lactuca and/or Fucus extract comprises mucopolysaccharides in a percentage by weight of from about 10% to about 95%, with respect to the total weight of the extract, such as about 20%, 30%, 40%, 50% , 60%, 70%, 80% or 90%).

Said (a.3) extract (or fermentation product) of Ulva Lactuca and/or Fucus (preferably Fucus vesiculosus) ? obtained by methods and equipment suitable for the extraction of seaweed known to the person skilled in the art (for example extraction including a fermentation step). Said extract of Ulva Lactuca and Fucus can? be obtained starting from a mixture of Ulva Lactuca and Fucus or by extracting the Ulva Lactuca and Fucus separately and combining the two extracts obtained.

Said (a.3) analogue of a vegetable chondroitin sulphate ? a product that does not include derivatives of animal origin, and advantageously? ?allergen free?.

An embodiment of said (a.3) analog of a vegetable chondroitin sulphate usable in the context of the present invention ? a compound comprising or, alternatively, consisting of an extract of Ulva Lactuca and Fucus vesiculosus and, in addition, wheat maltodextrin and, optionally, sodium hyaluronate, wherein said compound does not include derivatives of animal origin and ? ?allergen free? having the following characteristics: powder form, density? (bulk density): 0.4-0-6 g/ml, particle size: >95% through 30# (US sieve analysis), quantity? As, Pb, Cd, Hg according to EP 7.0 standard (As < 1ppm, Pb <3 ppm, Cd <1 ppm, Hg <0.1 ppm), TVC bacteria < 3.0 x 10<3 >cfu/g, yeasts < 3.0 x 10<3 >cfu/g; solubility? in water: about 2 g/L contains only products permitted by EU legislation for food ingredients; and wherein said compound comprises in weight percent an extract of Ulva Lactuca from about 25% to 50% and an extract of Fucus vesiculosus from about 25% to 50%, maltodextrin from about 5% to 30%, and, optionally, sodium hyaluronate from about 1% to 15%, wherein said percentages are with respect to the total weight of the compound.

Said (a.3) analogue of a vegetable chondroitin sulphate can? comprising said extract of at least one seaweed (Ulva Lactuca and/or Fucus) in a weight percentage ranging from 30% to 95% with respect to the total weight of (a.3) (for example, about 35%, 40%, 50 %, 60%, 70% or 80% or 90%), preferably from 40% to 95%, more? preferably from 60% to 90%; and/or wherein said extract of at least one seaweed comprises an extract of Ulva Lactuca and an extract of Fucus (preferably Fucus vesiculosus) in a weight or percentage ratio (e.g. powder product) Ulva Lactuca : Fucus = about 2:1 to 1:2, preferably 1:1.

Said (a.3) analogue of a vegetable chondroitin sulphate can? comprising said extract of at least one seaweed (Ulva Lactuca and/or Fucus) in a weight percentage ranging from 30% to 95% with respect to the total weight of (a.2) (for example, about 40%, 50%, 60 %, 70%, 80% or 90%; Ulva Lactuca : Fucus percentage ratio = about 2:1 to 1:2, preferably 1:1, if both are present) and said hyaluronic acid or a salt thereof in a percentage by weight ranging from 1% to 30% of the total weight of (a.2) (for example, about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15 %, or 20%), and optionally at least one additive and/or excipient; for example said extract of at least one seaweed (Ulva Lactuca and/or Fucus) from 60% to 90% and hyaluronic acid or a salt thereof from 1% to 20%, or said extract of at least one seaweed (Ulva Lactuca and/or or Fucus) from 65% to 85% and hyaluronic acid or a salt thereof from 1% to 15%, or said extract of at least one seaweed (Ulva Lactuca and/or Fucus) from 70% to 80% and hyaluronic acid or a its salt from 1% to 10%.

Hyaluronic acid (HA for short; for example, CAS 9004-61-9) ? a macromolecule, such as an unsulphured glycosaminoglycan without a protein core.

In the context of the present invention with the term ?hyaluronic acid? (or in short (b)) means a hyaluronic acid or a salt of hyaluronic acid of acceptable pharmaceutical or food grade. Said salt of hyaluronic acid ? preferably a salt of an alkali metal or of an alkaline earth metal, for example selected from the group comprising or, alternatively, consisting of sodium hyaluronate, potassium hyaluronate, calcium hyaluronate and magnesium hyaluronate; more preferably sodium hyaluronate.

Hyaluronic acid used in the context of the present invention together with chondroitin sulfate (for example (a.1), (a.2) or (a.3)) can be of animal or plant origin.

The hyaluronic acid of vegetable origin can be obtained by microbial fermentation of a vegetable substrate (for example soy), a biotechnological process which consists in letting particular yeasts or bacteria ferment which produce it spontaneously.

Said (b) hyaluronic acid, present in the mixture of the invention together with (a) a chondroitin sulfate (a.1, a.2 or a.3), is preferably a hyaluronic acid (linear or branched, preferably linear) having an average molecular weight ranging from about 1 kDa to about 10,000 kDa (e.g., 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, 3000 kDa, 3500 kDa, 4000 kDa, 4500 kDa, 5000 kDa, 6000 kDa, 7 000 kDa, 8000 kDa or 9000 kDa), preferably from about 100 kDa to about 2000 kDa, plus? preferably from about 200 kDa to about 1500 kDa or from about 400 kDa to about 1000 kDa; advantageously ? a sodium hyaluronate having an average molecular weight ranging from 400 kDa to 1000 kDa (example, CAS No. 9067-32-7).

An example of sodium hyaluronate powder usable in the context of the present invention (included in the mixture or composition of the invention, together with (a), such as (a.1), (a.2) or (a.3))? a sodium hyaluronate (e.g. CAS No. 9067-32-7) having the following characteristics (European reference method or European Pharmacopoeia, Eu. Pharm. for short): appearance (EP <1472>): white or almost white powder, very hygroscopic; solubility? (EP <1472>): sparingly 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 solution S (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; viscosity intrinsic at 25?C (Eu. Pharm.:2.2.9) 1.35-1.60 m<3>/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? (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 usable in the context of the present invention (included in the mixture or composition of the invention, together with (a), such as (a.1), (a.2) or (a.3)) is? a sodium hyaluronate (for example CAS n. 9067-32-7) obtained by fermentation (or biotechnological process), food grade and having the following characteristics: average molecular weight from 600 kDa to 800 kDa (chromatographic method), powder, quantity ? minimum 90%-91% (w/w), glucuronic acid not less than 42% (w/w), loss on drying not more than 10% (w/w), preferably pH 6.0-7.5 or 5.0-8.0 (5% aqueous solution).

The object of the invention is a composition comprising said mixture of the invention (which comprises or, alternatively, consists of (a) chondroitin sulphate (a.1, a.2 or a.3) and (b) hyaluronic acid, or their salts ), and at least one carrier and/or at least one additive and/or excipient of pharmaceutical or food grade.

According to one aspect, the composition of the present invention comprises said mixture of the invention ((a) and (b)) and at least one carrier.

According to one aspect, the composition of the present invention comprises said mixture of the invention (a) and (b)) and at least one additive and/or excipient.

According to one aspect, the composition of the present invention comprises said mixture of the invention ((a) and (b)), at least one carrier and at least one additive and/or excipient.

Said at least a carrier ? selected from the group comprising or alternatively consisting of: mannitol, lactose, dextran, metal stearate (preferably magnesium stearate), and mixtures thereof.

Preferably the composition of the invention comprises or alternatively consists of (a) chondroitin sulfate (a.1, a.2 or a.3) and (b) hyaluronic acid, or salts thereof (for example, chondroitin sulfate sodium and sodium hyaluronate), and mannitol.

Mannitol (or D(?) Mannitol, or E421 according to European legislation), alternatively called mannite, is a chiral alditol, with six hydroxyl groups at the level of the aliphatic chain composed of six saturated carbon atoms (IUPAC name (2R,3R,4R,5R)hexane-1,2,3,4,5,6-hexol, brute formula C6H14O6, molecular weight (u) 182.17, example of CAS nr 69-65-8). The mannitol present in the mixture of the invention performs various functions, increasing and/or assisting the therapeutic action of the hyaluronic acid itself (for example, synergistic action):

- mannitol acts as a carrier of chondroitin sulphate and/or hyaluronic acid by transporting and conveying it and, therefore, making chondroitin sulphate and/or hyaluronic acid more? easily available in the upper respiratory tract;

- mannitol makes the dry powder for inhalation more? sliding.

Lactose (IUPAC name ?-D-galactopyranosyl-(1?4)-D-glucopyranose, for example CAS 63-42-3) ? a disaccharide and a dextrorotatory reducing sugar. The lactose molecule? consisting of a molecule of D-galactose and one of D-glucose joined by a glycosidic bond (acetal) ?(1?4).

Both lactose and mannitol may both be included/contained in the dry inhalation powder mixtures or compositions of the present invention. Their presence (singly or in combination) helps to: (i) improve the efficiency with which the volume present in the blister of the dry powder inhaler of the invention is emptied after respiratory activation (act of inhaling performed by the ?user who, by applying pressure with his fingers, pierces the walls of the blister), (ii) improve the turbulence and dispersion of chondroitin sulfate and/or hyaluronic acid inside the small airways, (iii) avoid particle aggregation inhalation powder such as chondroitin sulfate and/or hyaluronic acid (or their salts).

The lactose and/or mannitol particles generally have such a particle diameter (for example about 100 ?m) that they cannot penetrate into the deep parts of the respiratory system, therefore most of the lactose and/or mannitol present in the mixture or in the composition, are deposited in the oropharynx, and then pass into the stomach after being swallowed.

A metal stearate? a salt that derives from stearic acid (IUPAC name octadecanoic acid, crude formula C18H36O2, example of CAS nr 57-11-4) once salified. Said stearate of a metal, pu? be comprised in the mixture or composition of the invention (together with a chondroitin sulfate and hyaluronic acid and, optionally, with a mannitol and/or lactose) and be 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.

Said at least one additive and/or excipient ? different from said at least one carrier and pu? be selected from any additive and/or excipient known to the person skilled in the art of dry powders for inhalation, for example it can? be selected from the group comprising or, alternatively, consisting of: maltodextrin, leucine, sodium citrate and mixtures thereof, or any other additive and/or excipient known to the person skilled in the art.

In one aspect, the composition of the present invention (comprising (a) and (b) and optionally a carrier and/or an excipient) can further comprise a basic substance, such as for example aluminum hydroxide (Al(OH)3), magnesium hydroxide (Mg(OH)2) or magnesium trisilicate.

Preferably, the mixture comprising chondroitin sulphate and hyaluronic acid or, alternatively, the individual components of the mixture (such as chondroitin sulphate and/or hyaluronic acid) have a mass median aerodynamic diameter (in short, MMAD) in the range from 0.5 ?m to 50 ?m (e.g. about 1 ?m, 2 ?m, 3 ?m, 4 ?m, 5 ?m, 6 ?m, 7 ?m, 8?m, 9 ?m, 10 ?m, 11 ?m, 12 ?m, 13 ?m, 14 ?m, 15 ?m, 16 ?m, 18 ?m, 20 ?m, 22 ?m, 24 ?m, 26 ?m, 28 ?m, 30 ?m , 35 ?m, 40 ?m, (all+0.5 ?m)), preferably from 5 ?m to 20 ?m, plus? preferably from 5 ?m to 10 or 15 ?m.

Said a mass median aerodynamic diameter (MMAD) pu? be understood as the diameter of each component of the mixture (chondroitin sulphate and/or hyaluronic acid) or, alternatively, as the diameter of the mixture of chondroitin sulphate and hyaluronic acid.

The mass median aerodynamic diameter (MMAD) of the powder (or dry powder) of the blend or composition of the present invention or, alternatively, of the individual components of the blend (such as chondroitin sulfate and/or hyaluronic acid)? measured according to standard methods and equipment known to the person skilled in the sector of inhalation powders (for example, using a cascade impactor (NGI, from English Next Generation Impactor) as indicated by Eu. Pharm. 8.0, 2.9.18).

The mixture of the invention or, alternatively, the single components of the mixture (such as chondroitin sulfate and/or hyaluronic acid) exhibit a heterogeneity? of particle sizes with geometric standard deviation (GSD) values >1.22. Does the geometric standard deviation (GSD) measure the variability? the diameter of the particles of an aerosol; it provides an indication of the distribution of inhalable particle diameters and differentiates aerosols into two classes: monodisperse, with GSD values < 1.22 and heterodisperse with GSD values >1.22. Usually aerosolized formulations are heterodisperse formulations, that is? composed of particles of different sizes. For example, the geometric standard deviation for a mixture of the invention consisting of sodium chondroitin sulfate, sodium hyaluronate (e.g., molecular weight 400 kDa-1000 kDa), and mannitol, ? included in the range from 1.3 to 2.8, preferably from 1.8 to 2.1, confirming the heterogeneity particle size (of hyaluronate and/or chondroitin sulphate) which will be distributed both in the upper airways (in a high percentage) and in the first lower airways (in a minimum percentage).

The size distribution of chondroitin sulfate and/or hyaluronic acid powders, as raw materials of the mixture or composition of the invention, can be determined with a laser refractometer after dispersion of the powder in an organic solvent. For example, the median volume diameter (Dx(50)) of a chondroitin sulfate and/or of a hyaluronic acid (or salts thereof, for example sodium) which can be used in the mixtures or compositions of the invention ? between 1 ?m and 100 ?m (for example, 5 ?m, 10 ?m, 15 ?m, 20 ?m, 35 ?m, 45 ?m, 55 ?m, or 80 ?m), preferably from 5 ?m m to 50 ?m, more? preferably from 5 ?m to 10 ?m or 20 ?m (result of three replicates of the size distribution curves). Said median volume diameter (Dx(50)) pu? be understood as the diameter of each component of the mixture (chondroitin sulphate and/or hyaluronic acid) or, alternatively, as the diameter of the mixture of chondroitin sulphate and hyaluronic acid.

The particle size distribution of the powder of hyaluronic acid or a salt thereof (e.g. sodium hyaluronate) or of chondroitin sulphate or a salt thereof (e.g. chondroitin sulphate sodium), as raw material of the mixture of the invention, or, the particle size distribution of their mixture can be determined with a particle sizer (e.g. Accusizer<TM >Particle Sizer Model 770; particle sizing system, Santa Barbara California, USA). The mean volumetric diameter (DMV) of a chondroitin sulfate and/or of a hyaluronic acid (or sodium hyaluronate) usable or present in the mixtures or compositions of the invention ? ranging from 1 ?m to 100 ?m (for example, 5 ?m, 10 ?m, 15 ?m, 20 ?m, 30 ?m, 35 ?m, 45 ?m, 55 ?m, or 80 ?m), preferably from 25?m to 50?m, more? preferably from 5 ?m to 10 ?m or 20 ?m. Said volumetric mean diameter (DMV) pu? be understood as the diameter of each component of the mixture (chondroitin sulphate and/or hyaluronic acid) or, alternatively, as the diameter of the mixture of chondroitin sulphate and hyaluronic acid.

The mean volumetric diameter (DMV) of a carrier (for example, mannitol) present in the mixtures or compositions of the invention? ranging from 1 ?m to 150 ?m (for example, 5 ?m, 10 ?m, 15 ?m, 20 ?m, 30 ?m, 40 ?m, 50 ?m, 60 ?m, 70 ?m, 80 ? m, 90 ?m, 100 ?m, 110 ?m, 120 ?m, 130 ?m, or 140 ?m).

According to an example of the mixture or composition of the invention, the weight ratio (weight:weight ratio, w/w for short) [hyaluronic acid:chondroitin sulfate] or [HA:CS], or salts thereof, is ranging from 1:1 to 1:60 (for example, 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1: 45, 1:50, or 1:55), preferably from 1:5 to 1:50, plus? preferably from 1:10 to 1:45 (e.g. about 1:40).

According to an example of the composition of the invention, the weight ratio of the mixture of the invention to the carrier (?mixture of the invention:carrier?, as weight:weight ratio, in short w/w), in which the mixture comprises or consists of hyaluronic acid and chondroitin sulfate, ? between 10:90 and 90:10 (for example, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60: 40, 65:35, 70:30, or 80:20), preferably from 30:70 to 70:30.

Hyaluronic acid (or a salt thereof, preferably sodium hyaluronate) can be present in the mixture of the invention in a percentage by weight from 1% to 50% with respect to the total weight of said mixture of the invention (for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45%, 50%, 60%,), preferably 1% to 30% (e.g., 5% or 10%).

Chondroitin sulfate (or a salt thereof, preferably sodium chondroitin sulfate) can be present in the mixture of the invention in a percentage by weight from 30% to 99% with respect to the total weight of said mixture of the invention (for example, 35%, 40%, 45%, 50%, 55%, 65%, 70%, 75%, 80%, 85%, 95%, or 98%), preferably from 60% to 95%.

Hyaluronic acid (or a salt thereof, preferably sodium hyaluronate) can be present in the composition of the invention in a percentage by weight of from 0.5% to 50% with respect to the total weight of said composition of the invention (for example, 1%, 5%, 10%, 15%, 20%, 25 %, 30%, 35%, 40%, or 45%), preferably 1% to 15% (e.g., 5%).

Chondroitin sulfate (or a salt thereof, preferably sodium chondroitin sulfate) can be present in the composition of the invention in a percentage by weight of from 1% to 70% with respect to the total weight of said composition of the invention (for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 45%, 50%, 55%, 60%, or 65%), preferably from 5% to 40%.

Said at least one carrier, for example mannitol or lactose or a metal stearate (e.g. magnesium stearate) or a mixture thereof, can be present in the composition of the invention in a percentage by weight from 10% to 95% with respect to the total weight of said mixture or composition of the invention (for example, 20%, 30%, 40%, 45%, 50%, 55% %, 65%, 70%, 75%, 80%, 85% or 90%), preferably from 40% to 80% (e.g., 65%).

Furthermore, in the composition of the invention can? at least one additive and/or excipient be present in a percentage by weight of from 0.5% to 40% with respect to the total weight of said composition of the invention (for example, 1%, 2%, 3%, 4%, 5% , 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, or 35%).

According to one aspect of the invention, the mixture or composition of the present invention does not include lactoferrin and/or N-acetylcysteine (NAC) or a salt thereof and/or cannabidiol (CBD).

According to one aspect of the invention, the blend or composition of the present invention is not a blend or composition in solution or suspension or dispersion, and it is not a blend or composition in tablet form (as is, chewable or dissolve in mouth).

The mixture or composition of the invention in dry powder form may be in solid micronized dry powder form.

In the context of the present invention, with the term ?dry powder? a powder having a low water content is intended. For example, a dry powder of the composition of the invention, comprising or alternatively consisting of chondroitin sulfate, hyaluronic acid and said at least one carrier (preferably mannitol or lactose), has a water content in the range from 0.5 % to 25% or 30% by weight of the total powder weight (e.g., 1%, 2%, 3%, 4%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 9%, 10%, 15%, or 20%) preferably 5% to 8% (e.g., about 6.5% or 7.5%).

For example, a hyaluronic acid powder or a chondroitin sulfate powder which can be used in the mixture of the present invention have a water content ranging from 0.5% to 25% by weight with respect to the total weight of the powder (for example , 1%, 2%, 4%, 6%, 8%, 10%, 12%, 14%, 16%, 18% or 20%) preferably from 10% to 20%.

Said water contents are determined by methods and equipment known to those skilled in the art, for example by thermogravimetric analysis (TGA).

The object of the present invention are said mixtures or compositions of the invention in the form of dry powder for inhalation (comprising or, alternatively, consisting of chondroitin sulfate, hyaluronic acid and, optionally, at least one carrier and/or an additive/excipient) for use as medicament.

The subject of the present invention are said mixtures or compositions of the invention in the form of dry powder for inhalation (comprising or, alternatively, consisting of chondroitin sulphate, hyaluronic acid and, optionally, at least one carrier and/or an additive/excipient) for use in a method of treatment, preventive and/or curative, of a pathology and/or symptom affecting the mucous membranes and/or tissues of the oral cavity, the upper and lower respiratory tracts (preferably the upper respiratory tracts) and the esophagus, caused from gastric reflux in esophageal and/or extra-esophageal areas.

The subject of the present invention are said mixtures or compositions of the invention in the form of dry powder for inhalation (comprising or, alternatively, consisting of chondroitin sulphate, hyaluronic acid and, optionally, at least one carrier and/or an additive/excipient) for use in a method of treatment, preventive and/or curative, of a pathology and/or symptom affecting the mucous membranes and/or tissues of the oral cavity, the upper and lower respiratory tracts (preferably the upper respiratory tracts) and the esophagus, caused from bacterial or non-bacterial (e.g. virus) infections.

The subject of the present invention are said mixtures or compositions of the invention in the form of dry powder for inhalation (comprising or, alternatively, consisting of chondroitin sulphate, hyaluronic acid and, optionally, at least one carrier and/or an additive/excipient) for use in a method of treatment, preventive and/or curative, of a pathology and/or symptom affecting the mucous membranes and/or tissues of the oral cavity, the upper and lower respiratory tracts (preferably the upper respiratory tracts) and the esophagus, caused from irritating factors, such as cigarette smoke, dust, pollution and various allergens.

Said pathologies and/or symptoms affecting the mucous membranes and tissues of the oral cavity, the upper and lower respiratory tracts (preferably the upper respiratory tracts) and the esophagus are preferably ulcers, lacerations and/or inflammations affecting the said mucous membranes and/or or fabrics.

Furthermore, the object of the present invention is a kit of the invention (as described in the following of the present invention: comprising an inhaler for dry powders and at least one blister (or sealed and openable closed container) comprising the composition or mixture of the invention in the form of dry powder) for use according to said method of treatment, preventive and/or curative, of a pathology and/or symptom (for example ulcers, lacerations and/or inflammation) affecting the mucous membranes and/or tissues of the oral cavity, the upper and lower respiratory tract (preferably of the upper respiratory tract) and of the esophagus, caused by gastric reflux in oesophageal and/or extra-esophageal areas or caused by bacterial or non-bacterial infections (for example by viruses) or caused by irritating factors, such as for example cigarette smoke, dust, pollution and various allergens.

Said method of treatment provides for the administration by inhalation (by mouth aspiration) of said mixture or composition of the invention in a quantity therapeutically effective (as established by a person skilled in the art) to a subject having need. This administration can be carried out using the kit of the invention.

Preferably, said pathologies and/or symptoms (for example ulcers, lacerations and/or inflammation) affecting the mucous membranes and/or tissues of the oral cavity, the upper and/or lower respiratory tract and/or the esophagus are selected from the group which includes or, alternatively, consists of:

- gastroesophageal reflux disease (GERD), laryngopharyngeal reflux disease (RLF), lesions or ulcers of the mucosa or tissues of the cavity oral, lesions or ulcers affecting the mucosa or tissues of the pharyngolaryngeal tract, lesions or ulcers affecting the mucosa or tissues of the oesophageal tract, oesophageal ulcers, de-epithelialization of the oesophageal mucosa;

- mucositis, mouth ulcers, aphthoid lesions;

- acute or chronic inflammation of the mucosa or tissues of the oral cavity, acute or chronic inflammation of the mucosa or tissues of the pharyngolaryngeal tract, acute or chronic inflammation of the mucosa or tissues of the oesophageal tract, oesophagitis or acute or chronic inflammation of the mucosa of the esophagus;

- chronic cough, bronchospasm, sore throat, laryngitis, hypopharyngeal globe or bolus sensation, heartburn, dysphonia, nasopharyngeal inflammation, laryngospasm, hoarseness, pharyngeal globe, dysphonia, dysphagia, excessive throat clearing, throat pain or burning, postnasal drip, pharyngitis.

Preferably, said pathologies and/or symptoms (for example inflammation and/or bacterial or viral infections) affecting the mucous membranes and/or tissues of the upper and/or lower respiratory tract are selected from the group which includes or, alternatively, consists of:

cold, sinusitis, rhinitis, mucus secretion in the nose and/or throat area, mucus hypersecretion and a disease and/or symptom associated/or with this mucus hypersecretion, tracheitis, pharyngitis, laryngitis, acute laryngotracheobronchitis, epiglottitis, bronchiectasis, respiratory complications , asthma, chronic obstructive pulmonary disease (COPD), bronchitis, bronchiolitis, emphysema, cystic fibrosis, cough, whooping cough, pneumonia, pleurisy, or bronchiolitis.

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

The mixtures or compositions of the invention, according to any of the described aspects or embodiments, can be used as adjuvants of further therapeutic approaches for the treatment of said pathologies and/or symptoms of the oral cavity and of the upper and lower respiratory tracts ( preferably of the upper respiratory tract) and/or of the esophagus.

The mixture or composition of the invention in the form of dry powder for inhalation is effective in the treatment of said pathologies and/or symptoms affecting the mucous membrane and/or tissues of the oral cavity, the respiratory tract (preferably the upper respiratory tract) and/ or esophagus when administered in a daily dosage of hyaluronic acid (or its salt, e.g. sodium hyaluronate) in the range of 1 mg to 100 mg (e.g., about 5 mg, 7 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 90 mg), preferably 10 mg to 50 mg, and in a daily dosage of chondroitin sulfate ( or a salt thereof, e.g. chondroitin sulfate sodium) in the range of 10 mg to 2000 mg (e.g., about 50 mg, 70 mg, 100 mg, 0 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, 1800 mg or 2000 mg), preferably from 50 mg to 500 mg.

The aforementioned daily dosages can be administered to the subject in need in a single dose (single dose, for example of about 10 mg of hyaluronic acid or one of its salts) or in repeated doses, such as two, three, four or five doses daily (e.g. 2x, 3x, 4x or 5x 10mg hyaluronic acid or its salt).

The mixture or composition of the invention can be produced in the form of dry powder for inhalation by processes known to the person skilled in the art in the field of drugs or inhalable products. For example, the mixture or composition of the invention can be prepared by a mechanical mixing process of the individual components. Once said individual components have been well homogenized and distributed between them, the final mixture or composition is housed within the volume present and delimited by the walls of the blister.

The mixture or composition of the invention is administered by means of an inhaler for dry powders, an object known in the art and suitable for inhaling said dry powder by mouth (DPI, dry powder inhaler), such as a single-dose inhaler or multidose, single use or reusable after each dose, preferably single dose.

The object of the present invention is a kit for the administration by inhalation of the mixture or composition of the invention (in short, kit of the present invention) in which said kit comprises:

- a single-dose dry powder inhaler (in short, inhaler of the present invention) having the characteristics set forth below and in the patent document EP 3386575 B1 incorporated by reference in the present description in the parts describing the inhaler, 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 mixture or composition in dry powder form of the invention according to any of the aspects or embodiments described in the present invention (mixture comprising chondroitin sulphate and hyaluronic acid or their salts and, preferably, having the characteristics defined in the present invention, such as mass median aerodynamic diameter (MMAD), weight ratio, etc.), wherein said blister is housed in a housing present in said inhaler in order to administer said mixture or composition by inhalation by aspiration for mouth, aspiration exerted by a person having need? of a treatment.

In this 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 inside it a mixture or composition of the invention) can be prepared and sold separately from the inhaler of the invention. In this case the user houses/positions the blister in the housing present in said inhaler at the time of using the inhaler.

According to said first aspect, the inhaler present in the kit can? be single-use (disposable) or reusable; in the case of a multipurpose inhaler, the kit will contain? for example an inhaler and a specific number of blisters to be inserted from time to time on the same inhaler; in the case of disposable inhaler (disposable) the kit will contain? for example ?n? inhalers and ?n? blister.

In a second aspect of the kit of the present invention, said blister (comprising inside it a mixture or composition of the invention) ? fixedly inserted into said inhaler of the present invention at the time of its production (for example by the manufacturer). According to said according to aspect the kit ? single use.

Said single-dose inhaler for dry powder of the invention (Figures 1-6) comprises a substantially pipe-shaped hollow body which comprises a first portion (1), for housing a blister (or cartridge (C)) comprising the mixture or composition of the invention, and a second portion (2) connected to said first portion (1) for the delivery of said mixture or composition of the invention (powder) by means of a primary air flow (FP) which carries the powder from an internal drop area (5), located on the bottom of said first portion (1), along a dispensing duct (3) whose end? ? suitable to be placed in the mouth of a subject, said delivery duct (3) being divided horizontally by a separator septum (4) into an upper duct (3a) which delivers said primary air flow (FP) and a lower duct ( 3b) which delivers a dust-free secondary air flow (FS), the intake of the air forming the primary flow (FP) being achieved through at least three air inlets (7) formed in the first portion (1) which are preferably arranged symmetrically with respect to the longitudinal centerline plane of the inhaler, the aspiration of the air which forms the secondary flow (FS) being achieved through an air intake (8) obtained at the end of the inhaler. distal of said lower duct (3b); the inhaler being characterized in that said support base for said blister pack (or cartridge (C)) includes a plurality of of horizontal support surfaces (9) projecting within the first portion (1), and oriented flow channels (11) formed in the support base extending between said at least three vents (7) and the inner region dust drop (5).

The single-dose inhaler of the invention ? operated by a person who needs to inhale the mixture or composition of the invention contained in the blister by means of the steps of: (I) exerting pressure on the blister (for example with a finger) in order to break the lower portion of the blister and the transfer by gravity of the mixture or composition of the invention from the blister to said internal zone of gravity (5) of the inhaler; (II) to aspirate with the mouth positioned at that extremity? of said delivery duct (3) of the inhaler with a force sufficient to cause the aspiration of the mixture or composition of the invention by said subject, for example with a flow ranging from 30 L/min to 150 L/min ( e.g. 40 L/min, 50 L/min, 60 L/min, 70 L/min, 80 L/min, 90 L/min, 100 L/min, 110 L/min, 120 L/min, 130 L/min ml or 140 L/min, L/min = litre/minute) preferably from 60 L/min to 100 L/min, for example about 80 L/min. The emitted fractions of hyaluronic acid and/or chondroitin sulphate (or their salts, for example sodium hyaluronate and sodium chondroitin sulphate) are comprised from 70% to 99.9%, preferably from 80% to 99% or from 90% to 99% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 98%), expressed as a percentage of 100% of the hyaluronic acid and/or chondroitin (or their salts) present in the mixture or composition of the invention.

The administration of the mixtures or compositions of the invention, comprising hyaluronic acid and chondroitin sulphate (or their salts), in the form of dry powder for inhalation using the kit of the invention, activated by the aspiration of the subject in need, is such as to make effective the administration of the effective dose and maximize the intrinsic efficacy of the mixtures or compositions of the invention itself.

Furthermore, the mixture or composition of the invention in the form of a dry powder for inhalation (according to any of the aspects or embodiments described in the present invention) exhibit good flowability, good uniformity and smoothness. distribution of the active ingredients (i.e. hyaluronic acid and chondroitin sulphate) and adequate stability? chemistry and physics before use.

The term "good flow" refers to a composition that can be easily managed during the preparation process and ? able to guarantee an accurate and reproducible administration of the therapeutically effective dose when administered with the device of the invention by suction action of the subject, for all the doses envisaged in the treatment plan. The characteristics of the flow can be evaluated by measuring the Carr index; a Carr index less than 25 ? usually taken to indicate good flow characteristics.

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

The expression "chemically stable" refers to a formulation that meets the requirements of the ICH Q1A guideline referring to "Stability testing of new active substances (and medicinal products)".

The expression "physically stable" refers to a formulation in which if multiple components of the dry powder particles of the composition of the invention are present, these components do not substantially separate during the dry powder preparation process and/or during the time between the preparation and the use of the composition.

The tendency to separate can? be evaluated according to Staniforth et al., J. Pharm. Pharmacol., 34.700-706, 1982, what? incorporated herein by reference in its entirety, and ? considered acceptable if the distribution of the active ingredient in the dry powder composition after testing, expressed as relative standard deviation (RSD), does not change significantly from that of the composition before testing.

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

Unless otherwise specified, the expression composition or mixture or other which includes a component in an amount? ?in the range from x to y? do you mean that this component can? be present in the composition or mixture or other in all quantities? present in said range, even if not explicit, including extremes of the range.

Unless otherwise specified, a statement that a composition or mixture ?comprises? one or more components or substances means that other components or substances may be present in addition to the one, or those, specifically indicated.

EXPERIMENTAL PART (I)

In vitro efficacy test on cell lines.

The purpose of the present test is to evaluate in vitro the effect of a mixture according to the present invention (comprising sodium chondroitin sulphate and sodium hyaluronate) against a large group of viruses covering a broad spectrum of characteristics and replication strategies, such as: ADV-5, Coxsackievirus B5 (COXB5), Herpes Simplex Virus type 1 (HSV-1), Human Herpesvirus-6 (HHV-6), Influenza Virus A/H1N1, Mumps Virus (MV), Porcine Parvovirus ( PPV), Porcine Reproductive and Respiratory Syndrome Virus (PRRSV), RNA virus (e.g. Coronavirus) and DNA virus.

Cell lines of different origins can be used to cultivate said viruses, such as for example: two monkey kidney lines, such as VERO cells for ADV-5, COXB5, HSV-1 and MV and MARC145 cells for PRRSV; the human T leukemia lymphoblast line JJHAN for HHV-6; the MDCK Canine Kidney Line for Influenza Virus; the PK15 porcine cell line for PPV.

The activity antiviral of the mixture of the present invention ? been evaluated by virus titration assay by adding the mixture of the present invention at different times to the cell lines in which the virus is present. been cultured and titrating the virus to a final time.

EXPERIMENTAL PART (II)

Determination of the respirable fraction (FPF), the Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) by Next Generation Impactor (NGI) of the samples of a dry powder inhaler of the invention loaded with the mixture of the invention comprising sodium hyaluronate and sodium chondroitin sulfate.

1. PURPOSE

Purpose of this experimental study? determine the potential particle deposition in the various respiratory districts of the powder comprising sodium hyaluronate and sodium chondroitin sulphate (mixture of the invention) loaded by blister on the inhaler of the invention (DM class I).

2.1. Determination of the aerodynamic parameters The measurement of the aerodynamic parameters is carried out using a cascade impactor (NGI ? Next Generation Impactor (Figure 7)) as indicated by Eu. Pharm. 8.0, 2.9.18 - PREPARATIONS FOR INHALATION: AERODYNAMIC ASSESSMENT OF FINE PARTICLES.

The purpose of the analysis is to identify the mass of sodium hyaluronate (Na-HA) and/or sodium chondroitin sulphate (Na-CS) which is deposited at the level of the different ?stages? of the instrument (based on different dimensional ranges) to a pressure drop and a speed? of air flow that mimics the inspiratory act. From such data? possible to obtain the fraction of fine particles (FPF), i.e. the fraction of particles of a powder in the form of an aerosol, capable of depositing in the deep airways (lungs, bronchioles, alveoli) with an aerodynamic diameter between 0.5 ? m and 5 ?m.

2.2. Determination of the Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) values

From what has been found through the analysis of the distribution of the dust particles emitted within the various stages of the NGI, the Median Aerodynamic Diameter of the Mass (MMAD) and the Geometric Standard Deviation (GSD) of the particles are obtained respectively.

The mass median aerodynamic diameter (MMAD) ? a parameter that can indicate the particle size pi? frequent produced during the aerosolization of the product.

The Geometric Standard Deviation (GSD) measures instead the variability? of the particle diameter of an aerosol. It provides an indication of the distribution of inhalable particle diameters and differentiates aerosols into two classes: monodisperse, with GSD values <1.22 and heterodisperse with GSD values >1.22. Usually the aerosolized formulations are heterodisperse, that is? composed of particles of different sizes.

EXPERIMENTAL PART (III)

Characterization of the inhalation mixture comprising sodium hyaluronate and sodium chondroitin sulfate

1A. Dimensional granulometric analysis

The dimensional analysis of the sample is performed with an Accusizer C770 granulometer (Santa Barbara, CA) by means of ?Single Particle Optical Sensing analysis?. The analysis is carried out in acetonitrile and the results obtained represent the mean of three measurements (n=3). The dimensions were expressed as mean volumetric diameter (DMV) and the degree of polydispersity? expressed as a span calculated according to equation 1 (Eq.1):

Span = (Dv0.9- Dv0.1)/ Dv0.5 (Eq.1)

1B. Determination of the size distribution of the sodium hyaluronate and/or sodium chondroitin sulfate powder of the corresponding mixture using a laser refractometer after dispersion of the powder in an organic solvent.

2. Morphological analysis by Scanning Electron Microscopy (SEM)

The particle morphology of ?Hyal? (hyaluronic acid or hyaluronate) ? studied by Scanning Electron Microscopy (SEM)

The micrographs are obtained with a FE-SEM LEO 1525 Zeiss - One Zeiss Drive microscope.

3. Thermogravimetric analysis

The thermogravimetric analysis (TGA) is performed with a TG-DTA Netzsch STA 490 C thermal analyzer in order to determine the moisture content? in the sample

4. Smoothness

The flowability of the mixture of the present invention or of its components is measured by determining the compressibility index? (C.I.) and of the Hausner ratio (H.R.), according to equations 2 and 3, by reprocessing the initial and final volume data (after subjecting the sample to 1250 strokes using a Tap density tester, ERWEKA, Germany) in compliance with the provisions of the <European Pharmacopoeia (Ph. Eur. 9th Ed.).>

where: V0 represents the initial or uncompressed volume of powder and Vf corresponds to the final compressed volume (after 1250 strokes). The classification is made in accordance with what is reported in the Ph. Eur table.

9th Ed. (Table 2).

5. Uniformity? of content

The homogeneity? of the mixture of the invention is verified by uniformity test? of content performed on 20 samples in accordance with what is prescribed in Ph. Eur. 9th Ed. Does the preparation satisfy the test if each individual content ? between 85% and 115% of the average content. The preparation does not satisfy the essay if pi? of an individual content ? outside the aforementioned limits, or if only one of them ? outside the limits between 75% and 125% of the average content. If only an individual content ? outside the limits between 85% and 115%, but ? included within the limits of 75% - 125%, it is necessary to determine the individual contents of another twenty units, taken at random. The preparation satisfies the essay if not more? of one of the individual contents, of the thirty units?, ? outside the limits of the range of 85% - 115% of the average content and none ? outside the limits between 75% and 125% of the average content.

6. Determination of the fraction emitted

The percentage of the emitted fraction of the sodium hyaluronate / sodium chondroitin sulphate mixture? was measured using a glass impact separator, the Glass Twin Stage Impinger (Milan, Italy, Figures 18 and 18A) whose characteristics comply with what is reported in Ph. Eur. 9th Ed.

The Glass Twin Stage Impinger allows you to simulate lung deposition in vitro, allowing you to evaluate the quantity? of active ingredient which is deposited in the upper and lower airways.

From this analysis? possible to calculate the fraction emitted (EF) (Eq. 4).

EF%= [(Dose c.s.1 (?g)+Dose c.s.2 (?g)) / Nominal dose (?g)] X 100 (Eq.4)

By nominal dose is meant the quantity? of sample loaded in the blister of the inhaler of the invention.

By c.s.1 and c.s.2 we mean the separation chamber 1 (stage 1) and separation chamber 2 (stage 2) of the Glass Twin Stage Impinger.

EF means the percentage of powder loaded in the blister released by the inhaler of the invention and which is found in the Twin Stage Impinger.

EXPERIMENTAL PART (IV)

Preliminary study of the resistance of the kit of the invention (powder inhaler in blister) and dose delivered of a mixture of sodium hyaluronate and sodium chondroitin sulphate loaded in the blister.

In order to determine the performance of the inhaler of the invention with respect to its capacity? to issue a quantity? of powder equal to the quantity? loaded in the blister (mixture of the invention), a series of investigations listed below are carried out:

A. Determination of the resistance to air flow of the inhaler of the invention.

B. In vivo determination of the inhalation pattern in volunteers using the empty (powder-free) inhaler of the invention.

C. In vivo determination of the pattern in volunteers using the inhaler of the invention loaded with the mixture of the invention in powder form and measurement of the quantity? of dust emitted.

Claims (10)

1. A mixture in the form of a powder or dry powder for oral inhalation, wherein said mixture comprises or, alternatively, consists of: (a) a chondroitin sulfate or salt thereof of acceptable pharmaceutical or food grade, e (b) a hyaluronic acid or salt thereof of acceptable pharmaceutical or food grade. 2. The mixture according to claim 1, wherein a weight:weight ratio of [hyaluronic acid:chondroitin sulfate], or salts thereof, is included in the range from 1:1 to 1:60, preferably from 1:5 to 1:50, more? preferably from 1:10 to 1:45. 3. The mixture according to claim 1 or 2, wherein said hyaluronic acid or a salt thereof has an average molecular weight ranging from 100 kDa to 2000 kDa, preferably from 600 kDalton to 1000 kDalton; preferably in which said hyaluronic acid ? of animal or vegetable origin. 4. The mixture according to any one of the preceding claims, wherein said chondroitin sulfate is chosen from the group consisting of: - a chondroitin sulphate of animal origin, - a chondroitin sulfate of vegetable origin having an average molecular weight of 1 kDalton to 20 kDalton, and - an analogue of a chondroitin sulphate of vegetable origin comprising or, alternatively, consisting of an extract of Ulva Lactuca and an extract of Fucus vesiculosus. 5. A dry powder composition for oral inhalation comprising: the mixture in the form of powder or dry powder for inhalation according to any one of the preceding claims, e at least one carrier for dry powders for inhalation, and/or at least one pharmaceutical or food grade additive and/or excipient; preferably in which said carrier ? selected from the group comprising or alternatively consisting of: mannitol, lactose, alkali or alkaline earth metal stearate, and a mixture thereof. 6. A kit for inhaled dry powder administration, wherein said kit comprises: - at least one blister (C) comprising the mixture or composition in the form of dry powder for inhalation according to any one of the preceding claims; and - an inhaler for dry powder comprising a substantially pipe-shaped hollow body comprising a first portion (1) for housing said blister pack (C), and a second portion (2) connected to said first portion (1) for delivery of said mixture or composition in the form of dry powder by means of a primary air flow (FP) which carries the powder from an internal drop zone (5), located on the bottom of said first portion (1), along a duct of delivery (3) whose extremity? ? suitable to be placed in the mouth of a subject, said delivery duct (3) being divided horizontally by a separator septum (4) into an upper duct (3a) which delivers said primary air flow (FP) and a lower duct ( 3b) which delivers a dust-free secondary air flow (FS), the intake of the air forming the primary flow (FP) being achieved through at least three air inlets (7) formed in the first portion (1) which are preferably arranged symmetrically with respect to the longitudinal centerline plane of the inhaler, the aspiration of the air which forms the secondary flow (FS) being achieved through an air intake (8) obtained at the end of the inhaler. distal of said lower duct (3b), the inhaler being characterized in that said support base for the blister (C) includes a plurality of of horizontal support surfaces (9) projecting within the first portion (1), and oriented flow channels (11) formed in the support base extending between said at least three vents (7) and the inner region dust drop (5). 7. The mixture or composition or kit according to any one of the preceding claims for use as a medicament. 8. The mixture or composition or kit according to any one of claims 1-7 for use in a treatment method, preventive and/or curative, of ulcers, lacerations, inflammations, pathologies and/or symptoms affecting the mucous membranes and/or o of the tissues of the oral cavity, of the upper and lower respiratory tracts and/or of the esophagus caused by gastric or biliary or mixed reflux in an esophageal and/or extra-esophageal area, or, alternatively, caused by bacterial or non-bacterial infections, or, alternatively, caused by irritating factors, preferably cigarette smoke, dust, pollution and various allergens; preferably in which said ulcers, lacerations, inflammations, pathologies and/or symptoms affect the mucous membranes and tissues of the oral cavity and upper respiratory tract. 9. The mixture or composition or kit for use according to claim 8, wherein said ulcers, lacerations, inflammations, pathologies and/or symptoms affecting the mucous membranes and/or tissues of the oral cavity, upper and lower respiratory tracts and/or of the esophagus caused by gastric or biliary or mixed reflux in an esophageal and/or extra-esophageal area are selected from the group which includes or, alternatively, consists of: - gastroesophageal reflux disease (GERD), laryngopharyngeal reflux disease (RLF), lesions or ulcers of the mucosa or tissues of the cavity oral, lesions or ulcers affecting the mucosa or tissues of the pharyngolaryngeal tract, lesions or ulcers affecting the mucosa or tissues of the oesophageal tract, oesophageal ulcers, de-epithelialization of the oesophageal mucosa, ; - mucositis, mouth ulcers, aphthoid lesions; - acute or chronic inflammation of the mucosa or tissues of the oral cavity, acute or chronic inflammation of the mucosa or tissues of the pharyngolaryngeal tract, acute or chronic inflammation of the mucosa or tissues of the oesophageal tract, oesophagitis or acute or chronic inflammation of the mucosa of the esophagus; - chronic cough, bronchospasm, sore throat, laryngitis, sensation of hypopharyngeal globe or bolus, heartburn, dysphonia, nasopharyngeal inflammation, laryngospasm, hoarseness, pharyngeal globe, dysphonia, dysphagia, excessive throat clearing, throat pain or burning, postnasal drip, pharyngitis. 10. The mixture or composition or kit for use according to claim 8, wherein said inflammations, pathologies and/or symptoms affecting the mucous membranes and/or tissues of the upper and lower respiratory tracts caused by bacterial or non-bacterial infections are selected from the group which includes or alternatively consists of: cold, sinusitis, rhinitis, mucus secretion in the nose and/or throat area, mucus hypersecretion and a disease and/or symptom associated with this mucus hypersecretion, tracheitis, pharyngitis, laryngitis, acute laryngotracheobronchitis, epiglottitis, bronchiectasis, respiratory complications, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, bronchiolitis, emphysema, cystic fibrosis, cough, whooping cough, pneumonia, pleurisy, or bronchiolitis.