RU2805512C2 - Composition containing a mucolytic agent for treating mucuus hypersecrection and a device for its dosing - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: group of inventions relates to a composition in the form of a powder for oral inhalation. The composition in the form of a dry powder for oral inhalation contains N-acetylcysteine or its salt in an amount of 0.1–60% relative to the total weight of the composition and hyaluronic acid or its salt in an amount of 40–90% relative to the total weight of the composition, pharmaceutically acceptable or food grade additive and/or excipient, wherein the said composition is intended for the prevention and/or treatment of mucus hypersecretion and a disease, symptom and/or disorder associated with the said mucus hypersecretion in a subject in need. Also the following is disclosed: a dosing device for administering dry powder by oral inhalation.

EFFECT: expansion of the arsenal of agents for a specific purpose.

11 cl, 4 dwg, 6 tbl, 1 ex

Description

The present invention relates to a composition in the form of a powder (dry powder) for oral inhalation, preferably for oral aspiration, containing a mucolytic agent, preferably N-acetylcysteine. The present invention further contemplates the composition for use in a method of treating mucus hypersecretion (or bronchial mucus) and related diseases, symptoms or disorders in a subject in need. Finally, the present invention relates to a dosing device for administration by inhalation via oral aspiration of said composition in dry powder form to a specified subject in need.

The airways and lungs (respiratory system) are affected by serious diseases caused by bacteria, viruses and toxic substances that can easily enter the respiratory system through inhaled air. Inflammations, infections or allergies of the respiratory system are usually associated with hypersecretion of mucus. In physiological situations, respiratory system mucus (or bronchial mucus), a liquid and viscous substance, serves to moisten the respiratory tract and to trap any possible foreign particles and microorganisms. In cases of inflammation or infection or allergies of the respiratory system, mucus production increases, starting with hypersecretion of mucus (or production of sputum) with increased consistency (viscosity). Said mucus hypersecretion aims to trap and expel by coughing up pathogenic microorganisms that trigger said inflammation or infection or allergy.

Changes in mucus production and mucociliary clearance are usually treated with mucolytic/mucoregulatory drugs and expectorants. Mucolytic/mucoregulatory drugs act on mucus hypersecretion and the characteristics of mucus produced, and are used as symptomatic and adjuvant drugs in the treatment of inflammatory diseases, infections or allergic reactions of the respiratory tract. Mucolytic/mucoregulatory agents are capable of modifying the chemical/physical properties of bronchial secretions, facilitating their passage and reducing their production. Given that overproduction of mucus and modification of its characteristics (for example, increased viscosity) can cause obstructive symptoms that force the system to use the cough reflex to clear the airways, drugs that act on mucus secretion are also actively involved in cough control.

Depending on their mechanism of action, there are two types of mucolytic/mucoregulating drugs:

- direct acting drugs or thinning mucolytic/mucoregulatory drugs, which are drugs that can act on mucus already formed or present in the respiratory tract, for example, compounds that destroy mucus polymers (for example, N-acetylcysteine);

- indirectly acting mucolytic/mucoregulatory drugs that can affect the production of mucus by mucus-secreting cells. They alter the secretion and characteristics of mucus (eg, sobrerol and carbocysteine) or the stickiness of mucus (eg, ambroxol and bromhexine).

Drugs and other treatments currently available on the market for the treatment of mucus hypersecretion and related diseases, symptoms or disorders are often ineffective or only partially effective. In addition, some of the prior art products may cause side effects such as taste disturbances, intestinal disturbances, nausea, dyspepsia, vomiting, dry mouth, abdominal pain, sometimes urticaria, skin rash, erythema, dermatitis, dizziness, shortness of breath, angioedema.

Moreover, most of the drugs and other agents currently on the market for the treatment of mucus hypersecretion are in the form of solutions or suspensions. When these solutions or suspensions are to be administered into the lungs by inhalation, this occurs using nebulizers. These devices dispense solutions and suspensions in the form of a low-viscosity spray and are usually accompanied by a face mask so that the subject can inhale the low-viscosity spray through the mouth or nose. However, nebulizers are typically large and non-portable devices and are therefore not suitable for easy and convenient drug administration, as is the case with the present invention.

Another problem associated with the use of nebulizers is the difficulty of obtaining accurate information about the dose actually dosed to the subject. There is also a general lack of precision, reproducibility and efficiency when it comes to drug administration, resulting in the need to increase the administered dose to ensure the desired therapeutic effect is achieved, which entails wastage of drug and an increased risk of side effects.

When these drugs are in the form of a fine powder for administration by inhalation, they should be administered using a dosing device. Dosing devices currently available on the market do not always guarantee effective drug administration and are often difficult to handle and activate.

In addition, delivery of compositions in dry powder form to the respiratory tract is known to have some disadvantages. The inhalation device must ensure that the maximum possible proportion of active particles is released into the lungs, including a significant proportion in the deepest part of the lungs. Thus, dry powder compositions are capable of increasing the proportion of active particles that are delivered to the lower respiratory tract or deep part of the lungs.

The type of dry powder inhaler used will influence the effectiveness of the release of active particles into the respiratory tract. In addition, the chemical/physical properties of the powder influence both the efficiency and reproducibility of the release of active particles and where they are deposited in the respiratory tract.

Thus, there is a great demand in society for adequate treatment of mucus hypersecretion (or bronchial mucus) and its associated diseases, symptoms or disorders.

The technical problem addressed and solved by the present invention is to provide a workable solution for effective therapeutic and non-therapeutic treatment of mucus hypersecretion and mucus hypersecretion-related diseases, symptoms and/or disorders, capable of overcoming the currently unresolved disadvantages of the prior art, in particularly regarding ineffectiveness and/or the presence of side effects and/or problems associated with administration.

Moreover, the technical problem addressed and solved by the present invention is to provide new compositions containing as the active agent a mucolytic agent in the form of a dry powder, suitable for inhalation administration, having good flowability, good uniformity of distribution of the active agent, adequate chemical and physical stability before use and no tendency to agglomerate, and thus being easy to handle and administer.

Moreover, the technical problem addressed and solved by the present invention is to provide both novel compositions in dry powder form and an inhalation device capable of producing a highly respirable fraction and providing an accurate therapeutically active dose of the active ingredient.

To overcome these technical problems, the present invention provides a composition in the form of a powder, preferably a dry powder, suitable for inhalation administration by oral aspiration, containing a mucolytic agent (active agent), preferably N-acetylcysteine, and optionally other components (first and/or second auxiliary agent) which facilitate the administration of said composition in the form of a powder, preferably a dry powder, by inhalation via oral aspiration. Such a composition is capable of effectively and rapidly treating mucus hypersecretion and diseases, symptoms or disorders associated with said mucus hypersecretion in both pathological and healthy subjects (who have not yet been diagnosed with pathology). In addition, the composition does not have the side effects present in the prior art treatments, is easy to administer by inhalation, easy to manufacture and is cost effective.

In addition, the present invention provides a device for administering a composition according to the invention in the form of a powder for inhalation, preferably an inhalation activated by oral aspiration, which is easy to use, which improves the subject's adherence to therapy, and has an optimal capacity for administering the composition according to the invention and , thus the active ingredient it contains.

These and other objects, which will be clear from the following detailed description, are achieved by the composition of the present invention due to the technical characteristics stated in the accompanying claims.

After intensive research and development, the Applicant has discovered that administration of the composition according to the present invention by inhalation via oral aspiration is capable of effectively and rapidly treating mucus hypersecretion and mucus hypersecretion-related diseases, symptoms and/or disorders.

Furthermore, after intensive research and development, the Applicant has discovered that the use of a dosing device according to the invention for administering the composition according to the invention in powder form by oral inhalation, preferably by oral aspiration, improves the administration of the composition according to the invention and thus the active ingredient contained therein.

In addition, this device is easy to use and, therefore, it improves the subject's adherence to therapy.

The specified therapeutic or non-therapeutic pharmacological therapeutic activity of the composition is due to the mucolytic present in the composition, such as, for example, N-acetylcysteine, additional components, if present in the composition in addition to the mucolytic, which make it possible to obtain an optimal powder for its administration by inhalation, and a dosing device , by which the composition of the invention is administered in powder form into the respiratory system by oral aspiration.

Figures

Fig. 1 is a graph presenting the average viscosity values of mucus collected from subjects suffering from cystic fibrosis, before and after treatment of the mucus using saline or using compositions 1-4 in accordance with the invention (ETA: average viscosity measured at 37° C. in mPa.s).

Fig. 2 is a graph representing the average viscosity values of mucus collected from subjects suffering from cystic fibrosis, before and after treatment of the mucus using saline or using compositions 5-12 in accordance with the invention (ETA: average viscosity measured at 37° C. in mPa.s).

Fig. 3 - single-dose reusable device according to the invention.

Fig. 4 - single-dose reusable device according to the invention, where the loading device is made in the form of a capsule.

Detailed Description of the Invention

It is an object of the present invention to provide a composition in powder (dry powder) form suitable for administration by oral inhalation (in short, the inventive composition or composition) containing (i) a mixture M (in short, the inventive mixture or mixture) containing or, alternatively, consisting of a mucolytic agent (the active ingredient of the composition according to the invention), and optionally (ii) at least one pharmaceutically acceptable or nutritional additive and/or excipient.

In a preferred embodiment, said mucolytic agent is N-acetylcysteine or a pharmaceutically acceptable or edible salt thereof, for example N-acetylcysteine L-lysine salt (NAL).

N-acetylcysteine (IUPAC name 2R-acetamido-3-sulfanylpropanoic acid, CAS 616-91-1) is a derivative of the amino acid cysteine N-acetylate that has antioxidant and mucolytic activity. Antioxidants are substances that slow down or prevent the oxidation of other substances. Mucolytics are substances that make the mucus secreted by the respiratory system more liquid and facilitate the work of removing mucus by the bronchi and trachea. It is known that the main determinants of the viscosity and elasticity of secretions of the respiratory system are fucomucins and IgG immunoglobulins. N-acetylcysteine, in particular, is characterized by the ability to break down sulfur bridges in proteins: in the case of mucus, N-acetylcysteine depolymerizes mucoprotein complexes (glycoprotein agglomerates) into smaller units having a lower viscosity and has an important mucolytic and thinning effect on mucous membranes and mucous membranes. purulent discharge.

In one embodiment, said (i) mixture M contains, in addition to the mucolytic agent, preferably N-acetylcysteine or a pharmaceutically acceptable or edible salt thereof (e.g. NAL), also a first excipient selected from the group consisting of or alternatively consisting of lactose , dextran, mannitol and mixtures thereof; more preferably lactose.

Preferably said (i) mixture M contains N-acetylcysteine and lactose.

Lactose (IUPAC name β-D-galactopyranosyl(1→4)D-glucopyranose, CAS 63-42-3) is a disaccharide and dextrorotatory reducing sugar. The lactose molecule consists of residues of D-galactose and D-glucose molecules linked by a β(1–4)-gliosidic bond (acetal). 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 of blister emptying after respiratory activation, turbulence and distribution of the drug in the small airways. Lactose particles have such a diameter (> 50 µm) that they cannot penetrate into the deep parts of the respiratory system, so most of the lactose settles in the oropharynx before reaching the stomach after ingestion.

In one embodiment, said (i) mixture M contains, in addition to a mucolytic agent, preferably N-acetylcysteine or a salt thereof, and optionally said first auxiliary agent selected from the group consisting of, or alternatively consisting of, lactose, dextran, mannitol and mixtures thereof , also a second auxiliary agent, wherein said second agent is a metal stearate or a derivative thereof selected from the group consisting of 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, (i) mixture M may contain said second auxiliary agent as an alternative to said first auxiliary agent or in the presence of said first auxiliary agent.

In one embodiment, said (i) mixture of M, in addition to the mucolytic agent, preferably N-acetylcysteine or a pharmaceutically acceptable or edible salt thereof, and lactose also contains magnesium stearate.

Preferably said (i) mixture M contains N-acetylcysteine, lactose and magnesium stearate.

Alternatively, said (i) mixture M contains N-acetylcysteine 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 manufacture of solid compositions, preferably tablets, to facilitate the release of powder or granulate from the metal walls of processing equipment.

In a preferred embodiment, said (i) mixture M contains, in addition to a mucolytic agent, preferably N-acetylcysteine or a salt thereof, also hyaluronic acid or a pharmaceutically acceptable or edible salt thereof.

In one embodiment, said (i) mixture M contains said mucolytic agent, preferably N-acetylcysteine or a salt thereof, hyaluronic acid or a salt thereof, and said first auxiliary agent, preferably lactose.

In one embodiment, said (i) mixture M contains said mucolytic agent, preferably N-acetylcysteine or a salt thereof, hyaluronic acid or a salt thereof, and said second auxiliary agent, preferably magnesium stearate.

In one embodiment, said (i) mixture M contains said mucolytic agent, preferably N-acetylcysteine or a salt thereof, hyaluronic acid or a salt thereof, and said first adjuvant, preferably lactose, and said second adjuvant, preferably magnesium stearate.

In a preferred embodiment, said (i) mixture M contains, in addition to the mucolytic agent, preferably N-acetylcysteine or its pharmaceutically acceptable or edible salt, lactose and/or magnesium stearate, as well as hyaluronic acid or its pharmaceutically acceptable or edible salt.

The presence of hyaluronic acid in the composition of the invention in combination with said mucolytic agent, preferably N-acetylcysteine, increases the mucolytic effectiveness of the mucolytic agent (reduction of mucus viscosity and ease of expectoration/removal of mucus in a subject suffering from mucus overproduction). Thus, a low % mucolytic agent, preferably N-acetylcysteine, can be used in the compositions of the invention.

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

Hyaluronic acid (CAS 9004-61-9) is a non-sulfated glycosaminoglycan without a protein core. Hyaluronic acid (HA) and its salts are macromolecules. In particular, hyaluronic acid or a salt thereof, preferably sodium hyaluronate, in the context of the present invention preferably has an average molecular weight of from 20 kDa to 4000 kDa, preferably from 50 kDa to 1500 kDa, even more preferably from 150 kDa to 1000 kDa.

In one embodiment, the composition of the invention comprises said (i) mixture M, containing or alternatively consisting of: a mucolytic agent, preferably N-acetylcysteine or a salt thereof, with a concentration (%) by weight ranging from 50% to 95% relative to the total weight of mixture M, preferably from 55% to 90%, more preferably from 60% to 85%; and, if present, lactose with a concentration (%) by weight ranging from 5% (or 4.9% in the case of magnesium stearate) to 40%, based on the total weight of mixture M, preferably from 10% to 35 %, more preferably from 15% to 30%; and, if present, magnesium stearate with a concentration (%) by weight ranging from 0.1% to 20% based on the total weight of mixture M, 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, containing or alternatively consisting of: % by weight N-acetylcysteine (present as such or in salt form), ranging from 0.1% to 60% based on the total weight of mixture M, 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, containing or alternatively consisting of: % by weight N-acetylcysteine (present as such or in salt form), ranging from 0.1% to 60% relative to the total weight of mixture M, preferably from 5% to 50%, more preferably from 10% to 40%; and % by weight of hyaluronic acid (present as such or in salt form) ranging from 40% to 90% based on the total weight of mixture M, 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 containing or alternatively consisting of: % by weight N-acetylcysteine (present as such or in salt form) ranging from 0.1% to 58 % relative to the total weight of mixture M, preferably from 5% to 50%, more preferably from 10% to 40%; and % by weight of hyaluronic acid (present as such or in salt form) ranging from 40% to 90% relative to the total weight of mixture M, preferably from 50% to 80%, more preferably from 60% to 80%; and, if present, % by weight of the first adjuvant, preferably lactose, or the second adjuvant, preferably magnesium stearate, ranging from 2% to 35% with respect to the total weight of mixture M, preferably from 10% to 30%, more preferably 15% to 25%.

In a further preferred embodiment, the composition of the invention comprises said (i) mixture M containing or alternatively consisting of: % by weight N-acetylcysteine (present as such or in salt form) ranging from 0.1% to 50 % based on the total weight of mixture M, preferably from 5% to 50%, more preferably from 10% to 40%; and % by weight of hyaluronic acid (present as such or in salt form) ranging from 40% to 90% relative to the total weight of mixture M, preferably from 50% to 80%, more preferably from 60% to 80%; and, if present, % by weight of the first adjuvant, preferably lactose, and the second adjuvant, preferably magnesium stearate, ranging from 10% to 40% with respect to the total weight of mixture M, preferably from 15% to 35%, more preferably 20% to 30%.

Examples of % by weight of the mixture M according to the invention are shown in Table 1 and Table 4.

The composition of the invention is in the form of a powder, preferably a dry powder, containing said composition in the form of a powder, preferably a dry powder, the particle diameter (average particle diameter) being such as to make the composition suitable for administration by oral inhalation. Preferably, the composition of the invention in powder (dry powder) form has a particle diameter (average particle diameter) in the range of 1 μm to 200 μm, preferably 1 μm to 100 μm, more preferably 1 μm to 50 μm.

In a preferred embodiment, the composition of the invention in powder form contains NAC and optionally said first adjuvant and second adjuvant, and/or hyaluronic acid or salts thereof, wherein the average particle diameter is in the range from 0.1 μm to 10 μm, preferably from 0.5 µm to 5 µm, more preferably from 1 µm to 5 µm.

In the context of the present invention, the expression "average particle diameter" refers to the size of a particle containing all components of the composition, for example, depending on the embodiment, a particle containing NAC or NAC and HA, or NAC and HA and lactose, or NAC and HA and stearate magnesium

Powder particles can mainly be divided into inhalable and inhalable. The inhaled fraction is represented by a suspension of particles of various diameters (usually from 10 microns to 100 microns), the sizes of which are such that they determine the interaction with the human respiratory system.

The inhalable fraction is a suspension of particles with a grain size class (usually <4 microns) that allows reaching the non-ciliated part of the lung (alveolar region) due to respiratory movements.

In the context of the present invention, the expression "dry powder" is used to mean a powder with a low moisture (water) content, for example, a powder having a moisture content in the range of 0.01% to 10% by weight based on the total weight of the powder, preferably from 0 .1% to 5%, more preferably 0.1% to 3%.

The composition of the present invention, optionally in addition to said first auxiliary agent, preferably lactose, and, if present, said second auxiliary agent, preferably magnesium stearate and/or hyaluronic acid or a salt thereof, contains additional (ii) pharmaceutical or food additives and/or excipients, that is, substances without therapeutic activity suitable for pharmaceutical or food use. In the context of the present invention, acceptable ingredients for pharmaceutical or food use include all excipients known to those skilled in the art, such as, by way of non-limiting example, diluents, solvents (including water, glycerin, ethyl alcohol), solubilizers, thickeners, sweeteners, flavorings , dyes, lubricants, surfactants, antimicrobial agents, antioxidants, preservatives, pH stabilizing buffers and mixtures thereof.

The composition according to the present invention, in addition to the components of the above (i) mixture M (such as a mucolytic agent (NAC or a salt thereof), and optionally a first and second auxiliary agent, and/or hyaluronic acid or a salt thereof), and optionally additional ( ii) additives and/or excipients, may also contain additional active ingredients such as, by way of non-limiting example, anti-inflammatory agents, antioxidants, antibacterial agents, disinfectants, vasoconstrictors, probiotics, herbal extracts, vitamins, mineral salts, others mucolytics and mainly products for the treatment of inflammation, infections, or allergic reactions of the respiratory system.

In a preferred embodiment, the composition of the present invention is prepared using a method of mechanical mixing of the individual components.

In an alternative embodiment, the composition of the invention is prepared using a spray drying process. The composition of the invention may be a pharmaceutical composition, a nutraceutical composition, a nutritional supplement or a food supplement for special medical purposes, or a composition for a medical device.

The expression "medical device" in the context of the present invention is used in accordance with the meaning established by Italian Legislative Decree No. 46 of February 24, 1997 or in accordance with the new Medical Device Regulation (UE) 2017/745 (MDR), i.e. means a substance or other product, used alone or in combination, identified by the manufacturer as intended for use in humans for the diagnosis, prevention, control, therapy or mitigation of disease, a product that does not have a primary effect in or on the body of the person for which it is intended, neither by pharmacological or immunological means, nor by a metabolic process, but its function can be enhanced by such means.

An object of the present invention is a composition according to the invention as defined above (such as containing a mucolytic agent, preferably N-acetylcysteine or a salt thereof, and optionally a first and/or second auxiliary agent such as lactose and magnesium stearate, and/or hyaluronic acid or its salt) for use as a medicine.

It is further an object of the present invention to provide a composition of the invention as defined above (such as comprising a mucolytic agent, preferably N-acetylcysteine or a salt thereof, and optionally a first and/or second auxiliary agent such as lactose and magnesium stearate, and/or hyaluronic acid or a salt thereof) for use in a method of preventing and/or treating mucus hypersecretion and a disease, symptom and/or disorder associated with said mucus hypersecretion in a subject in need, preferably wherein said composition for use is administered by oral inhalation activated by aspiration of the subject .

In one embodiment, the composition of the invention is for use in a method of treating inflammation or infection or allergic reactions of the respiratory system associated with mucus hypersecretion. Preferably, said inflammations or infections or allergic reactions of the respiratory system are selected from the group consisting of, or alternatively consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis, whooping cough, pneumonia, pleurisy, bronchiolitis, colds, sinusitis , rhinitis, tracheitis, pharyngitis, laryngitis, epiglottitis and bronchiectasis.

It is further an object of the present invention to provide a dosing device (in short, a device of the invention or simply a device) for administering a composition of the invention in the form of a powder, preferably a dry powder, to a subject in need by oral inhalation, said device releasing an effective dose (a predetermined effective dose) compositions of the invention when activated by a subject through oral aspiration (in short, a device of the invention or a dosing device of the invention).

The dosing device of the invention is a modern propellant-free inhaler that releases an effective dose of the composition of the invention by activation by the subject through oral aspiration.

In the context of the present invention, the expression "oral aspiration" or "oral aspiration action" is used to mean that a subject inhales or exhales through the mouth in a single action (single aspiration action) with a force of such intensity as to allow the device of the invention to dispense a predetermined dose compositions according to the invention in powder form in the dosing device in question.

The predetermined dose of the composition of the invention that can be dosed by the device of the invention via oral aspiration to the subject may vary depending on changes in 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 according to the invention allows, using only one oral aspiration action, to dose the composition according to the invention in the form of a dry powder in the range of 10 mg to 70 mg, preferably from 20 mg to 50 mg. more preferably 35 mg to 40 mg.

Alternatively, a specified dose of the composition of the invention in dry powder form, ranging from 10 mg to 70 mg, preferably from 20 mg to 50 mg, more preferably from 35 mg to 40 mg, can be dosed by the device of the invention by n number oral aspirations, where n is a number ranging from 2 to 4, preferably 2.

In addition, in order to achieve the daily intake of the composition of the invention required for the specified subject, the administration of the specified predetermined dose dosed by the device of the invention through one or more oral aspiration actions of the subject can be administered only 1 time per day or repeated 2 or 3 times, or 4, or 5, or 6 times a day.

The dispensing device of the invention may be a disposable or reusable type. In a preferred embodiment, the device of the present invention is a reusable type device, capable of containing a single dose or multiple doses.

The dosing device of the invention, in the case where it is a reusable type device, may be a single-dose type or a multi-dose type; in case the dosing device is a multi-dose type, it may include a dosage indicator. In a preferred embodiment, the dosing device of the invention is a disposable, single-dose type device.

The dosing device of the invention is intended for administering dry powder by oral inhalation, said device comprising:

- a compartment for accommodating powder containing a composition in the form of a dry powder in accordance with any of the embodiments of the invention;

- an aspiration channel, the first end of which is directly or indirectly connected to the powder accommodating compartment, and the second end of which allows the subject to perform an oral aspiration action; and optional

- a compartment for housing a loading device, wherein said loading device, single-dose or multi-dose, contains the composition according to the invention in powder form;

and wherein said dosing device of the invention is designed to dispense a dose of said composition after oral aspiration to a subject requiring said administration.

When the device of the invention is reusable, the composition of the invention is loaded into the powder accommodating compartment using said loading device containing the composition of the invention; said loading device may be a single-dose loading device (eg a capsule or sachet) or a multi-dose loading device, preferably a single-dose loading device. In addition, the boot device can be located inside the device according to the invention (internal boot device) or outside the device according to the invention (external boot device).

In an embodiment of a refillable device, said loading device is an external loading device located outside the device, and the device is designed to allow direct transfer of a single dose of said composition from the external loading device (single-dose or multi-dose) to the powder receiving compartment (refillable device). direct download). For example, said single-dose external loading device is a sachet containing the composition of the invention in dry powder form.

In an alternative embodiment of a reusable device, said loading device is an internal loading device located within the device in a loading device housing compartment, and the device is designed to allow indirect transfer of a single dose of said composition from the internal loading device (single-dose or multi-dose) to compartment to accommodate the powder by applying pressure to the device which causes the internal loading device (reusable indirect loading device) to open or, alternatively, by applying pressure to the internal loading device. For example, said single-dose internal loading device is a capsule containing the composition of the invention in the form of a dry powder, for example a capsule made of a flexible material such as an aluminum capsule.

The expression "single-dose", "reusable" dosing 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 that is separate or separable from the dosing device (eg, a pouch or capsule). Said single dose of the composition of the invention is transferred from the single-dose container in the dispensing device to the powder accommodating compartment, and finally, said single dose of the composition of the invention is dosed by the dispenser to the subject via oral aspiration by the subject (e.g., through one or more aspiration acts). The advantage of a "single dose" dosing device is that there is no risk of the subject taking more than one dose, ensuring maximum safety.

The expression "multi-dose", "reusable" dosing device is used in the context of the present invention to mean that a multiple dose of the composition of the invention in powder form is contained in a multi-dose container that is separate or separable from the dosing device. Such a multi-dose container containing a specified number of doses of the composition of the invention is inserted into the dispensing device of the invention (into the loading device housing compartment) before dispensing the specified number of doses. A single dose of the composition of the invention is then transferred from said multi-dose container to a dispensing device in the powder accommodating compartment, for example, by applying pressure to the device or to a multi-dose container inserted into the device by the subject (e.g., pressure is applied by the subject's hand to a portion of the device or to the multi-dose container). container to load a single dose of the composition to be dispensed into a special compartment for accommodating the powder; multi-dose, reusable, indirect-acting dispensing device). Finally, a single dose of a composition of the invention loaded into the dispensing device (the loading device receiving compartment) is dispensed by the dispensing device to the subject through oral aspiration by the subject (eg, through one or more aspiration actions).

The dispensing device of the invention, in the case of a single-dose reusable type, may be a "direct loading type" (with an external loading device) or an "indirect loading type" (with an internal loading device).

In one embodiment, the dispensing device of the invention is of the single-dose, reusable, indirect loading type, in which the powder (dry powder) is contained in the device (inner container) and is released into the dispensing device (powder receiving compartment) when pressed by the subject.

In an alternative embodiment, the dispensing device of the invention is of the single-dose, reusable, direct-load type.

The expression "single-dose", "reusable" direct-load 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 separate from the device (outer container), such as a pouch. A single dose of the composition of the invention is directly transferred from the single-dose container to the dispensing device of the invention (powder receiving compartment) prior to dosing, for example, by opening the single-dose container (e.g., sachet) by the subject and directly transferring the composition of the invention in powder form from the single-dose container to dosing device, more precisely, into the compartment for placing the powder. Finally, the composition of the invention is dosed by a dosing device to a subject through oral aspiration by the subject (eg, through one or more aspiration actions).

The expression "single-dose", "reusable" indirect loading 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 separate from the device, for example, a capsule. Such a container containing the composition of the invention is inserted into the dispensing device (into the loading device receiving compartment) before dispensing. An opening is then created in said single-dose container, for example by applying pressure to the dispensing device by the subject such that the composition is released into the dispensing device, more specifically the powder receiving compartment. Finally, a single dose of the composition of the invention is dosed by a dosing device to the subject through oral aspiration by the subject (eg, through one or more aspiration actions).

The dosing device according to the invention allows the composition according to the invention to be dosed in the form of a powder cloud, which remains persistent for some time and guarantees more effective inhalation, as well as an even and optimal distribution of the active ingredient or active ingredients contained in the composition in the respiratory system, resulting in positive effects in terms of therapeutic results.

An object of the present invention is a method of treating mucus hypersecretion and a disorder associated with said mucus hypersecretion, such as inflammation or infection or an allergic reaction of the respiratory system, in a subject in need, wherein said method of treatment comprises administering a composition of the invention as defined above by inhalation through oral aspiration by a subject using a dosing device of the present invention.

An object of the present invention is to provide a non-therapeutic use of a composition of the invention as defined above for the non-therapeutic treatment of mucus hypersecretion and a disorder associated with said mucus hypersecretion in a subject in need, wherein said non-therapeutic use involves administering said composition by inhalation by oral aspiration using a dosing device according to the present invention.

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

Preferably, said inflammation or infection or allergic reaction of the respiratory system is selected from the group consisting of, or alternatively consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis, whooping cough, pneumonia, pleurisy, bronchiolitis, colds, sinusitis , rhinitis, tracheitis, pharyngitis, laryngitis, epiglottitis and bronchiectasis.

It is further an object of the present invention to use said dosing device (in short, a device of the invention, simply a device) for administering a composition of the invention in the form of a powder, preferably a dry powder, to a subject in need by oral inhalation, wherein said device releases an effective dose (predetermined effective dose) of a composition according to the invention when activated by a subject through oral aspiration (in short, a device according to the invention or a dosing device according to the invention).

Finally, it is an object of the present invention to provide a kit comprising (a) a composition of the invention according to any one of the embodiments of the invention, (b) a dosing device in accordance with the invention for administering the composition of the invention to a subject in need; (c) instructions for administering the composition of the invention using (b) a dosing device; and optionally (d) an additional active ingredient, which may be in the form of a composition according to the invention and/or different from it.

The expression "method of treatment" in the context of the present invention is used to mean an action involving the administration of a substance or mixture of substances, or combinations thereof, for the purpose of eliminating, reducing/reducing or preventing a pathology or disease, and its symptoms or disorders.

Unless otherwise indicated, reference to the fact that a composition “contains” one or more components or substances means that other components or substances may be present in addition to the one or those specifically stated.

As shown in the experimental part described below, the compositions of the present invention containing N-acetylcysteine, alone or in combination with hyaluronic acid and/or lactose and/or magnesium stearate, in the form of a powder, preferably a dry powder, for inhalation by oral aspiration , are effective for the therapeutic and non-therapeutic treatment of mucus hypersecretion (or bronchial mucus) and various diseases, symptoms or disorders of the respiratory system associated with said bronchial mucus hypersecretion.

Moreover, administration of the compositions of the invention by means of a dosing device of the invention activated by aspiration by the subject being administered is such as to activate the delivery of an effective dose and to maximize the intrinsic effectiveness of the compositions of the invention.

The inventive composition according to any of the embodiments defined herein exhibits good flowability, good uniformity of distribution of the active ingredient (mucolytic agent, N-acetylcysteine) and adequate chemical and physical stability before use.

In addition, the composition of the invention, when inhaled using an inhalation device of the invention, activated by a single aspiration action from the subject to whom the composition is administered, produces a good respirable fraction and an accurate therapeutically active dose of the active ingredient (mucolytic agent, N-acetylcysteine or salts thereof).

The expression “good flowability” refers to a composition that is easy to handle during manufacture and is capable of accurately and reproducibly delivering a therapeutically effective dose when administered using a device of the invention through aspiration of the subject. Flow characteristics can be assessed by measuring the Carr index; A Carr index below 25 is generally used to indicate good flow characteristics.

The expression “uniformity of distribution” refers to a composition in which, when mixed, the homogeneity of the active ingredient content, expressed as relative standard deviation (RSD), is less than 5%.

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

The expression “physically stable” refers to a composition in which, if multiple components of the dry powder particles of the composition of the invention are present, these components are not substantially separated during the process of making the dry powder and/or during the time between manufacture and use of the composition.

The propensity to separate can be assessed in accordance with the work of Staniforth et al., J. Pharm. Pharmacol., 34.700-706, 1982, which is incorporated herein by reference in its entirety, and is 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 the composition before the test.

The expression "inhalable fraction" refers to the percentage of particles of the active ingredient (mucolytic agent, N-acetylcysteine or salts thereof) that reach the lungs (lower regions) of the subject. The inhalable fraction, also called the fine particle fraction (FPF), is assessed in vitro using a suitable device, such as a Multistage Cascade Impactor or a Multi Stage Liquid Impinger (MLSI), according to the procedures described in the usual pharmacopoeia. The fine particle fraction (FPF) is calculated from the relationship between the distributed dose and the mass of fine particles (fine particle dose, abbreviated FPD). An inhalable fraction of more than 30% is an indicator of good inhalation ability.

The expression “precise therapeutically active dose of an active ingredient” refers to a composition in which the variation between the average daily dose absorbed and the average dose released is 15% or less, preferably less than 10%.

In the context of the present invention, the expressions "active agent" and "active ingredient" are synonymous and refer to a mucolytic agent, preferably N-acetylcysteine, and a pharmaceutically acceptable or edible salt thereof.

Embodiments (Frnr) of the present invention are listed below:

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

(i) a mixture M containing, or alternatively consisting of, a mucolytic agent, and optionally

(ii) at least one pharmaceutically acceptable or nutritional additive and/or excipient.

FR2. Composition according to FR1, wherein said mucolytic agent is N-acetylcysteine or a pharmaceutically acceptable or edible salt thereof.

FR3. Composition according to FR1 or FR2, where said (i) mixture M additionally contains lactose.

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

FR5. The composition according to any one of FR1-FR4, wherein said (i) mixture M further contains hyaluronic acid or a pharmaceutically acceptable or edible salt thereof.

FR6. The composition according to any one of FR1 to FR5, wherein (i) the mixture M contains or, alternatively, consists of: a mucolytic agent, preferably N-acetylcysteine or a salt thereof, with a concentration by weight ranging from 50% to 95% relative to the total the mass of the mixture M, preferably from 55% to 90%, more preferably from 60% to 85%; a concentration by weight of lactose ranging from 5% to 40% relative to the total weight of the mixture, preferably from 10% to 35%, more preferably from 15% to 30%; and, if present, magnesium stearate, at a concentration by weight ranging from 0.1% to 20% based on 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 of preventing and/or treating mucus hypersecretion and a mucus hypersecretion-related disease, symptom and/or disorder in a subject in need.

FR8. Composition for use according to FR7, wherein said disease, symptom and/or disorder associated with said mucus hypersecretion is an inflammation or infection or allergic reaction of the respiratory system, preferably said inflammation or infection or allergic reaction of the respiratory system is selected from the group containing or alternatively consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis, whooping cough, pneumonia, pleurisy, bronchiolitis, colds, sinusitis, rhinitis, tracheitis, pharyngitis, laryngitis, epiglottitis and bronchiectasis.

FR9. A dosing device for administering a composition in powder form according to any one of FR1 to FR6 to a specified subject in need by oral inhalation, wherein said device releases an effective dose of said composition upon activation by the subject through oral aspiration.

FR10. Set containing:

(a) a composition according to any one of FR1 to FR6, preferably said composition is placed in a container;

(b) device according to FR9; And

(c) instructions for use of said composition (a) and said device (b).

FR11. Non-therapeutic use of a composition according to any one of FR1 to FR6, wherein said use is for the non-therapeutic treatment of mucus hypersecretion and a disorder associated with said mucus hypersecretion in a subject in need, wherein said non-therapeutic use involves administering said composition by inhalation by oral aspiration using a dosing device according to clause 9.

Experimental part (I)

The viscosity of mucus produced by patients suffering from cystic fibrosis, whose mucus has particularly altered viscoelastic characteristics, was measured for the purpose of in vitro evaluation of the compositions in accordance with the present invention (Compositions 1-4 having the composition shown in table 1). For the purposes of this evaluation, only mucus samples having a viscosity between 4000 mPa.s and 10,000 mPa.s (millipascal x second or PI: Poiseuille) measured at 37°C were considered.

Viscosity at baseline conditions (Measurement A, before incubation) was measured for each mucus sample (750 μl). Each mucus sample was then incubated at 37°C for 30 minutes, respectively, with saline (50 ml) (saline was used as a control) and NAC (NAC in saline) containing one of the following: Composition 1 (70 µg) (NAC 71), Composition 2 (70 µg) (NAC71+LM), Composition 3 (70 µg) (NAC75+L), Composition 4 (70 µg) (NAC80+L); thus, a viscosity measurement was performed on each sample (Measurement B, after incubation) (Table 2 and Fig. 1). The indicated viscosities (Measurements A and B) were measured at 37°C and are shown in FIG. 1 as the average viscosity value (ETA) in mPa s.

The instrument used to measure viscosity is a rotating concentric cylinder rheometer that uses the sinusoidal oscillation method (Mucorheometer ESLAB, Milan) to measure mucus in the range from 500 mPa s to 80,000 mPa s.

Table 1

Composition 1 Composition 2 Composition 3 Composition 4 NAC 71% 71% 75% 80% L / 25% 25% 20% M / 4% / /

NAC - N-acetylcysteine; L - lactose; M - magnesium stearate, % by weight relative to the total weight of the mixture M

results

Table 2 shows a descriptive analysis of the viscosity measurements (in mPa.s at 37°C) before and after incubation (Measurements A and B), and FIG. 1 shows the average viscosity values (ETA, average viscosity values at 37°C) shown in Table 2 using a bar graph.

Table 3 shows the statistical analysis of the differences; ANOVA was performed using the Kruskal-Wallis test for repeated measures and using Dunnett's test for post hoc analysis (significance level, P < 0.05): differences were significant before and after treatment, while they were not significant between different formulations after treatment with N-acetylcysteine (Compositions 1-4).

table 2

Dunnett's multiple comparison test Difference Significance level of median variation (P>0.05) Saline A vs NAC71 A 55.40 *** Saline A vs NAC71 A+LM 52.90 ** Saline A vs NAC75 A+L 46.80 * Saline A vs NAC80 A+L 60.10 *** NAC71 B vs NAC71 A 53.35 ** NAC71 B+LM vs NAC71 A+LM 52.45 ** NAC75 B+L vs NAC75 A+L 42.30 insignificant NAC80 B+L vs NAC80 A+L 57.2 ***

* significant; ** more significant; *** even more significant

conclusions

The results obtained (Table 2, Table 3 and FIG. 1) show that Compositions 1-4 according to the invention containing N-acetylcysteine alone or in combination with lactose and/or magnesium stearate in powder form for inhalation by oral aspiration are effective in relation to reducing the viscosity of bronchial mucus obtained from patients suffering from cystic fibrosis.

Thus, the compositions of the invention are highly effective in the treatment of hypersecretion of bronchial mucus in various diseases of the respiratory system.

Experimental part (II)

The viscosity of mucus obtained from patients, in accordance with the conditions and methods described in experimental part (I), was measured for the purpose of in vitro evaluation of the compositions in accordance with the present invention (Compositions 5-12 having the composition indicated in table 4).

NAC - N-acetylcysteine; HA: hyaluronic acid; L - lactose; M - magnesium stearate; % by weight relative to the total mass of mixture M

results

Table 5a and Table 5b show a descriptive analysis of the viscosity measurement data (in mPa.s at 37°C) before and after incubation (Measurements A and B) of Formulations 5-12 from Table 4, and FIG. 2, using a bar graph, shows the average viscosity values (ETA, average viscosity values at 37°C) of Compositions 5-15 from Table 4, listed in Table 6 for Compositions 5-12.

Table 6 shows the statistical analysis of the differences for Compositions 5-12; ANOVA was performed using the Kruskal-Wallis test for repeated measures and using Dunnett's test for post hoc analysis (significance level, P < 0.05): the differences are statistically significant between pre- and post-treatment for the 10% NAC concentration used and 20%. (Fig. 2)

Table 6

Dunnett's multiple comparison test Difference Significance of median variation (P>0.05) Saline B vs Saline A -6.364 ns Saline B vs NAC 5% IA 75% B 6,636 ns Saline B vs NAC 5% IA 75% A 66.18 ns Saline B vs NAC 10% IA70% B -2.136 ns Saline B vs NAC 10% IA 70% A 87.82 * Saline B vs NAC 20% IA 60% B -28.09 ns Saline B vs NAC 20% IA 60% A 107.5 ** Saline B vs NAC 5% IA 91% Mg B -18.45 ns Saline B vs NAC 5% IA 91% Mg A 77.18 ns Saline B vs NAC 10% IA 86% Mg B -1.273 ns Saline B vs NAC 10% IA 86% Mg A 91.09 * Saline B vs NAC 20% IA 76% Mg B -26.68 ns Saline B vs NAC 20% IA 76% Mg A 107.8 ** Saline B vs IA 80%+L 20% B 6,182 ns Saline B vs IA 80%+L 20% A 45.14 ns Saline B vs NAC 80 + L B 5,959 ns Saline B vs NAC 80 + L A 124.2 *** Saline A vs NAC 5% IA 75% B 13.00 ns Saline A vs NAC 5% IA 75% A 72.55 ns Saline A vs NAC 10% IA70% B 4.227 ns Saline A vs NAC 10% IA 70% A 94.18 * Saline A vs NAC 20% IA 60% B -21.73 ns Saline A vs NAC 20% IA 60% A 113.9 *** Saline A vs NAC 5% IA 91% Mg B -12.09 ns Saline A vs NAC 5% IA 91% Mg A 83.55 ns Saline A vs NAC 10% IA 86% Mg B 5,091 ns Saline A vs NAC 10% IA 86% Mg A 97.45 ** Saline A vs NAC 20% IA 76% Mg B -20.32 ns Saline A vs NAC 20% IA 76% Mg A 114.2 *** Saline A vs IA 80%+L 20% B 12.55 ns Saline A vs IA 80%+L 20% A 51.50 ns Saline A vs NAC 80 + L B 12.32 ns Saline A vs NAC 80 + L A 130.6 *** NAC 5% IA 75%B vs NAC 5% IA 75% A 59.55 ns NAC 5% IA 75%B vs NAC 10% IA70% B -8.773 ns NAC 5% IA 75%B vs NAC 10% IA 70% A 81.18 ns NAC 5% IA 75%B vs NAC 20% IA 60% B -34.73 ns NAC 5% IA 75%B vs NAC 20% IA 60% A 100.9 ** NAC 5% IA 75%B vs NAC 5% IA 91% Mg B -25.09 ns NAC 5% IA 75%B vs NAC 5% IA 91% Mg A 70.55 ns NAC 5% IA 75%B vs NAC 10% IA 86% Mg B -7.909 ns NAC 5% IA 75%B vs NAC 10% IA 86% Mg A 84.45 ns NAC 5% IA 75%B vs NAC 20% IA 76% Mg B -33.32 ns NAC 5% IA 75%B vs NAC 20% IA 76% Mg A 101.2 ** NAC 5% IA 75%B vs IA 80%+L 20% B -0.4545 ns NAC 5% IA 75%B vs IA 80%+L 20% A 38.50 ns NAC 5% IA 75%B vs NAC 80% + L20% B -0.6773 ns NAC 5% IA 75%B vs NAC 80% + L20% A 117.6 *** NAC 5% IA 75% A vs NAC 10% IA70% B -68.32 ns NAC 5% IA 75% A vs NAC 10% IA 70% A 21.64 ns NAC 5% IA 75% A vs NAC 20% IA 60% B -94.27 * NAC 5% IA 75% A vs NAC 20% IA 60% A 41.36 ns NAC 5% IA 75% A vs NAC 5% IA 91% Mg B -84.64 ns NAC 5% IA 75% A vs NAC 5% IA 91% Mg A 11.00 ns NAC 5% IA 75% A vs NAC 10% IA 86% Mg B -67.45 ns NAC 5% IA 75% A vs NAC 10% IA 86% Mg A 24.91 ns NAC 5% IA 75% A vs NAC 20% IA 76% Mg B -92.86 * NAC 5% IA 75% A vs NAC 20% IA 76% Mg A 41.64 ns NAC 5% IA 75% A vs IA 80%+L 20% B -60.00 ns NAC 5% IA 75% A vs IA 80%+L 20% A -21.05 ns NAC 5% IA 75% A vs NAC 80% + L20% B -60.22 ns NAC 5% IA 75% A vs NAC 80% + L20% A 58.03 ns NAC 10% IA70% B vs NAC 10% IA 70% A 89.95 * NAC 10% IA70% B vs NAC 20% IA 60% B -25.95 ns NAC 10% IA70% B vs NAC 20% IA 60% A 109.7 *** NAC 10% IA70% B vs NAC 5% IA 91% Mg B -16.32 ns NAC 10% IA70% B vs NAC 5% IA 91% Mg A 79.32 ns NAC 10% IA70% B vs NAC 10% IA 86% Mg B 0.8636 ns NAC 10% IA70% B vs NAC 10% IA 86% Mg A 93.23 * NAC 10% IA70% B vs NAC 20% IA 76% Mg B -24.55 ns NAC 10% IA70% B vs NAC 20% IA 76% Mg A 110.0 *** NAC 10% IA70% B vs IA 80%+L 20% B 8,318 ns NAC 10% IA70% B vs IA 80%+L 20% A 47.27 ns NAC 10% IA70% B vs NAC 80% + L20% B 8,095 ns NAC 10% IA70% B vs NAC 80% + L20% A 126.3 *** NAC 10% IA 70% A vs NAC 20% IA 60% B -115.9 *** NAC 10% IA 70% A vs NAC 20% IA 60% A 19.73 ns NAC 10% IA 70% A vs NAC 5% IA 91% Mg B -106.3 ** NAC 10% IA 70% A vs NAC 5% IA 91% Mg A -10.64 ns NAC 10% IA 70% A vs NAC 10% IA 86% Mg B -89.09 * NAC 10% IA 70% A vs NAC 10% IA 86% Mg A 3.273 ns NAC 10% IA 70% A vs NAC 20% IA 76% Mg B -114.5 *** NAC 10% IA 70% A vs NAC 20% IA 76% Mg A 20.00 ns NAC 10% IA 70% A vs IA 80%+L 20% B -81.64 ns NAC 10% IA 70% A vs IA 80%+L 20% A -42.68 ns NAC 10% IA 70% A vs NAC 80% + L20% B -81.86 ns NAC 10% IA 70% A vs NAC 80% + L 20% A 36.39 ns NAC 20% IA 60% B vs NAC 20% IA 60% A 135.6 *** NAC 20% IA 60% B vs NAC 5% IA 91% Mg B 9,636 ns NAC 20% IA 60% B vs NAC 5% IA 91% Mg A 105.3 ** NAC 20% IA 60% B vs NAC 10% IA 86% Mg B 26.82 ns NAC 20% IA 60% B vs NAC 10% IA 86% Mg A 119.2 *** NAC 20% IA 60% B vs NAC 20% IA 76% Mg B 1,409 ns NAC 20% IA 60% B vs NAC 20% IA 76% Mg A 135.9 *** NAC 20% IA 60% B vs IA 80%+L 20% B 34.27 ns NAC 20% IA 60% B vs IA 80%+L 20% A 73.23 ns NAC 20% IA 60% B vs NAC 80% + L20% B 34.05 ns NAC 20% IA 60% B vs NAC 80% + L20% A 152.3 *** NAC 20% IA 60% A vs NAC 5% IA 91% Mg B -126.0 *** NAC 20% IA 60% A vs NAC 5% IA 91% Mg A -30.36 ns NAC 20% IA 60% A vs NAC 10% IA 86% Mg B -108.8 ** NAC 20% IA 60% A vs NAC 10% IA 86% Mg A -16.45 ns NAC 20% IA 60% A vs NAC 20% IA 76% Mg B -134.2 *** NAC 20% IA 60% A vs NAC 20% IA 76% Mg A 0.2727 ns NAC 20% IA 60% A vs IA 80%+L 20% B -101.4 ** NAC 20% IA 60% A vs IA 80%+L 20% A -62.41 ns NAC 20% IA 60% A vs NAC 80% + L20% B -101.6 ** NAC 20% IA 60% A vs NAC 80% + L20% A 16.66 ns NAC 5% IA 91% Mg B vs NAC 5% IA 91% Mg A 95.64 * NAC 5% IA 91% Mg B vs NAC 10% IA 86% Mg B 17.18 ns NAC 5% IA 91% Mg B vs NAC 10% IA 86% Mg A 109.5 *** NAC 5% IA 91% Mg B vs NAC 20% IA 76% Mg B -8.227 ns NAC 5% IA 91% Mg B vs NAC 20% IA 76% Mg A 126.3 *** NAC 5% IA 91% Mg B vs IA 80%+L 20% B 24.64 ns NAC 5% IA 91% Mg B vs IA 80%+L 20% A 63.59 ns NAC 5% IA 91% Mg B vs NAC 80% + L20% B 24.41 ns NAC 5% IA 91% Mg B vs NAC 80% + L20% A 142.7 *** NAC 5% IA 91% Mg A vs NAC 10% IA 86% Mg B -78.45 ns NAC 5% IA 91% Mg A vs NAC 10% IA 86% Mg A 13.91 ns NAC 5% IA 91% Mg A vs NAC 20% IA 76% Mg B -103.9 ** NAC 5% IA 91% Mg A vs NAC 20% IA 76% Mg A 30.64 ns NAC 5% IA 91% Mg A vs IA 80%+L 20% B -71.00 ns NAC 5% IA 91% Mg A vs IA 80%+L 20% A -32.05 ns NAC 5% IA 91% Mg A vs NAC 80% + L20% B -71.22 ns NAC 5% IA 91% Mg A vs NAC 80% + L20% A 47.03 ns NAC 10% IA 86% Mg B vs NAC 10% IA 86% Mg A 92.36 * NAC 10% IA 86% Mg B vs NAC 20% IA 76% Mg B -25.41 ns NAC 10% IA 86% Mg B vs NAC 20% IA 76% Mg A 109.1 *** NAC 10% IA 86% Mg B vs IA 80%+L 20% B 7.455 ns NAC 10% IA 86% Mg B vs IA 80%+L 20% A 46.41 ns NAC 10% IA 86% Mg B vs NAC 80% + L 20% B 7,232 ns NAC 10% IA 86% Mg B vs NAC 80% + L20% A 125.5 *** NAC 10% IA 86% Mg A vs NAC 20% IA 76% Mg B -117.8 *** NAC 10% IA 86% Mg A vs NAC 20% IA 76% Mg A 16.73 ns NAC 10% IA 86% Mg A vs IA 80%+L 20% B -84.91 ns NAC 10% IA 86% Mg A vs IA 80%+L 20% A -45.95 ns NAC 10% IA 86% Mg A vs NAC 80% + L20% B -85.13 ns NAC 10% IA 86% Mg A vs NAC 80% + L20% A 33.12 ns NAC 20% IA 76% Mg B vs NAC 20% IA 76% Mg A 134.5 *** NAC 20% IA 76% Mg B vs IA 80%+L 20% B 32.86 ns NAC 20% IA 76% Mg B vs IA 80%+L 20% A 71.82 ns NAC 20% IA 76% Mg B vs NAC 80% + L20% B 32.64 ns NAC 20% IA 76% Mg B vs NAC 80% + L 20% A 150.9 *** NAC 20% IA 76% Mg A vs IA 80%+L 20% B -101.6 ** NAC 20% IA 76% Mg A vs IA 80%+L 20% A -62.68 ns NAC 20% IA 76% Mg A vs NAC 80% + L20% B -101.9 ** NAC 20% IA 76% Mg A vs NAC 80% + L20% A 16.39 ns IA 80%+L 20% B vs IA 80%+L 20% A 38.95 ns IA 80%+L 20% B vs NAC 80% + L20% B -0.2227 ns IA 80%+L 20% B vs NAC 80% + L20% A 118.0 *** IA 80%+L 20% A vs NAC 80% + L20% B -39.18 ns IA 80%+L 20% A vs NAC 80% + L20% A 79.07 ns NAC 80% + L20% B vs NAC 80% + L20% A 118.3 ***

ns: not significant, * significant; ** more significant; *** even more significant

conclusions

The results show that acetylcysteine (NAC), taken alone and also in combination with hyaluronic acid (HA), was effective in reducing the viscosity of bronchial mucus. NAC breaks down the disulfide bonds of glycoprotein agglomerates by chemically breaking down the glycoprotein structures into less viscous components.

At low concentrations of NAC there are no significant effects, for example, in Composition 5 containing 5% by weight NAC. However, the addition of HA has been shown to increase the effect of NAC, hence compositions containing NAC at 10% or 20% are effective.

Thus, a medical device that provides NAC and HA in dry powder form for inhalation via oral aspiration may be very useful in the treatment of bronchial hypersecretion in various respiratory diseases.

Claims (20)

1. Composition in the form of a dry powder for oral inhalation, containing: (i) N-acetylcysteine or its salt in an amount of 0.1-60% relative to the total weight of the composition, and (ii) hyaluronic acid or its salt in an amount of 40-90% relative to the total weight of the composition, and (iii) a pharmaceutically acceptable or nutritional supplement and/or excipient, wherein said composition is for the prevention and/or treatment of mucus hypersecretion and a disease, symptom and/or disorder associated with said mucus hypersecretion in a subject in need. 2. The composition according to claim 1, which further contains a first auxiliary agent selected from the group consisting of lactose, dextran, mannitol and mixtures thereof, preferably lactose. 3. The composition according to claim 1 or 2, which further contains a second auxiliary agent, wherein said second agent is a metal stearate or a derivative thereof selected from the group consisting of 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. 4. Composition according to any one of paragraphs. 1-3, which contains, % by weight: (i) N-acetylcysteine or a salt thereof, ranging from 0.1% to 58%, preferably from 5% to 50%, more preferably from 10% to 40%, based on the total weight of the composition; (ii) hyaluronic acid or a salt thereof ranging from 40% to 90%, preferably from 50% to 80%, more preferably from 60% to 80%, based on the total weight of the composition; (iii) a first adjuvant, preferably lactose, and/or a second adjuvant, preferably magnesium stearate, ranging from 2% to 35%, preferably from 10% to 30%, more preferably from 15% to 25%, relative to the total mass of the composition. 5. Composition according to any one of paragraphs. 1-4, wherein said disease, symptom and/or disorder associated with said mucus hypersecretion is an inflammation, infection or allergic reaction of the respiratory system. 6. The composition of claim 5, wherein said inflammation, infection or allergic reaction of the respiratory system is selected from the group consisting of, or alternatively consisting of: asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, cystic fibrosis, whooping cough, pneumonia, pleurisy, bronchiolitis, colds, sinusitis, rhinitis, tracheitis, pharyngitis, laryngitis, epiglottitis and bronchiectasis. 7. A dosing device for administering dry powder by oral inhalation, where said device contains: - a compartment for storing powder containing a composition in the form of a dry powder according to any one of claims. 1-6, - an aspiration channel, the first end of which is directly or indirectly connected to the powder accommodating compartment, and the second end of which allows the subject to perform an oral aspiration action; wherein said powder accommodating compartment is loaded with said composition in the form of a dry powder by means of a loading device containing said composition, the device being designed to deliver a dose of said composition after said oral aspiration by a subject requiring said administration. 8. The device according to claim 7, wherein said loading device is a single-dose or multi-dose type device. 9. The device according to claim 7 or 8, where the device further comprises a compartment for housing a loading device, which contains the specified composition in the form of a dry powder. 10. The device of claim 7 or 8, wherein said loading device is an external loading device located outside the device, the device being designed to directly transfer a single dose of said composition from the external loading device to the powder receiving compartment. 11. The device of claim 9, wherein said loading device is an internal loading device located within the device in said loading device housing compartment, the device being designed to allow a single dose of said composition to be indirectly transferred from the external loading device to a compartment for accommodating powder by applying pressure to the device or to the internal loading device, causing the internal loading device to open.

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