WO2022053969A1 - Hyaluronic acid or salt thereof for inhalation use in the treatment of respiratory diseases, and an inhaler device containing the same - Google Patents
Hyaluronic acid or salt thereof for inhalation use in the treatment of respiratory diseases, and an inhaler device containing the same Download PDFInfo
- Publication number
- WO2022053969A1 WO2022053969A1 PCT/IB2021/058205 IB2021058205W WO2022053969A1 WO 2022053969 A1 WO2022053969 A1 WO 2022053969A1 IB 2021058205 W IB2021058205 W IB 2021058205W WO 2022053969 A1 WO2022053969 A1 WO 2022053969A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mixture
- composition
- sodium hyaluronate
- hyaluronic acid
- mannitol
- Prior art date
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title claims abstract description 90
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- 229940035034 maltodextrin Drugs 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000003300 oropharynx Anatomy 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 210000003456 pulmonary alveoli Anatomy 0.000 description 1
- 238000007430 reference method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000005801 respiratory difficulty Effects 0.000 description 1
- 210000001533 respiratory mucosa Anatomy 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0001—Details of inhalators; Constructional features thereof
- A61M15/002—Details of inhalators; Constructional features thereof with air flow regulating means
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
- A61M15/003—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using capsules, e.g. to be perforated or broken-up
- A61M15/0031—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using capsules, e.g. to be perforated or broken-up by bursting or breaking the package, i.e. without cutting or piercing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M11/00—Sprayers or atomisers specially adapted for therapeutic purposes
- A61M11/001—Particle size control
- A61M11/003—Particle size control by passing the aerosol trough sieves or filters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/06—Solids
- A61M2202/064—Powder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2205/00—General characteristics of the apparatus
- A61M2205/70—General characteristics of the apparatus with testing or calibration facilities
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2209/00—Ancillary equipment
- A61M2209/02—Equipment for testing the apparatus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2209/00—Ancillary equipment
- A61M2209/06—Packaging for specific medical equipment
Definitions
- the present invention relates to a mixture or a composition in form of dry powder for inhalation comprising hyaluronic acid or a salt thereof, preferably sodium hyaluronate. Furthermore, the present invention relates to a mixture or a composition in form of dry powder for inhalation comprising hyaluronic acid or a salt thereof, preferably sodium hyaluronate, and mannitol.
- the present invention relates to a kit for the administration of dry powder through the inhalation route, said kit comprising a dry powder inhaler and a blister, wherein said blister contains - therein - said mixtures or compositions in form of dry powder comprising a hyaluronic acid or a salt thereof, preferably sodium hyaluronate, or a hyaluronic acid or a salt thereof, preferably sodium hyaluronate, and mannitol.
- diseases or symptoms of the respiratory tract are the diseases that affect the organs of the upper and/or lower respiratory system, such as nose, throat, pharynx, larynx, trachea, bronchi, bronchioles, alveoli and/or pulmonary area, mainly caused by bacteria or viruses.
- any condition or disease affecting the respiratory system is considered a respiratory disease or disorder.
- Millions of people worldwide suffer from respiratory diseases, particularly diseases or symptoms of the upper respiratory tract, such as nose, throat, pharynx, larynx, trachea, and upper part of the bronchi.
- Products of the prior art include products in form of dry powders to be administered by inhalation.
- the administration of active substances in form of powder through the inhalation route may entail problems such as: cause coughing in the subject to whom the powder is administered, difficulty in dosing low dosages which are constant and repeatable throughout the treatment due to the limited emission capabilities of the inhalers, powder packing problems, difficulty on the part of the subject in using inhalers, difficulty in regulating the dosage by the subject in case of multidose inhalers, problems relating to bacterial sterility in case of multi-use inhalers.
- the Applicant addresses and solves the problem of the treatment of diseases and/or symptoms of the upper and lower respiratory tract, preferably of the upper respiratory tract (for example, rhinitis, sinusitis, raucousness and sore throat, etc.), such as respiratory diseases and/or symptoms caused by baderia or viruses (for example, virus belonging to the strain SARS-CoV-2), by providing mixtures or compositions in form of dry powders for inhalation (through the mouth) comprising hyaluronic acid or a salt thereof (in short , mixtures or compositions of the invention), preferably hyaluronic acid or a salt thereof and mannitol.
- diseases and/or symptoms of the upper and lower respiratory tract preferably of the upper respiratory tract (for example, rhinitis, sinusitis, raucousness and sore throat, etc.), such as respiratory diseases and/or symptoms caused by baderia or viruses (for example, virus belonging to the strain SARS-CoV-2)
- kits in short, kit of the invention
- DPI dry powder inhaler
- single-dose blister or the like
- said kit is effective for the administration of hyaluronic acid or a salt thereof to a subject in need through the inhalation route.
- blister or “single-dose blister” are used to indicate a dosed and sealed container having a volume suitable to house a mixture or a composition of the present invention, said blister being pierceable by applying a pressure exerted manually by a subjed, for example, a plastic and/or aluminium container or cartridge comprising a pierceable aluminium sheet on one side.
- the mixtures or compositions of the invention based on hyaluronic acid or a salt thereof have no relevant side effects and they can be administered to all categories of subjects in need, including the elderly, pregnant or breastfeeding women, paediatric subjects (0-12 years), subjects with respiratory complications or other comorbidities.
- kits or inhaler for dry powders of the invention are easy to prepare and cost-effective, same case applying to the kit or inhaler for dry powders of the invention are simple to construd and cost-effective.
- both the kit of the invention and the inhaler for dry powders of the invention are simple to use for any type of subjed, induding subjeds with respiratory difficulties, for example subjects with adhmatic subjeds, children and the elderly.
- the easy use of the device of the invention allows to improve the adherence of the subject to the therapy.
- the device of the invention is of the disposable type, it is free from bacterial sterility- related problems.
- FIG. 10 A diagram of the respiratory tract of a human subjed is reported in Figure 10.
- the terms "lower respiratory tract” and “lower respiratory airways” and “deep respiratory tract” are synonyms used interchangeably and they mainly represent the lower part of the bronchi, lungs, bronchioles, alveoli.
- upper respiratory tract and “upper respiratory airways” are synonyms used interchangeably and they mainly represent nose, throat, pharynx, larynx, trachea, and upper part of the bronchi.
- Fig.1 relates to an upper perspective view of the inhaler seen from the distal end thereof;
- Fig.2 relates to a lower perspective view of the inhaler seen from the distal end thereof;
- Fig.3 relates to a top plan view of the inhaler;
- Fig.4 relates to a view similar to the preceding one with the cartridge mounted on the inhaler;
- Fig.5 relates to a sectional view of the inhaler along the longitudinal centreline plane thereof, with the blister (or cartridge) mounted thereon;
- Fig.6 relates to a view similar to the preceding one with the blister open for dispensing the mixture or composition of the invention
- Fig.7 relates to a schematic representation of a Next Generation Impactor (NGI) as laid down by the Eu. Pharm. 8.0, 2.9.18 guidelines;
- NTI Next Generation Impactor
- Fig.8 relates to a cumulative percentage of mass of Na-HA (sodium hyaluronate) with respect to the particle size distribution in terms of aerodynamic diameter;
- Fig. 9 reports the mean values and the standard deviation of the amount of Na-HA (sodium hyaluronate) in mg, deposited in the various stages of the Next Generation Impactor (NGI);
- NTI Next Generation Impactor
- Fig.10 relates to a schematic representation of the ramifications present at the level of the bronchial tree;
- Fig.11 reports a correlation between the particle size and the deposition site at the level of the respiratory system;
- Fig.12 reports a granulometric distribution of sodium hyaluronate for aerosol;
- Figs. 13A, 13B, 13C and 13D report the micrographs of the particles of sodium hyaluronate
- Fig.14 relates to a granulometric distribution of sodium hyaluronate (Hyal);
- Figs. 16 and 17 report the micrographs of the sodium hyaluronate particles;
- Figs. 18 and 18A report a Glass Twin Stage Impinger compliant with the Ph. Eur. 9a Ed. guidelines; separator with the inhaler of the invention paired thereto;
- Fig.19 relates to a granulometric distribution of sodium hyaluronate (Hyal);
- Fig.20 relates to a thermogravimetric analysis (TGA) curve of sodium hyaluronate (Hyal);
- Fig.21 relates to a size distribution as volume diameter of sodium hyaluronate raw material measured using a laser difffadometer;
- Figs.22 and 23 report the images of the morphology of the sodium hyaluronate-mannitol mixture of the invention.
- Fig.24 relates to a chart DP1 ⁇ 2 against Q for the calculation of the resistance of the inhaler of the invention
- Fig.25 reports the dynamic flow curves carried out by volunteers on the inhaler of the invention empty
- Fig.26 reports the dynamic flow curves carried out by volunteers on inhalers of the invention loaded with the mixture of the invention
- Fig.27 shows a relationship between the dose emitted and the volume of air inhaled by volunteers with inhalers of the invention loaded with 27.8 mg of sodium hyaluronate-mannitol mixture of the invention.
- Forming an object of the present invention is a mixture in form of dry powder for inhalation (inhalation through the mouth) comprising or, alternatively, consisting of hyaluronic acid or an acceptable pharmaceutical or food grade salt thereof (in short, mixture of the invention).
- Forming an object of the present invention is a composition in form of dry powder for inhalation comprising said mixture of the invention (comprising or, alternatively, consisting of hyaluronic acid or a salt thereof and, optionally, a carrier) and at least one acceptable pharmaceutical or food grade additive and/or exdpient.
- hyaluronic acid is used to indicate a hyaluronic acid and/or an acceptable pharmaceutical or food grade hyaluronic acid salt.
- Hyaluronic acid (for example, CAS 9004-61-9) is a macromolecule, such as a non-sulfurated glycosaminoglycan and devoid of protein core.
- hyaluronic acid in short HA
- HA hyaluronic acid
- HA by combining with the mucus, HA is capable of playing and carrying out a respiratory tract protection role; (b) being one of the main constituents of the cell matrix, HA incorporates fibres and fibrous constituents of the matrix (such as elastin and collagen), and thus 1) HA proteds the lung tissue matrix from the degradation of elastic fibres, and 2) HA acts as a barrier against the "destructive" activities of elastases;
- HA plays a fundamental role in the hydration of impaired bronchial secretions.
- the hyaluronic acid (HA) (or sodium hyaluronate (HA-Na)) comprised in the mixture or composition of the invention in form of a dry inhalable powder deposits mainly at the level of the upper respiratory tract, creating a kind of homogeneous "coating" well distributed on the mucosa, and it exerts the action thereof for the protection of the respiratory mucosa in such site.
- the hyaluronic acid of the mixture or composition of the present invention deposits mainly at the level of the upper respiratory tract.
- the hyaluronic acid or the salt thereof, comprised in the mixture or composition of the invention (optionally combined with a carrier, preferably mannitol) advantageously has an average molecular weight comprised from 100 KDa to 4000 KDa, preferably from equal to or greater than 500 kDa to equal to or less than 2000 kDa, more preferably from 700 kDa to 1000 kDa, for example 200 kDa, 300 kDa, 400 kDa, 550 kDa, 600 kDa, 750 kDa, 800 kDa, 850 kDa, 900 kDa, 950 kDa, 1100 kDa, 1200 kDa, 1400 kDa, 1600 kDa or 1800 kDa, 2000 kDa, 2200 kDa, 2400 kDa, 2600 kDa, 2800 kDa, 3000 kDa or 3500 kDa (kD
- Said hyaluronic acid may be linear or branched, preferably linear (for example, linear HA with average molecular weight comprised from 700 kDa to 1000 kDa).
- hyaluronic acid salt is intended to indicate, for example, an alkali metal or alkaline earth metal, preferably sodium, potassium, magnesium or caldum salt, more preferably sodium salt (sodium hyaluronate -HA-Na).
- powdered sodium hyaluronate for inhalation that can be used in the context of the present invention (comprised in the mixture or composition of the invention, optionally in the presence of at least one carrier, preferably mannitol) is a sodium hyaluronate (for example CAS No. 9067-32-7) having the following characteristics (European reference method or European Pharmacopoeia, in short Eu. Pham.):
- the mixture of the invention comprises or, alternatively, consists of hyaluronic acid or a salt thereof, and at least one carrier, wherein said at least one carrier is selected from the group comprising or, alternatively consisting of: mannitol, lactose, dextran, metal stearate (preferably magnesium stearate) and mixtures thereof; preferably the mixture of the invention comprises or, alternatively, consists of hyaluronic acid or a salt thereof (for example sodium hyaluronate), and mannitol; more preferably the mixture of the invention consists of sodium hyaluronate and mannitol.
- the lactose and/or mannitol partides have a particle size diameter such (for example about 100 ⁇ m) that they cannot penetrate into the deep parts of the respiratory system. Therefore, most of the lactose present in the mixture or in the composition deposits in the oropharynx before moving on to the stomach after being swallowed.
- the metal stearate is a salt derived from stearic acid (I UP AC name octadecanoic acid, brute formula C18H3602, example of CAS No. 57-114) orree sallfied.
- composition of the present invention may comprise said at least one acceptable pharmaceutical or food grade additive and/or exdpient
- Said at least one additive and/or exdpient is different from said at least one carrier and it can be selected from any additive and/or exdpient known to the person skilled in the art of dry powders for inhalation, for example it can be seleded from the group comprising or, alternatively, consisting of: maltodextrin, leudne, sodium dtrate and mixtures thereof, or any other additive and/or exdpient known to the person skilled in the art.
- the single-dose inhaler of the invention is activated by a subject in need of inhaling 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 using a finger) so as to break the lower portion of the blister and transfer the mixture or composition of the invention by dropping from the blister to said inner drop region (5) of the inhater; (II) aspirating with the mouth positioned on said end of said dispensing duct (3) of the inhaler with a force sufficient to cause aspiration of the mixture or composition of the invention by said subject, for example with a flow comprised from 30 L/min to 150 L/min (for example 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/ml or 140 L/min) preferably from 60 L/min to 100 L/min, for example of about 80 L/min.
- a flow comprised from 30 L
- the expression "good flowability” refers to a composition that can be easily handled during the preparation process and it is capable of guaranteeing an accurate and reprodudble administration of the therapeutically effective dose when administered using the device of the invention by means of the aspiration action of the subject, for all doses provided for in the treatment plan.
- the flow characteristics can be evaluated by measuring the Carr index; a Carr index lower than 25 is usually used to indicate good flow characteristics.
- treatment method is used to indicate an intervention on a subject in need, comprising the administration of a composition or mixture of substances in a therapeutically effective amount (as established by a person skilled in the art), with the aim of eliminating, reducing/decreasing or preventing a disease or ailment and the symptoms or disorders thereof.
- a composition comprising the mixture according to any one of the preceding daims and at least one acceptable pharmaceutical or food grade additive and/or excipient.
- a dry powder inhaler of the comprising a substantially pipe-shaped hollow body comprising a first portion (1), for housing said blister (or cartridge (C)), and a second portion (2) connected to said first portion (1) for dispensing said powder mixture or composition by means of a primary air flow (FP) which carries the powder from an inner drop region (5), located at the bottom of said first portion (1), along a dispensing duct (3) whose end is suitable to be placed in the mouth of a subject, said dispensing duct (3) being horizontally partitioned - by a partitioning septum (4) - into an upper duct (3a) which dispenses the primary air flow (FP) and a lower duct (3b) which dispenses a powder-free secondary air flow (FS), the aspiration of the air forming the primary air flow (FP) being obtained by means of at least three air intakes (7) formed in the first portion (1) which are preferably arranged symmetrically with respect to the longitudinal centreline plane of the inhaler, the aspiration of the air
- FR11 The mixture or composition according to any one of FR1-9 or the kit according to FR10 for use as medicament.
- EXPERIMENTAL PART Determination of the respirable fraction (FPF), the mass median aerodynamic diameter (MMAD) and Geometric Standard Deviation (GSD) - using a Next Generation Impactor (NGI) - of the samples of a dry powder inhaler of the invention loaded with the mixture of the invention consisting of sodium hyaluronate and mannitol.
- FPF respirable fraction
- MMAD mass median aerodynamic diameter
- GSD Geometric Standard Deviation
- NTI Next Generation Impactor
- the fine particle fraction (FRF) i.e. the particle fraction of a powder in the form of an aerosol, capable of depositing at the level of the deep airways (lungs. bronchioles ⁇ alveoli) having an aerodynamic diameter comprised between 0.5 ⁇ m and 5 ⁇ m
- the cumulative value of fine particle fraction (FPF) is about 2.6% confirming the deposition of the product at the level of these regions, even if in reduced percentages.
- MMAD Mass Median Aerodynamic Diameter
- the particle sizes were measured using the granulometer AccusizerTM Particle Sizer Model 770; particle sizing system, Santa Barbara California, USA
- Thermogravimetric analysis was carried out using a TG-DTA Netzsch STA 490 C thermal analyser under the following operating conditions: heating rate 10oC/min, air flow 30 ml/min.
- thermogravimetric analysis was also carried out on the Hyal (batch no 1000007837)/mannitol mixture (36:64) which showed a water content equal to 7.47% (thermogravimetric analysis curve not reported), similarly to what was previously obtained for the mixture of the present invention.
- Hyal particles The morphology of the Hyal particles was studied using a Scanning Electron Microscope (SEM). The micrographs were obtained with an FE-SEM LEO 1525 Zeiss - LEO Electron Microscopy Inc., One Zeiss Drive (Thomwood, NY) microscope. As observable from Figures 16 and 17 the particles show an elongated shape in accordance with what is observed for all the altergon batches analysed (altergon batches code: 395133101). 3.4. Flowability
- Hval C.I.: 20: H.R.: 1.25 (equivalent to Fair. Table 2).
- the Glass Twin Stage Impinger allows to simulate in vitro deposition at the pulmonary level, allowing to evaluate the amount of active ingredient which deposits at the level of the upper and lower airways. 7 mL and 30 mL of a 0.8% w/v NaCI solution were respectively placed in the upper (stage 1) and lower
- C.S.1 and c.s.2 are used to indicate the separation chamber 1 (stage 1) and separation chamber 2 (stage 1)
- EF is used to indicate the percentage of powder loaded into the blister released by the inhaler of the invention and found in the Twin Stage Impinger.
- Hyal particles are distributed in the Twin Stage Impinger as follows:
- Two hyaluronate-mannitol mixtures were prepared using three different types of hyaluronate (an aerosol hyaluronate and an injectable hyaluronate) and mannitol Pearlitol® 100 SD.
- the mixtures were prepared using a hyaluronate:carrier ratio equal to 36:64.
- the two mixtures were uniform in terms of content.
- the aerodynamic characteristics of the mixtures were evaluated using a Glass Twin Stage Impinger (Disa, Milan, Italy) ( Figure 18A). 7 mL and 30 mL of a sodium chloride solution (NaCI, 0.8% w N) were introduced into the upper and lower separation chambers, respectively.
- NaCI sodium chloride solution
- the mixture deposited in the upper part was collected with 100 mL of 0.8% w N NaCI, while the one in the lower part was collected with 250 mL of 0.8% w/V NaCI. Subsequently, the sodium hyaluronate, collected in each of the two parts of the Twin Stage Impinger, was quantified using the spectrophotometric method and this allowed to calculate the emitted fraction (FE%) as a percentage of the nominal dose (DN) through the equation 4 (Eq.4).
- DN is used to indicate the amount of sodium hyaluronate introduced into the blister and therefore introduced into the inhaler of the invention before the pump of the Twin Stage Impinger is actuated.
- DN was calculated through the content uniformity test, carried out according to the European Pharmacopoeia guidelines (VIII Edition, pages 309-310).
- the DN values, for each of the prepared mixtures, are reported in Table 3.
- the data obtained from the test in the Twin Stage Impinger are reported in Tables 4 and 5 for mixture no 1 (hyaluronate for aerosol, samples 14) and for mixture no 2 (injectable hyaluronate, samples 16-17) and, respectively.
- Table 5 (captions as per Table 5). The mixture deposited in the inhaler and the one remaining in the blister were also collected using, for each aliquot, 25 mL of 0.8% w/V NaCI and the sodium hyaluronate was then quantified. The results obtained are reported in Tables 6 and 7. Table 6
- the hyaluronate selected is hyaluronate for aerosol.
- the mixture no 1 is characterised by a greater EF% and by a greater breathable fraction with respect to the ones obtained with the mixture no 2.
- the amount of mixture no 2 deposited at the level of the blister and of the inhaler is greater than the amount of mixture no I.
- the weighings, the loading and unloading of the mixer were carried out in an environment with a temperature of 22oC ⁇ 1 and a relative humidity of 30% ⁇ 1.
- the particle sizes were measured using the granulometer AccusizerTM Particle Sizer Model 770; particle sizing system, Santa Barbara California, USA
- the analyses were carried out using acetonitrile as a dispersing medium given that none of the components, Hyal and mannitol, is soluble in this solvent.
- Preparation of the sample to be analysed 1 mg of sample was dispersed in 1 ml of solvent and sonicated in ultrasonic bath for 1 minute.
- Hyal Thermogravimetric analysis on Hyal This analysis was carried out on the Hyal sample, taken immediately after opening the sealed bag, in order to accurately determine the water content given its known hygroscopicity.
- Thermogravimetric analysis was carried out using a TG-DTA Netzsch STA 490 C thermal analyser under the following operating conditions: heating rate 10°C/minute, air flow 30 ml/minute.
- the mixture was prepared complying with the Hyal/mannitol ratio 36:64 w/w.
- the V mixer was loaded with a total amount of the two powders such to occupy a volume of 6 Litres (half the volume with respect to the total capacity of the mixer equal to 12 Litres).
- the mixer was loaded with the two raw materials, Hyal and mannitol, according to the following order and amounts:
- Hyal Given the high hygroscopicity of Hyal, in order to reduce the times of exposure to air to the minimum, the weighings were progressively carried out according to the order described above. Furthermore, given the adhesiveness of the powder, an excess of 0.2 grams was weighed for each weighing of Hyal.
- the images show the two types of particles present in the mixture batch L 4130618, that is sodium hyaluronate, present as elongated fibres, and sprav-dried mannitol.
- the latter which shows particles around 100 ⁇ m, does not appear to have potentially breathable fine particles.
- Sodium hvaluronate particles have a fibrous shape which benefits their inhalation use, given that the aerodynamic diameter of a particle also depends on the shape thereof.
- Most sodium hvaluronate fibres are longer than 10 ⁇ m, but the diameter thereof is often less than 5 ⁇ m.
- the measurement of the resistance of the inhaler of the invention (DPI) against the inhalation flow of air was carried out after the construction of a mouthpiece adapter of the inhaler made of silicone material (rubber adaptor).
- the DPI not containing the powder activated by manually squeezing the "reservoir” blister, was positioned with the mouthpiece in the adaptor at the inlet of the measuring device and verifying the sealing thereof.
- Inhaler and mouthpiece were attached to an apparatus for collecting the emitted dose (DUSA) and connected to a aspirating pump by means of an instrument called TPK.
- the TPK system provides two pressure values (P3 and P2) whose ratio, if less than or equal to 0.5, indicates the presence of sonic air flow.
- P3 and P2 two pressure values whose ratio, if less than or equal to 0.5, indicates the presence of sonic air flow.
- T able 10 non-sonic flow, that is subject to variations of the aspiration pump or in the device.
- the subsequent chart ( Figure 24) shows how to calculate the resistance of the device, value corresponding to the slope of the straight line which interpolates the flow values measured at the selected pressure drop values.
- the resistance of the inhaler is equal to 0.0134 kPa 1 ⁇ 2 /L min -1 , considered to be a very low resistance, similar to the inhaler Rotahaler®.
- the measuring system manufactured by us, consists of a flowmeter connected to a PC capable of measuring the air flow inhaled by the volunteer.
- the volunteer is trained to evacuate the lungs by exhaling before bringing the DPI to the mouth and performing an inspiratory action which has a significant initial ramp.
- Figure 25 shows the dynamic inspiratory action performed by the recruited volunteers.
- the air flow curves show that the ascent ramp of the inhalation of the volunteers is quite steep and that the flow peak is comprised between 40 LVmin and 80 LVmin, values capable of generating a ⁇ 1 kPa pressure drop.
- the duration of the inhalation action falls between 1 and 2 seconds.
- Figure 26 shows the flow curves recorded with the same volunteers when the inhaler of the invention is loaded with the powder. It is dear that the presence of the powder affected the shape of the flow profiles which showed peaks of small magnitude, between values of 20 L/min and 60 L/min, even if more prolonged by a few fractions of a second. Some volunteers feared the arrival of powder in the throat, hence inspired less intensely but longer than the powder-free tests.
- Table 11 shows the amount of powder extracted and the volumes of air mobilised during inhalation by each volunteer. There is a relationship between the volume of air inhaled and the amount of powder extracted, as also observable from Figure 27. The amount extracted increases as the volume of inhaled air increases, approaching complete extraction. Table 11
- the use of the inhaler of the invention requires that the inhalation action be intense at the beginning and prolonged for a couple of seconds.
- the resistance thereof is very low and - given that it reaches flows from 70 L/min to 100 L/min - it is possible to extract a good amount of sodium hyaluronate.
- NaHA powder Although having a high volume diameter. NaHA powder has a low aerodynamic diameter due to the influence of the particles thereof.
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Abstract
The present invention relates to a mixture or composition in the form of dry powder for inhalation comprising hyaluronic acid or a salt thereof for use in the treatment of diseases of the upper and lower respiratory tract. Furthermore, the present invention relates to a kit for the administration of dry powder through the inhalation route comprising a dry powder inhaler and a blister, wherein said blister comprises said mixture or composition comprising hyaluronic acid or a salt thereof.
Description
HYALURONIC ACID OR SALT THEREOF FOR INHALATION USE IN THE TREATMENT OF RESPIRATORY DISEASES, AND AN INHALER DEVICE CONTAINING THE SAME
The present invention relates to a mixture or a composition in form of dry powder for inhalation comprising hyaluronic acid or a salt thereof, preferably sodium hyaluronate. Furthermore, the present invention relates to a mixture or a composition in form of dry powder for inhalation comprising hyaluronic acid or a salt thereof, preferably sodium hyaluronate, and mannitol. Said mixtures or compositions being for use in the treatment of diseases of the upper and lower respiratory tract, preferably of the upper respiratory tract Furthermore, the present invention relates to a kit for the administration of dry powder through the inhalation route, said kit comprising a dry powder inhaler and a blister, wherein said blister contains - therein - said mixtures or compositions in form of dry powder comprising a hyaluronic acid or a salt thereof, preferably sodium hyaluronate, or a hyaluronic acid or a salt thereof, preferably sodium hyaluronate, and mannitol.
As the very name indicates, diseases or symptoms of the respiratory tract are the diseases that affect the organs of the upper and/or lower respiratory system, such as nose, throat, pharynx, larynx, trachea, bronchi, bronchioles, alveoli and/or pulmonary area, mainly caused by bacteria or viruses. In short, any condition or disease affecting the respiratory system is considered a respiratory disease or disorder. Millions of people worldwide suffer from respiratory diseases, particularly diseases or symptoms of the upper respiratory tract, such as nose, throat, pharynx, larynx, trachea, and upper part of the bronchi.
Despite the presence of many products for the treatment of diseases of the respiratory tract on the market, the demand for products that are effective, free of side effects, easy to use and cost-effective remains high. Products of the prior art include products in form of dry powders to be administered by inhalation. However, the administration of active substances in form of powder through the inhalation route may entail problems such as: cause coughing in the subject to whom the powder is administered, difficulty in dosing low dosages which are constant and repeatable throughout the treatment due to the limited emission capabilities of the inhalers, powder packing problems, difficulty on the part of the subject in using inhalers, difficulty in regulating the dosage by the subject in case of multidose inhalers, problems relating to bacterial sterility in case of multi-use inhalers.
Therefore, there remains a need to have a device for administering active substances in powdered form through the inhalation route which is free from the limits and drawbacks present in the current devices available on the market.
The Applicant addresses and solves the problem of the treatment of diseases and/or symptoms of the upper and lower respiratory tract, preferably of the upper respiratory tract (for example, rhinitis, sinusitis, raucousness and sore throat, etc.), such as respiratory diseases and/or symptoms caused by baderia or viruses (for example, virus belonging to the strain SARS-CoV-2), by providing mixtures or compositions in form of dry powders for inhalation (through the mouth) comprising hyaluronic acid or a salt thereof (in short , mixtures or compositions of the invention), preferably hyaluronic acid or a salt thereof and mannitol. Furthermore, the Applicant addresses and solves the problem of the treatment of said diseases and/or symptoms of the upper and lower respiratory tract, by providing a kit (in short, kit of the invention) comprising a specific single-dose dry powder inhaler (DPI ) (in short, inhaler of the invention), and a single-dose blister (or the like) comprising a mixture or composition of the invention, wherein said kit is effective for the administration of hyaluronic acid or a salt thereof to a subject in need through the inhalation route.
In the context of the present invention, the terms "blister" or "single-dose blister" are used to indicate a dosed and sealed container having a volume suitable to house a mixture or a composition of the present invention, said blister being pierceable by applying a pressure exerted manually by a subjed, for example, a plastic and/or aluminium container or cartridge comprising a pierceable aluminium sheet on one side.
Besides being effective in the treatment of diseases and/or symptoms of the upper and lower respiratory tract, in particular of the upper respiratory tract, the mixtures or compositions of the invention based on hyaluronic acid or a salt thereof have no relevant side effects and they can be administered to all categories of subjects in need, including the elderly, pregnant or breastfeeding women, paediatric subjects (0-12 years), subjects with respiratory complications or other comorbidities.
Furthermore, the mixtures or compositions of the invention based on hyaluronic acid or a salt thereof are easy to prepare and cost-effective, same case applying to the kit or inhaler for dry powders of the invention are simple to construd and cost-effective. Furthermore, both the kit of the invention and the inhaler for dry powders of the invention are simple to use for any type of subjed, induding subjeds with respiratory difficulties, for example subjects with adhmatic subjeds, 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 the device of the invention is of the disposable type, it is free from bacterial sterility- related problems. Lastly, if the blister comprising the mixture or composition of the invention is inserted into the inhaler of the invention by the manufacturer of the kit of the present invention, instead of being inserted by the user, the use of the device of the invention is even simpler and more intuitive for the subject in need. A diagram of the respiratory tract of a human subjed is reported in Figure 10.
In the context of the present invention the terms "lower respiratory tract" and "lower respiratory airways" and "deep respiratory tract" are synonyms used interchangeably and they mainly represent the lower part of the bronchi, lungs, bronchioles, alveoli.
In the context of the present invention the terms "upper respiratory tract" and "upper respiratory airways" are synonyms used interchangeably and they mainly represent nose, throat, pharynx, larynx, trachea, and upper part of the bronchi.
These and other objects which will be apparent from the detailed description that follows are achieved by the mixtures, compositions and kit of the present invention thanks to the technical characteristics present in the description and claimed in the attached claims.
FIGURES
Fig.1 relates to an upper perspective view of the inhaler seen from the distal end thereof;
Fig.2 relates to a lower perspective view of the inhaler seen from the distal end thereof; Fig.3 relates to a top plan view of the inhaler;
Fig.4 relates to a view similar to the preceding one with the cartridge mounted on the inhaler;
Fig.5 relates to a sectional view of the inhaler along the longitudinal centreline plane thereof, with the blister (or cartridge) mounted thereon;
Fig.6 relates to a view similar to the preceding one with the blister open for dispensing the mixture or composition of the invention;
Fig.7 relates to a schematic representation of a Next Generation Impactor (NGI) as laid down by the Eu. Pharm. 8.0, 2.9.18 guidelines;
Fig.8 relates to a cumulative percentage of mass of Na-HA (sodium hyaluronate) with respect to the particle size distribution in terms of aerodynamic diameter; Fig. 9 reports the mean values and the standard deviation of the amount of Na-HA (sodium hyaluronate) in mg, deposited in the various stages of the Next Generation Impactor (NGI);
Fig.10 relates to a schematic representation of the ramifications present at the level of the bronchial tree; Fig.11 reports a correlation between the particle size and the deposition site at the level of the respiratory system; Fig.12 reports a granulometric distribution of sodium hyaluronate for aerosol;
Figs. 13A, 13B, 13C and 13D report the micrographs of the particles of sodium hyaluronate;
Fig.14 relates to a granulometric distribution of sodium hyaluronate (Hyal);
Figs. 15A, 15B and 15C report the thermogravimetric analysis (TGA) curve of sodium hyaluronate (Hyal), mannitol and sodium hyaluronate: mannitol mixture = 36:64, respectively; Figs. 16 and 17 report the micrographs of the sodium hyaluronate particles;
Figs. 18 and 18A report a Glass Twin Stage Impinger compliant with the Ph. Eur. 9a Ed. guidelines; separator with the inhaler of the invention paired thereto;
Fig.19 relates to a granulometric distribution of sodium hyaluronate (Hyal);
Fig.20 relates to a thermogravimetric analysis (TGA) curve of sodium hyaluronate (Hyal); Fig.21 relates to a size distribution as volume diameter of sodium hyaluronate raw material measured using a laser difffadometer;
Figs.22 and 23 report the images of the morphology of the sodium hyaluronate-mannitol mixture of the invention;
Fig.24 relates to a chart DP½ against Q for the calculation of the resistance of the inhaler of the invention; Fig.25 reports the dynamic flow curves carried out by volunteers on the inhaler of the invention empty;
Fig.26 reports the dynamic flow curves carried out by volunteers on inhalers of the invention loaded with the mixture of the invention;
Fig.27 shows a relationship between the dose emitted and the volume of air inhaled by volunteers with inhalers of the invention loaded with 27.8 mg of sodium hyaluronate-mannitol mixture of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Forming an object of the present invention is a mixture in form of dry powder for inhalation (inhalation through the mouth) comprising or, alternatively, consisting of hyaluronic acid or an acceptable pharmaceutical or food grade salt thereof (in short, mixture of the invention).
Forming an object of the present invention is a composition in form of dry powder for inhalation comprising said mixture of the invention (comprising or, alternatively, consisting of hyaluronic acid or a salt thereof and, optionally, a carrier) and at least one acceptable pharmaceutical or food grade additive and/or exdpient.
Hereinafter, the term "hyaluronic acid" is used to indicate a hyaluronic acid and/or an acceptable pharmaceutical or food grade hyaluronic acid salt.
Hyaluronic acid (for example, CAS 9004-61-9) is a macromolecule, such as a non-sulfurated glycosaminoglycan and devoid of protein core.
At the respiratory level, hyaluronic acid (in short HA), which is synthesised by the interstitial nasopharyngeal and pulmonary fibroblasts, the submucosal tracheobronchial glands and the goblet lining cells, is capable of performing various functions:
(a) by combining with the mucus, HA is capable of playing and carrying out a respiratory tract protection role;
(b) being one of the main constituents of the cell matrix, HA incorporates fibres and fibrous constituents of the matrix (such as elastin and collagen), and thus 1) HA proteds the lung tissue matrix from the degradation of elastic fibres, and 2) HA acts as a barrier against the "destructive" activities of elastases;
(c) thanks to the ability thereof to bind and retain a large number of water molecules in the interfibrillar spaces, HA plays a fundamental role in the hydration of impaired bronchial secretions.
Once inhaled by aspiration through the mouth by the user, the hyaluronic acid (HA) (or sodium hyaluronate (HA-Na)) comprised in the mixture or composition of the invention in form of a dry inhalable powder deposits mainly at the level of the upper respiratory tract, creating a kind of homogeneous "coating" well distributed on the mucosa, and it exerts the action thereof for the protection of the respiratory mucosa in such site. Advantageously, thanks to the partide size and the molecular weight of hyaluronic acid as selected and defined in the present description, the hyaluronic acid of the mixture or composition of the present invention deposits mainly at the level of the upper respiratory tract.
The hyaluronic acid or the salt thereof, comprised in the mixture or composition of the invention (optionally combined with a carrier, preferably mannitol) advantageously has an average molecular weight comprised from 100 KDa to 4000 KDa, preferably from equal to or greater than 500 kDa to equal to or less than 2000 kDa, more preferably from 700 kDa to 1000 kDa, for example 200 kDa, 300 kDa, 400 kDa, 550 kDa, 600 kDa, 750 kDa, 800 kDa, 850 kDa, 900 kDa, 950 kDa, 1100 kDa, 1200 kDa, 1400 kDa, 1600 kDa or 1800 kDa, 2000 kDa, 2200 kDa, 2400 kDa, 2600 kDa, 2800 kDa, 3000 kDa or 3500 kDa (kDa abbreviation of kiloDalton, for example 1000 Dalton = 1 kDa).
Said hyaluronic acid may be linear or branched, preferably linear (for example, linear HA with average molecular weight comprised from 700 kDa to 1000 kDa).
In the context of the present invention the expression hyaluronic acid salt is intended to indicate, for example, an alkali metal or alkaline earth metal, preferably sodium, potassium, magnesium or caldum salt, more preferably sodium salt (sodium hyaluronate -HA-Na).
An example of powdered sodium hyaluronate for inhalation that can be used in the context of the present invention (comprised in the mixture or composition of the invention, optionally in the presence of at least one carrier, preferably mannitol) is a sodium hyaluronate (for example CAS No. 9067-32-7) having the following characteristics (European reference method or European Pharmacopoeia, in short Eu. Pham.):
- appearance (EP <1472>): white or almost white, highly hygroscopic powder;
- solubility (EP <1472>): poorly sduble or water-soluble, practically insoluble in acetone and anhydrous ethanol;
- IR spectrum identification (Eu. Pharm.:2.2.24); sodium identification (Eu. Pharm.:2.3.1): sodium reaction; appearance in S solution (Eu. Pharm.:2.2.1);
absorbance at 600 nm of S solution (Eu. Pharm.:2.2.25) (0.33% solution, on dry product): ≤ 0.01; pH (Eu. Pharm.: 2.2.3) (0.5% in water, on dry product) 5.0 + 8.5;
- intrinsic viscosity at 25°C (Eu. Pharm.:2.2.9) 1.35-1.60 m3/Kg; loss on drying (LCD) (0.500 g at 100°C- 110ºC on diphosphorus pentoxide R for 6 hours; Eu. Pharm.:2.2.32) ≤ 15.0% (6.0%-8.0%); - sodium hyaluronate content (Eu. Pharm.:2.2.25): 95.0%-105.0%;
- compressibility index 16.66-21.46; Hauser ratio 1.20-1.27;
- average molecular weight from 700 kDa to 1000 kDa (S/ze Exclusion chromatography method SEC
TDA). According to an embodiment, the mixture of the invention comprises or, alternatively, consists of hyaluronic acid or a salt thereof, and at least one carrier, wherein said at least one carrier is selected from the group comprising or, alternatively consisting of: mannitol, lactose, dextran, metal stearate (preferably magnesium stearate) and mixtures thereof; preferably the mixture of the invention comprises or, alternatively, consists of hyaluronic acid or a salt thereof (for example sodium hyaluronate), and mannitol; more preferably the mixture of the invention consists of sodium hyaluronate and mannitol.
Further examples of mixtures of the invention comprising hyaluronic acid or a salt thereof (preferably sodium hyaluronate) are: hyaluronic acid and lactose, hyaluronic acid and dextran, hyaluronic acid and metal stearate (magnesium stearate), hyaluronic acid and mannitol and metal stearate (magnesium stearate), hyaluronic acid and ladose and metal stearate (magnesium stearate), hyaluronic acid and dextran and metal stearate (magnesium stearate).
Mannitol (or D(-)mannitol, or E421 according to European regulation), alternatively referred to as mannite, is a chiral alditol, with six hydroxyl groups at the level of the aliphatic chain consisting of six saturated carbon atoms (lUPAC name (2R,3R,4R,5R)hexan-1,2,3,4,5,6-hexol, brute formula C6H1406, molecular weight (u) 182.17, example of CAS No. 69-65-8). The mannitol present in the mixture of the invention performs various functions, increasing and/or assisting the therapeutic action of hyaluronic acid (for example, synergistic action):
- mannitol ads as a carrier of hyaluronic acid (and/or sodium hyaluronate) transporting it and carrying it and, therefore, making HA (and/or HA-Na) more readily available at the level of the upper respiratory tract;
- mannitol draws water into the lumen of the respiratory tract, making the mucus more fluid and, therefore, easier to eliminate;
- mannitol makes the dry powder for inhalation more flowable.
Lactose (lUPAC name β-D-galadopyranosyl (1→4) D-glucopyranose, for example CAS 63- 42- 3) is a disaccharide and a dextrorotatory redudng sugar. The ladose molecule consists of a D-galactose and of a D-glucose molecule linked by a glyosidic bond (acetal) β(1 - 4).
Both lactose and mannitol may be both comprised/contained in the mixtures or compositions in form of dry powders for inhalation of the present invention. Their presence (individually or combined) helps to: (i) improve the effidency with which the volume present in the blister of the dry powder inhaler of the invention is emptied after respiratory adivation (inhalation by the user who - by exerting pressure with the fingers thereof - pierces the walls of the blister), (ii) improve the turbulence and the dispersion of hyaluronic acid or a salt thereof in the small airways, (iii) avoid aggregation of the particles of the powder to be inhaled such as HA and/or HA-Na. The lactose and/or mannitol partides have a particle size diameter such (for example about 100 μm) that they cannot penetrate into the deep parts of the respiratory system. Therefore, most of the lactose present in the mixture or in the composition deposits in the oropharynx before moving on to the stomach after being swallowed. The metal stearate is a salt derived from stearic acid (I UP AC name octadecanoic acid, brute formula C18H3602, example of CAS No. 57-114) orree sallfied. Said metal stearate, comprised in the mixture or composition of the invention (together with a hyaluronic acid and, optionally, with a mannitol and/or lactose) can be selected from the group comprising or, alternatively, consisting of: magnesium stearate, zinc stearate, caldum stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and mixtures thereof; preferably magnesium stearate.
Furthermore, the composition of the present invention may comprise said at least one acceptable pharmaceutical or food grade additive and/or exdpient Said at least one additive and/or exdpient is different from said at least one carrier and it can be selected from any additive and/or exdpient known to the person skilled in the art of dry powders for inhalation, for example it can be seleded from the group comprising or, alternatively, consisting of: maltodextrin, leudne, sodium dtrate and mixtures thereof, or any other additive and/or exdpient known to the person skilled in the art.
Preferably, the hyaluronic acid or a salt thereof (for example, sodium hyalironate) comprised in the mixture or composition in form of dry powder of the invention have amass median aerodynamic diameter (in short, MMAD) comprised in the range from 0.5 μm to 30 μm (for example about 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 18 μm, 20 μm, 22 μm, 24 μm, 26 μm o 28 μm (all±0.5 μm)), preferably from 5 μm to 20 μm, more preferably from 8 μm to 15 μm (for example, 10.5±1.4 μm or about 13-14 μm).
The mass median aerodynamic diameter (MMAD) of the dry powder of the mixture or composition of the present invention is measured according to standard methods and equipment known to the person skilled in the art of inhalation powders (for example, using a next generation impactor (NGI) as laid down by the Eu. Pharm. 8.0, 2.9.18 guidelines).
The mixture or composition of the invention has a heterogeneity of the partide size of hyaluronic acid or a salt thereof (preferably sodium hyaluronate), with geometric standard deviation (GSD) values >1.22. Geometric standard deviation (GSD) measures the variability of the partide diameter of an aerosol; it provides an indication of the distribution of inhalable partide diameters and it differentiates aerosols into two dasses: monodisperse, with GSD values < 1.22 and heterodisperse with GSD values >1.22. Usually, the aerosolized formulations are heterodisperse formulations, i.e. consisting of partides of different sizes. For example, the geometric standard deviation for a mixture of the invention, consisting of sodium hyaluronate (for example, molecular weight 700 kDa-1000 kDa and MMAD 10.5±1.4 μm) and mannitol, is comprised in the range from 1.3 to 2.8, preferably from 1.8 to 2.1, confirming the heterogeneity of the partide size of sodium hyaluronate which will be distributed both at the level of the upper airways (in high percentage) and at the level of the first lower airways (in a minimal percentage).
The size distribution of the powder of hyaluronic acid or a salt thereof, as the raw material 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 sodium hyaluronate that can be used in the mixtures or compositions of the invention is comprised from 10 μm to 100 μm (for example, 20 μm, 35 μm, 45 μm, 55 μm, or 80 μm), preferably from 25 μm to 50 μm , more preferably from 30 μm to 40 μm (result of three replicas of the size distribution curves). The granulometric distribution of the powder of hyaluronic acid or a salt thereof (e.g. sodium hyaluronate) as the raw material of the mixture of the invention, or, the granulometric distribution of hyaluronic acid or a salt thereof (e.g. sodium hyaluronate) comprised in the mixture of the invention (i.e. hyaluronic or hyaluronate/mannitol), or, the granulometric distribution of mannitol comprised in the mixture of the invention (i.e. hyaluronic or hyaluronate/mannitol) can be determined with a granulometer (for example, Accusizer™ Partide Sizer Model 770; particle sizing system, Santa Barbara California, USA). The volumetric mean diameter (VMD) of a sodium hyaluronate which can be used or present in the mixtures or compositions of the invention is comprised from 10 μm to 100 μm (for example, 20 μm, 35 μm, 45 μm, 55 μm, or 80 μm), preferably from 25 μm to 50 μm, more preferably from 30 μm to 40 μm.
The volumetric mean diameter (VMD) of a mannitol present in the mixtures or compositions of the invention is comprised from 20 μm to 150 μm (for example, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, or 140 μm). The powder of hyaluronic acid or a salt thereof ( i.e. sodium hyaluronate) which can be used in the invention, although with high volume diameter, has a low aerodynamic diameter due to the influence of the shape of the partides thereof, such as a tubular shape (elongated shape with reduced diameter) as reported in the micrographs.
Following an inhalation - by aspiration through the oral route - of said mixture or composition of the invention (according to any one of the described aspeds or embodiments, for example comprising only hyaluronic acid or hyaluronic acid and a carrier, preferably mannitol) said hyaluronic acid or a salt thereof is distributed in the respiratory tract as follows, wherein the percentages by weight are percentages with respect to 100% by weight of the aspirated hyaluronic acid:
- from 65%±0.05% a 90%±0.05% (for example, 60%, 75%, 80% or 85%), preferably from 70% to 89%, at the level of throat-oropharynx;
- from 10%±0.05% to 35%±0.05% (for example, 15%, 20%, 25% o 30%), preferably from 10% to 30%, at the level of pharynx, trachea and upper part of the bronchi (for example, pharynx about 19%, trachea about 4 %, upper part of the bronchi about 1.094%);
- from 0.05% to 5% (for example, 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, or 4.5%) at the level of the lower respiratory tract, such as the lower part of the bronchi, bronchioles, alveoli and/or pulmonary area. It is presumed that said distribution of hyaluronic acid mainly in the upper respiratory tract is due to the value of the mass median aerodynamic diameter (MMAD) of hyaluronic acid or the salt thereof.
On the other hand, following an inhalation - by aspiration through the oral route - of said mixture or composition of the invention (for example, sodium hyaluronate and mannitol), said carrier (for example mannitol), if present, does not go pad the throat given that the partides thereof are large in size, for example comprised from 80 μm to 120 μm, preferably from 90 μm to 110 μm, for example about 100 μm.
According to an asped of the invention, in the mixture of the invention comprising or, alternatively, consisting of hyaluronic acid or a salt thereof (preferably sodium hyaluronate) and a carrier, preferably mannitol, the [hyaluronic acid or a salt thered:carrier] weight ratio (weight:weight ratio, in short w/w) is comprised in the range from 10:90 to 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 40:60, for example 32:68, 34:66, 36:64, or
38:62. For example, a mixture of the invention may comprise - on an amount of about 28 mg - a mixture of about 10 mg of sodium hyaluronate and about 18 mg of mannitol.
The hyaluronic acid or a salt thereof (preferably sodium hyaluronate), may be present in the mixture or composition of the invention (comprising hyaluronic acid or a salt thereof and said at least one carrier, preferably mannitol) in a percentage by weight from 10% to 90% with resped to the total weight of said mixture or composition of the invention (for example, 20%, 30%, 40%, 45%, 50%, 55%, 65%, 70%, 75%, or 80%), preferably from 55% to 75% (for example, 65%).
Said at least one carrier, for example mannitol or ladose or a metal stearate (e.g. magnesium stearate) or a mixture thereof, may be present in the mixture or composition of the invention (comprising hyaluronic acid or a salt thereof and said at lead one carrier) in a percentage by weight from 10% to 90% 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%, or 80%), preferably from 55% to 75% (for example, 65%). Furthermore, at lead one aciditive and/or exdpient may be present in the compodtion of the invention in a percentage by weight from 0.5% to 20% with respect to the total weight of said composition of the invention (for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, or 18%).
According to an asped of the invention, the mixture or compodtion of the invention does not comprise lactoferrin and/or N-acetylcydeine (MAC) or an acceptable pharmaceutical or food grade salt thereof and/or cannabidiol (CBD).
According to an aspect of the invention, the mixture or compodtion of the invention is not a mixture or compodtion in form of solution or suspendon or disperdon or colloidal.
The mixture or compodtion of the invention compridng hyaluronic acid or a salt thereof, and, optionally, said at lead one carrier (preferably sodium hyaluronate and mannitol) can be in solid form of micronized dry powder.
In the context of the present invention, the term "dry powder" is used to indicate a powder having a low water content For example, a powder compridng the mixture of a hyaluronic acid or a salt thereof and said at lead one carrier (preferably sodium hyaluronate and mannitol) has a content comprised in the range from 0.5% to 10% or 15% by weight with resped to the total weight of the powder (for example, 1%, 2%, 3%, 4%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, or 9%) preferably from 5% to 8% (for example about
6.5% or 7.5%). For example, a powder of a hyaluronic acid or a salt thereof (preferably sodium hyaluronate) which can be used in the mixture of the present invention has a content comprised in the range 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% or 18%) preferably from 10% to 20% (for example about 12% or 18%).
Said water content is determined using methods and equipment known to the person skilled in the art for example by means of thermogravimetric analysis (TGA).
Forming an object of the present invention are said mixtures or compositions of the invention in form of dry powder for inhalation (comprising or, alternatively, consisting of hyaluronic acid or a salt thereof and, optionally, at least one carrier, preferably sodium hyaluronate and mannitol) for use as medicament, such as for use in a method for the preventive and/or curative treatment of a disease or symptom of the respiratory tract, preferably of the upper respiratory tract (such as nose, throat, pharynx, larynx, trachea, and/or upper part of the bronchi), by administering said mixture or composition of the invention to a subject in need through the inhalation route (through oral aspiration).
Furthermore, forming an objed of the present invention is a kit of the invention (as described hereinafter in the present invention: comprising a dry powder inhaler and at least one blister (or sealed and openable container) comprising the dry powder) for use in a method for the preventive and/or curative treatment of a disease and/or a symptom of the upper and lower respiratory tract, preferably of the upper respiratory tract, by administering said mixture or composition of the invention to a subject in need through the inhalation route.
Said disease or said symptom of the upper and lower respiratory tract, preferably of the upper respiratory tract, may be selected from the group comprising or, alternatively, consisting of: cold, sinusitis, rhinitis, mucus secretion in the nose and/or throat area, mucus hypersecretion and of a disease, symptom and/or disorder assodated with said mucus hypersecretion, tracheitis, pharyngitis, laryngitis, acute laryngotracheobronchitis, epiglottitis, bronchiectasis, respiratory complications, asthma, chronic obstructive pulmonary disease (CORD), bronchitis, bronchiolitis, emphysema, cystic fibrosis, cough, pertussis, pneumonia, pleuritis, or bronchiolitis.
Said diseases and/or said symptoms of the respiratory tract may be of baderial or viral origin. An example of a viral infection treated using the mixture or composition of the invention is an infection caused by a virus of the family Coronaviiidae, subfamily: Coronavirinae, genus: Betacoronavims, spedes: severe acute respiratory syndrome-related coronavirus (in short, SARSr-CoV or SARS-coronavirus), such as for example the strain severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
The mixtures or compositions of the invention, according to any one of the described aspects or embodiments, may be for use as adjuvants of further therapeutic approaches for the treatment of diseases or symptoms of the respiratory tract.
The mixture or composition of the invention in form of dry powder for inhalation is effective in the treatment of diseases or symptoms of the respiratory tract, preferably of the lower respiratory tract, in a daily dosage of hyaluronic acid or a salt thereof (for example sodium hyaluronate) comprised in the range from 1 mg to 100 mg (for example 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 from 10 mg to 50 mg, more preferably from 10 mg to 30 mg. The aforementioned daily dosages may be administered to the subject in need in a single dose (one dose, for example about 10 mg of hyaluronic acid or a salt thereof) or in repeated doses, such as two, three, four or five daily doses (for example 2x, 3x, 4x or 5 x 10mg of hyaluronic acid or a salt thereof).
The mixture or composition of the invention is produced in form of dry powder for inhalation through processes known to the person skilled in the art in the pharmaceutical or inhalable products industry. For example, the mixture or composition of the invention can be prepared through a process for the mechanical mixing of the individual components. Once said individual components have been well homogenised and distributed with respect to each other, the final mixture or composition is housed inside the volume present and delimited by the walls of the blister.
The composition of the invention is administered by means of a dry powder inhaler (DPI), object known in the art and suitable for the inhalation of said dry powder through the mouth , such as a single-dose or multidose inhaler, disposable or reusable after each dosage, preferably single-dose. Forming an object of the present invention is a kit for the administration of the mixture or composition of the invention through the inhalation route (in short, kit of the present invention) wherein said kit comprises:
- a single-dose dry powder inhaler (in short, inhaler of the present invention) having the characteristics reported below and in patent document EP 3386575 B1 incorporated for 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 form of dry powder of the invention according to any one of the aspects or embodiments described in the present invention (mixture comprising hyaluronic acid or a salt thereof or, alternatively, hyaluronic acid or a salt thereof and at least one carrier, for example sodium hyaluronate and mannitol, and 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 for inhalation through oral aspiration exerted by a subject in need of a treatment.
In the present description the terms "blister " and "cartridge" (or cartridge (C)) are synonyms and used interchangeably.
In a first aspect of the kit of the present invention, said at least one blister (comprising - therein - a mixture or composition of the invention) can be prepared and sold separately from the inhaler of the invention. In this case, the user will house/position the blister in the housing present in said inhaler at the time of use of the inhaler. According to said first aspect, the inhaler present in the kit may be single-use (disposable) or multi-use; in the case of multi-use inhaler, the kit will for example contain one inhaler and a certain number of blisters to be inserted into the inhaler whenever required; in the case of a single-use (disposable) inhaler, the kit will for example contain V inhalers and V blisters.
In a second aspect of the kit of the present invention, said blister (comprising - therein - a mixture or composition of the invention) is fixedly inserted into said inhaler of the present invention at the time of the manufacturing thereof (for example by the manufacturer). According to said second aspect, the kit is disposable.
Said single-dose dry powder inhaler of the invention (Figures 1-6) comprises a substantially pipe-shaped hollow body comprising a first portion (1), for housing a blister (or a cartridge (C)), comprising the mixture or composition of the invention, and a second portion (2) connected to said first portion (1) for dispensing said mixture or composition of the invention (powder) by means of a primary air flow (FP) which carries the powder from an inner drop region (5), located at the bottom of said first portion (1), along a dispensing duct (3) whose end is suitable to be placed in the mouth of a subject, said dispensing duct (3) being horizontally partitioned - by a partitioning septum (4) - into an upper duct (3a) which dispenses the primary air flow (FP) and a lower duct (3b) which dispenses a powder-free secondary air flow (FS), the aspiration of the air forming the primary air flow (FP) being obtained by means of at least three air intakes (7) formed in the first portion (1) which are preferably arranged symmetrically with respect to the longitudinal centreline plane of the inhaler, the aspiration of the air forming the secondary flow (FS) being obtained by means of an air intake (8) obtained at the distal end of said lower duct (3b), the inhaler being characterised in that said base for supporting said blister (or cartridge (C)) includes a plurality of horizontal support surfaces (9) projecting into the first portion (1), oriented flow channels (11) formed in the support base extending between said at least three air intakes (7) and the inner powder-drop region (5). The single-dose inhaler of the invention is activated by a subject in need of inhaling 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 using a finger) so as to break the lower portion of the blister and transfer the mixture or composition of the invention by dropping from the blister to said inner drop region (5) of the inhater; (II) aspirating with the mouth positioned on said end of said dispensing duct (3) of the inhaler with a force sufficient to cause aspiration of the mixture or composition of the invention by said subject, for example
with a flow comprised from 30 L/min to 150 L/min (for example 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/ml or 140 L/min) preferably from 60 L/min to 100 L/min, for example of about 80 L/min. The emitted fraction of hyaluronic acid or a salt thereof (for example sodium hyaluronate) is comprised from 80% to 99.9%, preferably about ≥90% (from 90% to 99%, for example 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 98%), percentage expressed with respect to 100% of hyaluronic acid or a salt thereof present in the mixture of the invention.
The administration of the mixtures or compositions of the invention, comprising hyaluronic acid or a salt thereof, in form of dry powder for inhalation using the kit of the invention, actuated by the aspiration of the subject in need, is such to make the administration of the effective dose effective and maximising the inherent efficacy of the mixtures or compositions of the invention.
Furthermore, the mixture or composition of the invention in form of dry powder for inhalation, according to any one of the aspects or embodiments described in the present invention, shows a good flowability, a good uniformity of distribution of the active ingredient (i.e., hyaluronic acid) and an appropriate chemical and physical stability prior to use.
The expression "good flowability" refers to a composition that can be easily handled during the preparation process and it is capable of guaranteeing an accurate and reprodudble administration of the therapeutically effective dose when administered using the device of the invention by means of the aspiration action of the subject, for all doses provided for in the treatment plan. The flow characteristics can be evaluated by measuring the Carr index; a Carr index lower than 25 is usually used to indicate good flow characteristics.
The expression "distribution uniformity" refers to a composition in which, when mixing, the content uniformity of the active ingredient, expressed as the relative standard deviation (RSD), is lower than 5%. The expression "chemically stable" refers to a formulation that meets the requirements of the ICH Q1A guidelines referring to "Stability testing of novel active substances (and medicinal products)".
The expression "physically stable" refers to a formulation in which if several components of the dry powder particles of the composition of the invention are present, these components substantially do not separate during the process for preparing the dry powder and/or over the time comprised between the preparation and the use of the composition.
The tendency to separate can be evaluated according to Staniforth et al., J. Pharm. Pharmacol., 34.700- 706, 1982, which is wholly incorporated herein for reference, and it is considered acceptable if the distribution of the active ingredient in the dry powder composition after the test, expressed as the relative standard deviation (RSD), does not change significantly with respect to that of the composition prior to the test.
The expression "accurate therapeutically active dose of the active ingredient" refers to a composition in which the variation between the average dispensed daily intake and the average emitted dose is equal to or lower than 15%, preferably lower than 10%. Unless specified otherwise, the expression composition or mixture or other comprising a component at an amount "comprised in a range from x to y" is used to indicate that said component may be present in the composition or mixture or other at all the amounts present in said range, even though not specified, extremes of the range comprised.
Unless specified otherwise, the indication that a composition or mixture "comprises" one or more components or substances means that other components or substances can be present besides the one, or the ones, indicated specifically.
In the context of the present invention, the expression "treatment method" is used to indicate an intervention on a subject in need, comprising the administration of a composition or mixture of substances in a therapeutically effective amount (as established by a person skilled in the art), with the aim of eliminating, reducing/decreasing or preventing a disease or ailment and the symptoms or disorders thereof.
In the context of the present invention, the term "subject/s" is used to indicate human or animal subjects, preferably mammals (e.g. pets such as dogs, cats, horses, sheep or cattle). Preferably, the compositions of the invention are for use in methods for the treatment of human subjects.
Embodiments of the present invention (FRn) are reported below:
FR1. A mixture in the form of a dry powder for inhalation comprising or, alternatively, consisting of hyaluronic acid or an acceptable pharmaceutical or food grade salt thereof.
FR2. The mixture according to FR1, wherein said mixture further comprises at least one carrier, wherein said at least one carrier consists of mannitol; preferably wherein said mixture consists of hyaluronic acid or a salt thereof and mannitol; more preferably, wherein said mixture comprises or, alternatively, consists of sodium hyaluronate and mannitol.
FR3. The mixture according to FR1, wherein said mixture further comprises at least one carrier, wherein said at least one carrier is selected from the group comprising or, alternatively, consisting of: mannitol, lactose, dextran, metal stearate and mixtures thereof; preferably wherein said metal stearate is selected from the group comprising or, alternatively, consisting of: magnesium stearate, zinc stearate, caldum stearate, sodium stearate, lithium stearate, sodium stearyl fumarate, sodium stearoyl lactylate and mixtures thereof, preferably magnesium stearate.
FR4. The mixture according to any one of FR1-3, wherein said hyaluronic acid or a salt thereof, preferably sodium hyaluronate, has an average molecular weight comprised from greater than 500 kDa to 2000 kDa, preferably from 700 kDa to 1000 kDa.
FR5. The mixture according to any one of FR1-4, wherein said mixture comprises said hyaluronic acid or a salt thereof having a mass median aerodynamic diameter (MMAD) comprised in the range from 1 μm to 30 μm, preferably from 5 μm to 20 μm, more preferably from 8 μm to 15 μm.
FR6. The mixture according to any one of FR2-5, wherein said hyaluronic acid or a salt thereof and said at least one carrier, preferably mannitol, are comprised in a [hyaluronic acid or a salt thereof:carrier ]weight:weight ratio comprised in the range from 10:90 to 90:10, preferably from 30:70 to 40:60, more preferably from 35±2:65±2.
FR7. A composition comprising the mixture according to any one of the preceding daims and at least one acceptable pharmaceutical or food grade additive and/or excipient.
FR8. The mixture according to FR5 or FR6 or the composition according to FR7, wherein following an inhalation of said mixture or composition by aspiration through the oral route, said hyaluronic acid or a salt thereof is distributed in the respiratory tract as follows, wherein the percentages are percentages with respect to 100% of the aspirated hyaluronic acid:
- from 70% to 90% at the level of throat-oropharynx.
- from 10%±0.05% to 30%±0,05% at the level of pharynx, trachea and upper part of the bronchi.
- from 0.05% to 1% at the level of the lower respiratory tract, such as the lower part of the bronchi, bronchides, alveoli and/or pulmonary area.
FR9. The mixture or composition according to any one of FR1-8, wherein said mixture or composition does not comprise ladoferrin and/or N-acetylcysteine (NAC) or an acceptable pharmaceutical or food grade salt thereof and/or cannabidiol (CBD).
FR10. A kit for the administration of the mixture or composition through the inhalation route according to any one of FR1-9, wherein said kit or device comprises:
- at least one blister (or cartridge) comprising said mixture or composition according to any one of FR1-9, wherein said mixture or composition are in form of dry powder; and
- a dry powder inhaler of the comprising a substantially pipe-shaped hollow body comprising a first portion (1), for housing said blister (or cartridge (C)), and a second portion (2) connected to said first portion (1) for dispensing said powder mixture or composition by means of a primary air flow (FP) which carries the powder from an inner drop region (5), located at the bottom of said first portion (1), along a dispensing duct (3) whose end is suitable to be placed in the mouth of a subject, said dispensing duct (3) being horizontally partitioned - by a partitioning septum (4) - into an upper duct (3a) which dispenses the primary air flow (FP) and a lower duct (3b) which dispenses a powder-free secondary air flow (FS), the aspiration of the air forming the primary air flow (FP) being obtained by means of at least three air intakes (7) formed
in the first portion (1) which are preferably arranged symmetrically with respect to the longitudinal centreline plane of the inhaler, the aspiration of the air forming the secondary flow (FS) being obtained by means of an air intake (8) obtained at the distal end of said lower duct (3b), the inhaler being characterised in that said base for supporting the blister (cartridge (C)) includes a plurality of horizontal support surfaces (9) projecting into the first portion (1), oriented flow channels (11) formed in the support base extending between said at least three air intakes (7) and the inner powder-drop region (5).
FR11. The mixture or composition according to any one of FR1-9 or the kit according to FR10 for use as medicament.
FR12. The mixture or composition according to any one of FR1-9 or the kit according to FR10 for use in a method for the preventive and/or curative treatment of a disease and/or symptom of the respiratory tract, preferably of the upper respiratory tract
FR13. The mixture or composition or the kit for use according to FR12, wherein said disease or symptom is selected from the group comprising or, alternatively, consisting of: cold, sinusitis, rhinitis, mucus secretion in the nose and/or throat area, mucus hypersecretion and of a disease, symptom and/or disorder associated with said mucus hypersecretion, tracheitis, pharyngitis, laryngitis, acute laryngotracheobronchitis, epiglottitis, bronchiectasis, respiratory complications, asthma, chronic obstructive pulmonary disease (CORD), bronchitis, bronchiolitis, emphysema, cystic fibrosis, cough, pertussis, pneumonia, pleuritis, or bronchiolitis.
FR14. The mixture or composition or the kit for use according to FR12 or FR13, wherein said disease and/or symptom of the respiratory tract, preferably of the upper respiratory tract, is of viral origin, preferably caused by a virus of the strain severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
EXPERIMENTAL PART (I) Determination of the respirable fraction (FPF), the mass median aerodynamic diameter (MMAD) and Geometric Standard Deviation (GSD) - using a Next Generation Impactor (NGI) - of the samples of a dry powder inhaler of the invention loaded with the mixture of the invention consisting of sodium hyaluronate and mannitol. 1. PURPOSE
The purpose of the present experimental study is to determine the potential particle deposition in the various respiratory regions of the powder consisting of sodium hyaluronate and mannitol (mixture of the invention), loaded - using blisters - onto the inhaler of the invention (DM class I). 2. INTRODUCTION
Two representative batches of the product (batch nº L3120618 and L4130618) were analysed using a Next Generation Impactor (NGI) compliant with the Eu. Pham. 8.0, 2.9.18 guidelines- PREPARATIONS FOR INHALATION: AERODYNAMIC ASSESSMENT OF FINE PARTICLES. The tests carried out on the products belonging to the device production line (batch nº L4130618) provided performance compliant with the specifications reported in the monograph 2.9.18 della Eu. Pham 8.0.
2.1. MATERIAL
The analysis in question was carried out on a mixture according to the present invention in form of powder consisting of sodium hvaluronate (Na-HA) (average molecular weight 700-1000kDa) and mannitol in a [sodium hvaluronate:mannitol] weight: weight ratio of about 34:66.
3. RESULTS
3.1. Determination of aerodynamic parameters The measurement of aerodynamic parameters was carried out using a Next Generation Impactor (NGI (Figure 7)) as laid down by the Eu. Phann. 8.0, 2.9.18 guidelines - PREPARATIONS FOR INHALATION: AERODYNAMIC ASSESSMENT OF FINE PARTICLES.
The purpose of the analysis is to identify the mass of sodium hyaluronate (Na-HA) which is deposited at the level of the various "stages" of the instrument (based on different size ranges) at a 1.2 kPa pressure drop and an 80 l/min air flow rate that mimics the inspiratory action. After emptying the devices in the instrument, the following was observed:
• The devices analysed showed a fraction of the emitted dose at around 90% - meeting the criteria provided for by the Eu. Pham. 8.0 guidelines according to which the total mass of the emitted dose must be comprised between 75% and 125%.
• The devices emptied completely thus confirming the performance thereof.
• The analysis of the residual powder retained by each stage of the instrument showed that:
Most of the product (about 70-75%) was distributed at the induction port and pre-separator level, potentially mimicking the size of particles that they impact at the throat-oropharynx level.
About 25% of the dose of powder emitted is deposited between stages 1, 2 and 3 (stage 1 = about 19%, stage 2 = 4.2% stage 3 = 1.094%) which may be compared to pharynx, trachea and the upper part of the bronchi.
At the level of stages 4, 5, 6 and 7, the deposition of particles is almost zero (Stage 4 = 0.16%, stage 5, 6 and 7 = 0), resulting in a low percentage (about 1-5%) of Na-HA at the deep lower airways.
The fine particle fraction (FRF), i.e. the particle fraction of a powder in the form of an aerosol, capable of depositing at the level of the deep airways (lungs. bronchioles· alveoli) having an aerodynamic diameter comprised between 0.5 μm and 5 μm, was obtained from this data. For the product subject of evaluation, the cumulative value of fine particle fraction (FPF) is about 2.6% confirming the deposition of the product at the level of these regions, even if in reduced percentages.
3.2. Determination of the Mass Median Aerodynamic Diameter (MMAD) and Geometric Standard Deviation (GSD) values
From what was observed through the analysis of the particle size distribution of the powder emitted in the various stages of the NGI, the Mass Median Aerodynamic Diameter (MMAD) and the Geometric Standard Deviation (GSD) of the particles, respectively, were obtained.
The Mass Median Aerodynamic Diameter (MMAD) is a parameter capable of indicating the most frequent particle size produced during the aerosolization of the product In the specific case of the mixture of the invention under analysis, the observed value of MMAD, for Na-HA is of 10.5±1.4 μm for 13.7 μm, further triplicate test) (Figure 8).
Geometric Standard Deviation (GSD) instead measures the variability of the particle diameter of an aerosol. It provides an indication of the distribution of inhalable particle diameters and it differentiates aerosols in two classes: monodisperse, with GSD values < 1.22 and heterodisperse with GSD values >1.22. Usually the aerosolized formulations are heterodisperse, i.e. consisting of particles of different sizes. The Geometric Standard Deviation for the mixture of the invention under analysis is 1.8 for 2.1 μm. further triplicate test) (Figure 9), confirming the heterogeneity of the particle sizes that will be distributed both at the level of the upper airways and at the level of the first lower airways.
Overall, the aerodynamic assessment of the sodium hyaluronate mixture loaded into the inhaler of the invention showed the following parameters (Table 1):
4. CONCLUSIONS
In recent years, there has been observed an increasing interest in the use of dry powder inhalers to allow the dispensing of fine powder particles containing one or more functional substances, capable of depositing (depending on the size) at the level of the upper and/or lower respiratory tract The human respiratory tract is a branched system of channels with more than 23 bifurcations that start from the mouth up to reaching the pulmonary alveoli, assuming the characteristic appearance of an overtμmed tree (Figure 10). Generally, the respiratory system can be divided into two main macro-areas: upper and lower airways. The upper airways comprise: nose, mouth, pharynx, larvnx and trachea, while the lower airways include bronchi, bronchioles and alveoli (hence the whole lung region). These regions differ in structure, airflow patterns, function and sensitivity to deposited particles. To obtain the desired effect, a powder particle intended for inhalation must deposit at the level of the target site. The particle deposition depends mainly on the properties of the particles (size/aerodynamic diameter, shape and density) and on the physiology of the respiratory tract The relationship between the size of the aerodynamic particles and respiratory deposition has been extensively studied, finding that more than 90% of the particles with an aerodynamic diameter greater than 10 μm deposit mainly at the upper airways, while the critical aerodynamic diameter to reach the lungs was observed to be <5 μm (Figure 11). However, it should be pointed out that particles with larger geometric diameters can also be equally used for inhalation should they have low densities (e.g. porous structures). Such particles can have an aerodynamic diameter between 1 and 5 μm, although the geometric diameter thereof could be much larger (for example from 10 μm to 30 μm).
In the specific case of the mixture of the invention under analysis, the aerodynamic parameters of the powder consisting of Na-HA and mannitol, loaded into the inhaler of the invention, were analysed. The
aerodynamic assessment of the functional substance (sodium hyaluronate, Na-HA) was evaluated during the analysis while that of mannitol was not evaluated given that - serving as a carrier and consisting of large particle sizes (about 100 μm), the aerodynamic behaviour thereof is sufficiently characterised (inert substance which does not go past the throat). The study showed that Na-HA powder predominantlv deposits at the level of the upper airways, UD to reaching the first part of the lower airways (primary bronchi) and in a lesser percentage in the second part of the lower airways.
EXPERIMENTAL PART (II) DIMENSIONAL ANALYSIS OF SODIUM HYALURONATE FOR AEROSOL
Sample analysed: Sodium hyaluronate for aerosol (Altergon), supplier batch 1000007025.
1. Particle size analysis
The sample size analysis was carried out using an Accusizer C770 granulometer C770 (PSS Inc., Santa Barbara, CA) by means of ‘Single Particle Optical Sensing analysis.
The analysis was carried out in acetonitrile and the results obtained represent the mean of three measurements (n=3). The dimensions were expressed as the volumetric mean diameter (VMD) and the degree of polydispersity expressed as span calculated according to equation 1 (Eq.1): Span = (Dv0,9- Dv0,1)/ Dv0,5 (Eq.1)
Preparation of the sample to be analysed: 1 mg of sodium hyaluronate was dispersed in 1 ml of acetonitrile and sonicated in an ultrasonic bath for 1 min.
The analysis was found to be reproducible in all replicates analysed. The data obtained from the calculation of the span suggests that the population has a low polydispersity index, and therefore it is sufficiently homogeneous from a dimensional point of view as observable from the distribution curve reported in Figure 12: VMD: 30.19 ± 0.62 μm: Moda: 27.87 μm, Median (D50): 28.38 ± 0.89 pm; Span: 1.10, (n=3 ± SD).
2. Scanning electron microscope (SEM)
The micrographs were obtained with an FE-SEM LEO 1525 Zeiss - LEO Electron Microscopy Inc., One Zeiss Drive (Thomwood, NY) microscope.
Preparation of the sample: sodium hyaluronate (Altergon), supplier batch 1000007025 in solid state, was deposited on the stub under a nitrogen stream and subjected to metallisation for 5 minutes with chromium in an argon atmosphere.
The micrographs obtained (Figures 13A 13B, 13C and 13D) show that the tested sodium hyaluronate particles are mainlv in the form of verv irreaular small aggrgaates whose size is close to the measured
VMD.
EXPERIMENTAL PART (III)
STUDY OF SODIUM HYALURONATE BATCH nº 1000004982 and CHARACTERISATION OF THE Hyal/MANNITOL MIXTURE.
1. Raw materials
Sodium hyaluronate (Hyal) (Altergon) Batch 1000004982, altergon code: 395133101.
Mannitol - Peariitol 100 SD (Roquette Frères, Lestrem Cedex, France). 2. Mixer
V mixer (Artha Division, MAG spa Laboratories), capacity 200 ml. Mixing conditions: 40 rpm, 8 minutes.
3. Characterisation of sodium hyaluronate 3.1. Dimensbnal analysis
The particle sizes were measured using the granulometer Accusizer™ Particle Sizer Model 770; particle sizing system, Santa Barbara California, USA
The analyses were carried out using acetonitrile as a dispersing medium given that none of the components, Hyal and mannitol, is soluble in this solvent. Preparation of the sample to be analysed: 1 mg of sample was dispersed in 1 ml of solvent and sonicated in ultrasonic bath for 1 min.
The results obtained represent the mean of five measurements (n=5). The dimensions were expressed as the volumetric mean diameter (VMD) and the degree of polydispersity was expressed as span, calculated according to equation 1 (Eq. 1):
Span = (Dv0,9- Dv0,1)/ Dv0,5(Eq.1)
Partide size analysis carried out on Hyal (Figure 14: VMD: 39.59 ± 1.31 μm; Moda 34.58 μm, Median (D50): 36.32 ± 1.66 μm; Span: 1.07 (n=5, ± SD)) gave a volumetric mean diameter (VMD) of about 39 μm. The calculated span (1.07) shows that the population is rather homogeneous.
3.2. Thermogravimetric analysis
Thermogravimetric analysis (TGA) was carried out using a TG-DTA Netzsch STA 490 C thermal analyser under the following operating conditions:
heating rate 10ºC/min, air flow 30 ml/min.
The results obtained on the sample of Hyal (batch 1000004982) showed an 18.27% moisture content (Figure 15A). The same analysis was then carried out both on mannitol· which did not show a significant loss of water (Figure 15B) and on the Hval/mannitol mixture (36:64). The result obtained for the latter showed a 6.50% water content (Figure 15C).
The thermogravimetric analysis was also carried out on the Hyal (batch nº 1000007837)/mannitol mixture (36:64) which showed a water content equal to 7.47% (thermogravimetric analysis curve not reported), similarly to what was previously obtained for the mixture of the present invention.
3.3. Morphological analysis
The morphology of the Hyal particles was studied using a Scanning Electron Microscope (SEM). The micrographs were obtained with an FE-SEM LEO 1525 Zeiss - LEO Electron Microscopy Inc., One Zeiss Drive (Thomwood, NY) microscope. As observable from Figures 16 and 17 the particles show an elongated shape in accordance with what is observed for all the altergon batches analysed (altergon batches code: 395133101). 3.4. Flowability
The flowability of Hyal was measured by determining the compressibility index (C./.) and the Hausner ratio (H.R.), according to equations 2 and 3, by re-processing the initial and final volume data (after subjecting the sample to 1250 beats by using a Tap density tester, ERWEKA, Germany) in compliance with the guidelines laid down by the European Pharmacopoeia (Ph. Eur. 9a Ed.). ..= 0- 0*100.2
..= 0.3 where: V0 represents uncompressed or initial powder volume and Vf corresponds to the final compressed volume (after 1250 beats). The classification is carried out according to what is reported in the Ph. Eur. 9a Ed. table (Table 2). The results obtained for the batch taken into account are:
Hval: C.I.: 20: H.R.: 1.25 (equivalent to Fair. Table 2).
4. CHARACTERISATION OF THE Hyal/MANNITOL MIXTURE.
4.1. Content uniformity The homogeneity of the sodium hyaluronate (Hyaiymannitol mixture (prepared in a V mixer, mixing time 40 rpm for 8 minutes) was verified using a content uniformity test carried out on 20 samples as laid down by the Ph. Eur. 9a Ed. guidelines. The preparation meets the test requirements if each individual content is comprised between 85% and 115% of the mean content The preparation does not meet the test requirements if more than one individual content exceeds the aforementioned limits, or if only one of them exceeds the limits comprised between 75% and 125% of the mean content If only one individual content exceeds the limits comprised between 85% and 115%, but it comprised is within the 75% to 125% limits, the individual content of other twenty units, taken randomly, must be determined. The preparation meets the test requirements if not more than one of the individual contents, of the thirty units, exceeds the limits of the 85% - 115% range of the mean content and none exceeds the limits comprised between 75% and 125% of the mean content
The requirements of the test carried out on the 20 samples taken from the mixture were met given that the mean content of Hyal of a sample falls within the 95% to 111 % range.
4.2. Determination of the emitted fraction The percentage of the emitted fraction of the sodium hyaluronate (Hyaiymannitol mixture was measured using a glass twin stage impinger (Disa, Milan, Italy, Figure 18 and 18A) whose characteristics comply with the requirements laid down by the Ph. Eur. 9a Ed. guidelines.
The Glass Twin Stage Impinger allows to simulate in vitro deposition at the pulmonary level, allowing to evaluate the amount of active ingredient which deposits at the level of the upper and lower airways. 7 mL and 30 mL of a 0.8% w/v NaCI solution were respectively placed in the upper (stage 1) and lower
(stage 2) separation chamber (Figure 18). After connecting all the components, a vacuum pump was
connected to the apparatus adjusting the aspiration to 60±5 L/min. The powder inhaler of the invention with the special blister comprising the mixture of the invention was then connected and the pump was actuated for a few seconds before dispensing the powder dose so as to stabilise the aspiration conditions. The pump was then kept running for 5 seconds after breaking the blister, as laid down by the European Pharmacopoeia (Ph. Eur. 9a Ed.) guidelines.
The powder deposited in each separation chamber was recovered by first removing the starting solution and subsequently washing each chamber with additional fractions of 0.8% w/v NaCI aqueous solution. The quantitative determination of Hval (sodium hvaluronate) was carried out following the colorimetric method (spectrophotometric method). Such analysis allowed to calculate the emitted fraction (EF) (EQ. 4).
EF%= [(Dose c.s.1 (μg)+Dose c.s.2 (μg)) / Nominal dose (μg)j X 100 (q.4)
The expression nominal dose is used to indicate the amount of hyaluronate loaded into the blister of the inhaler of the invention. C.S.1 and c.s.2 are used to indicate the separation chamber 1 (stage 1) and separation chamber 2 (stage
2) (Figure 18).
EF is used to indicate the percentage of powder loaded into the blister released by the inhaler of the invention and found in the Twin Stage Impinger.
The results obtained (n=5) showed that the use of the batch of sodium hvaluronate nº 1000004982 allows to obtain a 100% emitted fraction (EF%).
Furthermore, Hyal particles are distributed in the Twin Stage Impinger as follows:
- separation chamber 1: 90±3.17%
- separation chamber 2: 10.34±3.58% (n=5).
In the tests carried out in the EXPERIMENTAL PART (111.1) (hereinafter) on the mixture prepared with the batch of sodium hyaluronate nº 1000007025 the following results were obtained:
- separation chamber 1: 68.16±1.39%
- separation chamber 2: 30.65±2.74% (n=5). EXPERIMENTAL PART (III.1)
Evaluation of the aerodynamic characteristics of the hyaluronate-mannitol mixture.
Two hyaluronate-mannitol mixtures were prepared using three different types of hyaluronate (an aerosol hyaluronate and an injectable hyaluronate) and mannitol Pearlitol® 100 SD. The mixtures were prepared using a hyaluronate:carrier ratio equal to 36:64. The two mixtures were uniform in terms of content. The
aerodynamic characteristics of the mixtures were evaluated using a Glass Twin Stage Impinger (Disa, Milan, Italy) (Figure 18A). 7 mL and 30 mL of a sodium chloride solution (NaCI, 0.8% w N) were introduced into the upper and lower separation chambers, respectively. After connecting all the components, a pump was connected to the apparatus and the aspiration was adjusted to 60±5 L/min. The inhaler of the invention with the special blister comprising the mixture of the invention was then connected and the pump was actuated for a few seconds before dispensing the powder dose so as to stabilise the aspiration conditions. The pump was then kept running for 5 seconds after breaking the blister, as laid down by the European Pharmacopoeia guidelines (VIII Edition, pages 309-310).
The mixture deposited in the upper part was collected with 100 mL of 0.8% w N NaCI, while the one in the lower part was collected with 250 mL of 0.8% w/V NaCI. Subsequently, the sodium hyaluronate, collected in each of the two parts of the Twin Stage Impinger, was quantified using the spectrophotometric method and this allowed to calculate the emitted fraction (FE%) as a percentage of the nominal dose (DN) through the equation 4 (Eq.4).
EF%= [(IS(s)+ IS(i))/ DN] X 100 (q.4)
Where IS(s) and IS(i) are the amounts of sodium hyaluronate respectively collected in the upper part and in the lower part of the Twin Stage Impinger.
DN is used to indicate the amount of sodium hyaluronate introduced into the blister and therefore introduced into the inhaler of the invention before the pump of the Twin Stage Impinger is actuated. For each of the mixtures tested, DN was calculated through the content uniformity test, carried out according to the European Pharmacopoeia guidelines (VIII Edition, pages 309-310). The DN values, for each of the prepared mixtures, are reported in Table 3.
The data obtained from the test in the Twin Stage Impinger are reported in Tables 4 and 5 for mixture nº 1 (hyaluronate for aerosol, samples 14) and for mixture nº 2 (injectable hyaluronate, samples 16-17) and, respectively.
Table 4. Samp.": I. Cage: internal part of the Blister containing the powder. Coefficient of variation (CV%) = (Standard/mean deviation) x 100.
Table 5 (captions as per Table 5).
The mixture deposited in the inhaler and the one remaining in the blister were also collected using, for each aliquot, 25 mL of 0.8% w/V NaCI and the sodium hyaluronate was then quantified. The results obtained are reported in Tables 6 and 7.
Table 6
Table 7
Conclusion: selecting a type of hyaluronate. According to the results obtained with the Twin Stage Impinger test, it was possible to select the hyaluronate which produces the mixture with the most optimal aerodynamic characteristics for the preparation of an inhalation powder. The hyaluronate selected is hyaluronate for aerosol. As indicated in Tables 4 and 5, the mixture nº 1 is characterised by a greater EF% and by a greater breathable fraction with respect to the ones obtained with the mixture nº 2. As a matter fact, as indicated in Tables 6 and 7, the amount of mixture nº 2 deposited at the level of the blister and of the inhaler is greater than the amount of mixture nº I.
During the analysis under the Twin Stage Impinger, no deformations and/or breakage of the inhaler and the cage present in the blister were observed (Figure 18A) and no trace of the aluminium film, the material that the blister is made of, was released.
Furthermore, it was observed that the type of polypropylene, both when manufacturing the inhaler and when manufacturing the cage, does not alter the performance of the inhaler.
EXPERIMENTAL PART (IV)
PREPARATION OF A SODIUM HYALURONATE AND MANNITOL MIXTURE (36:64 w/w) FOR SCALE- UP TESTS
A. MATERIALS AND EQUIPMENT AND CONDITIONS - Raw materials
Sodium hyaluronate (in short, Hyal) (Altergon) Batch 100007837, altergon code: 395133101. Mannitol - Peariitol® 100 SD (Roquette Frères, Lestrem Cedex, France). - Mixer
V mixer, model MP-6, capacity 12 Litres, stainless steel caps and flow breaker blades (Multigel srl, Firenze, Italia).
- Weighing scale
The weighings were carried out with a Gibertini EU-C 7500 technical weighing scale with division d=0.1 g. - Processing conditions
The weighings, the loading and unloading of the mixer were carried out in an environment with a temperature of 22ºC ± 1 and a relative humidity of 30% ± 1.
- Packaging the mixtures
After preparation, the mixtures were stored in heat sealed PE bags and subsequently placed in HOPE containers (CurTec, Rijen, The Netherlands) supplied by Altergon Italia S.r.L.
- Storage conditions
After packaging, the mixtures were stored in rooms at a temperature of 22ºC ± 1 and relative humidity of 30% ± 1. 1. CHARACTERISATION OF RAW MATERIALS
1 . 1 . Dimensbnal analysis
The particle sizes were measured using the granulometer Accusizer™ Particle Sizer Model 770; particle sizing system, Santa Barbara California, USA
The analyses were carried out using acetonitrile as a dispersing medium given that none of the components, Hyal and mannitol, is soluble in this solvent. Preparation of the sample to be analysed: 1 mg of sample was dispersed in 1 ml of solvent and sonicated in ultrasonic bath for 1 minute.
The results obtained represent the mean of five measurements (n=5). The dimensions were expressed as the volumetric mean diameter (VMD) and the degree of polvdisoersitv was expressed as span, calculated according to equation 1 (Eq. 1): Span = (Dv0,9- Dv0,1 )/ Dv0,5(Eq.1)
1.1.1. Sodium hyaluronate
Particle size analysis carried out on Hyal (Figure 19): VMD:30.14 ± 0.8 μm; Moda: 27.87 μm; Median (D50): 27.87 pm; Span: 1.05 (n=5, ± SD)) gave a volumetric mean diameter (VMD) of about 30 μm. The calculated span (1.05) shows that the population is rather homogeneous.
1.2. Thermogravimetric analysis on Hyal This analysis was carried out on the Hyal sample, taken immediately after opening the sealed bag, in order to accurately determine the water content given its known hygroscopicity.
Thermogravimetric analysis (TGA) was carried out using a TG-DTA Netzsch STA 490 C thermal analyser under the following operating conditions: heating rate 10°C/minute, air flow 30 ml/minute.
The results obtained showed that the sample contains 12.67% moisture (Figure 20).
2. PREPARATION OF THE SODIUM HYALURONATE/MANNITOL MIXTURE 2.1. Determination of the amount of raw materials to be loaded into the mixer.
The mixture was prepared complying with the Hyal/mannitol ratio 36:64 w/w.
The V mixer was loaded with a total amount of the two powders such to occupy a volume of 6 Litres (half the volume with respect to the total capacity of the mixer equal to 12 Litres).
To determine the amount of Hyal and mannitol to be loaded, the bulk density value of the mixture (measured previously) which is equal to 0.504 g/ml (Table 8) was taken into account.
Table 8
2.2. Loading the mixer.
The mixer was loaded with the two raw materials, Hyal and mannitol, according to the following order and amounts:
- Mannitol (200 g) (Loading carried out by the right cone of the mixer),
- Hyal (50 g) (Loading carried out by the right cone of the mixer),
- Hyal (50 g) (Loading carried out by the right cone of the mixer),
- Mannitol (150 g) (Loading carried out by the right cone of the mixer), - Hyal (50 g) (Loading carried out by the right cone of the mixer),
- Hyal (50 g) (Loading carried out by the right cone of the mixer),
- Mannitol (200 g) (Loading carried out by the right cone of the mixer),
- Hyal (50 g) (Loading carried out by the left cone of the mixer),
- Hyal (50 g) (Loading carried out by the left cone of the mixer), - Hyal (24.86 g) (Loading carried out by the left cone of the mixer),
- Mannitol (27.536 g) (Loading carried out by the left cone of the mixer).
Given the high hygroscopicity of Hyal, in order to reduce the times of exposure to air to the minimum, the weighings were progressively carried out according to the order described above. Furthermore, given the adhesiveness of the powder, an excess of 0.2 grams was weighed for each weighing of Hyal.
1.3. Mixing conditions.
In order to optimise the mixing conditions , a 40 rpm speed and a total mixing time were used: 7 minutes + 8 minutes. The mixture obtained after 15 minutes of mixing met the content uniformity test requirements given that all the values fall within the limits laid down by the pH. EUR. 9th Ed guidelines. This first result allowed to define the optimal mixing conditions using a 12-litre V mixer:
Rotation speed: 40 rpm
Mixina time: 15 minutes
Eight mixing cycles were carried out. Specifically:
five mixtures of Hyal and mannitol were prepared complying with the 36/64 w/w ratio up to obtaining a final volume of 6 litres. three mixtures were prepared with higher amounts of Hyal and mannitol, but complying with the 36/64 w/w ratio, up to obtaining a final total volume of 6.923 litres. The first test carried out showed that this slight increase in volume (0.923 litres) does not affect the efficiency of the mixing which, according to the content uniformity test carried out, allowed to obtain a uniform final product
All the other prepared mixtures were subjected to a content uniformity test, whose requirements were found to have been met in all cases.
EXPERIMENTAL PART (V)
Preliminary study of the resistance of the kit of the invention (inhaler + powder in blisters) and the emitted dose of a sodium hyaluronate and mannitol mixture loaded in the blister in an amount of 27.8 mg. In order to determine the performance of the inhaler of the invention as regards the ability thereof to emit an amount of powder equal to 28 mg (mixture of the invention), of which 10 mg of sodium hyaluronate as such, several investigations were carried out as follows:
1. Determination of the morphology of the mannitol powders (Perlitol®), sodium hyaluronate and of the corresponding mixture (mixture of the invention).
2. Determination of the resistance of the inhaler of the invention against the airflow.
3. In vivo determination of the inhalation pattern in volunteers using the inhaler of the invention empty (without powder).
4. In vivo determination of the pattern in volunteers using the inhaler of the invention loaded with the powdered mixture of the invention and measurement of the amount of powder emitted.
The procedures applied for the determinations and the results obtained were as follows:
1. Determination of the size distribution of the sodium hyaluronate powder and the morphology of the mannitol, sodium hyaluronate powders and the corresponding mixture. The size distribution of the raw material sodium hyaluronate powder, batch 1000007837, was determined with a laser refractometer after dispersion of the powder in an organic solvent. Figure 21 (Table 9) reports three replicas of the size distribution curves. The median volume diameter falls between 20 μm and 30 μm.
Table 9. Coefficient of variation (Cv%) = (Standard/Mean deviation) x 100
The morphology of the mixture of the mannitol powders (Periitol 100 SD) and sodium hyaluronate (NaHA) was determined by means of a scanning electron microscope (SEM) under the conditions reported under the micrographs of Figures 22 and 23 (such as, Mag=200X, EHT=1,00kV, WD=5,5 mm FIB Imaging =SEM, Scan Rotation = 0,0º Off, Tilt Com. = off 54, 0º, Signal A = SE2, FIB Probe = 30 KV:20pA, System Vacuum = 2.28 e-006 Torr).
The images show the two types of particles present in the mixture batch L 4130618, that is sodium hyaluronate, present as elongated fibres, and sprav-dried mannitol. The latter, which shows particles around 100 μm, does not appear to have potentially breathable fine particles.
Sodium hvaluronate particles have a fibrous shape which benefits their inhalation use, given that the aerodynamic diameter of a particle also depends on the shape thereof. The particles in the form of elongated fibre, transported in a laminar air flow, align with the smaller dimension thereof along the flow lines. Most sodium hvaluronate fibres are longer than 10 μm, but the diameter thereof is often less than 5 μm.
Lastly, it should be observed that the mixture is not interactive· given that there are no hvaluronate particles adhered to the surface of the carrier mannitol (Periitol® 100 SD) just like significant cakings of Na-HA particles are not observed. 2. Determination of the resistance of the inhaler of the invention against the airflow.
The measurement of the resistance of the inhaler of the invention (DPI) against the inhalation flow of air was carried out after the construction of a mouthpiece adapter of the inhaler made of silicone material (rubber adaptor). The DPI not containing the powder, activated by manually squeezing the "reservoir" blister, was positioned with the mouthpiece in the adaptor at the inlet of the measuring device and verifying the sealing thereof. Inhaler and mouthpiece were attached to an apparatus for collecting the emitted dose (DUSA) and connected to a aspirating pump by means of an instrument called TPK.
After the system was switched on and the air flow was activated, the flow capable of generating a 4 kPa pressure drop through the device was determined. The TPK system provides two pressure values (P3 and P2) whose ratio, if less than or equal to 0.5, indicates the presence of sonic air flow. Lastly, the guidelines
recommend to activate the device for a period of time such to allow 4 litres of air to flow through. This time is calculated using the formula: T= 240/Q
The values measured are reported in Table 10 below:
T able 10 "non-sonic flow, that is subject to variations of the aspiration pump or in the device.
This makes the < 5μm cut off of the fine fraction of the FSI no longer reliable.
The resistance of the device is calculated by means of the following formula: ΔΡ½= * where ΔΡ is the pressure drop in kPa, Q is the flow in L min -1 and R is the resistance of the device in kPa½ /L min -1.
The subsequent chart (Figure 24) shows how to calculate the resistance of the device, value corresponding to the slope of the straight line which interpolates the flow values measured at the selected pressure drop values. The resistance of the inhaler is equal to 0.0134 kPa½ /L min -1, considered to be a very low resistance, similar to the inhaler Rotahaler®.
3. In vivo determination of the inhalation pattern in volunteers using the inhaler of the invention empty.
We recruited volunteers in order to verily the functioning of an inhaler of the invention in vivo. The measuring system, manufactured by us, consists of a flowmeter connected to a PC capable of measuring the air flow inhaled by the volunteer. The volunteer is trained to evacuate the lungs by exhaling before bringing the DPI to the mouth and performing an inspiratory action which has a significant initial ramp. Figure 25 shows the dynamic inspiratory action performed by the recruited volunteers.
The air flow curves show that the ascent ramp of the inhalation of the volunteers is quite steep and that the flow peak is comprised between 40 LVmin and 80 LVmin, values capable of generating a <1 kPa pressure drop. The duration of the inhalation action falls between 1 and 2 seconds.
4. In vivo determination of the inhalation pattern of volunteers with the inhaler of the invention loaded with the powdered mixture and measurement of the amount of powder emitted.
Figure 26 shows the flow curves recorded with the same volunteers when the inhaler of the invention is loaded with the powder. It is dear that the presence of the powder affected the shape of the flow profiles
which showed peaks of small magnitude, between values of 20 L/min and 60 L/min, even if more prolonged by a few fractions of a second. Some volunteers feared the arrival of powder in the throat, hence inspired less intensely but longer than the powder-free tests.
When measuring the flow, the amount of powder extracted by the volunteer during inhalation from the device was also determined. Table 11 shows the amount of powder extracted and the volumes of air mobilised during inhalation by each volunteer. There is a relationship between the volume of air inhaled and the amount of powder extracted, as also observable from Figure 27. The amount extracted increases as the volume of inhaled air increases, approaching complete extraction.
Table 11
5. CONCLUSION
The use of the inhaler of the invention requires that the inhalation action be intense at the beginning and prolonged for a couple of seconds. As regards the structure of the inhaler of the invention, the resistance thereof is very low and - given that it reaches flows from 70 L/min to 100 L/min - it is possible to extract a good amount of sodium hyaluronate.
Though having a high volume diameter. NaHA powder has a low aerodynamic diameter due to the influence of the particles thereof.
Claims
1. A mixture in the form of a dry powder for inhalation comprising or, alternatively, consisting of hyaluronic acid or an acceptable pharmaceutical or food grade salt thereof.
2. The mixture according to daim 1, wherein said mixture comprises or, alternatively, consists of sodium hyaluronate and mannitol; wherein said sodium hyaluronate has an average molecular weight comprised from greater than 500 kDa to 2000 kDa; wherein said sodium hyaluronate has a mass median aerodynamic diameter (MMAD) comprised in the range from 0.5 μm to 30 μm; wherein a [sodium hyaluronate: mannitol] weight: weight ratio is comprised in the range from 25:75 to 45:55.
3. The mixture according to daim 1 or 2, wherein said mixture comprises or, alternatively, consists of sodium hyaluronate and mannitol; wherein said sodium hyaluronate has an average molecular weight comprised from 700 kDa to 1000 kDa; wherein said sodium hyaluronate has a mass median aerodynamic diameter (MMAD) comprised in the range from 1 μm to 20 μm, preferably from 8 μm to 15 μm; wherein a [sodium hyaluronate: mannitol] weight: weight ratio is comprised in the range from 30:70 to 40:60, preferably from 34±1 :66±1.
4. A composition comprising the mixture according to any one of daims 1 to 3 and at least one acceptable pharmaceutical or food grade additive and/or exdpient.
5. The mixture or composition according to any one of the preceding daims, wherein said mixture or composition do not comprise ladoferrin and/or N-acetylcysteine (NAG) or an acceptable pharmaceutical or food grade salt thereof and/or cannabidiol (CBD).
6. A kit for the administration of dry powder through the inhalation route, wherein said kit comprises:
- at least one blister comprising said mixture or composition according to any one of the preceding daims; and
- a dry powder inhaler comprising a substantially pipe-shaped hollow body comprising a first portion (1) for housing said blister (C), and a second portion (2) connected to said first portion (1) for dispensing said mixture or composition in the form of dry powder by means of a primary air flow (FP) which carries the
powder from an inner drop region (5), located on the bottom of said first portion (1), along a dispensing duct (3) whose end is suitable to be arranged in the mouth of a subject, said dispensing duct (3) being divided horizontally by a partitioning septum (4) into an upper duct (3a) which dispenses said primary air flow (FP) and a lower duct (3b) which dispenses a secondary air flow (FS) devoid of powder, the suctioning of the air forming the primary flow (FP) being obtained by means of at least three air intakes (7) formed in the first portion (1) which are preferably arranged symmetrically with respect to the longitudinal centreline plane of the inhaler, the suctioning of the air forming the secondary flow (FS) being provided by means of an air intake (8) obtained at the distal end of said lower duct (3b), the inhaler being characterised in that said support base for the blister (C) includes a plurality of horizontal support surfaces (9) projecting into the first portion (1), and oriented flow channels (11) formed in the support base extending between said at least three air intakes (7) and the inner powder drop region (5).
7. The mixture or the composition or the kit according to any one of the preceding claims for use as medicament.
8. The mixture or composition or kit according to any one of the preceding claims for use in a method for the preventive and/or curative treatment of a disease and/or symptom of the upper and lower respiratory tract; preferably of the upper respiratory tract; more preferably, wherein said upper respiratory tract comprises or, alternatively, consists of nose, throat, pharynx, trachea and upper part of the bronchi.
9. The mixture or the composition or the kit for use according to claim 8, wherein said disease or said symptom are selected from the group comprising or, alternatively, consisting of: cold, sinusitis, rhinitis, mucus secretion in the nose and/or throat area, mucus hypersecretion and of a disease, symptom and/or disorder associated with said mucus hypersecretion, tracheitis, pharyngitis, laryngitis, acute laryngotracheobronchitis, epiglottitis, bronchiectasis, respiratory complications, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, bronchiolitis, emphysema, cystic fibrosis, cough, pertussis, pneumonia, pleuritis, or bronchiolitis.
10. The mixture or the composition or the kit for use according to claim 8 or 9, wherein, following an inhalation of said mixture or composition by aspiration through the mouth, said hyaluronic acid or a salt thereof, preferably sodium hyaluronate, is distributed in the respiratory tract as follows, wherein the percentages are percentages by weight with respect to 100% by weight of the aspirated hyaluronic acid:
- from 65% to 90%, preferably from 70% to 89%, at the level of throat-oropharynx;
- from 5%±0.05% to 35%±0.05%, preferably from 10% to 30%, at the level of pharynx, trachea and upper part of the bronchi;
- from 0.05% to 5%, preferably from 1% to 3%, at the level of the lower respiratory tract, preferably lower part of the bronchi, bronchioles, alveoli and/or pulmonary area.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202180071725.8A CN116568280A (en) | 2020-09-09 | 2021-09-09 | Hyaluronic acid or salt thereof for inhalation treatment of respiratory diseases and inhaler device comprising same |
| MX2023002789A MX2023002789A (en) | 2020-09-09 | 2021-09-09 | Hyaluronic acid or salt thereof for inhalation use in the treatment of respiratory diseases, and an inhaler device containing the same. |
| EP21783349.0A EP4210672A1 (en) | 2020-09-09 | 2021-09-09 | Hyaluronic acid or salt thereof for inhalation use in the treatment of respiratory diseases, and an inhaler device containing the same |
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|---|---|---|---|
| IT102020000021361 | 2020-09-09 | ||
| IT102020000021361A IT202000021361A1 (en) | 2020-09-09 | 2020-09-09 | HYALURONIC ACID OR A SALT THEREOF FOR INHALATION USE IN THE TREATMENT OF RESPIRATORY DISEASES, AND AN INHALER DEVICE CONTAINING THE SAME |
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| WO2022053969A1 true WO2022053969A1 (en) | 2022-03-17 |
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| PCT/IB2021/058205 WO2022053969A1 (en) | 2020-09-09 | 2021-09-09 | Hyaluronic acid or salt thereof for inhalation use in the treatment of respiratory diseases, and an inhaler device containing the same |
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| Country | Link |
|---|---|
| EP (1) | EP4210672A1 (en) |
| CN (1) | CN116568280A (en) |
| IT (1) | IT202000021361A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE202011103553U1 (en) * | 2010-07-30 | 2011-11-10 | Eupharma S.R.L. | Inhalation preparations in the form of solutions or dry powder for the removal of mucous secretions from the respiratory system |
| WO2020031099A1 (en) * | 2018-08-07 | 2020-02-13 | Sofar S.P.A. | Composition containing a mucolytic agent for the treatment of mucus hypersecretion and a device for the dosing thereof |
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| IT201600093878A1 (en) | 2016-09-19 | 2018-03-19 | Hollycon Italy Pte Ltd S R L | SINGLE-DOSE INHALER TO LOSE FOR POWDER MEDICINES |
-
2020
- 2020-09-09 IT IT102020000021361A patent/IT202000021361A1/en unknown
-
2021
- 2021-09-09 WO PCT/IB2021/058205 patent/WO2022053969A1/en active Application Filing
- 2021-09-09 EP EP21783349.0A patent/EP4210672A1/en active Pending
- 2021-09-09 MX MX2023002789A patent/MX2023002789A/en unknown
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE202011103553U1 (en) * | 2010-07-30 | 2011-11-10 | Eupharma S.R.L. | Inhalation preparations in the form of solutions or dry powder for the removal of mucous secretions from the respiratory system |
| WO2020031099A1 (en) * | 2018-08-07 | 2020-02-13 | Sofar S.P.A. | Composition containing a mucolytic agent for the treatment of mucus hypersecretion and a device for the dosing thereof |
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