EP3518903A1 - Mélange particulaire, destiné à être utilisé de préférence pour la prophylaxie et/ou le traitement d'un trouble respiratoire - Google Patents

Mélange particulaire, destiné à être utilisé de préférence pour la prophylaxie et/ou le traitement d'un trouble respiratoire

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Publication number
EP3518903A1
EP3518903A1 EP17783777.0A EP17783777A EP3518903A1 EP 3518903 A1 EP3518903 A1 EP 3518903A1 EP 17783777 A EP17783777 A EP 17783777A EP 3518903 A1 EP3518903 A1 EP 3518903A1
Authority
EP
European Patent Office
Prior art keywords
μηι
substance
particulate
expectorant
particulate mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP17783777.0A
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German (de)
English (en)
Inventor
Bart Zonnenberg
Constantin Adams
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Riethmueller Anke Ingeborg
Original Assignee
Riethmueller Anke Ingeborg
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Riethmueller Anke Ingeborg filed Critical Riethmueller Anke Ingeborg
Publication of EP3518903A1 publication Critical patent/EP3518903A1/fr
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/02—Ammonia; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • 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
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics

Definitions

  • a particulate mixture preferably for use in the prophylaxis and / or treatment of respiratory distress
  • the invention relates to a particulate substance mixture, preferably for use in the prophylaxis and / or treatment of an airway disorder, a pharmaceutical composition, preferably for use in the prophylaxis and / or treatment of an airway disorder, a dosage unit, a device for administering the particulate mixture, the drug or the dosage unit and a method for producing the particulate mixture or drug.
  • cystic fibrosis also known as cystic fibrosis (CF)
  • PCD primary ciliary dyskinesia
  • COPD chronic obstructive pulmonary disease
  • Characteristic of the above-mentioned diseases is the often very limited ability of the affected patients to liquefy and cough up the bronchial secretions.
  • the viscous mucus in the bronchi can cause chronic cough, bronchiectasis, frequent lung infections and severe pneumonia.
  • the treatment of respiratory diseases includes a variety of different approaches, such as administration of secretolytics, antibiotics, fat soluble vitamins, and the like, as well as anti-inflammatory therapy.
  • Pulmozym ® For example, one approach in the administration of so-called Pulmozym ®.
  • This is a recombinant human deoxyribonuclease, ie an enzyme that cleaves extracellular DNA.
  • the bronchial mucus liquefied and better solved.
  • the disadvantage is that this is a relatively expensive form of treatment. To make matters worse, that this treatment approach is relatively complicated by the requirement of a special inhalation device.
  • usually several inhalational administration throughout the day are required for the affected patients receive a sufficient amount of Pulmozym ®. This not only makes the treatment time-consuming for the affected patients, but also restricts their mobility.
  • An alternative treatment approach is the wet inhalation of hypertonic saline.
  • Halotherapy takes place in a climatically suitable chamber or salt cave. This is a special room in which small amounts of micronized saline are released into the room air. For treatment, the affected patients spend 30 to 60 minutes in the chamber and inhale the salt released into the room air.
  • Halotherapy generally improves lung function parameters and exacerbation frequency.
  • Clinical studies performed on a mixed population of asthma, COPD, bronchiectasis and CF patients have resulted in a positive effect on lung function and improvement of disease symptoms.
  • positive effects could be achieved (see Hedman et al., 2006, The Effect of Salt Chamber Treatment on Bronchial Hyperresponsiveness in Asthmatics, Allergy 61, pages 605-610, Chervinskaya and Zilber (1995), Halotherapy for Treatment of Respiratory Diseases, Journal of Aerosol Medicine 3, pages 221-232, Chervinskaya (2003), Halotherapy of Respiratory Diseases, Physiotherapy, Balneology and Rehabilitation 6, pages 8-15).
  • cystic fibrosis or cystic fibrosis
  • halo therapy has a positive influence on pulmonary secretolysis and pulmonary function parameters.
  • halo therapy has the disadvantage that it is usually associated with a considerable effort for the affected patients.
  • a session in the air-conditioned chamber usually takes about 45 minutes and must be repeated regularly over a period of several days or daily.
  • air-conditioned chambers are not available to the majority of affected patients.
  • halotherapy is increasingly being taken up for the so-called wellness area.
  • Respiratory treatments are often performed by wet inhalation with hypertonic saline.
  • the lung function improves, and it
  • the chronic inflammation and frequency of infection exacerbate due to the improved bronchial lavage.
  • Patients benefit from the osmotic effect of hypertonic saline, which increases the water content in the bronchial mucus produced and causes improved pulmonary clearance and secretion (see Ratjen (2006), Restoring Airway Surface Liquid in Cystic Fibrosis, New England Journal of Medicine 354, pages 291-293).
  • WO01 / 62264 A2 discloses a modified form of halotherapy for the treatment of common colds and influenza in which sodium chloride is administered to the patient as a dry powder by means of a dispenser, wherein the sodium chloride is in the form of an aerosol and the aerosol particles have an average particle diameter of 2 ⁇ to 6 ⁇ have.
  • the present invention therefore an object of the invention to provide an improved therapy, preferably of respiratory disorders or diseases, which at least largely bypasses known from the prior art disadvantages.
  • the invention relates to a particulate, preferably pulverulent, mixture of substances, preferably for use in the prophylaxis and / or treatment of an airway disorder or disease.
  • the particulate mixture is characterized in particular by having an expectorant substance and amorphous, ie noncrystalline, silica.
  • the inventors have recognized that agglomeration or agglomeration of expectorant substance particles in the presence of amorphous silicon dioxide particles as release agents can be prevented, but at least prevented or delayed over a relatively long period of time, for example over a period of 1 to 2 years.
  • the risk of a treatment failure as a result of particle agglomeration or -Verrosempung eliminate, but at least noticeably lower.
  • Another advantage is a significantly improved long-term stability and storage life.
  • a further advantage is that very high treatment concentrations, in particular of the expectorant substance, in the ambient air can be achieved by the particulate design of the substance mixture in dry inhalation administration.
  • the treatment concentrations may be, for example, 2 mg / m 3 to 15 mg / m 3 of room air.
  • a daily administration of approximately 5 ml of hypertonic saline solution by means of an inhalation nebuliser would be required during the day.
  • the treatment time in the case of the substance mixture according to the invention can be noticeably shortened, in particular to a few seconds, in particular if the substance mixture is administered by means of capsule inhalation, preferably cumulative capsule inhalation.
  • the substance mixture is particularly suitable for a repeated administration per day, without this being associated with a considerable expenditure of time for the patient. This in turn allows patient treatment without significant impairment of quality of life.
  • pillate substance mixture is to be understood as meaning a mixture of substances which is in the form of particles, preferably in the form of powder particles.
  • airway disorder is to be understood as meaning a disorder or a disorder of the respiratory tract or a part thereof
  • the respiratory tract can be the respiratory tract of a human or of a non-human mammal human patients.
  • airway disorder is to be understood as meaning preferably a disorder or disease of the respiratory tract or a part thereof in a human.
  • Respiratory tracts are all parts of the respiratory system which serve as pathways between the outside world and the alveoli.
  • the airways can be divided into upper respiratory tract and lower respiratory tract.
  • the upper respiratory tract includes the nasal cavity and paranasal sinuses, the oral cavity and the pharynx.
  • Lower airways include the larynx, trachea, bronchi, bronchioles such as bronchioles (bronchioli lobulares), terminal bronchi (bronchioli terminales) and respiratory bronchioles (bronchioli respirtra), alveolar ducts and alveoli.
  • the term "expectorant substance” is to be understood as meaning a substance which promotes or favors a solution or detachment of mucus, in particular bronchial or nasal mucus, preferably bronchial mucus, for example by expectoration, coughing, sneezing and / or
  • the term “expectorant” should therefore be understood as meaning, in particular, secretolytics, mucolytics and / or secretomotor agents.
  • suitable expectorant substances reference is made to the statements made below.
  • secretolytic or “secretolytically active substance” is intended to mean a substance which stimulates the production of thin-bodied mucus, in particular bronchial or nasal mucus, preferably bronchial mucus.
  • mucolytic agent or “mucolytically active substance” is to be understood as meaning a substance which liquefies existing mucus, in particular existing bronchial or nasal mucus, preferably existing bronchial mucus.
  • secretomotor moiety or “secretomotor-active substance” is intended to mean a substance which excites the motility of the cilia, in particular of the nasal mucosa or bronchi, preferably the bronchi, and thus for a better removal of the mucus, in particular bronchial or nasal mucus, preferably nasal mucus.
  • expectorant in the context of the present invention may also mean an expectorant substance (singular) or a plurality, in particular a mixture, of different expectorant substances (plural).
  • the expression "fumed silica” should preferably be understood to mean an amorphous and, in particular, nonporous silica powder having an average particle diameter of 5 nm to 50 nm, a specific surface area of 50 m 2 / g to 600 m 2 / g, in particular 50 m 2 / g to 400 m 2 / g, and a density of 30 kg / m 3 to 250 kg / m 3 , in particular 160 kg / m 3 to 190 kg / m 3 , has Such a silicon dioxide
  • the powder is usually produced by flame hydrolysis, using sand as the starting material, first reducing the sand with carbon, then converting the resulting silicon to silicon tetrachloride with chlorine, followed by high-temperature pyrolysis of silicon tetrachloride with oxyhydrogen to form a homogeneous mixture of vaporous silicon tetrachloride, hydrogen, oxygen and an inert gas burned
  • precipitated silicon dioxide is to be understood as meaning an amorphous silicon dioxide produced mainly by precipitation processes starting from water glass, the water glass being obtainable by digestion of quartz sand with sodium carbonate or potassium carbonate.
  • average particle diameter is to be understood as follows in the context of the present invention.
  • the starting point for the following statements is the fact that the particles of a substance or mixture usually have no constant uniform particle diameter, even after previous comminution steps. Rather, there is a particle size distribution between larger and smaller particles.
  • distribution curves are usually used to show the distribution of the particles around an "average particle size.” Often there is a monomodal distribution of the particles around one (single) average, but there are also multimodal distributions with at least two different particle size distributions possible.
  • the graphically represented distribution curve can also be reproduced on the basis of diameter values.
  • the so-called D50 value indicates the mean particle size.
  • the D50 value means that 50% of the particles are smaller than the specified value. Unless otherwise stated, the expression "average particle diameter" referred to in the present invention corresponds to this D 50 value.
  • a mean particle diameter of ⁇ 5 ⁇ m therefore means that 50% of the corresponding particles have a diameter of ⁇ 5 ⁇ m.
  • Particle size distributions can be determined in different ways, particle particle analysis by means of laser diffraction being particularly suitable for the particle sizes mentioned in the present invention.
  • Laser diffraction laser diffractometry
  • Particle analysis by means of laser diffraction is described in ISO 13320-1, the contents of which are expressly referred to and incorporated herein by reference.
  • a commercially available device for this laser diffractometry is the scattered light meter LS 13320 from Beckman Coulter, California, USA. With this device, the average particle diameter of the substances used in the example part of this patent application were determined.
  • the term "powder” is to be understood as meaning a particulate substance or a particulate mixture whose particles have an average particle diameter ⁇ 20 ⁇ m, in particular from 0.1 ⁇ m to 18 ⁇ m, preferably ⁇ 10 ⁇ m, more preferably 0.1 ⁇ m to 6 ⁇ m ⁇ , more preferably 0.1 ⁇ to 5 ⁇
  • the term "powder” in the context of the present invention a particulate matter or a particulate mixture to be understood whose particles have an average particle diameter ⁇ 5 ⁇ , in particular from 0.1 ⁇ to 4 ⁇ , preferably from 0.1 ⁇ to 3 ⁇ , more preferably from 0.1 ⁇ to 2 ⁇ , more preferably from 0.1 ⁇ to 1 ⁇ have.
  • dry powder is intended to mean an anhydrous or substantially anhydrous powder.
  • dry salt in the context of the present invention means an anhydrous or substantially anhydrous salt, preferably an anhydrous or substantially anhydrous inorganic salt.
  • the term "essentially anhydrous powder” is to be understood as meaning preferably a powder which has a water content of ⁇ 0.4% by weight, in particular ⁇ 0.3% by weight, preferably ⁇ 0.2% by weight, more preferably ⁇ 0.1% by weight, based on the total weight of the powder.
  • the term "essentially anhydrous salt” in the context of the present invention should preferably be understood as meaning a salt which has a water content ⁇ 0.4% by weight, in particular ⁇ 0.3% by weight, preferably ⁇ 0.2% by weight, particularly preferably ⁇ 0.1 wt .-%, based on the total weight of the salt.
  • dry inhalation is to be understood as the inhalative administration of a dry powder, in particular dry salt.
  • micronization is to be understood as meaning a process or process for significant reduction of particles by grinding or atomization particulate substances or particulate mixtures with a mean particle diameter ⁇ 20 ⁇ , in particular 0.1 ⁇ to 18 ⁇ , preferably ⁇ 10 ⁇ , more preferably 0.1 ⁇ to 6 ⁇ , more preferably 0.1 ⁇ to 5 ⁇ , can be produced.
  • micronization in the context of the present invention means a milling or sputtering process, by means of which particulate or particulate mixtures having an average particle diameter ⁇ 5 ⁇ , in particular from 0.1 ⁇ to 4 ⁇ , preferably from 0.1 ⁇ to 3 ⁇ , more preferably from 0.1 ⁇ to 2 ⁇ , more preferably from 0.1 ⁇ to 1 ⁇ , can be produced.
  • capsule inhalation is to be understood as meaning the inhalation or inhalative administration of a capsule content, in particular of a particulate, preferably pulverulent, capsule content.
  • the amorphous silica is a synthetic silica.
  • the amorphous silica may be fumed silica, preferably silicon dioxide prepared by flame hydrolysis and then milled, or by flame hydrolysis, and subsequently atomized.
  • the amorphous silica may be silica produced by flame hydrolysis and subsequently micronized.
  • the amorphous silica may be precipitated silica, preferably precipitated and then ground or precipitated and then sputtered silica.
  • the amorphous silica may be precipitated and subsequently micronized silica.
  • the amorphous silicon dioxide it is particularly preferred for the amorphous silicon dioxide to be hydrophilic, ie not hydrophobized, silica.
  • This has the advantage that the amorphous silicon dioxide can bind any traces of moisture or water present in the particulate substance mixture due to its hydrophilic character, whereby a retrograde, the particle agglomeration or -Verissempung favoring water absorption by the expectorant substance prevents, however, at least can be significantly delayed.
  • This improves, in particular lengthen, the therapeutic effectiveness of the particulate substance mixture, for example by ensuring that the substance mixture, in particular the expectorant substance and / or the amorphous silicon dioxide, also has a particle size which is sufficient for pulmonary deposition over a relatively long period of time.
  • amorphous silica is a hydrophilic silica which is commercially available 300 Pharma under the name AEROSIL ® 200 or Aerosil ® Pharma.
  • AEROSIL ® 200 or Aerosil ® Pharma may be in the amorphous silicon dioxide act 300 Pharma a mixture of AEROSIL ® 200 Pharma and AEROSIL ®.
  • the amorphous silicon dioxide is in a further embodiment in the form of particles, hereinafter also referred to as amorphous silicon dioxide particles, preferably in the form of aerosol particles, hereinafter also referred to as amorphous silica aerosol particles before.
  • the amorphous silica particles, in particular amorphous silica aerosol particles are preferably not in agglomerated form. In other words, it is preferred according to the invention if the amorphous silicon dioxide particles, in particular the amorphous silica aerosol particles, do not form agglomerates.
  • the amorphous silica particles in particular the amorphous silica aerosol particles, do not agglomerate, at least for a period of 6 months to 24 months, in particular 12 months to 24 months, i. do not form agglomerates.
  • the amorphous silicon dioxide in particular the amorphous silicon dioxide particles or amorphous silica aerosol particles, an average particle diameter ⁇ 20 ⁇ , in particular 0.1 ⁇ to 18 ⁇ , preferably ⁇ 10 ⁇ , more preferably 0.1 ⁇ to 6 ⁇ , particularly preferably 0.1 ⁇ to 5 ⁇ , on.
  • the amorphous silica in particular the amorphous silica particles or amorphous silica aerosol particles, an average particle diameter ⁇ 5 ⁇ , in particular from 0.1 ⁇ to 4 ⁇ , preferably from 0.1 ⁇ to 3 ⁇ , more preferably from 0.1 ⁇ to 2 ⁇ , most preferably from 0.1 ⁇ to 1 ⁇ on.
  • the mean disclosed in this paragraph Particle diameters for the amorphous silica have proven to be particularly advantageous for stabilizing the expectorant.
  • the amorphous silicon dioxide in particular the amorphous silicon dioxide particles or amorphous silica aerosol particles, a proportion of 0.1 wt .-% to 10 wt .-%, in particular 0.1 wt .-% to 5 wt .-%, preferably 0.1 wt .-% to 4 wt .-%, more preferably 0.1 wt .-% to 3 wt .-%, particularly preferably 0.2 wt .-% to 2 wt .-%, most preferably 0.5 wt .-% to 2 wt .-%, based on the total weight of the particulate mixture.
  • the amorphous silicon dioxide has a purity of> 99 wt .-%, preferably> 99.9 wt .-%, on.
  • the amorphous silicon dioxide has a specific surface area, in particular a BET surface area (according to DIN-ISO 9277 or DIN-66131), of 50 m 2 / g to 450 m 2 / g, in particular 70 m 2 / g 400 m 2 / g, preferably 100 m 2 / g to 280 m 2 / g, more preferably 150 m 2 / g to 350 m 2 / g, particularly preferably 170 m 2 / g to 330 m 2 / g, on.
  • a specific surface area in particular a BET surface area (according to DIN-ISO 9277 or DIN-66131), of 50 m 2 / g to 450 m 2 / g, in particular 70 m 2 / g 400 m 2 / g, preferably 100 m 2 / g to 280 m 2 / g, more preferably 150 m 2 / g to 350 m 2
  • the amorphous silica is in the form of a powder, in particular in the form of a ground or atomized, preferably micronized, powder.
  • the amorphous silicon dioxide is particularly preferably in the form of a dry powder, in particular in the form of a ground or atomized, preferably micronized, dry powder.
  • any biocompatible or medically acceptable substance may be considered as an expectorant substance, as long as the substance has expectorant properties in the sense of the present invention.
  • the expectorant substance is a substance that can be pulverized, preferably dry-powdered, ground or atomized, in particular microsizable.
  • the substance is a bronchial mucus-dissolving substance or an expectorant, ie a substance which promotes the expulsion or exhalation of bronchial mucus.
  • the substance is a secretolytically active substance.
  • the substance is a mucolytically active substance.
  • the substance is a secreto-motorically active substance.
  • the expectorant is an organic substance.
  • the organic substance may be an organic molecular compound, a mixture of different organic molecular compounds, an organic salt or an organic salt mixture, i. a mixture of different organic salts, act.
  • the expectorant may be selected from the group consisting of emetine, saponins, acetylcysteine, bromhexine, ambroxol, clenbuterol, and mixtures of at least two of said organic compounds.
  • the expectorant is an inorganic substance.
  • the inorganic substance may be an inorganic molecular compound, a mixture of different inorganic molecular compounds, an inorganic salt or an inorganic salt mixture, i. a mixture of different inorganic salts, act.
  • the expectorant is an inorganic salt or inorganic salt mixture.
  • the expectorant in particular the inorganic salt, an inorganic alkali metal salt, an inorganic alkali metal salt mixture, an inorganic alkaline earth metal salt, an inorganic alkaline earth metal salt mixture or a mixture of at least two of said salts or salt mixtures.
  • the expectorant in particular the inorganic salt, selected from the group consisting of inorganic sodium salt, inorganic potassium salt, inorganic magnesium salt, inorganic Caiciumalz and mixtures of at least two of said salts.
  • the expectorant, in particular the inorganic salt is selected from the group consisting of sodium chloride (NaCl), sodium sulfate (NaSO 4 ), sodium bicarbonate (NaHCO 3 ), magnesium chloride (MgCl 2 ), magnesium sulfate (MgSO 4 ), Calcium chloride (CaCl 2 ), calcium sulfate (CaSO 4 ), ammonium chloride (NH 4 Cl) and mixtures of at least two of said salts.
  • the expectorant in particular the inorganic salt, is sodium chloride or a sodium chloride-containing salt mixture, such as, for example, a mixture of sodium chloride and magnesium chloride.
  • the expectorant substance is present in the form of particles, hereinafter also referred to as expectorant substance particles, preferably in the form of aerosol particles, also referred to below as expectorant substance-aerosol particles.
  • the expectorant substance particles, in particular the expectorant substance aerosol particles are preferably not present in agglomerated form. In other words, it is preferred according to the invention if the expectorant substance particles, in particular the expectorant substance aerosol particles, do not form agglomerates.
  • the expectorant substance particles in particular the expectorant substance aerosol particles, do not agglomerate, at least for a period of 6 months to 24 months, in particular 12 months to 24 months, i. do not form agglomerates.
  • the expectorant substance in particular the expectorant substance particles or expectorant substance aerosol particles, an average particle diameter ⁇ 20 ⁇ , in particular 0.1 ⁇ to 18 ⁇ , preferably ⁇ 10 ⁇ , more preferably 0.1 ⁇ to 6 ⁇ , more preferably 0.1 ⁇ to 5 ⁇ , on.
  • the mean particle diameters disclosed in this paragraph allow good pulmonary depositions without manifesting unwanted side effects.
  • the expectorant substance in particular the expectorant substance particles or expectorant substance aerosol particles, has a mean particle diameter ⁇ 5 ⁇ m in a particularly preferred embodiment.
  • expectorant substances having such a particle size dust-like substance particles
  • Side effects such as pulmonary obstruction, However, irritation or taste intolerance were not detected.
  • the expectorant substance in particular the expectorant substance particles or expectorant substance aerosol particles, an average particle diameter of 0.1 ⁇ to 4 ⁇ , in particular 0.1 ⁇ to 3 ⁇ , preferably 0.1 ⁇ to 2 ⁇ , more preferably 0.1 ⁇ to 1 ⁇ , on.
  • the amorphous silicon dioxide particles, in particular the amorphous silica aerosol particles, and the expectorant substance particles, in particular the expectorant substance aerosol particles are each in the form of independently formed particles, in particular aerosol particles.
  • the amorphous silicon dioxide particles, in particular the amorphous silica aerosol particles, and the expectorant substance particles, in particular the expectorant substance aerosol particles are not interconnected, in particular neither agglomerate with each other nor glued together or otherwise materially connected.
  • the amorphous silicon dioxide particles, in particular the amorphous silica aerosol particles, and the expectorant substance particles, in particular the expectorant substance aerosol particles do not coat one another.
  • the expectorant substance in particular the expectorant substance particles or expectorant substance aerosol particles, has a proportion of 90% by weight to 99.9% by weight, in particular 95% by weight to 99.5% by weight, preferably 96% by weight % to 99 wt%, more preferably 96.5 wt% to 98.5 wt%, most preferably 97 wt% to 98 wt%, based on the total weight of the particulate mixture.
  • the expectorant substance has a purity of> 99 wt .-%, preferably> 99.9 wt .-%, on.
  • the purity levels mentioned in the previous paragraph have been found to be particularly suitable for the prophylaxis and / or treatment of respiratory disorders and resulted in the patients treated according to the invention to particularly good results.
  • the degrees of purity can be ensured by appropriate selection of the expectorant substance to be used.
  • suitable salts for example, by the company Sanal Salt, AkzoNobel, Wuppertal, Germany, marketed under the name Sanal ® SQ used.
  • the expectorant substance is in the form of a powder, in particular in the form of a ground or atomized, preferably micronized, powder.
  • the expectorant substance is particularly preferably in the form of a dry powder, in particular in the form of a ground or atomized, preferably micronized, dry powder.
  • the particulate substance mixture further comprises a filler.
  • the filler may in particular be selected from the group consisting of mannitol, lactol, lactide, talc, and mixtures of at least two of said fillers.
  • the filler is in the form of particles, hereinafter also referred to as filler particles, preferably in the form of aerosol particles, also referred to below as filler aerosol particles.
  • the filler in particular the filler particles or filler aerosol particles, an average particle diameter ⁇ 20 ⁇ , in particular 0.1 ⁇ to 18 ⁇ , preferably ⁇ 10 ⁇ , more preferably 0.1 ⁇ to 6 ⁇ , more preferably 0.1 ⁇ to 5 ⁇ , on.
  • the filler, in particular the filler particles or filler aerosol particles a mean particle diameter ⁇ 5 ⁇ , in particular from 0.1 ⁇ to 4 ⁇ , preferably from 0.1 ⁇ to 3 ⁇ , more preferably from 0.1 ⁇ to 2 ⁇ , most preferably from 0.1 ⁇ to 1 ⁇ , on.
  • the filler is in the form of a powder, in particular in the form of a ground or atomized, preferably micronized, powder.
  • the filler is particularly preferably in the form of a dry powder, in particular in the form of a ground or atomized, preferably micronized, dry powder.
  • the substance mixture according to the invention is preferably a particulate substance mixture for use in the prophylaxis and / or treatment of an airway disorder.
  • the airway disorder may basically be an airway disorder in a human or a non-human mammal.
  • the respiratory tract disorder is a human respiratory tract disorder or disease.
  • the respiratory tract disorder may be, in particular, a chronic respiratory disease.
  • the respiratory disorder is preferably a lung disease, in particular chronic lung disease.
  • the airways disorder is selected from the group consisting of chronic bronchitis, chronic obstructive pulmonary disease, chronic obstructive pulmonary disease (COPD), bronchial asthma, bronchiectasis, pulmonary fibrosis such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and pulmonary emphysema.
  • the respiratory disorder is particularly preferably chronic bronchitis, chronic obstructive bronchitis, chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF).
  • COPD chronic obstructive pulmonary disease
  • COPD cystic fibrosis
  • the particulate mixture is prepared for administration by inhalation, preferably dry inhalation.
  • the particulate substance mixture is used for administration by inhalation, preferably dry inhalation.
  • the particulate mixture may in principle be prepared or used for nasal or oral administration. According to the invention, it is particularly preferred if the particulate substance mixture is prepared for oral administration or is used for oral administration.
  • the particulate substance mixture is prepared for a capsule inhalation.
  • the particulate substance mixture is used for capsule inhalation.
  • the particulate mixture is in the form of a powder, in particular in the form of a ground or atomized, preferably micronized, powder.
  • the particulate mixture is particularly preferably in the form of a dry powder, in particular in the form of a ground or atomized, preferably micronized, dry powder.
  • the particulate mixture is a medical, i. a powder useful in the medical field, in particular for use in the prophylaxis and / or treatment of a disease, preferably dry powder.
  • the powdery mixture has an average particle diameter ⁇ 20 ⁇ m, in particular 0.1 ⁇ m to 18 ⁇ m, preferably ⁇ 10 ⁇ m, more preferably 0.1 ⁇ m to 6 ⁇ m, particularly preferably 0.1 ⁇ m to 5 ⁇ m.
  • the powdery mixture has an average particle diameter ⁇ 5 ⁇ , in particular from 0.1 ⁇ to 4 ⁇ , preferably 0.1 ⁇ to 3 ⁇ , more preferably 0.1 ⁇ to 2 ⁇ , most preferably 0.1 ⁇ to 1 ⁇ , on.
  • the particulate mixture is anhydrous.
  • the particulate mixture has a water content ⁇ 1% by weight, in particular ⁇ 0.4% by weight, preferably ⁇ 0.3% by weight, more preferably ⁇ 0.2% by weight, most preferably ⁇ 0.1% by weight , based on the total weight of the particulate mixture.
  • the particulate substance mixture is present in a dosage unit in an amount of 1 mg to 1000 mg and either in particular 500 mg to 1000 mg, or in particular 100 mg to 500 mg, more preferably 100 mg to 200 mg. Also preferred are dosage units of 50 mg to 100 mg.
  • the indicated amounts are those which have proven themselves as a dosage unit and have been optimized in particular for an inhalation process, preferably a dry inhalation process.
  • the dosage unit is a capsule.
  • This has the advantage that the particulate mixture can be provided in the desired amount and concentration. This allows for optimal and simplified handling and, moreover, ensures that no contamination can take place.
  • the use of a dosage unit has the advantage that the risk of water absorption by the expectorant substance can be further reduced.
  • a capsule is basically any suitable for the formulation of particulate mixtures hard or soft capsule into consideration.
  • Hard and soft capsules usually consist essentially of gelatin or other materials, such as Hydroxyp- ropylmethylcellulose (HPMC).
  • Hard capsules usually have two cylinders closed against each other, which are hemispherically closed at one end.
  • Such capsules can be filled, for example, on a large scale with the expectorant substance and the amorphous silicon dioxide in the desired amount and concentration and in compliance with appropriate hygienic and atmospheric conditions.
  • the capsules may via conventional inhalation devices such as the so-called Osmohaler ® RS are 01 Plastiape ®, is applied.
  • Osmohaler ® RS are 01 Plastiape ®
  • the inventors were able to determine that the clinical compatibility and acceptance of such a capsule preparation by the patients was optimal.
  • the particulate substance mixture consists of the expectorant substance and the amorphous silicon dioxide and optionally of an additive, in particular a filler.
  • an additive in particular a filler.
  • the particulate substance mixture is present as a medicament or medicament or pharmaceutical preparation.
  • the particulate substance mixture is a drug or medicament or a pharmaceutical preparation.
  • the invention relates to a pharmaceutical composition, preferably for use in the prophylaxis and / or treatment of an airway disorder.
  • the pharmaceutical is particularly characterized by the fact that it has a particulate mixture according to the first aspect of the invention or consists of such a particulate mixture.
  • the medicament is prepared for administration by inhalation, preferably dry inhalation.
  • the drug is used for inhalative, preferably dry inhalation, administration.
  • the medicament is prepared for capsule inhalation.
  • the drug is used for capsule inhalation.
  • the medicament may in principle be prepared for nasal or oral administration. According to the invention, it is particularly preferred if the medicament is prepared for oral administration or is used for oral administration.
  • the medicament is in the form of a powder, in particular in the form of a ground or atomized, preferably micronized, powder.
  • the medicament is particularly preferably in the form of a dry powder, in particular in the form of a ground or atomized, preferably micronized, dry powder.
  • the medicament according to the invention is preferably a medicament for use in the prophylaxis and / or treatment of an airway disorder.
  • the airway disorder may basically be an airway disorder in a human or a non-human mammal.
  • the respiratory disorder is preferably a human respiratory tract disorder or disease.
  • the respiratory tract disorder may be, in particular, a chronic respiratory disease.
  • the respiratory disorder is preferably a lung disease, in particular chronic lung disease.
  • the airways disorder is selected from the group consisting of chronic bronchitis, chronic obstructive pulmonary disease, chronic obstructive pulmonary disease (COPD), bronchial asthma, bronchiectasis, pulmonary fibrosis such as cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and pulmonary emphysema.
  • the respiratory disorder is particularly preferably chronic bronchitis, chronic obstructive bronchitis, chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF).
  • COPD chronic obstructive bronchitis
  • COPD chronic obstructive pulmonary disease
  • CF cystic fibrosis
  • a third aspect of the invention relates to a dosage unit which comprises a particulate substance mixture according to the first aspect of the invention or a medicament according to the second aspect of the invention.
  • a fourth aspect of the invention relates to a device for administering a particulate substance mixture, a drug or a dosage unit.
  • the device is characterized in particular by the fact that it comprises a particulate substance mixture according to the first aspect of the invention, a medicament according to the second aspect of the invention or a dosage unit according to the third aspect of the invention.
  • the device is preferably an inhalation device, in particular a dry inhalation device.
  • the device preferably comprises the particulate mixture or drug formulated in a capsule.
  • a suitable device for example, the above-mentioned Osmohaler ® represents.
  • the invention relates to a process for the preparation of a particulate substance mixture, in particular according to the first aspect of the invention or of a medicament, in particular according to the second aspect of the invention.
  • the method comprises the following steps: a) providing a particulate, preferably pulverulent, substance mixture comprising an expectorant substance and amorphous silicon dioxide and b) grinding or atomizing, preferably micronizing, the particulate substance mixture.
  • the invention is further based on the surprising finding that, when amorphous silicon dioxide particles are added to expectorant substance particles, agglomeration or agglomeration of the expectorant substance particles may be avoided or at least significantly slowed down before a micronization process is carried out.
  • step b) is carried out by means of spray drying or a grinding gas, in particular in an air jet mill, preferably in an opposed jet mill.
  • the substance mixture is transferred after performing step b) in a dosage unit, preferably encapsulated.
  • the expectorant substance in particular of the particulate substance mixture, the expectorant substance as well as the amorphous silicon dioxide, reference is likewise made to the statements made within the scope of the previous description in order to avoid unnecessary repetitions.
  • the embodiments described there in relation to the particulate substance mixture, the expectorant substance and the amorphous silicon dioxide also apply mutatis mutandis to the process according to the invention.
  • the salt and silicon grains were crushed by cyclone technology to form an aerosol to the desired size.
  • This cyclone produced a certain velocity at which the salt and silicon grains rotated. Based on the size of the turbulence chamber, it was first filled with a small amount of salt and silicon grains before the cyclone was started. This minimum charge was necessary to achieve optimum concentration of salt and silica in the cyclone. Too low or too high a density resulted in an insufficient particle quality. Once the cycle started, the particles were mechanically comminuted. Once the particles had reached the desired size, they were precipitated by means of the existing negative pressure in the cyclone chamber and transported out of the Micronizer. Too large particles remained in the cyclone until their decreasing weight allowed precipitation by means of negative pressure.
  • the size of the salt and silica particles could be adjusted. Cyclonic velocity and length of the Micronizer tube were other parameters that were critical to aerosol quality. The discharge amount of particles of the desired size was about 1 g / min. During this process, 1 g of salt and silicon dioxide were also actively transported per minute from a dosing system into the cyclone chamber to ensure the desired density and thus the quality of the aerosol. The Micronizer SaltPro 3K was able to continuously produce aerosol, guaranteeing delivery of around 1 g / min. 2. Formulation of the micronized powder mixture into a hard capsule
  • halotherapy For five consecutive days, the therapeutic effect of halotherapy was tested for 45 minutes on six volunteer CF patients. This took place in the facilities of the sports and bathing center Fildorado GmbH, Filderstadt, Germany. Prior to the initiation of therapy for 45 minutes, immediately thereafter, and one hour after therapy, secrolysis was examined by sputum amount, possibly increased elimination of leucocytes and Pseudomonas bacteria in sputum, and pulmonary function parameters FVC, FEV1, and MMEF. As side effects the side effects were observed. Unlike hypertonic sodium chloride therapy, no antiobstructive therapeutic such as a ⁇ -sympathomimetic was administered at the beginning of halotherapy. Patients were constantly monitored clinically and by pulse oximetry during therapy.
  • the treatment according to the invention was carried out in parallel on 15 volunteer CF patients. Each patient was added anhydrous medical sodium chloride (Sanal ® SQ), and amorphous hydrophilic silica (Aerosil ® 200 Pharma, Evonik Industries) administered ⁇ each in the form of aerosol particles having a mean particle diameter of ⁇ . 1
  • the powder mixture was provided for these purposes by the University Pharmacy of Tübingen in hard capsules (50 mg per capsule).
  • probatorisch ® Osmohaler, RS-01 Plastiape ®, Italy
  • 15 voluntary adults with two capsules with a Osmohaler left inhale.
  • the patients were also previously not premedicated with ß-sympathomimetics.
  • the reference Halotherapy showed an increase in sputum production during and after 45 minutes of therapy, as well as a significant reduction in the leucocyte count and bacterial count of Pseudomonas aeruginosa in the sputum compared to the pre-treatment period.
  • the pulmonary function parameters FVC, FEV1 and MMEF improved after five days.
  • the 15 patients treated according to the invention initially showed a readily tolerated inhalation of the administered anhydrous powder mixture (sodium chloride and amorphous, hydrophilic silicon dioxide) of a total of 100 mg. Patients were examined clinically and spirometrically before and after inhalation. Side effects such as pulmonary obstruction, increased coughing or taste intolerance did not appear. All patients showed increased sputum production.
  • the inventors were thus able to show impressively that the use of expectorant substance particles in combination with amorphous silicon dioxide particles are outstandingly suitable for the prophylaxis and / or treatment of respiratory disorders.

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Abstract

L'invention concerne un mélange particulaire, destiné à être utilisé de préférence pour la prophylaxie et/ou le traitement d'un trouble respiratoire, ce mélange comprenant une substance mucolytique et du dioxyde de silicium amorphe. L'invention concerne en outre un médicament, une unité de dosage, un dispositif d'administration d'un mélange particulaire, d'un médicament ou d'une unité de dosage, ainsi qu'un procédé de fabrication d'un mélange particulaire ou d'un médicament.
EP17783777.0A 2016-09-27 2017-09-27 Mélange particulaire, destiné à être utilisé de préférence pour la prophylaxie et/ou le traitement d'un trouble respiratoire Ceased EP3518903A1 (fr)

Applications Claiming Priority (2)

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DE102016218604.3A DE102016218604A1 (de) 2016-09-27 2016-09-27 Partikuläres Stoffgemisch, vorzugsweise zur Verwendung bei der Prophylaxe und/oder Behandlung einer Atemwegsstörung
PCT/EP2017/074513 WO2018060257A1 (fr) 2016-09-27 2017-09-27 Mélange particulaire, destiné à être utilisé de préférence pour la prophylaxie et/ou le traitement d'un trouble respiratoire

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CN109432328B (zh) * 2019-01-11 2021-10-12 首都医科大学附属北京胸科医院 一种治疗支气管扩张的中药及其制备方法

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IT1204826B (it) 1986-03-04 1989-03-10 Chiesi Farma Spa Composizioni farmaceutiche per inalazione
WO2001062264A2 (fr) 2000-02-23 2001-08-30 The Procter & Gamble Company Procede d'halotherapie
DE602004012904T2 (de) * 2004-11-18 2009-04-16 Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A. Trockenpulver mit levothyroxin-natrium mit verabreichung über einen inhalator
EP2050437A1 (fr) 2007-10-15 2009-04-22 Laboratoires SMB Compositions de poudre sèche pharmaceutiquement améliorées pour l'inhalation
EP2072042A1 (fr) 2007-12-21 2009-06-24 Lek Pharmaceuticals D.D. Ingrédient pharmaceutique actif sur support solide amorphe et avec solubilité améliorée
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CA2759041A1 (fr) * 2009-04-24 2010-10-28 Schering Corporation Preparations d'agglomerat utiles dans des inhalateurs a poudre seche
GB201102237D0 (en) 2011-02-09 2011-03-23 Kuecept Ltd Particle formulation
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CA3038414A1 (fr) 2018-04-05
US20210008090A1 (en) 2021-01-14

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