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EP2026785A1 - Formulation d'aérosol sans gaz propulseur destinée à être inhalée, contenant du bromure d'ipratropium et du sulfate de salbutamol - Google Patents

Formulation d'aérosol sans gaz propulseur destinée à être inhalée, contenant du bromure d'ipratropium et du sulfate de salbutamol

Info

Publication number
EP2026785A1
EP2026785A1 EP07728942A EP07728942A EP2026785A1 EP 2026785 A1 EP2026785 A1 EP 2026785A1 EP 07728942 A EP07728942 A EP 07728942A EP 07728942 A EP07728942 A EP 07728942A EP 2026785 A1 EP2026785 A1 EP 2026785A1
Authority
EP
European Patent Office
Prior art keywords
propellant
acid
free solution
salbutamol
formulation according
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
EP07728942A
Other languages
German (de)
English (en)
Inventor
Christel Schmelzer
Rainer Weitzel
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.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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 Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim International GmbH
Priority to EP07728942A priority Critical patent/EP2026785A1/fr
Publication of EP2026785A1 publication Critical patent/EP2026785A1/fr
Ceased legal-status Critical Current

Links

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
    • A61K31/33—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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • 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
    • 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
    • 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
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/08—Bronchodilators

Definitions

  • the present invention relates to propellant-free aerosol formulations for inhalation containing ipratropium bromide and salbutamol.
  • the present invention relates to propellant-free solution formulations for inhalation, in a solvent selected from the group consisting of water, ethanol and water-ethanol mixture, the active ingredients salbutamol, optionally in the form of its pharmacologically acceptable acid addition salts, and Ipratropium bromide and optionally further excipients, wherein the Weight ratio of salbutamol to ipratropium bromide in a range of 5: 1 to 5.5: 1.
  • solution formulations according to the invention contain no further active ingredients.
  • the weight ratio of salbutamol / ipratropium bromide is based on the mass ratio of salbutamol contained in the solution formulation to ipratropium bromide contained in the solution.
  • the salbutamol is preferably present in the formulations according to the invention in the form of one of its acid addition salts with pharmacologically acceptable acids.
  • Preferred acid addition salts of salbutamol are selected from the salts of hydrochloric, hydrobromic, nitric, sulfuric and phosphoric acids.
  • Particularly preferred according to the invention is the salbutamol in the form of its
  • Sulfuric acid addition salt used in the formulations of the invention. If appropriate, this acid addition salt is also referred to as salbutamol sulphate in the context of the present invention.
  • the ipratropium bromide can be used in the preparation of the formulations according to the invention in anhydrous form or else in the form of one of its hydrates, preferably in the form of its monohydrate.
  • the pharmaceutical formulations according to the invention contain as solvent pure water, pure ethanol or mixtures of ethanol and water. If ethanol-water mixtures are used, the percentage by weight of ethanol in these mixtures is preferably in the range between 5 and 99% ethanol, especially preferably in the range of 10 to 96% ethanol. Very particularly preferred pharmaceutical formulations for the purposes of the present invention contain as solvent pure water, pure ethanol or ethanol-water mixtures containing between 50 and 92%, more preferably between 69 and 91% ethanol.
  • other co-solvents can be used in addition to ethanol and water. These are preferably selected from the group of alcohols or ethers, such as isopropanol or tetrahydrofuran. According to the invention, however, a further solvent is not used.
  • compositions which are particularly preferred according to the invention contain exclusively water as solvent.
  • the formulations according to the invention usually contain pharmacologically acceptable acids for adjusting the pH.
  • the pH of the formulation according to the invention is preferably in the range from 3.0 to 4.0, preferably from 3.1 to 3.7, particularly preferably from 3.3 to 3.5.
  • Particularly preferred solution formulations have a pH of 3.4.
  • inorganic or organic acids can be used as pharmacologically acceptable acids for adjusting the pH.
  • preferred inorganic acids are selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
  • particularly suitable organic acids are selected from the group consisting of ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid.
  • Preferred inorganic acids are hydrochloric acid and sulfuric acid, wherein the hydrochloric acid is of particular importance according to the invention.
  • ascorbic acid, fumaric acid and citric acid are preferred, with citric acid being particularly preferred according to the invention.
  • mixtures of said acids can be used, especially in cases of acids, in addition to their
  • Acidification properties also other properties, e.g. as flavorants or antioxidants, such as citric acid or ascorbic acid.
  • pharmacologically acceptable bases for accurate titration of the pH can be used.
  • Suitable bases are, for example Alkali hydroxides and alkali carbonates. Preferred alkali ion is sodium. If such bases are used, care must be taken that the resulting salts, which are then present in the finished pharmaceutical formulation, are also pharmacologically acceptable with the abovementioned acid.
  • auxiliaries which may optionally be present in the solutions according to the invention in addition to the active ingredients salbutamol and ipratropium bromide are, in particular and according to the invention, preferably preservatives and complexing agents.
  • complexing agents are understood to mean molecules capable of complexing. Cations, more preferably metallic cations, are preferably to be complexed by these compounds.
  • the formulations according to the invention contain as complexing agents preferably editic acid (EDTA) or a known salt thereof, e.g. Sodium EDTA, or disodium EDTA. Preference is given to using disodium edetate, if appropriate in the form of its hydrates, particularly preferably in the form of its dihydrate.
  • the content of disodium edetate is preferably in a range from 0 to 100 mg per 100 g, more preferably in a range from 5 to 70 mg per 100 g of the formulation according to the invention.
  • the formulations according to the invention preferably contain a complexing agent, more preferably disodium edetates in an amount of about 40 to 60 mg per 100 g, more preferably from about 45 to 55 mg per 100 g, especially preferably about 50 mg per 100 g of the formulation according to the invention.
  • Preservatives may be used to protect the formulation from contamination by germs. Suitable preservatives are those known in the art, in particular benzalkonium chloride, cetylpyridinium chloride or benzoic acid or benzoates such as sodium benzoate in those known from the prior art Concentrations.
  • benzalkonium chloride is added.
  • the amount of benzalkonium chloride is between 1 mg and 50 mg per 100 g formulation, preferably about 2 to 15 mg per 100 g, more preferably about 3 to 12 mg per 100 g, more preferably about 10 mg per 100 g of the formulation of the invention.
  • Benzalkonium chloride can also be used according to the invention in admixture with other preservatives.
  • ipratropium bromide is usually contained in an amount of 125-200 mg per 100 g of solution.
  • the formulations according to the invention preferably contain the active ingredient ipratropium bromide in an amount of 150-190 mg per 100 g solution, more preferably in an amount of 160-180 mg per 100 g solution. From these quantities, the corresponding amounts of inventively particularly preferred Ipratropium bromide monohydrate can be readily calculated by one skilled in the art.
  • compositions according to the invention contain, in addition to the abovementioned amounts of ipratropium bromide, an amount of salbutamol such that the weight ratio of salbutamol to ipratropium bromide ranges from 5.1: 1 to 5.4: 1.
  • the weight ratio of salbutamol to ipratropium bromide is in a range from 5.2: 1 to 5.3: 1.
  • compositions according to the invention contain per 100 g of solution 160-190 mg, preferably 170-180 mg of ipratropium bromide monohydrate and 900-1200 mg, preferably 1000-1100 mg of salbutamol sulphate.
  • a further aspect of the present invention relates to the use of the pharmaceutical formulations according to the invention for the preparation of a medicament for the treatment of respiratory diseases selected from the group consisting of obstructive pulmonary diseases of different origin, pulmonary emphysema of different origin, restrictive lung diseases, interstitial lung diseases, cystic fibrosis, bronchitis of different origin , Bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.
  • respiratory diseases selected from the group consisting of obstructive pulmonary diseases of different origin, pulmonary emphysema of different origin, restrictive lung diseases, interstitial lung diseases, cystic fibrosis, bronchitis of different origin , Bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary edema.
  • the above-mentioned use is for the manufacture of a medicament for the treatment of obstructive lung diseases selected from the group consisting of bronchial asthma, pediatric asthma, severe asthma, acute asthma attack, chronic bronchitis, and chronic obstructive pulmonary disease (COPD) for the preparation of a medicament for the treatment of asthma bronchial or COPD according to the invention is particularly preferred.
  • obstructive lung diseases selected from the group consisting of bronchial asthma, pediatric asthma, severe asthma, acute asthma attack, chronic bronchitis, and chronic obstructive pulmonary disease (COPD) for the preparation of a medicament for the treatment of asthma bronchial or COPD according to the invention is particularly preferred.
  • COPD chronic obstructive pulmonary disease
  • compositions according to the invention for the manufacture of a medicament for the treatment of emphysema of the lungs originating in COPD (chronic obstructive pulmonary disease) or ⁇ l-proteinase inhibitor deficiency.
  • restrictive lung diseases selected from the group consisting of allergic alveolitis, restrictive pulmonary diseases induced by occupational noxae, such as asbestosis or silicosis and restriction due to lung tumors such as lymphangiosis carcinomatosa. brochoalveolar carcinoma and lymphomas.
  • interstitial lung diseases which are selected from the group consisting of infectious pneumonias, such as due to infection with viruses, bacteria, fungi, protozoa, helminths or other pathogens, pneumonitis due to different causes such as aspiration and left ventricular failure, radiation-induced pneumonitis or fibrosis, collagenoses such as lupus erythematosus, sytemic scleroderma or sarcoidosis, granulomatosis such as Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).
  • infectious pneumonias such as due to infection with viruses, bacteria, fungi, protozoa, helminths or other pathogens
  • pneumonitis due to different causes such as aspiration and left ventricular failure
  • radiation-induced pneumonitis or fibrosis such as lupus erythematosus, sytemic scleroderma or sarcoidos
  • compositions according to the invention for the production of a medicament for the treatment of cystic fibrosis or cystic fibrosis.
  • bronchitis such as Bronchitis due to bacterial or viral infection, Allergic bronchitis and Toxic bronchitis.
  • ARDS adult respiratory distress syndrome
  • the pharmaceutical formulations according to the invention for the manufacture of a medicament for the treatment of pulmonary edema, for example toxic pulmonary edema after aspiration or inhalation of toxic substances and foreign substances.
  • the present invention relates to the use of the pharmaceutical formulations of the invention for the manufacture of a medicament for the treatment of asthma or COPD.
  • a medicament for the treatment of asthma or COPD Of particular importance is also the above-mentioned use for the preparation of a medicament for the treatment of inflammatory and obstructive airway diseases, particularly preferably asthma or COPD, several times a day, preferably three to four times daily.
  • the present invention relates to a method for the treatment of the abovementioned diseases, characterized in that one or more of the abovementioned pharmaceutical formulations according to the invention are administered in therapeutically effective amounts.
  • the present invention furthermore relates to the use of the abovementioned pharmaceutical formulations for the preparation of a medicament for the treatment of one of the abovementioned disorders, in particular asthma or COPD, characterized in that about 5 to 25 ⁇ l (microliter), preferably about 7 to 20 ⁇ l, per drug administration the solutions of the invention are applied.
  • Particularly preferred is the use of the abovementioned pharmaceutical formulations for the preparation of a medicament for the treatment of one of the abovementioned disorders, in particular of asthma or COPD, characterized in that per drug administration about 10 to 13 ul of the solutions according to the invention are administered.
  • the use of the abovementioned pharmaceutical formulations for the preparation of a medicament for the treatment of one of the abovementioned diseases, in particular asthma or COPD characterized in that the abovementioned amounts of solution are administered once to twice per application, the single application per application is particularly preferred according to the invention.
  • the use of the abovementioned pharmaceutical formulations for the preparation of a medicament for the treatment of one of the abovementioned disorders, in particular asthma or COPD characterized in that the abovementioned drug administration at least once daily, once or twice, preferably once per application, preferably at least twice daily, more preferably three to four times daily.
  • the present invention further relates to a method for the treatment of one of the abovementioned disorders, in particular asthma or COPD, characterized in that about 5 to 25 .mu.l (microliters), preferably about 7 to 20 .mu.l of the solutions according to the invention are administered per drug administration.
  • a method for treating one of the abovementioned disorders, in particular asthma or COPD in which about 10 to 13 .mu.l of the solutions according to the invention are administered per drug administration.
  • a method for the treatment of one of the abovementioned disorders is particularly preferred in that the abovementioned amounts of solution are administered once to twice per application, the single application per application being particularly preferred according to the invention.
  • a method for the treatment of one of the abovementioned disorders is particularly preferred, characterized in that the abovementioned, once or twice, preferably once per application taking place drug delivery at least once a day, preferably at least twice daily, more preferably three to four times daily.
  • the formulations according to the invention can be inhaled perorally or pernasally.
  • a liquid, dispensing with propellant gases, formulation by means of suitable inhalers offers.
  • the inhalative administration of such a formulation can be carried out both orally and nasally.
  • Particularly suitable are those inhalers which can nebulise a small amount of a liquid formulation in the therapeutically necessary dosage within a few seconds in a therapeutically inhalation suitable aerosol.
  • Such a device for the propellant-free administration of a metered quantity of a liquid medicament for inhalation use is described in detail, for example, in International Patent Application WO 91/14468 as well as in WO 97/12687 (there Figures 6a and 6b and the associated description).
  • a drug solution is transferred by means of high pressure of up to 600 bar into a respirable aerosol and sprayed.
  • the solution formulations are stored in a reservoir. It is necessary that the active substance formulations used have a sufficient storage stability and at the same time are such that they can be applied directly for the medical purpose as far as possible without further manipulation. Furthermore, they must not contain components which may interact with the inhaler in such a way that the inhaler or the pharmaceutical grade of the solution or of the aerosol produced could be damaged.
  • a special nozzle is used, as described, for example, WO 94/07607 or WO 99/16530. Both are hereby incorporated by reference.
  • the invention Drug formulations must also have sufficient pharmaceutical quality, ie they should be pharmaceutically stable over a storage period of a few years, preferably at least one year, more preferably two years.
  • These propellant-free solution formulations must also be able to be atomized under pressure by means of an inhaler, wherein the mass discharged in the generated aerosol is reproducibly within a defined range.
  • the medicament formulations according to the invention are preferably used in an inhaler of the type described above in order to produce therefrom the propellant-free aerosols according to the invention. For this reason, reference should again be made expressly to the patent documents described at the outset, to which reference is hereby incorporated by reference.
  • WO 97/12687 a further developed embodiment of the preferred inhaler is disclosed in WO 97/12687 (see there in particular FIGS. 6a and 6b and the relevant parts of the description).
  • This nebuliser (Respimat ®) can advantageously be used to produce the inhalable aerosols according to the invention. Due to its cylindrical shape and a handy size of less than 9 to 15 cm in length and 2 to 4 cm in width, this device can always be carried by the patient. The nebulizer sprays a defined volume of
  • the preferred atomizer consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing, a spring and a reservoir, characterized by a pump housing which is fixed in the upper housing part, and at its one end a nozzle body with the nozzle or nozzle arrangement carries, a hollow piston with valve body, - a Abretesfiansch, in which the hollow piston is fixed, and located in the
  • Upper housing part is located, a locking body, which is located in the upper housing part, a spring housing with the spring therein, which is rotatably mounted on the upper housing part by means of a pivot bearing, - a lower housing part, which is attached to the spring housing in the axial direction.
  • the hollow piston with valve body corresponds to a disclosed in WO 97/12687 devices. It partially protrudes into the cylinder of the pump housing and is arranged axially displaceably in the cylinder.
  • FIGS. 1-4 in particular FIG. 3, and the associated parts of the description of the abovementioned International Patent Application.
  • the hollow piston with valve body exerts on its high pressure side at the time of release of the spring a pressure of 5 to 60 MPa (about 50 to 600 bar), preferably 10 to 60 MPa (about 100 to 600 bar) on the fluid, the measured Wirkstoffiösung. Volumes of from 10 to 50 microliters are preferred, volumes of from 10 to 20 microliters are particularly preferred, and a volume of from 10 to 15 microliters per stroke is very particularly preferred.
  • the valve body is preferably attached to the end of the hollow piston, which faces the nozzle body.
  • the nozzle in the nozzle body is preferably microstructured, i. produced by microtechnology.
  • Microstructured nozzle bodies are disclosed, for example, in WO-99/16530; This document is hereby incorporated by reference, in particular to the figure 1 and its description disclosed therein.
  • the nozzle body consists e.g. of two fixed plates of glass and / or silicon, at least one plate of which has one or more microstructured channels connecting the nozzle inlet side to the nozzle outlet side.
  • On the nozzle outlet side is at least one round or non-round aperture of 2 to 10 micrometers in depth and 5 to 15 micrometers in width, the depth being preferably 4.5 to 6.5 micrometers and the length 7 to 9 micrometers.
  • the jet directions of the nozzles in the nozzle body can be parallel to one another or they are inclined towards one another in the direction of the nozzle opening.
  • the jet directions may be inclined at an angle of 20 degrees to 160 degrees to each other, preferably an angle of 60 to 150 degrees, particularly preferably 80 to 100 °.
  • the nozzle orifices are preferably located at a distance of 10 to 200 microns, more preferably at a distance of 10 to 100 microns, more preferably 30 to 70 microns. Most preferred are 50 microns.
  • the jet directions accordingly meet in the vicinity of the nozzle openings.
  • the liquid pharmaceutical formulation meets the nozzle body with an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized via the nozzle openings into an inhalable aerosol.
  • the preferred particle sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.
  • the locking mechanism includes a spring, preferably a cylindrical helical compression spring, as a memory for the mechanical energy.
  • the spring acts on the output flange as a jump piece whose movement is determined by the position of a locking member.
  • the path of the output flange is precisely limited by an upper and a lower stop.
  • the spring is preferably transmitted via a force translating gear, e.g. a fferschubgetriebe, stretched by an external torque that is generated when turning the upper housing part against the spring housing in the lower housing part.
  • the upper housing part and the output flange contain a single or multi-start wedge gear.
  • the locking member with engaging locking surfaces is arranged annularly around the output flange.
  • the ring is arranged in a plane perpendicular to the atomizer axis. After tensioning the spring, the locking surfaces of the locking member push in the path of the output flange and prevent the relaxation of the spring.
  • the Sprerrglied is triggered by a button.
  • the release button is connected or coupled to the locking member.
  • the shutter button is parallel to the ring plane, and preferably in the atomizer, moved; while the deformable ring is deformed in the ring plane. Constructive details of the locking mechanism are described in WO 97/20590.
  • the lower housing part is pushed in the axial direction over the spring housing and covers the storage, the drive of the spindle and the reservoir for the fluid.
  • the upper housing part When actuating the atomizer, the upper housing part is rotated against the lower housing part, wherein the lower housing part entrains the spring housing.
  • the spring is compressed and tensioned via the screw slide, and the lock engages automatically.
  • the angle of rotation is preferably an integer fraction of 360 degrees, for example 180 degrees.
  • the driven part Simultaneously with the tensioning of the spring, the driven part is in Housing upper part shifted by a predetermined path, the hollow piston is withdrawn within the cylinder in the pump housing, whereby a subset of the fluid from the reservoir is sucked into the high-pressure chamber in front of the nozzle.
  • the storage container contains the aerosol preparation according to the invention.
  • the sputtering process is initiated by lightly pressing the shutter button.
  • the blocking mechanism clears the way for the stripping section.
  • the tensioned spring pushes the piston into the cylinder of the pump housing.
  • the fluid exits the nozzle of the atomizer in atomized form.
  • the components of the atomizer are made of a functionally suitable material.
  • the housing of the atomizer and, as far as the function permits, other parts are preferably made of plastic, e.g. by injection molding. Physiologically harmless materials are used for medical purposes.
  • FIGS. 6 a / b of WO 97/12687 describe the nebuliser (Respimat®) with which the aqueous aerosol preparations according to the invention can advantageously be inhaled.
  • FIG. 6 a shows a longitudinal section through the atomizer with the spring tensioned
  • FIG. 6 b shows a longitudinal section through the atomizer with the spring relaxed.
  • the upper housing part (51) contains the pump housing (52), at the end of which the holder (53) for the atomizer nozzle is mounted. In the holder is the nozzle body (54) and a filter (55).
  • the hollow piston (57) fastened in the output flange (56) of the locking mechanism projects partially into the cylinder of the pump housing. At its end, the hollow piston carries the valve body (58).
  • the hollow piston is sealed by means of the seal (59).
  • the stop (60) on which the output flange rests with a relaxed spring.
  • the stop (61) On which the output flange rests when the spring is tensioned.
  • the locking member (62) slides between the stop (61) and a Support (63) in the upper part of the housing.
  • the release button (64) is in communication with the locking member.
  • the upper housing part ends in the mouthpiece (65) and is closed with the attachable protective cap (66).
  • the spring housing (67) with compression spring (68) is rotatably supported by means of the snap lugs (69) and pivot bearing on the upper housing part.
  • the lower housing part (70) is pushed.
  • the replaceable reservoir (71) for the fluid (72) to be atomized is closed with the stopper (73) through which the hollow piston protrudes into the reservoir and with its end immersed in the fluid (stock of drug solution).
  • the spindle (74) for the mechanical counter is mounted in the lateral surface of the spring housing.
  • the drive pinion (75) At the end of the spindle, which faces the upper housing part, there is the drive pinion (75). The rider (76) sits on the spindle.
  • the nebulizer described above is suitable for nebulizing the aerosol preparations according to the invention to form an aerosol suitable for inhalation.
  • the mass expelled in at least 97%, preferably at least 98% of all actuations of the inhaler (puffs) a defined quantity with a tolerance of not more than 25%, preferably from 20 % of this amount.
  • a defined quantity with a tolerance of not more than 25%, preferably from 20 % of this amount.
  • between 5 and 30 mg of formulation per stroke are applied as a defined mass, more preferably between 5 and 20 mg.
  • the formulation according to the invention can also be nebulized by means of inhalers other than those described above, for example jet stream inhalers.
  • the present invention further relates to an inhalation kit consisting of one of the pharmaceutical preparations according to the invention described above and an inhaler suitable for the nebulization of this pharmaceutical formulation.
  • the present invention preferably relates to an inhalation kit consisting of one of the pharmaceutical preparations according to the invention the inhaler described above and the Respimat ® described above.
  • Pure water is placed in a container and mixed with stirring at room temperature with ipratropium bromide monohyrate, salbutamol sulphate, benzalkonium chloride (anhydrous) and disodium edetate dihydrate.
  • the amounts of the constituents used in each case result from the formulation constituents explained below.
  • the resulting solution is adjusted to a pH of 3.4 with 1N aqueous hydrochloric acid.

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Abstract

La présente invention concerne des formulations d'aérosol sans gaz propulseur destinées à être inhalées, contenant du bromure d'ipratropium et du salbutamol.
EP07728942A 2006-05-19 2007-05-09 Formulation d'aérosol sans gaz propulseur destinée à être inhalée, contenant du bromure d'ipratropium et du sulfate de salbutamol Ceased EP2026785A1 (fr)

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Application Number Priority Date Filing Date Title
EP07728942A EP2026785A1 (fr) 2006-05-19 2007-05-09 Formulation d'aérosol sans gaz propulseur destinée à être inhalée, contenant du bromure d'ipratropium et du sulfate de salbutamol

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP06114260 2006-05-19
EP06118115 2006-07-28
PCT/EP2007/054490 WO2007134967A1 (fr) 2006-05-19 2007-05-09 Formulation d'aérosol sans gaz propulseur destinée à être inhalée, contenant du bromure d'ipratropium et du sulfate de salbutamol
EP07728942A EP2026785A1 (fr) 2006-05-19 2007-05-09 Formulation d'aérosol sans gaz propulseur destinée à être inhalée, contenant du bromure d'ipratropium et du sulfate de salbutamol

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EP2026785A1 true EP2026785A1 (fr) 2009-02-25

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EP (1) EP2026785A1 (fr)
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JP2009537475A (ja) 2009-10-29
US20140228397A1 (en) 2014-08-14
US9238031B2 (en) 2016-01-19
CA2652699A1 (fr) 2007-11-29
CA2652699C (fr) 2014-11-04
WO2007134967A1 (fr) 2007-11-29
JP5317961B2 (ja) 2013-10-16
US20150306087A1 (en) 2015-10-29
US20100056559A1 (en) 2010-03-04

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