EP2094245A2 - Formulation poudreuse stable contenant un nouvel anticholinergique - Google Patents

Formulation poudreuse stable contenant un nouvel anticholinergique

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Publication number
EP2094245A2
EP2094245A2 EP07822237A EP07822237A EP2094245A2 EP 2094245 A2 EP2094245 A2 EP 2094245A2 EP 07822237 A EP07822237 A EP 07822237A EP 07822237 A EP07822237 A EP 07822237A EP 2094245 A2 EP2094245 A2 EP 2094245A2
Authority
EP
European Patent Office
Prior art keywords
acid
group
spray
powder formulation
salt
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.)
Withdrawn
Application number
EP07822237A
Other languages
German (de)
English (en)
Inventor
Michael Trunk
Claudius Weiler
Werner Pieroth
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
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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 filed Critical Boehringer Ingelheim International GmbH
Priority to EP07822237A priority Critical patent/EP2094245A2/fr
Publication of EP2094245A2 publication Critical patent/EP2094245A2/fr
Withdrawn legal-status Critical Current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
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a spray-dried powder formulation comprising particles which contain the following components i) to iii): i) anticholinergics, in particular at least one compound of formula 1
  • R and R ' are each hydrogen or together form a group selected from a single bond, -CH 2 - and -O-, and wherein
  • X ⁇ means a negatively charged anion
  • an organic, physiologically harmless, sterically demanding acid selected from the group consisting of ascorbic acid, a fruit or edible acid, preferably citric acid, tartaric acid, malic acid, lactic acid, acetic acid, ⁇ -hydroxycaprylic acid or gluconic acid, and a mono-, di- or trihydric carboxylic acid, preferably fumaric acid, oxalic acid, succinic acid or a sterically demanding amino acid.
  • a a group is selected from
  • R and R ' are each hydrogen or together form a group selected from a single bond, -CH 2 - and -O-, and wherein
  • Suitable powder formulations containing at least one compound of formula 1 must meet various requirements:
  • the powder formulations must contain particles that are "inhalable”, i. the particles must have a relatively small mean diameter, preferably .30 ⁇ m, to be still “respirable”, i. to enable a topical application in the lungs
  • the powder formulation must have sufficient stability over a longer period of time when stored at room temperature
  • the mean geometric diameter of particles can be determined experimentally, for example, by a laser diffraction method with a laser from Sympatec (50 mm focal length) in the case of dry dispersion (Rodos 3 bar).
  • micronized powder formulations containing a compound according to formula 1 as active ingredient usually after a short time under the action of moisture on a particle growth, so that the particles are then only conditionally "respirable".
  • a spray-dried powder formulation comprising particles which contain the following components i) to iii): i) an anticholinergic, preferably a compound of formula 1.
  • a a group is selected from
  • R and R 1 are each hydrogen or together form a group selected from a single bond, -CH 2 - and -O-, and wherein
  • X denotes a negatively charged Anton, ii) at least one embedding material selected from the group consisting of mono- or disaccharides, oligosaccharides, polymers, sugar alcohols and cholesterol, and
  • an organic, physiologically acceptable, sterically demanding acid selected from the group consisting of ascorbic acid, a fruit or edible acid, preferably citric acid, tartaric acid, malic acid, lactic acid, acetic acid, ⁇ -hydroxycaprylic acid or gluconic acid, and one-, two- or trivalent carboxylic acid, preferably fumaric acid, oxalic acid, succinic acid or a sterically demanding amino acid
  • the stabilizing effect of the organic, physiologically harmless, sterically demanding acid preferably selected from ascorbic acid, a fruit or edible acid, more preferably citric acid, tartaric acid, malic acid, lactic acid, acetic acid, ⁇ -hydroxycaprylic acid or gluconic acid, and a mono-, di- or tri-valent carboxylic acid, more preferably fumaric acid, oxalic acid, succinic acid or a sterically demanding amino acid, on the anticholinergic, preferably on the compound of formula 1 causes.
  • the powder molding according to the invention has inhalable, ie respirable particles sizes and also a homogeneous distribution of the compound of formula 1 in the particles.
  • the powder formulation according to the invention fulfills all the requirements which a powder formulation containing a compound of formula 1 must fulfill as an active ingredient.
  • the spray-dried powder formulation according to the invention contains as organic, physiologically harmless, sterically demanding acid according to iii) preferably an acid selected from ascorbic acid, a mono-, di- or trihydric carboxylic acid and a fruit acid or edible acid.
  • a mono-, di- or trihydric carboxylic acid in the context of the invention is understood as meaning C 2 -C 10, preferably C 3 -C 6 -carboxylic acids having in each case one, two or three carboxyl groups, fumaric acid, oxalic acid, succinic acid, Citric acid, tartaric acid, malic acid, lactic acid, acetic acid, ⁇ -hydroxycaprylic acid, gluconic acid and sterically demanding amino acids are preferred, citric acid is particularly preferred.
  • the spray-dried powder formulation according to iii) particularly preferably contains citric acid in the concentration which is necessary in order to obtain the ready-to-spray solution containing the anticholinergic according to i), preferably a compound according to formula% and the at least one embedding material, as organic, physiologically harmless, sterically demanding acid ii) to impart a pH of ⁇ 7, preferably of ⁇ 6, more preferably of ⁇ 5, especially of ⁇ 4.
  • the spray-dried powder formulation according to the invention additionally contains the salt of an organic, physiologically acceptable, sterically demanding acid, preferably selected from the group consisting of ascorbate, the salt of a fruit or edible acid, preferably citrate, tartrate, malate, lactate, acetate , ⁇ -hydroxycapronate or gluconate and the salt of a mono-, di- or trihydric carboxylic acid, preferably fumarate, oxalate, succinate or the salt of a sterically demanding amino acid. Citrate is particularly preferred here.
  • This additional salt of an organic, physiologically harmless, sterically demanding acid is preferably an alkali metal salt, an alkaline earth metal salt or a zinc salt, preferably an alkali metal citrate, an alkaline earth metal citrate or a Zinkeitrat, particularly preferably sodium citrate, potassium citrate, magnesium citrate, calcium citrate or Zinkeitrat.
  • the additional salt of an organic, physiologically harmless, sterically demanding acid selected from the group consisting of ascorbate, the salt of a fruit or pleasure acid, preferably citrate, tartrate, malate, lactate, acetate, ⁇ -hydroxycapronate or gluconate and the salt of a , di- or trivalent carboxylic acid, preferably fumarate, oxalate, succinate or a sterically demanding amino acid, is preferably used here in the concentration such that a mono- or trivalent lares ratio of the anticholinergic to i), preferably the compound of formula 1, to the cation of the salt of 1: 1 to 1:12, preferably from 1: 2 to 1:10 and in particular from 1: 3 to 1: 8 results.
  • an organic, physiologically harmless, sterically demanding acid selected from the group consisting of ascorbate, the salt of a fruit or pleasure acid, preferably citrate, tartrate, malate, lactate, acetate, ⁇ -hydroxycapronate or gluconate and
  • the spray-dried powder formulation according to the invention preferably comprises a compound of formula 1 wherein X "'is an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, Succinate, benzoate and p-toluenesulfonate, especially bromide.
  • X "' is an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, Succinate, benzoate and p-toluenesulfonate, especially bromide.
  • the spray-dried powder formulation comprises a compound according to formula I according to i) wherein in the compound of formula 1 according to i) A
  • the spray-dried powder formulation comprises a compound according to formula i according to i) wherein in the compound of formula 1 according to i) A
  • the spray-dried powder formulation comprises a compound of formula 1 according to i) wherein in the compound of formula I according to i) A
  • the spray-dried powder formulation comprises as embedding material ii) an oligosaccharide selected from the group oligomaltose, oligofructose, cyclodextrins, dextranes, dextrins (eg cyclodextrins such as, for example, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, methyl ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin) and oligosaccharose.
  • an oligosaccharide selected from the group oligomaltose, oligofructose, cyclodextrins, dextranes, dextrins (eg cyclodextrins such as, for example, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, methyl ⁇ -cyclodext
  • the spray-dried powder formulation comprises as embedding material ii) a polymer selected from the group inulin, alginate, maltodextrin, starch, starch derivatives, cellulose, cellulose derivatives, PVP (Plasdone), gelatin, chitosan, dextrans, pectins, gum arabic , Polylactides, poly (lactide-co-glycolides) and polyvinyl alcohols.
  • a polymer selected from the group inulin, alginate, maltodextrin, starch, starch derivatives, cellulose, cellulose derivatives, PVP (Plasdone), gelatin, chitosan, dextrans, pectins, gum arabic , Polylactides, poly (lactide-co-glycolides) and polyvinyl alcohols.
  • the spray-dried powder formulation comprises as embedding material ii) a sugar alcohol selected from the group mannitol, xylitol and sorbitol.
  • the spray-dried powder formulation comprises as embedding material ii) cholesterol.
  • the spray-dried powder formulation according to the invention comprises, in addition to the constituents i) to iii), also further physiologically acceptable auxiliaries.
  • suitable physiologically acceptable auxiliaries which can be used to prepare the spray-dried powder formulations according to the invention are salts, for example sodium chloride, chloride, potassium chloride etc., especially but not exclusively in the form of their hydrates, complexing agents, flavorings, preservatives and vitamins.
  • the spray-dried powder formulation according to the invention comprises particles which have a mean aerodynamic diameter of ⁇ 15 .mu.m, preferably of .ltoreq.10 .mu.m, in particular of ⁇ 5 .mu.m.
  • Particularly preferred are spray-dried powder formulations according to the invention which contain particles which are "inhalable”.
  • “Inhalable particles” or “respirable particles” in the context of the present invention mean that these particles have a mean aerodynamic diameter which is small enough to achieve topical application in the lung. This is particularly the case when the particles have a mean aerodynamic diameter ⁇ 10 microns.
  • Cascade impactor method can be determined experimentally, which is described in the European Pharmacopeia, Supplement 2000 for the determination of MMAD.
  • the inhalable powders according to the invention can be administered, for example, by means of inhalers which dose a single dose from a supply by means of a measuring chamber (for example according to US 4570630A) or via other apparatuses (for example according to DE 36 25 685 A).
  • a measuring chamber for example according to US 4570630A
  • other apparatuses for example according to DE 36 25 685 A.
  • the inhalable powders according to the invention can also be applied by means of inhalers which contain the inhalable powder in a plurality of individually packaged doses (Pre-Metered Dry Powder Inhaler).
  • the several, individually packaged cans can in this case in the form of a multi-dose blister and in particular in the form of a circular disk arranged in a circular Wells can accommodate multiple single powder doses may be present.
  • the plurality of individually packaged cans may also be arranged in the form of a blister strip.
  • the inhalable powders according to the invention can also be filled into capsules which are used in inhalers as described, for example, in WO 94/28958.
  • This inhaler is characterized by a housing 1, comprising two windows 2, a deck 3, in which there are air inlet openings and which is provided with a strainer 5 fastened by means of a sieve housing 4, an inhalation chamber 6 connected to the deck 3, at which one with two grounded needles 7, provided against a spring 8 movable pusher 9 is provided, a hinged via an axis 10 with the housing 1, the deck 3 and a cap 11 mouthpiece 12, and air passage holes 13 for adjusting the flow resistance.
  • the powder formulation according to the invention is used in an inhaler according to US Pat. No. 5,590,645.
  • US 5,590,645 is hereby incorporated by reference.
  • US 5590645 describes an inhalation device for use in drug packaging in which at least one container for a pharmaceutical powder composition is defined by two peelable papers.
  • the powder formulation according to the invention is used in an inhaler according to US 4,627,432.
  • WO 95/16483 describes an inhaler for dispensing cans of a pharmaceutical powder composition
  • a pharmaceutical powder composition comprising a housing with a cylindrical container.
  • the container has several helically arranged compartments, all of which harbor a dose of the pharmaceutical composition.
  • this compartment must be placed in the airway of the inhaler by means of an indexing mechanism and the user sucks on the mouthpiece of the housing, which mouthpiece communicates with the air outlet of the airway. The airflow through the airway releases the single dose of material.
  • the container can represent a replaceable cartridge.
  • the powder formulation according to the invention is used in an inhaler according to WO 95/31238.
  • WO 95/31238 is hereby incorporated by reference.
  • WO 95/31238 describes a unit dose inhaler of a pharmaceutical powder composition having a housing for receiving a container, the container containing a plurality of sealed openings containing individually encapsulated doses of a medicament.
  • the container may be moved relative to the housing to sequentially place each opening in the airway communicating with the mouthpiece.
  • the inhaler contains a lancing device, e.g. a bolt that can be inserted into a selected opening to break the corresponding seal. The configuration and movement of the bolt are coordinated so that almost no powder is expelled during this process.
  • the powder formulation according to the invention is used in an inhaler according to WO 02/26302.
  • WO 02/26302 hereby incorporated by reference.
  • WO 02/26302 describes an inhaler for There would be single doses of a pharmaceutical powder composition having an airway through which the dose travels from an ejection zone to the outlet of the airway.
  • the airway has an inlet device arranged to form an air pocket that flows through a portion of the airway and expands from the ejection zone to the outlet.
  • the air pocket surrounds said dose preventing it from impacting the walls of the airway. This reduces the accumulation of material on the walls of the airway and thereby improves the consistency of the inkerator performance.
  • the inlet device includes a throat for producing a flow of rapidly flowing air, thereby forming a zone of low pressure in front of the ejection zone, which facilitates the ejection of the dose.
  • the powder formulation according to the invention is used in an inhaler according to WO 05/002654.
  • WO 05/002654 is hereby incorporated by reference.
  • WO 05/002654 describes an inhaler for dispensing individual individual doses of a pharmaceutical powder composition from corresponding pockets of a disc-shaped carrier by the destruction of a cover foil from the outside by pressure on the opposite surface.
  • the inhaler has correspondingly individual disaggregation accesses to each pocket, split air streams allowing for improved influx of the pharmaceutical composition, a switching mechanism for the external destruction of the pockets and a meter for the individual cans.
  • the invention further relates to a process for the preparation of a powder formulation containing particles, comprising the following steps:
  • a a group is selected from
  • R and R ' are each hydrogen or together form a group selected from a single bond, -CH 2 - and -O-, and wherein
  • step b) atomizing the solution from step a) in a hot air stream c) drying the atomized solution from step b) to form a powder containing particles.
  • step a) a solution of components i) to iii) is provided in a suitable solvent.
  • X preferably denotes an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-butadiene. Toluene sulfonate, especially bromide.
  • a solution comprising a compound of formula 1 according to i) is provided in step a), wherein in the compound of formula 1 according to i) A
  • R and R ' are each hydrogen.
  • R and R 1 together form a single bond.
  • a mono-, di- or trivalent carboxylic acid are C 2 - to C 10 -, preferably understood C 3 to C e -carboxylic acids, each with a, xyl phenomenon two or three carbonyl, wherein fumaric acid, oxalic acid, succinic acid Citric acid, tartaric acid, malic acid, lactic acid, acetic acid, ⁇ -hydroxycaprylic acid, gluconic acid or sterically demanding amino acids are preferred, citric acid is particularly preferred.
  • the ratio of the organic, physiologically harmless, sterically demanding acid, preferably citric acid, to the salt of the organic, physiologically harmless, sterically demanding acid, preferably citrate, in the solution adjusted such that the solution prepared in step a) containing an anticholinergic after i), preferably a compound according to formula 1 and at least one embedding material according to ii) has a pH of ⁇ 7, preferably of ⁇ 6, more preferably of ⁇ 5, in particular of ⁇ 4.
  • solvent water, any suitable organic solvent, a water / organ. Solvent mixture and a mixture of different organic solvents are used. Preference is given to the use of water, ethanol and an ethanol / water mixture as solvent.
  • the sputtering of the solution from step a) in step b) takes place by means of a nozzle.
  • This nozzle is preferably operated by liquid pressure or compressed air or inert gas.
  • the atomization pressure is chosen such that droplet sizes in the range of ⁇ 20 microns arise.
  • the droplet sizes of the atomized solution can be determined experimentally, for example, by means of a laser diffraction method with a laser from Sympatec (50 mm focal length, Mie evaluation).
  • the hot air stream from step b) has temperatures between 100 and 350 ° C., in particular between 120 and 200 ° C.
  • spray-dried particles having a mean aerodynamic diameter of ⁇ 15 ⁇ m, preferably of ⁇ 10 ⁇ m, in particular of ⁇ 5 ⁇ m, are formed.
  • a process according to the invention which, after drying in step c), produces spray-dried particles which are "inhalable", i.e. which have a diameter small enough to effect topical application in the lung.
  • an anticholinergic preferably a compound of formula 1.
  • X ⁇ means a negatively charged anion
  • the salt of an organic, physiologically harmless, sterically demanding acid according to iii) is preferably selected from the group consisting of ascorbate, the salt of a fruit or edible acid, preferably citrate, tartrate, malate, lactate, acetate, ⁇ Hydroxycapronate or gluconate, and the salt of a mono-, di- or tri-valent carboxylic acid, preferably fumarate, oxalate, succinate or the salt of a sterically demanding amino acid, for stabilizing a spray-dried powder formulation containing the following components i) to ii): i ) a compound of formula 1
  • a a group is selected from
  • R and R ' are each hydrogen or together form a group selected from a single bond, -CH 2 - and -O-, and wherein
  • X * means a negatively charged anion
  • This additional salt of an organic, physiologically harmless, sterically demanding acid is preferably used in such a concentration that a molar ratio of the anticholinergic according to i), in particular the compound according to formula 1, to the cation of the salt of 1: 1 to 1: 16, preferably from 1: 2 to 1:12 and in particular from 1: 3 to 1:11 results.
  • a mixture of an organic, physiologically acceptable, sterically demanding acid according to iii) is preferably selected from the group consisting of ascorbic acid, a fruit or edible acid, preferably citric acid, tartaric acid, malic acid, lactic acid, acetic acid, ⁇ -hydroxycaprylic acid or gluconic acid , and a mono-, di- or trihydric carboxylic acid, preferably fumaric acid, oxalic acid, succinic acid or a sterically demanding amino acid, and the salt of an organic, physiologically acceptable, sterically demanding acid according to iii) preferably selected from the group consisting of ascorbate, the salt a fruit or pleasure acid, preferably citrate, tartrate, malate, lactate, acetate, a-hydroxycapronate or gluconate, and the salt of a mono-, di- or trihydric carboxylic acid, preferably fumarate, oxalate, succinate or the salt of a
  • a a group is selected from
  • R and R ' are each hydrogen or together form a group selected from a single bond, -CH 2 - and -O-, and wherein
  • At least one embedding material selected from the group consisting of mono- or disaccharides, oligosaccharides, polymers, sugar alcohols and cholesterol.
  • citric acid and citrate preferably an alkali metal citrate, an alkaline earth metal citrate or Zinkeitrat, in particular sodium citrate, potassium citrate, magnesium citrate, calcium citrate or Zinkeitrat.
  • the ratio of the organic, physiologically acceptable, sterically demanding acid, preferably citric acid, to the salt of the organic, physiologically acceptable, sterically demanding acid, preferably citrate, in the solution is preferably adjusted in such a way that the solution prepared in step a) has a pH of approx of ⁇ 7, preferably of ⁇ 6, more preferably of ⁇ 5, in particular of ⁇ A.
  • a concentration of the salt of the organic, physiologically acceptable, sterically demanding acid is used, that a molar ratio of the anticholinergic to i), in particular the compound of formula 1, to the cation of the salt of 1: 1 to 1: 12, preferably from 1: 2 to 1:10 and especially from 1: 3 to 1: 8.
  • X "of the compound of formula 1 denotes an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate , especially bromide.
  • the embedding material ii) used is preferably a mono- or disaccharide selected from the group consisting of glucose, sucrose, fructose, maltose, lactose, cellobiose and trehalose, an oligosaccharide selected from the group of oligomaltose, oligofructose, cyclodextrins, dextrins and oligosaccharose Polymer selected from the group of inulin, alginate, maltodextrin, starch, starch derivatives, cellulose, cellulose derivatives, PVP (plasdone), gelatin, chitosan, dextrans, pectins, gum arabic, polylactides, poly (lactide-co-glycolides) and polyvinyl alcohols, a sugar alcohol selected from the group mannitol, xylitol and sorbitol or cholesterol used.
  • lactose lactose
  • the present invention further relates to the use of the spray-dried powder formulations according to the invention for the production of a medicament for the treatment of respiratory diseases, in particular for the treatment of COPD and / or asthma, wherein preferably the inhalers described above are used.
  • Citric acid 3.2 g (addition to pH 3, 7.9% based on the total solids of the particles)
  • K-Citrate Tribasic Monohydrate 0.99 g (2.5% based on the total solids of the particles) molar ratio of the anticholinergic to the K-ion is 1:11
  • Citric acid 2.4 g (addition to pH 3, 3% based on the total solids of the particles)
  • Citric acid 3.8 g (addition to pH 3, 4.7% based on the total solids of the particles)
  • Citric acid 5.2 g (addition to pH 3, 6.6% based on the total solids of the particles)
  • Zinc citrate dihydrate 3.0 g (3.8% based on the total solids of the particles) molar ratio of the anticholinergic to the Zn ion is 1: 8
  • Example 7 Solutions after step a) with citric acid and Mg citrate (1: 5 mol / mol).
  • T ⁇ -Mg-dicitrate nonahydrate 1 0 g (2.3% based on the total solids of the particles) molar ratio of the anticholinergic to the Mg ion is 1: 5 water 460 g
  • Spray Dried Powder Formulation 1 (Containing 2,2-diphenylpropionic acid ester methobromide and citric acid):
  • the solvent is placed in an Erlenmeyer flask.
  • the addition of the embedding material is carried out in portions with vigorous stirring (for example magnetic stirrer) and optionally with heating.
  • the spray drying is carried out by means of a modified BÜCHI Mini-Spray Dryer (B-191) in combination with a modified 0.5 mm two-fluid nozzle and with the exclusive use of N 2 as process and nozzle gas. Essentially all glass parts were replaced by metal parts and the aspirator was removed. Through the process gas inlet N 2 is supplied as drying gas (about 35 m 3 / h) so that the device is flowed through in the overpressure range. The outlet filter between the cyclone and the aspirator was removed and the gas outlet was led directly after the cyclone into a fume hood with integrated particle fine filter.
  • the two-fluid nozzle was made of stainless steel, whereby the 0.5 mm nozzle cap with mixing needle and nozzle cap nut were retained as central atomization unit.
  • the mass flow of the nozzle gas flow rate is determined via an external measuring device (Kobold MAS 3015) and decoupled from the original variable area flowmeter. Usually, the nozzle is operated at a gas pressure of about 6 bar overpressure.
  • the inlet temperature of the process gas is 150 0 C.
  • the mass flow rate of the spray solution is to be chosen in such a way that given a starting temperature of 82 ⁇ 3 ° C. After spray drying, the powder should be removed immediately. to be stored or further processed under exclusion of moisture.
  • Table 1 The process parameters used are shown in Table 1.
  • Spray Dried Powder Formulation 2 (Containing 2.2-Diphenylpropionic Acid Copoester Methobromide, Citric Acid and K-Citrate (1:11 mol / mol):
  • the solvent is placed in an Erlenmeyer flask.
  • the addition of the embedding material is carried out in portions with vigorous stirring (for example magnetic stirrer) and optionally with heating.
  • the spray drying is carried out as described in Example 1. The process parameters used are shown in Table 2.
  • Spray Dried Powder Formulation 3 (Containing 2.2-Diphenylpropionic Acid Copoester Methobromide, Citric Acid and Zinc Citrate) (1: 3 mol / mol):
  • the preparation of the spray-dried powder formulation 3 is carried out according to the preparation procedure for Example 2.
  • the process parameters used are shown in Table 3.
  • Spray Dried Powder Formulation 4 (Containing 2.2-Diphenylpropionic Acid Copoester Methobromide, Citric Acid and Zinc Citrate) (1: 6 mol / mol): Execution:
  • the preparation of the spray-dried powder formulation 4 is carried out according to the preparation instructions for Example 2.
  • the process parameters used are shown in Table 4.
  • the preparation of the spray-dried powder formulation 5 is carried out according to the preparation instructions for Example 2.
  • the process parameters used are shown in Table 5.
  • Spray-dried powder formulation 6 (containing 9-methyl-fluorene-9-carboxylic acid scopinester methobromide and citric acid):
  • the solvent is placed in an Erlenmeyer flask.
  • the addition of the embedding material is carried out in portions with vigorous stirring (for example magnetic stirrer) and optionally without heating.
  • Spray-dried powder formulation 7 (containing 9-methyl-fluorene-9-carboxylic acid scopinester methobromide, citric acid and Mg citrate) (1: 5 mol / mol):
  • the solvent is placed in an Erlenmeyer flask.
  • the addition of the embedding material is carried out in portions with vigorous stirring (for example magnetic stirrer) and optionally with heating.
  • the spray drying is carried out as described in Example 1. The process parameters used are shown in Table 7.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une formulation poudreuse séchée par pulvérisation comprenant des particules qui contiennent les éléments i) à iii) suivants : i) un composé de formule 1 dans laquelle A est un groupe choisi entre (1), (2) et (3) où R et R' représentent respectivement hydrogène ou forment ensemble un groupe choisi entre une simple liaison, -CH2- et -O-, et où X - est un anion chargé négativement; ii) au moins une matière d'incorporation choisie dans le groupe qui comprend des mono- ou disaccharides, des oligosaccharides, des polymères, des alcools de sucre et le cholestérol; iii) un acide organique, physiologiquement toléré, et stériquement exigeant, choisi dans le groupe qui comprend l'acide ascorbique, un acide carboxylique mono-, di- ou trivalent, de préférence de l'acide fumarique, de l'acide oxalique, de l'acide succinique ou un acide aminé stériquement exigeant, et un acide de fruit ou acide de consommation, de préférence de l'acide citrique, de l'acide tartrique, de l'acide malique, de l'acide lactique, de l'acide acétique, de l'acide α-hydroxycaprylique ou de l'acide gluconique. L'invention concerne également un procédé pour préparer cette formulation et l'utilisation d'un acide organique, physiologiquement toléré, stériquement exigeant, choisi dans le groupe qui comprend l'acide ascorbique, un acide de fruit ou un acide de consommation, de préférence de l'acide citrique, de l'acide tartrique, de l'acide malique, de l'acide lactique, de l'acide acétique, de l'acide α-hydroxycaprylique ou de l'acide gluconique et un acide carboxylique mono-, di-, ou trivalent, de préférence de l'acide fumarique, de l'acide oxalique, de l'acide succinique ou un acide aminé stériquement exigeant, pour stabiliser une formulation de poudre produite par séchage par pulvérisation, contenant le composé i) sus-mentionné de formule 1 et une matière d'incorporation ii) appropriée.
EP07822237A 2006-11-22 2007-11-06 Formulation poudreuse stable contenant un nouvel anticholinergique Withdrawn EP2094245A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP07822237A EP2094245A2 (fr) 2006-11-22 2007-11-06 Formulation poudreuse stable contenant un nouvel anticholinergique

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP06124578A EP1925296A1 (fr) 2006-11-22 2006-11-22 Formule de poudre stable contenant un nouveau anticholinergique
EP07822237A EP2094245A2 (fr) 2006-11-22 2007-11-06 Formulation poudreuse stable contenant un nouvel anticholinergique
PCT/EP2007/061910 WO2008061873A2 (fr) 2006-11-22 2007-11-06 Formulation poudreuse stable contenant un nouvel anticholinergique

Publications (1)

Publication Number Publication Date
EP2094245A2 true EP2094245A2 (fr) 2009-09-02

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EP06124578A Ceased EP1925296A1 (fr) 2006-11-22 2006-11-22 Formule de poudre stable contenant un nouveau anticholinergique
EP07822237A Withdrawn EP2094245A2 (fr) 2006-11-22 2007-11-06 Formulation poudreuse stable contenant un nouvel anticholinergique

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EP06124578A Ceased EP1925296A1 (fr) 2006-11-22 2006-11-22 Formule de poudre stable contenant un nouveau anticholinergique

Country Status (5)

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US (1) US20100047359A1 (fr)
EP (2) EP1925296A1 (fr)
JP (1) JP2010510278A (fr)
CA (1) CA2670153A1 (fr)
WO (1) WO2008061873A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1925295A1 (fr) * 2006-11-22 2008-05-28 Boehringer Ingelheim Pharma GmbH & Co. KG Formule de poudre stable contenant un nouveau anticholinergique
PT107312B (pt) * 2013-11-25 2022-05-10 Advanced Cyclone Systems S A Ciclone aglomerador de fluxo invertido e respectivo processo
CN111533959B (zh) * 2020-05-25 2021-11-23 上海邦成生物工程有限公司 低聚壳聚糖/木薯淀粉复合丙酸锌固形物及其制备方法

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Publication number Priority date Publication date Assignee Title
AU6014098A (en) * 1996-12-31 1998-07-31 Inhale Therapeutic Systems Aerosolized hydrophobic drug
US6667344B2 (en) * 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
WO2003024396A2 (fr) * 2001-09-17 2003-03-27 Glaxo Group Limited Formulations de medicament en poudre seche
DE10203741A1 (de) * 2002-01-31 2003-08-14 Boehringer Ingelheim Pharma Neue Fluorencarbonsäureester, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel
US20050112087A1 (en) * 2003-04-29 2005-05-26 Musso Gary F. Pharmaceutical formulations for sustained drug delivery
US7462367B2 (en) * 2003-07-11 2008-12-09 Boehringer Ingelheim International Gmbh Anticholinergic powder formulations for inhalation
DE10331350A1 (de) * 2003-07-11 2005-01-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pulverformulierungen für die Inhalation enthaltend ein neues Anticholinergikum
US20050186175A1 (en) * 2004-02-20 2005-08-25 Boehringer Ingelheim International Gmbh Pharmaceutical compositions based on benzilic acid esters and soluble TNF receptor fusion proteins
EP1718301A1 (fr) * 2004-02-20 2006-11-08 Boehringer Ingelheim International GmbH Compositions pharmaceutiques a base d'anticholinergiques et de pegsunercept

Non-Patent Citations (1)

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Title
See references of WO2008061873A2 *

Also Published As

Publication number Publication date
US20100047359A1 (en) 2010-02-25
WO2008061873A3 (fr) 2008-07-10
CA2670153A1 (fr) 2008-05-29
WO2008061873A2 (fr) 2008-05-29
EP1925296A1 (fr) 2008-05-28
JP2010510278A (ja) 2010-04-02

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