Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
  • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
  • C07C217/10—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
• • 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
  • A61K31/33—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
  • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/06—Antiabortive agents; Labour repressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• Salicylic acid salts process for their preparation and their use as medicaments
• the present invention relates to novel, substituted salicylic salts of salmeterol, processes for their preparation and their use as medicaments.
• R 1 and R 2 identical or different, denote hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogen, COOH, OH, -COOC ⁇ -C 4-alkyl, -CO-C 1 -C 4 -alkyl, -NH 2, -NH (C -C -alkyl), -N (C 1 -C 4 -alkyl) 2, -SO 2 -OH, -CF 3 or phenyl;
• R 3 is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogen, -CF 3 or phenyl, where the phenyl ring may optionally be mono-, di- or trisubstituted by one, two or three radicals selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, halogen or
• R 1 and R 2 identical or different, denote hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine, bromine, iodine, COOH, OH, -COOMethyl, -CO-methyl, -NH 2 , -NH ( Methyl), -N (methyl) 2 , -NH (ethyl), -N (ethyl) 2, -SO 2 -OH, -CF 3 or phenyl;
• R 3 is hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, fluorine, chlorine,
• R 1 and R 2 are identical or different and are hydrogen, methyl, ethyl, propyl, methoxy, fluorine, chlorine, bromine, iodine, -COOH, OH, -COOMethyl, -CO-methyl, -NH 2, -SO 2 -OH or -CF 3 ;
• R 3 is hydrogen, methyl, ethyl, methoxy, fluorine, chlorine, -CF 3 or phenyl, where the phenyl ring may optionally be monosubstituted or disubstituted by one or two radicals selected from the group consisting of fluorine, chlorine, bromine or -CF 3, with the proviso that not all of the radicals R " 1, R 2 and R 3 can simultaneously be hydrogen, mean, if appropriate in the form of their enantiomers, mixtures of the enantiomers or racemates.
• R 1 and R 2 are identical or different and are hydrogen, methyl, propyl, methoxy, chlorine, iodine, -COOH, OH, -COOMethyl, -CO-methyl, -NH 2, or -SO 2 -OH;
• R 3 is hydrogen or phenyl, where the phenyl ring may optionally be monosubstituted or disubstituted by one or two radicals, preferably a radical selected from the group consisting of
• R 1 and R 2 identical or different, denote hydrogen, methyl, propyl, methoxy, chlorine, iodine, -COOH, OH, -COOMethyl, -CO-methyl, -NH 2, or S ⁇ 2-OH;
• R 3 is hydrogen with the proviso that not all of the radicals R 1 , R 2 and R 3 can be hydrogen at the same time, optionally in the form of their enantiomers, mixtures of the enantiomers or racemates.
• R 3 is phenyl, where the phenyl ring may optionally be monosubstituted or disubstituted by one or two radicals, preferably a radical selected from the group consisting of fluorine, chlorine, bromine or -CF 3, preferably fluorine, optionally in the form of their enantiomers, Mixtures of the enantiomers or racemates.
• alkyl groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. If appropriate, the abbreviations Me, Et, Prop or Bu are also used to designate the groups methyl, ethyl, propyl or butyl. Unless otherwise stated, the definitions of propyl and butyl include all conceivable isomeric forms of the respective radicals. For example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl, etc.
• alkyloxy groups unless otherwise stated, branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom.
• alkyloxy groups unless otherwise stated, branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom.
• methylox, ethyloxy, propyloxy or butyloxy are mentioned.
• methyloxy, ethyloxy branched and unbranched alkyl groups having 1 to 4 carbon atoms which are linked via an oxygen atom.
• Propyloxy or butyloxy are optionally also the abbreviations MeO, EtO, PropO or BuO- used. Unless otherwise stated, the definitions propoxy and butoxy include all conceivable isomeric forms of the respective radicals. For example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec. Butyloxy and tert-butyloxy, etc.
• alkoxy is also used in the present invention instead of the name alkyloxy. Accordingly, the terms methoxy, ethoxy, propoxy or butoxy are also used to designate the groups methyloxy, ethyloxy, propyloxy or butyloxy.
• Halogen is in the context of the present invention for fluorine, chlorine, bromine or iodine. Unless otherwise indicated, fluorine and bromine are preferred halogens.
• the group CO denotes a carbonyl group.
• the salts of formula 1 represent novel acid addition salts of the salmeterol known in the art.
• Salmeterol has a center of chirality.
• the present invention relates to the salts of formula 1 in racemic or enantiomerically pure form.
• both the (R) - and the (S) - enantiomer is of particular importance.
• the present invention relates to the salts of formula 1 in the form of non-racemic mixtures of the two enantiomers.
• the radicals RR 2 and R r can, if not hydrogen, ortho, of the link may be arranged for each carboxyl group is meta or para with respect to them. If none of the radicals R ' ', R 2 and R 3 is hydrogen, the radical R 3 is preferably in the meta position and the radicals R 1 and R 2 are linked in the ortho and / or para position. If one of the radicals R 1 , R 2 and R 3 is hydrogen, at least one of the other radicals is preferably linked in the meta or para position, particularly preferably in the para position. Compounds in which the radical R 3 does not denote hydrogen are of particular importance in accordance with the invention. In these compounds, the radical R 3 is preferably located in the meta position relative to the carboxyl group.
• the preparation of the salts 1 according to the invention starting from the free base of salmeterol can be carried out analogously to processes known in the prior art for the formation of acid addition salts starting from secondary amines. It involves the reaction of the free base salmeterol with carboxylic acids of the formula 2
• the radicals R 1 , R 2 and R 3 may have the abovementioned meanings, in suitable solvents, preferably organic solvents.
• the acid 2 is taken up in a suitable solvent, preferably an organic solvent, more preferably a solvent selected from the group consisting of ethyl acetate, methanol, ethanol, isopropanol and diethyl ether or mixtures thereof.
• the abovementioned solvents can also be used in mixtures with tert-butyl methyl ether or cyclohexane.
• the acids 2 taken up in one of the abovementioned solvents are dissolved by heating, preferably with heating to the boiling point of the solvent. Salmeterol, optionally dissolved in one of the abovementioned solvents, is added to this solution. From the resulting solution, the salts 1 are optionally crystallized with cooling and isolated.
• the compounds of formula 1 are characterized by a variety of possible applications in the therapeutic field. Worthy of mention are those applications for which the salts of the formula 1 according to the invention can be used as betamimetics due to their pharmaceutical activity.
• bronchial asthma usually irritation-induced, paroxysmal bronchospasm with mucosal swelling and increased mucus production
• COPD chronic obstructive bronchitis
• the inhibition of premature onset labor and imminent abortion in obstetrics tocolytic
• Cardiac arrhythmia arrhythmic
• the therapy of circulatory shock vasodilation and cardiac output increase
• the treatment of itching and inflammation of the skin preferably used in the treatment of asthma or COPD.
• the salts of the formula can be used alone or in combination with other active ingredients. These are, in particular, anticholinergics, antiallergics, leukotriene antagonists, dopamine agonists, PDEIV inhibitors and corticosteroids, and combinations of active substances thereof.
• anticholinergics examples include ipratropium bromide, oxitropium bromide and, in particular, tiotropium bromide.
• Medicament combinations in addition to the compound of the invention of the formula Tiotropiumbromid are included as another active ingredient particularly preferred according to the invention. Of particular importance are those drug combinations which, in addition to the compound of formula 1, contain crystalline tiotropium bromide monohydrate, which can be obtained by the experimental procedure given in the experimental section.
• This combination is of particular importance in the treatment of asthma or COPD, especially COPD.
• corticosteroids which may optionally be used in combination with the compound of the formula 1 are compounds which are selected from the group consisting of flunisolides, beclomethasones, triamcinolones, budesonide, fluticasones, mometasones, ciclesonides, Rofleponide and Dexametasone.
• Preferred in the context of the present invention are the corticosteroids selected from the group consisting of flunisolides, beclomethasones, triamcinolones, budesonide, fluticasones, mometasones, ciclesonides and dexametasone, in which case the budesonide, fluticasone, mometasone and ciclesonide, in particular budesonide and fluticasone, have a special Meaning.
• corticosteroids instead of the term corticosteroids only the term steroids is used.
• Reference to steroids in the context of the present invention includes reference to salts or derivatives that may be formed by the steroids.
• Examples of possible salts or derivatives are: sodium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
• the corticosteroids may also be in the form of their hydrates.
• dopamine agonists which may optionally be used in combination with the compound of formula 1, are compounds which are selected from the group consisting of bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexole , Roxindol, Ropinirole, Talipexole, Terguride and Viozan.
• dopamine agonists are preferably used as combination partners with the compound of the formula selected from the group consisting of pramipexole, talipexole and viozan, with pramipexole being of particular importance.
• a reference to the aforementioned dopamine agonists in the context of the present invention includes a reference to their optionally existing pharmacologically acceptable acid addition salts and optionally their hydrates.
• physiological Compatible acid addition salts which can be formed from the aforementioned dopamine agonists are, for example, pharmaceutically acceptable salts which are selected from the salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic, lactic, citric, tartaric and maleic acids ,
• antiallergics which can be used according to the invention with the compound of formula 1 as a combination, called epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, cexchlorpheniramine, pheniramine, Doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozin.
• Preferred antiallergic agents which can be used in combination with the compound of the formula I in the context of the present invention are selected from the group consisting of epinastin,
• Reference to the aforementioned antiallergic agents in the context of the present invention includes a reference to their optionally existing pharmacologically acceptable acid addition salts.
• PDE-IV inhibitors which can be used in combination with the compound of formula 1 according to the invention are compounds which are selected from the group consisting of enprofylline, roflumilast, Ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A and AWD-12-281.
• Preferred PDE IV inhibitors are selected from the group consisting of Enprofylline, Roflumilast, Ariflo and AWD-12-281.
• Reference to the aforementioned PDE-IV inhibitors in the context of the present invention includes reference to their optionally existing pharmacologically acceptable acid addition salts.
• physiologically acceptable acid addition salts which can be formed by the abovementioned PDE-IV inhibitors
• pharmaceutically acceptable salts selected from the salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, acetic, fumaric, succinic and lactic acids , Citric acid, tartaric acid or maleic acid.
• the salts selected from the group consisting of acetate, hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate are preferred in this context.
• Suitable application forms for the application of the salts of the formula 1 are, for example, tablets, capsules, suppositories and powders, etc.
• Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to obtain the depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
• the tablets can also consist of several layers.
• Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
• the core can also consist of several layers.
• the dragee wrapper to achieve a depot effect of several layers, wherein the above mentioned in the tablets excipients can be used.
• Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or sugar, as well as a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
• a sweetener such as saccharin, cyclamate, glycerol or sugar
• a taste-improving agent e.g. Flavorings such as vanillin or orange extract.
• suspending aids or thickening agents such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
• the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
• inert carriers such as lactose or sorbitol
• Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
• auxiliaries for example, water, pharmaceutically acceptable organic solvents such as paraffins (eg petroleum fractions), oils of vegetable origin (eg peanut or sesame oil), mono- or polyfunctional alcohols (eg ethanol or glycerol), excipients such as natural minerals (eg kaolin, Clays, talc, chalk) synthetic minerals (eg fumed silica and silicates), sugars (eg, cane, milk and dextrose), emulsifiers (eg lignin, liquor liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and Sodium lauryl sulfate).
• paraffins eg petroleum fractions
• oils of vegetable origin eg peanut or sesame oil
• mono- or polyfunctional alcohols eg ethanol or glycerol
• excipients such as natural minerals (eg kaolin, Clays, talc,
• the application is carried out in the usual way, in the treatment of asthma or COPD, preferably by inhalation.
• the compounds may be used in the form of inhalable powders, propellant-containing inhalable solutions or suspensions or propellant-free inhalable solutions or suspensions.
• the salts may contain 1 either alone or in admixture with suitable physiologically acceptable excipients.
• suitable physiologically acceptable excipients eg glucose or arabinose
• disaccharides eg lactose, sucrose, maltose
• oligosaccharides and polysaccharides eg dextranes
• polyalcohols eg sorbitol, mannitol, xylitol
• salts eg sodium chloride, calcium carbonate
• lactose Preferably, mono- or disaccharides are used, wherein the use of lactose or glucose, in particular, but not exclusively in the form of their hydrates, is preferred. Lactose, most preferably lactose monohydrate, is used as adjuvant for the purposes of the invention.
• the propellant-containing inhalation-type inhalable aerosols which can be used in the context of the use according to the invention can dissolve the salts 1 in propellant gas or contain them in dispersed form.
• the propellant gases which can be used for the preparation of the inhalation aerosols are known from the prior art. Suitable propellant gases are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
• the abovementioned propellant gases can be used alone or in mixtures thereof.
• propellant gases are fluorinated alkane derivatives selected from TG 134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,3,3,3,3-heptafluoropropane) and mixtures thereof.
• the propellant-containing inhalation aerosols which can be used in the context of the use according to the invention can also contain further constituents, such as co-solvents, stabilizers, surfactants, antioxidants, lubricants and pH-adjusting agents. All of these ingredients are known in the art.
• suitable solvents are aqueous or alcoholic, preferably ethanolic, solutions.
• the solvent may be water only or it may be a mixture of water and ethanol.
• the relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70% by volume, in particular up to 60% by volume and more preferably up to 30% by volume.
• the remaining volume percentages are filled up with water.
• the solutions or suspensions containing auf are adjusted to a pH of from 2 to 7, preferably from 2 to 5, with suitable acids.
• acids selected from inorganic or organic acids can be used. Examples of particularly suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are:
• Ascorbic acid citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.
• Preferred inorganic acids are hydrochloric acid, sulfuric acid.
• organic acids ascorbic acid, fumaric acid and citric acid are preferable.
• mixtures of said acids may also be employed, particularly in the case of acids which, in addition to their acidification properties, also possess other properties, e.g. as flavorants, antioxidants or complexing agents, such as citric acid or ascorbic acid.
• Hydrochloric acid is particularly preferably used according to the invention for adjusting the pH.
• the tablets may, of course, besides the abovementioned excipients also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various adjuvants such as starch, preferably potato starch, gelatin and the like. Further, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting. In the case of aqueous suspensions, the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
• the dosage of the compounds according to the invention is naturally highly dependent on the mode of administration and the disease to be treated.
• the salts of the formula are already characterized by high efficacy at doses in the ⁇ g range. Even above the ⁇ g range, the compounds of the formula can be used meaningfully.
• the dosage can then also be in the gram range, for example.
• the salts of the formula according to the invention can optionally be used in combination with, for example, crystalline tiotropium bromide monohydrate.
• Tiotropium bromide can be obtained as described in European patent application EP 418 716 A1. From this, crystalline tiotropium bromide monohydrate is obtainable according to the procedure described below. 15.0 kg of tiotropium bromide are introduced into 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 ° C and stirred at a constant temperature until a clear solution is formed.
• Activated carbon (0.8 kg), moist with water, is slurried in 4.4 kg of water, this mixture is added to the tiotropium bromide-containing solution and rinsed with 4.3 kg of water. The resulting mixture is stirred for at least 15 minutes at 80-90 ° C and then filtered through a heated filter in a pre-heated to 70 ° C jacket temperature apparatus. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled at 3-5 ° C per 20 minutes to a temperature of 20-25 ° C. With cold water cooling, the apparatus is further cooled to 10-15 ° C and the crystallization is completed by at least one hour stirring.
• the crystals are isolated on a Nutschentrockner, the isolated crystal pulp with 9 L cold water (10-15 ° C) and cold acetone (10-15 ° C). The resulting crystals are dried at 25 ° C for 2 hours in a stream of nitrogen. Yield: 13.4 kg of crystalline tiotropium bromide monohydrate (86% of theory)
• the finely ground active substance, lactose and part of the corn starch are mixed together.
• the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet granulated and dried.
• the granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together.
• the mixture is compressed into tablets of suitable shape and size.
• Sorbitan trioleate 0.1 monofluorotrichloromethane
• the above-mentioned numerical values are given in% by weight.
• the suspension is filled in a conventional aerosol container with metering valve. Per actuation preferably 50 ul suspension are delivered. If desired, the active ingredient can also be metered in higher (for example 0.02% by weight).

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• 2002
  • 2002-09-06 EP EP02764875A patent/EP1429751A1/de not_active Withdrawn
  • 2002-09-06 WO PCT/EP2002/009975 patent/WO2003024440A1/de active Application Filing
  • 2002-09-06 CA CA002460440A patent/CA2460440A1/en not_active Abandoned
  • 2002-09-06 MX MXPA04002400A patent/MXPA04002400A/es active IP Right Grant
  • 2002-09-06 JP JP2003528537A patent/JP4199114B2/ja not_active Expired - Lifetime
  • 2002-09-11 UY UY27443A patent/UY27443A1/es not_active Application Discontinuation
  • 2002-09-12 PE PE2002000898A patent/PE20030444A1/es not_active Application Discontinuation

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