EP1753401A1 - Granulat rapidement soluble de bromhexine / hydrochlorure de bromhexine, procede de fabrication dudit granulat et son utilisation - Google Patents

Granulat rapidement soluble de bromhexine / hydrochlorure de bromhexine, procede de fabrication dudit granulat et son utilisation

Info

Publication number
EP1753401A1
EP1753401A1 EP05737936A EP05737936A EP1753401A1 EP 1753401 A1 EP1753401 A1 EP 1753401A1 EP 05737936 A EP05737936 A EP 05737936A EP 05737936 A EP05737936 A EP 05737936A EP 1753401 A1 EP1753401 A1 EP 1753401A1
Authority
EP
European Patent Office
Prior art keywords
soluble granules
bromhexine
granules according
cellulose
granulate
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Withdrawn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
EP05737936A
Other languages
German (de)
English (en)
Inventor
Martin Folger
Stefan Henke
Jens Schmalz
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 Vetmedica GmbH
Boehringer Ingelheim Animal Health USA Inc
Original Assignee
Boehringer Ingelheim Vetmedica GmbH
Boehringer Ingelheim Vetmedica 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 Vetmedica GmbH, Boehringer Ingelheim Vetmedica Inc filed Critical Boehringer Ingelheim Vetmedica GmbH
Publication of EP1753401A1 publication Critical patent/EP1753401A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the invention relates to a rapidly soluble granules of bromhexine / bromhexine hydrochloride, a process for its production and its use.
  • Bromhexine like its hydrochloride, is a mucolytic agent with the chemical name N-Cyclohexyl-N-methyl- (2-amino-3,5-dibromobenzyl) amine and the chemical formula:
  • bromhexine hydrochloride (trade name Bisolvon®) is even less soluble in water and poorly soluble in ethanol, methanol and methylene chloride. It is therefore not surprising that known bromhexine (hydrochloride) pharmaceutical formulations are largely represented in the field of dosage forms which are released over a long period of time or released with a time delay, which results in a sustained release or sustained release effect.
  • the release of the active ingredient is controlled by dissolving or corresponding permeability of an applied film or by specifically setting the porosity of a matrix in which the active ingredient is present in finely divided form.
  • Bromhexine / bromhexine hydrochloride-containing pharmaceuticals with a sustained release effect can be found, for example, in US Pat. No. 4,814,176 or US Pat. No. 4,777,033.
  • Numerous combination preparations containing brornhexine (hydrochloride) are also known, in which two or more pharmaceutically active constituents are present together in the dosage form. Reference is only made to US Pat. No.
  • 5,393,531 which discloses an aqueous solution or dispersion with at least two different pharmaceutically active substances, including bromhexine;
  • WO 9633704 which describes a composition of ibuprofen and bromhexine hydrochloride but in individual grains, or JP 63060926, where bromhexine hydrochloride is administered in combination with an antipyretic and analgesic.
  • the well-known Bisolvon® powder is currently on the market for chronic bronchopneumonia and enzootic pneumonia for pigs.
  • Various preparations for human pharmaceuticals are also commercially available.
  • a treatment of sick animals could be successfully carried out using drinking water.
  • the Bisolvon® powder is not soluble in drinking water in the required concentrations, other forms of administration and routes of administration had to be used. It would therefore be of great advantage to develop an appropriately water-soluble dosage form.
  • US Pat. No. 5,837,285 describes tablets for oral administration to humans or animals that dissolve quickly in the mouth and a pharmaceutically active ingredient (medicament) and a readily water-soluble carrier made from xylitol in a mixture with lactose or mannitol, bromhexine hydrochloride also being mentioned among a large variety of possible medicaments.
  • a pharmaceutically active ingredient medicament
  • a readily water-soluble carrier made from xylitol in a mixture with lactose or mannitol, bromhexine hydrochloride also being mentioned among a large variety of possible medicaments.
  • the moist mixture is first compressed in tablet form and the compressed tablets are then dried.
  • the present invention is therefore based on the object of providing a dosage form which contains bromhexine or bromhexine hydrochloride and which has water solubility so that the active ingredient can be released relatively quickly and completely.
  • An orally administrable pharmaceutical formulation should be provided.
  • Another object of the present invention is to provide a method which allows the formulation to be produced in a reproducible manner with a consistently high quality and without high cost.
  • step (b) spraying the granulation liquid obtained in step (a) in a fluidized bed in a countercurrent process at a constant supply air temperature onto a carrier comprising at least one carbohydrate,
  • bromhexine / bromhexine hydrochloride and citric acid are used in the granulating liquid and / or the carrier.
  • the teaching according to the invention provides water-soluble granules, in particular quick-dissolving granules, which contain the bromhexine / bromhexine hydrochloride, which is only sparingly soluble in water, as active ingredient.
  • “rapidly soluble granules” means that the granules dissolve completely in water within a few minutes. In experiments, a dissolution time of less than 15 minutes was carried out in a USP paddle apparatus (50 rpm) in the medium water (drinking water , Ingelheim, usual pH value and hardness) at room temperature, the granules completely dissolving and the active ingredient being released completely.
  • bromhexine / bromhexine hydrochloride is to be understood to mean that either bromhexine or its hydrochloride is contained in the rapidly soluble granules.
  • the granules according to the invention contain bromhexine or bromhexine hydrochloride as the active ingredient, which corresponds to the granulating liquid and / or the carrier is added, an addition to the carrier being particularly preferred.
  • a salt former in the form of citric acid is present in the granulating liquid and / or the carrier, which is used particularly preferably in the carrier. If bromhexine / bromhexine hydrochloride is also present in the carrier, it has proven to be advantageous if the two components are thoroughly mixed physically.
  • the citric acid in step (a) and / or (b) is particularly preferably in a range from 25% (w / w) to 100% (w / w), in particular 37.5% (w / w) to 62.5 % (w / w) before.
  • the binder contained in the granulating liquid is not particularly limited. Any binder known in the pharmaceutical field can be used. Examples include: polyvinyl pyrrolidone, cellulose ethers, gelatin, polyvinyl acetates, acrylic resins, copolymers and mixtures thereof, and starch and starch derivatives.
  • cellulose ethers should be understood to mean cellulose derivatives which are produced by partial or complete substitution of the hydrogen atoms or hydroxyl groups by alkyl and / or (ar) alkyl groups. These can also contain further functional groups. As is known, their solubility in water depends on Art and number of ether groups introduced, which should also include mixed cellulose ethers.
  • Particularly preferred cellulose ethers are therefore methyl cellulose, propyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl hydroxyethyl cellulose, methyl hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose and hydroxypropyl methyl cellulose. Hydroxypropylmethyl cellulose and methyl cellulose are very particularly preferred.
  • Preferred polyvinylpyrrolidones are, for example Kollidone and PVP 25000.
  • Preferred acrylic resins are, for example, Eudragit ®.
  • Cellulose ethers are very particularly preferred, optionally in a mixture with polyvinylpyrrolidone, optionally together with an acrylic resin and a polyethylene glycol.
  • the binder or binders in step (a) are expediently calculated in an amount of 1% (w / w) to 6% (w / w), in particular 2% (w / w) to 4.% (w / w) on dry product, available.
  • the granulating liquid is prepared in the form of a solution, i.e. the binder or binders are preferably present dissolved in the granulating liquid, so that a granulating liquid solution is produced in step (a).
  • a disperse system can also be produced.
  • the carrier used in step (b) according to the invention contains one or more carbohydrates. These are not particularly limited and can be selected from mono-, oligo- or polysaccharides and mixtures thereof.
  • the monosaccharides and oligosaccharides which can be used according to the invention and which are also summarized as “sugars” include, for example, monosaccharides such as glucose, mannose, galactose, fructose, sorbose, ribose, xylose and arabinose; disaccharides such as sucrose, lactose, maltose, cellobiose and dextrin or maltodextrin Mixtures of glucose and lactose are very particularly preferred.
  • polysaccharides which can be used in the carrier of the invention are starch, starch derivatives, gum arabic or tragacanth.
  • carbohydrate or carbohydrates in step (a) in an amount of 35% (w / w) to 75% (w / w), in particular 40% (w / w) to 60% (w / w) be used.
  • starch is subsumed under polysaccharides and thus under the group of carbohydrates.
  • starch is known to have binder properties, this classification is chosen for the person skilled in the art for reasons of clear assignment. It may be advantageous if one or more carbohydrates are additionally added to the granulating liquid in step (a) in addition to the binder. Starch is particularly preferably added to the granulating liquid.
  • auxiliaries can be used in the granulating liquid and / or the carrier, which are selected from the group consisting of sweeteners, flavors, sugar alcohols, fillers, disintegrants, disintegrants, flow or flow regulators, lubricants, release agents, pH corrections, in particular Buffer substances, antioxidants and dyes.
  • sweeteners are to be understood as meaning compounds of synthetic or natural origin which have no caloric value or which are negligible in relation to the sweetness.
  • Sweeteners which are particularly suitable according to the invention are saccharin, aspartame, cyclamate and acesulfame and their salts.
  • auxiliaries can be sugar alcohols, which are not sugars, but are polyhydroxy compounds formed from monosaccharides by reducing the carbonyl function, which taste sweet and are therefore known as sugar substitutes. Examples include: xylitol, sorbitol, mannitol, threitol and erythritol. Sorbitol and mannitol are particularly preferred.
  • Flavorings can also be used. Examples of this are vanilla, honey aroma, apple aroma and contramarum, the skilled worker being familiar with numerous other aroma substances which can be used.
  • auxiliaries are flow or flow regulating agents and lubricants.
  • silicon dioxide, talc, stearic acid, sodium stearyl fumarate, magnesium stearate and glycerol tribehenate are suitable for this purpose.
  • Magnesium stearate is preferably used according to the invention.
  • the granules according to the invention can also contain disintegrants, which are sometimes also referred to as disintegrants, such as modified or pregelatinized starch, CL-PVP (cross-linked PVP).
  • disintegrants such as modified or pregelatinized starch, CL-PVP (cross-linked PVP).
  • Fillers preferred according to the invention are glucose, lactose and starch.
  • rapidly soluble granules of the invention can contain one or more synthetic or natural, pharmaceutically acceptable dyes, preferably indigo caramine.
  • the granules of the invention may be present.
  • the invention also relates to a method for producing the rapidly soluble granules described above, comprising the steps:
  • step (b) Spraying the granulation liquid obtained in step (a) in a fluidized bed in a countercurrent process at a constant supply air temperature onto a support comprising at least one carbohydrate, bromhexine / bromhexine hydrochloride and citric acid being used independently of one another in the granulation liquid and / or the support become.
  • an aqueous granulating liquid is first prepared which contains one or more of the binders already explained in dissolved form, whereby “dissolved” in the sense of the invention is to be understood as defined above.
  • the granulating liquid is therefore preferably obtained as a real solution, but can also be a dispersion.
  • a mixture of two, three, four, five or even more binders is preferably used, particularly preferably two or three binders are used.
  • one or more of the auxiliaries explained in detail above and optionally one or more carbohydrates, such as starch, can be added.
  • Citric acid and the active ingredient in the form of bromhexine or bromhexine hydrochloride can also be used in the granulating liquid.
  • step (b) of the process according to the invention the granulating liquid is sprayed onto a carrier in a fluidized bed in a countercurrent process at a constant supply air temperature.
  • the carrier contains at least one carbohydrate, preferably a mixture of two, three, four, five or more carbohydrates. Two or three carbohydrates are particularly preferably used. Auxiliaries, citric acid and the active ingredient in the form of bromhexine or bromhexine hydrochloride can optionally be added again.
  • the bromhexine (hydrochloride) active ingredient is present either in the granulating liquid or in the carrier; this can also be present in the carrier and granulating liquid at the same time.
  • Citric acid is also present either in the granulating liquid or in the carrier, and can also be present in the carrier and granulating liquid at the same time.
  • Citric acid and bromhexine or bromhexine hydrochloride are both particularly preferably present in the carrier.
  • step (b) of the invention In addition to the fluidized bed granulation as used in step (b) of the invention, other granulation processes are also possible, for example in a compulsory mixer, V-blender or one-pot process, but these processes are less preferred.
  • step (b) granulation in a fluidized bed is preferably used, the fluidized bed chamber used being usually round, and the apparatus being cylindrical, ie having a diameter which is constant in height.
  • Preferred fluidized bed chambers are those in which the fluidized zone is conical, expanded upwards and only the adjoining calming zone is cylindrical after a conical transition piece.
  • the process can be carried out batchwise or continuously, regardless of the shape of the fluidized bed apparatus are carried out, however, in the sense of the present invention, the continuous process control is preferred.
  • the granulating liquid obtained in step (a) is introduced into the fluidized bed preferably via a single or multi-component nozzle or via several nozzles after step (b) of the process according to the invention.
  • a two-component nozzle is preferably used, atomization being carried out, for example, with air pressure.
  • the arrangement of the nozzle or nozzles and the spray direction can be as long as required, as long as an essentially uniform distribution of the liquid components in the fluidized bed is achieved.
  • the carrier is placed in the granulation system and swirled from below in the fluidized bed by appropriate supply air. In the meantime, the granulating liquid is sprayed onto the carrier from above. The countercurrent process is used.
  • the supply air temperature is set constant and is preferably in the range from 40 ° C. to 80 ° C., in particular 50 to 70 ° C., very particularly preferably in the range from 60 to 70 ° C.
  • Fluidized bed apparatuses which are preferably used have base plates with dimensions of at least 0.15 m.
  • fluidized bed apparatuses are preferred which have a base plate with a diameter of 0.4 m to 5 m, for example 1.2 m or 2.5 m.
  • fluidized bed apparatuses are also suitable which have a base plate with a diameter greater than 5 m.
  • a perforated base plate, a Conidu plate, a wire mesh or a combination base made of a perforated base plate with a grid can be used as the base plate.
  • the process according to the invention is preferably carried out at spray speeds of 1 to 20 rpm and in particular of 10 to 15 rpm, corresponding to 1 to 10 g / min and preferably 3 to 6 g / min.
  • the granules can be discharged from the fluidized bed by classifying the size of the granules.
  • This classification can For example, with a sieve device or by an opposed air flow (classifier air), which is regulated so that only particles from a certain particle size are removed from the fluidized bed and smaller particles are retained in the fluidized bed.
  • the water present in the granulating liquid is thus removed.
  • the water content of the products can be adjusted almost arbitrarily, according to the invention the water is removed almost completely. Drying is preferably carried out simultaneously with the granulation in the fluidized bed. The water evaporates in the fluidized bed, as a result of which dried to dried germs are likely to arise from the constituents of the carrier and the granulating liquid, the actual granulate build-up taking place through continuous embedding and / or coating and drying again.
  • a coating of the granulate can be carried out during or after the atomization of the granulation liquid, depending on the choice of the binder or binders.
  • the selection of the binder or binders determines whether they tend to accumulate in the outer area of the granules, for example in the form of a coating, or in the inner area of the granules.
  • a separate process step can also be followed, in which the gamulate obtained is additionally coated, for example with one or more of the binders described and, if appropriate, auxiliaries, as have already been explained.
  • Table 1 A selection of the components and compositions preferably used in the granules of the invention is listed in Table 1 below, neither the components nor the quantities to be understood as limiting, but only for guidance in order to provide an optimal composition for each application: Table 1: Selection of components and amounts preferred according to the invention
  • a polyethylene glycol Another object of the invention is the use of the rapidly soluble granules according to the invention for the manufacture of a medicament for the treatment or prevention of diseases in which bromhexine or bromhexine hydrochloride can be used therapeutically or preventively.
  • the water-soluble bromhexine / bromhexine hydrochloride granules according to the invention can be administered orally to humans and animals.
  • the granules according to the invention can also be used as medicaments in animals, in particular pigs. By mixing in the drinking trough, it is possible to treat sick animals using drinking water. Furthermore, the granulate according to the invention can be administered together with the animal feed, for example it can be added to the feed (top dressing) or be pressed or pelletized with feed.
  • the teaching according to the invention provides water-soluble granules which contain bromhexine or bromhexine hydrochloride as the active ingredient.
  • This granulate according to the invention is water-soluble, despite the bromhexine / bromhexine hydrochloride, which is hardly soluble in water per se, i.e. the granulate is completely dissolved in the medium of water within a few minutes and releases the active substance in its entirety. In the sense of the teaching according to the invention, this is defined as “quickly soluble”.
  • Another advantage is the gentle production of the bromhexine / bromhexine hydrochloride granules. Due to the formulation and the manufacturing process, the granulate therefore has very good flowability, consistently adjustable content, narrow particle size distribution and low dust formation, which ensures a high quality level of the granulate. In addition, the granulate according to the invention can be produced inexpensively.
  • the granules of the invention have further advantages: the quick-dissolving granules make taking them considerably easier, which is not only important in patients with swallowing problems can, but is also advantageous when administered to animals.
  • the granules according to the invention can be administered via the drinking water, which, in contrast to the powder known hitherto, makes the necessary high concentrations of active ingredient can be obtained to treat or prevent corresponding diseases.
  • the aforementioned improved flowability also results in higher dosing accuracy.
  • bromhexine / bromhexine hydrochloride it is also possible to mask the bitter taste of bromhexine / bromhexine hydrochloride by appropriate selection of the composition of the granulate, by suitable binders in the granulating liquid, appropriate carbohydrates in the carrier, such as sugar, or auxiliaries, such as sugar alcohols or sweeteners. If necessary, an additional coating of the granules can also be carried out. This gives tasty granules with the desired properties.
  • FIG. 1 illustrates the present methodology without restricting it to this.
  • FIG. 1 illustrates the present methodology without restricting it to this.
  • FIG. 1 shows:
  • FIG 1 shows an embodiment of the method of the invention.
  • the granulating liquid is produced in a container 10, which is provided with a stirrer 20.
  • binders for example a mixture of polyvinylpyrrolidone, Eudragit® and hydroxypropylmethyl cellulose with the addition of bromhexine / bromhexine hydrochloride, are dissolved in water with stirring.
  • “dissolved” should also include dispersed.
  • a granulating solution is preferably produced. This can also be accompanied by a carbohydrate, as in the present example, where cornstarch is additionally added.
  • the granulating liquid thus produced then becomes shown two-fluid nozzle 40, which sprays the granulating liquid, for example atomized with air pressure, downwards.
  • the supply air 60 is brought to a constant temperature, for example in the range from 60 ° C. to 70 ° C., preferably 70 ° C., and is conveyed from below through a sieving device 70 to the powder bed 80, which comprises the carrier , which is swirled by the temperature-controlled supply air 60.
  • the carrier is composed of at least one carbohydrate, for example a mixture of glucose, lactose and corn starch. In the present case, the citric acid is present in the carrier.
  • the granulating liquid from above i.e. in a countercurrent process, sprayed onto the swirled carrier, whereby the granulate builds up.
  • filters 90 are provided above the two-substance nozzle 40, through which the supply air is first filtered in order to trap entrained solid particles and then to be discharged via an exhaust air fan 100.
  • Granules were produced using the method according to the invention. For this, the compounds listed in Table 2 below were weighed:
  • the granulate was produced by the top spray fluidized bed process from Glatt, Binzen. First the system was preheated for 2 minutes (without product). Then the granulating solution was applied in countercurrent to the carrier in a fluidized bed. sprayed. The process conditions and the time sequence of the fluidized bed process are summarized in Tables 3 and 4 below:

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Granulat rapidement soluble obtenu par (a) préparation d'un liquide de granulation aqueux contenant au moins un liant et (b) pulvérisation du liquide de granulation obtenu à l'étape (a) dans un lit fluidisé selon un procédé de traitement à contre-courant avec température constante de l'air introduit sur un support contenant au moins un hydrate de carbone, la bromhexine / hydrochlorure de bromhexine et l'acide citrique étant introduits, indépendamment l'un de l'autre, dans le liquide de granulation et / ou dans le support. La présente invention permet d'obtenir, pour la première fois, un granulat hydrosoluble contenant de la bromhexine ou de l'hydrochlorure de bromhexine en tant qu'ingrédient actif. Ledit granulat est hydrosoluble malgré le fait que la bromhexine / chlorure de bromhexine est pratiquement insoluble dans l'eau, c'est-à-dire que ledit granulat se dissout complètement dans l'eau en quelques minutes et libère le principe actif dans son intégralité.
EP05737936A 2004-05-12 2005-05-04 Granulat rapidement soluble de bromhexine / hydrochlorure de bromhexine, procede de fabrication dudit granulat et son utilisation Withdrawn EP1753401A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004023930A DE102004023930A1 (de) 2004-05-12 2004-05-12 Schnell lösliches Granulat von Bromhexin/Bromhexinhydrochlorid, Verfahren zu dessen Herstellung und dessen Verwendung
PCT/EP2005/004822 WO2005110373A1 (fr) 2004-05-12 2005-05-04 Granulat rapidement soluble de bromhexine / hydrochlorure de bromhexine, procede de fabrication dudit granulat et son utilisation

Publications (1)

Publication Number Publication Date
EP1753401A1 true EP1753401A1 (fr) 2007-02-21

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Family Applications (1)

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EP05737936A Withdrawn EP1753401A1 (fr) 2004-05-12 2005-05-04 Granulat rapidement soluble de bromhexine / hydrochlorure de bromhexine, procede de fabrication dudit granulat et son utilisation

Country Status (6)

Country Link
US (1) US20050266073A1 (fr)
EP (1) EP1753401A1 (fr)
AR (1) AR048950A1 (fr)
DE (1) DE102004023930A1 (fr)
TW (1) TW200607531A (fr)
WO (1) WO2005110373A1 (fr)

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CN102293741B (zh) * 2011-08-24 2013-02-20 石家庄东方药业有限公司 一种盐酸溴己新注射液及其制备方法和用途
CN104287970A (zh) * 2014-11-07 2015-01-21 四川旭华制药有限公司 一种胶囊制粒机
CN112618493B (zh) * 2021-01-22 2022-07-15 青岛农业大学 一种兽用盐酸溴己新可溶性粉、制备方法及应用
CN118697713A (zh) * 2024-08-29 2024-09-27 山东则正医药技术有限公司 一种盐酸溴己新直服颗粒及其制备方法

Family Cites Families (4)

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Publication number Priority date Publication date Assignee Title
DE3126703A1 (de) * 1981-07-07 1983-01-27 Dr. Karl Thomae Gmbh, 7950 Biberach Bromhexin-retardform und verfahren zu ihrer herstellung
EP0627218B1 (fr) * 1992-02-18 2001-12-19 Nippon Shinyaku Company, Limited Procédé de preparation de tablettes à dissolution rapide et tablettes solubles rapidement comprenant xylitol
EP1121940A1 (fr) * 2000-01-31 2001-08-08 New Pharma Research Sweden AB Compositions pharmaceutiques comprenant des antibiotiques et bromhexine, et procédé pour leur préparation
US7799342B2 (en) * 2000-12-06 2010-09-21 Wyeth Llc Fast dissolving tablet

Non-Patent Citations (1)

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Title
See references of WO2005110373A1 *

Also Published As

Publication number Publication date
WO2005110373A1 (fr) 2005-11-24
TW200607531A (en) 2006-03-01
US20050266073A1 (en) 2005-12-01
AR048950A1 (es) 2006-06-14
DE102004023930A1 (de) 2005-12-08

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