• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    aqueous composition containing bromhexine. the present invention relates to an aqueous composition containing bromhexine, wherein the composition has an amount of sugar alcohols of less than 10 g based on 100 ml of the composition, as well as its use for secretolytic therapy in acute and bronchopulmonary diseases chronicles.
    公开号:BR112013000537B1
    申请号:R112013000537-8
    申请日:2011-07-07
    公开日:2021-07-27
    发明作者:Uwe Scheuring；Bernd Plohmann；Annette ZAMPONI
    申请人:Boehringer Ingelheim International Gmbh；
    IPC主号:
    专利说明:

    [001] The present invention relates to bromhexine which is a synthetic derivative of the plant active substance vasicin. It acts both secretalytically and secretomotorically in the bronchial tract region. In clinical studies it has been shown that this decreases coughing and facilitates the act of coughing. Mucus transport is promoted by reducing viscosity and activating the ciliary epithelium. As a result, bromhexine is used for secretory therapy in acute and chronic bronchopulmonary diseases, which occur together with a disturbance in mucus formation and transport.
    [002] Furthermore, it is known that bromhexine hydrochloride when stored, is subject to a slow decomposition process. Decomposition products are, according to the European monograph of bromhexine hydrochloride (Ph Eur monograph 0706), in particular (A) (2-amino-3,5-dibromophenyl)methanol, (B) 2-amino-3,5 -dibromo-benzaldehyde, (C) N-(2-aminobenzyl)-N-methylcyclohexanamine, (D) N-(2-amino-5-bromobenzyl)-N-methylcyclohexanamine and (E) (3RS)- 6,8-dibromo-3-cyclohexyl-3-methyl-1,2,3,4-tetrahydroquinazolin-3-ium.
    [003] For the stabilization of the composition containing bromhexine, JP 10101581 teaches the use of reducing agents and/or chelate complex formers.
    [004] JP 200281562 and JP 2007119453 teach the use of sugar alcohols for stabilizing the composition containing bromhexine. JP 63313725 teaches maltitol as a particularly suitable stabilizer. JP 10036292 and JP 10306038 teach as another advantage of sugar alcohols the masking of the inherent bitter taste of bromhexine.
    [005] A particularly stable aqueous composition containing bromhexine is marketed under the name Bisolvon® syrup (solution to drink). This composition contains bromhexine hydrochloride (8 mg/5 ml), maltitol syrup, benzoic acid, levomenthol, sucralose, flavors and purified water.
    [006] The aim of the present invention was to provide an aqueous solution of bromhexine, which stands out for a particularly high stability, that is, for a particularly low decomposition rate of bromhexine. By this means, in particular, a suitability of the composition for filling in film packaging should be obtained. Furthermore, the composition according to the invention, as possible, should stand out for its excellent masking of the bitter taste of bromhexine. Furthermore, the composition according to the invention, as possible, should also stand out due to a texture suitable for the taste.
    [007] According to the invention, these objectives are solved by an aqueous composition containing bromhexine, wherein the composition has an amount of sugar alcohols of less than 10 g based on 100 ml of the composition.
    [008] The compositions according to the invention surprisingly stand out, despite the low proportion of sugar alcohols suitable for stabilization, by a very low decomposition rate of bromhexine. Consequently, it is possible to dispense with the addition of reducing agents and/or chelate complex formers taught in the prior art.
    The compositions according to the invention, based on the per se known effect of bromhexine, are particularly suitable as cough juice or cough syrup.
    [0010] Accordingly, another object of the present invention relates to the use of a composition according to the invention, as defined herein, for secretory therapy in acute and chronic bronchopulmonary diseases.
    In the context of the present invention, the term "bromhexine" represents N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexanamine hydrochloride.
    [0012] Generally, the compositions according to the invention contain bromhexine in an amount of 0.04 to 0.4 g based on 100 ml of the composition. The amount of bromhexine indicated in each case refers to the amount of salt used. Preferably, the compositions according to the invention contain bromhexine in an amount of 0.08 to 0.32 g, for example in an amount of 0.16 g, in each case based on 100 ml of the composition.
    [0013] A special embodiment of the present invention relates to compositions according to the invention, which contain bromhexine as the only active substance, i.e. so-called monopreparations.
    [0014] In the context of the present invention, the term "sugar alcohol" represents compounds, which can be obtained by reducing a saccharide, in particular, a mono- or disaccharide. Conventional sugar alcohols as additives to pharmaceutical compositions are, for example, sorbitol, xylitol, maltitol, isomalitol, mannitol, threitol, erythritol and arabitol.
    [0015] The amount of sugar alcohols in the compositions according to the invention amounts to less than 10 g based on 100 ml of the composition. Preferably, the amount of sugar alcohols in the compositions according to the invention amounts to less than 5 g and particularly preferably less than 1 g, in each case based on 100 ml of the composition. A special embodiment of the invention relates to compositions, which are free from sugar alcohols.
    [0016] In the context of the present invention, the term "aqueous compositions" represents liquid compositions whose solvent consists of less than 50% by weight of water. The remaining solvent is generally selected here from alcohols such as ethanol, polyethylene glycol (macrogol), propylene glycol and glycerol. Preferably, however, the term "aqueous compositions" designates compositions whose solvents consist of less than 80% by weight, and particularly preferably less than 90% by weight, of water. A special embodiment relates to compositions according to the invention whose solvent consists exclusively of water. Such compositions are alcohol-free and thus fundamentally suitable for use with children.
    [0017] The proportion of solvent in the composition according to the invention generally amounts to less than 50% by weight. The compositions according to the invention are preferably characterized by a solvent content of at least 70% by weight and particularly preferably at least 80% by weight. The compositions according to the invention, owing to the dispensing of sugar alcohols for stabilization, also allow a solvent content of less than 90 or at least 95% by weight.
    [0018] Generally, the compositions according to the invention contain a suitable thickener. Hereby, the compositions according to the invention, depending on the form of administration desired, can be adjusted to the required viscosity. Therefore, the compositions according to the invention contain the thickener in an amount, which is suitable to adjust the desired viscosity. Generally, the compositions according to the invention contain the thickener in an amount of 0.05 to 5 g based on 100 ml of the composition according to the invention.
    Suitable thickeners are, for example, selected from hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose (MC), carboxymethylcellulose (CMC) and methylethylcellulose (MEC). Preferably, the thickeners are selected from hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC) and hydroxypropylcellulose (HPC). In particular, the thickener used according to the invention is hydroxyethylcellulose.
    The compositions according to the invention generally stand out for a viscosity in the range of 50 mPas to 30 Pas at a temperature of 20oC.
    [0021] A special embodiment relates to the composition according to the invention, wherein the composition is a cough syrup or cough syrup. These special administration forms generally have a viscosity of less than 100 mPas and in particular at least 120 mPas, each at a temperature of 20°C. The amount of thickener contained herein is generally in the range of 0.1 to 1 g based on 100 ml of the composition according to the invention.
    [0022] Generally, the compositions according to the invention contain a suitable sweetener. Preferably sweeteners according to the invention are used which are different from sugar alcohols, i.e. the compositions according to the invention in this embodiment are free of sugar alcohols.
    Suitable sweeteners are selected, for example, from sucralose, acesulfam, aspartame, cyclamate, saccharin, isomalt, maltitol, xylitol, lactitol, erythritol, alitame, thaumatin and neohesperidin dihydrochalcone. Preferably sucralose, acesulfam, aspartame, cyclamate, saccharin, alitame, thaumatin and neohesperidin dihydrochalcone are suitable. The sucralose sweetener is particularly preferred.
    The compositions according to the invention contain the sweetener generally in an amount of 0.01 g to 10 g based on 100 ml of the composition. Preferably, the compositions according to the invention contain the sweetener in an amount of 0.1 to 1 g and particularly preferably in an amount of 0.1 to 0.5 g, in each case based on 100 ml of the composition. according to the invention.
    [0025] Generally, the compositions according to the invention contain a suitable preservative.
    [0026] For the sake of clarity, the term "preservative" as used herein does not refer to sugar alcohols which, as is known, also have a preservative effect.
    [0027] Suitable preservatives are, for example, benzoic acid, sorbic acid, sulfurous acid or their salts. In particular, benzoic acid has proven to be a suitable preservative for bromhexine-containing compositions.
    The compositions according to the invention contain the preservative generally in an amount of 0.005 to 0.5 g based on 100 ml of the composition. Preferably, the compositions according to the invention contain the preservative in an amount of from 0.01 to 0.1 g, particularly preferably from 0.02 to 0.05 g, in each case based on 100 ml of the composition. .
    [0029] Generally, the compositions according to the invention have a pH value in the range from 2.0 to 6.0, preferably from 2.5 to 4.5. Particularly preferably, the pH value of the compositions according to the invention lies in a range from 3.0 to 4.0.
    Suitable acid regulators are, for example, malic acid, fumaric acid, lactic acid, citric acid, tartaric acid, orthophosphoric acid, metatartaric acid, adipic acid or succinic acid.
    [0031] If an acid or its salt in the compositions according to the invention is used as a preservative, the use of an additional acid regulator will generally be dispensed with. In a special embodiment, therefore, the composition according to the invention generally does not contain any acid regulator.
    [0032] In another preferred embodiment, the composition according to the invention does not contain reducing agents and/or chelate complex formers, such as tartaric acid, EDTA or the like.
    [0033] The composition according to one of the preceding claims, consisting of: a) bromhexine in an amount of 0.04 g to 0.4 g, b) thickener in an amount of 0.005 g to 5 g, c) sweetener in an amount from 0.01 g to 10 g, d) other suitable additives selected from preservatives, acid regulators, defoamers, flavorings and colorings, in an amount of 0 to 10 g and e) water ad 100 ml.
    [0034] With respect to the preferred quantity and quality of the components of this special embodiment, the foregoing applies.
    [0035] Suitable defoamers, such as, for example, simethicone, are known to the skilled person.
    [0036] Suitable flavorings and colorings are known to the skilled person.
    [0037] The preparation of the compositions according to the invention is carried out by conventional formulation techniques. In that case, it is not critical whether the components of the composition according to the invention are mixed with one another simultaneously or successively. Likewise, it is irrelevant, in which order. The components of the composition according to the invention can be supplied in pure form, in the form of solutions or in the form of partial compositions, which already contain various components of the composition according to the invention.
    [0038] By virtue of their high stability, the compositions according to the invention are suitable for filling in all conventional packaging forms. The compositions according to the invention, in addition to conventional filling in glass containers, are suitable, in particular, because of their high stability, also for filling in packages in chemically inert films. Suitable films are commercially available. Especially for the packaging in films of the compositions according to the invention, laminated films are suitable, such as are commercially available, for example, under the trade names Aclar® or Barex®.
    [0039] In the following, the invention is elucidated in detail based on non-limiting examples. Examples (A) Preparation example:
    To 60 ml of water was added hydroxyethylcellulose under stirring at 20 - 25°C. The mixture thus obtained was stirred for a further 30 minutes and then heated to about 85°C with stirring for a period of 60 minutes. Then benzoic acid (25.4 mg) was added and stirred for another 10 minutes. Then, 35 ml of water were added and the solution was cooled to 60oC. Bromhexine hydrochloride (160 mg) was added and stirred for 20 minutes. Then, the solution was cooled to 50°C, sucralose (225 mg) was added and the solution was stirred for 10 minutes. Then, it was cooled to room temperature and flavoring (41 mg) was added. After a further 30 minutes of stirring, it was made up to a total volume of 100 ml by addition of water. Then, the obtained composition was stirred for 10 minutes, filtered and filled in a sachet-type packaging machine or in brown glass vials.
    [0041] The composition according to the invention obtained in this way has a viscosity of 135 mPas. Viscosity was determined at a temperature of 20°C by means of a drop-bead viscometer according to the method of the European pharmacopoeia (European Pharmacopoeia, 6th edition, page 84, chapter 2.2.49). (B) Searches for stability
    [0042] To research stability, the composition obtained in (A), as well as a composition corresponding to Bisolvon® cough syrup (comparative example) were each filled in a film packaging (prepared from the company's Barex® films DanaPak) and in a commercially available brown glass bottle. The stability of the composition under controlled storage conditions (30oC, 75% purity) was evaluated based on the decomposition product E ((3RS)-6,8-dibromo-3-cyclohexyl-3-methyl-1,2 ,3,4-tetrahydroquinazolin-3-yl) described in the European monograph. For this purpose, the content of the samples of decomposition product E was determined by means of HPLC and UV detection.
    [0043] The results of this research are compiled below. a) Bisolvon® cough syrup (comparative example) Composition: Bromhexine hydrochloride (0.16 g/100 ml), liquid maltitol (50 g), benzoic acid (0.13 g/100 ml), flavoring, water.

    b) Composition according to the invention. Composition: according to the preparation example (A).
    [0044] The test results show that the compositions according to the invention stand out for a particularly low composition ratio of bromhexine compared to commercially available bromhexine-containing compositions.
    权利要求:
    Claims (8)
    [0001]
    1. Aqueous composition, characterized in that it consists of: (a) bromhexine in an amount of 0.04 g to 0.4 g; (b) thickener in an amount of 0.005 g to 5 g; (c) sweetener in an amount of 0.01 g to 10 g; (d) suitable additional additives selected from preservatives, acidity regulators, defoamers, flavorings and colorings in an amount of 0 to 10 g and (e) water up to 100 ml, the composition having a quantity of sugar alcohols of less than 10 g based on 100 ml of the composition.
    [0002]
    2. Composition according to claim 1, characterized in that it has a viscosity in the range of 50 mPas to 30 Pas at a temperature of 20oC.
    [0003]
    3. Composition according to claim 1 or 2, characterized in that it contains a suitable preservative.
    [0004]
    4. Composition according to claim 3, characterized in that the preservative is present in an amount of 0.01 g to 0.5 g based on 100 ml of the composition.
    [0005]
    5. Composition according to any one of claims 1 to 4, characterized in that it has a pH value in the range of 2.0 to 6.0.
    [0006]
    6. Composition according to any one of claims 1 to 5, characterized in that the composition has a water content of at least 70% by weight.
    [0007]
    7. Composition according to any one of claims 1 to 6, characterized in that it is a cough juice or cough syrup.
    [0008]
    8. Use of a composition as defined in any one of the preceding claims, characterized in that it is in the preparation of a composition for use in secretory therapy in acute and chronic bronchopulmonary diseases.
    类似技术:
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    法律状态:
    2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-07-24| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-02-05| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2021-05-25| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-07-27| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 07/07/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP10169236.6|2010-07-12|
    EP10169236|2010-07-12|
    PCT/EP2011/061527|WO2012007352A1|2010-07-12|2011-07-07|Aqueous composition comprising bromhexine|
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