• 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:
    A non-effervescent granulate containing N-acetylcysteine and maltodextrin is disclosed.
    公开号:CH712181A2
    申请号:CH00188/17
    申请日:2017-02-20
    公开日:2017-08-31
    发明作者:Stroppolo Federico；Granata Gabriele
    申请人:Alpex Pharma S A；
    IPC主号:
    专利说明:

    Description: [0001] The present invention relates to a pharmaceutical composition in the form of a non-effervescent granulate containing N-acetylcysteine and, more particularly, to a pharmaceutical composition in the form of a non-effervescent granulate containing N-acetylcysteine and maltodextrin.
    [0002] N-acetylcysteine, commonly known as NAC, is a synthetic modified N-acetylated amino acid used for many years as a mucolytic active ingredient.
    [0003] NAC is also used in different doses and in different formulations to treat paracetamol poisoning, amanita poisoning and other fungi, cystic fibrosis, dry eye syndrome, plaque dentistry, skin diseases and other pathologies.
    [0004] EP 2 558 065 A1, in the name of the Applicant, discloses stable effervescent formulations containing NAC and sucralose.
    One of the main problems related to the formulation of the NAC, in particular in the form of granules, is to provide a composition that is stable, both from the chemical point of view and from the physical point of view.
    The problem of stability is more obvious when effervescent granules of NAC are stored for a long time, especially at high ambient temperatures, as often happens in summer, or in regions where the climate is constantly hot.
    In fact, in effervescent granules heated above 40 C, the sodium bicarbonate present in the formulation begins to react, releasing CO 2 and water. Under these conditions, the stabilities of the effervescent granule and the NAC decrease.
    In addition, the effervescent granules contain a lot of sodium or potassium derived from carbonate or bicarbonate used for effervescence, which is not indicated in some patients with kidney or cardiovascular disease.
    Another problem in the formulation of granular NAC is to provide a granule which has a good flowability and which is in particular free-flowing, for preparing bags containing the granule, having a regularity of weight.
    In addition, there is a need for a granulate containing NAC having a volume (i.e., a bulk density and compacted) reduced, so as to easily fill bags.
    Accordingly, there is a need for a stable granule containing NAC that solves all the aforementioned technical problems. The inventors of the present application have surprisingly found that non-effervescent granules containing N-acetylcysteine and maltodextrin are very stable both physically and chemically, have good flowability and reduced volume and thus have many advantages from a formulation point of view in pharmaceutical technology.
    An object of the present invention is therefore a non-effervescent granule comprising: - at least 30% by weight of N-acetylcysteine, - at least 30% by weight of maltodextrin, - a slipperiness, - a sweetener, - an agent flavoring agent, wherein the weight ratio of N-acetylcysteine to maltodextrin is from about 0.8 to about 1.2.
    The non-effervescent granules of the present invention may contain 600 mg of NAC with a total weight of about 1.3 to 2.0 g and have increased stability compared to effervescent granules containing the same amount of NACs known in the art. art, as we can appreciate in the experimental part. The characterizing feature of the non-effervescent granule according to the present invention is the weight ratio of N-acetylcysteine to maltodextrin which is from about 0.8 to about 1.2.
    [0014] Preferably, the weight ratio of N-acetylcysteine to maltodextrin is from about 0.9 to about 1 and more preferably 0.9.
    A slider according to the present invention may be smoked colloidal silicon dioxide, known under the trade name Aerosil® 200, or precipitated silica known under the brand name Syloid®, or talc, preferably the slipper is smoked colloidal silicon dioxide.
    A sweetener according to the present invention may be any artificial or natural sweetener conventionally used in pharmaceutical technology, such as aspartame, saccharin, acesulfame potassium, sucralose, stevia, advantame, neotame, preferably the sweetener is sucralose.
    A flavoring agent according to the present invention may be any flavoring agent conventionally used in pharmaceutical technology, such as the aroma of orange, the aroma of lemon, the aroma of peppermint, the aroma of anise , the apricot aroma, the strawberry flavor, preferably the flavoring agent is the orange aroma, in particular the sensient orange aroma 00 285.
    According to another embodiment of the present invention, the non-effervescent granule may optionally further comprise a polyalcohol preferably chosen from sorbitol, xylitol, mannitol, maltitol, lactitol, more preferably mannitol. .
    According to a preferred embodiment of the present invention, the non-effervescent granule comprises N-acetylcysteine in an amount of about 30 to 45% by weight and maltodextrin in an amount of about 33 to 50% by weight.
    A non-effervescent granule comprising: - 30 to 45% by weight of N-acetylcysteine, - 33 to 50% by weight of maltodextrin, - 0.1 to 0.5% by weight of a slipper, - 2 to 6% by weight of a flavoring agent, - 0.7 to 2% by weight of a sweetener is a more preferred object of the present invention.
    The non-effervescent granulate according to the present invention can be prepared according to conventional granulation techniques which will be illustrated in detail in the experimental section.
    Specific examples of particularly preferred non-effervescent granules have the following quantitative composition (percentages by weight in parentheses): N-acetylcysteine 600 mg (44.78%)
    Maltodextrin 660 mg (49.25%)
    Orange flavor 60 mg (4.48%)
    Sucralose 18 mg (1.34%)
    Colloidal Silicon Dioxide 2 mg (0.15%)
    Total weight 1340 mg [0023] and N-acetylcysteine 600 mg (30.00%)
    Maltodextrin 660 mg (33.00%)
    Mannitol 660 mg (33.00%)
    Orange flavor 60 mg (3.00%)
    Sucralose 18 mg (0.90%)
    Colloidal Silicon Dioxide 2 mg (0.10%)
    Total weight 2000 mg [0024] In order to better illustrate the invention, without however limiting it, the following examples are now given.
    Example 1
    Preparation of a non-effervescent granule [0025] _
    Ingredients Composition per sachet Batch composition of 134 kg mg kg N-acetylcysteine 600 60
    Maltodextrin 660 66
    In a fluid bed granulator under the name Aeromatic S6, 60 kg of N-acetylcysteine, 66 kg of malto-dextrin, 1.8 kg of sucralose and 6 kg of orange flavor were placed.
    The mixture was granulated with 6 kg of purified water and then dried at 60 ° C until the relative humidity (RH) of the granule was below 0.5%.
    At the end of the process, the granulate was mixed for 15 minutes in a cubic mixer such as a Zanchetta silo mixer together with 0.2 kg of Aerosyl 200.
    With the aid of industrial equipment such as a Marchesini RC 600 filling machine, the sachets were filled with 1340 mg of granules in order to obtain 600 mg of N-acetylcysteine in each sachet.
    Characteristics of the non-effervescent granule
    Appearance of granules White to yellow granules without foreign bodies
    Particle size 90% to less than 500 pm 50% to less than 250 pm
    Apparent density 0.7
    Density after settlement 0.8
    Ability to flow as a 34 ° angle of repose
    Comparative Example 2
    Preparation of an effervescent granulate Γ00311
    In an Aeromatic S6 fluid bed granulator, 60 kg of N-acetylcysteine, 40 kg of citric acid, 42 kg of sodium bicarbonate, 7 kg of orange flavor and 1 kg of sucralose were placed.
    The mixture was granulated with 6 kg of purified water and then dried at 60 ° C until the relative humidity (RH) of the granule was below 0.5%.
    At the end of the process, the granulate was mixed for 15 minutes in a cubic mixer such as a Zanchetta silo mixer.
    With the aid of industrial equipment such as Marchesini RC 600 filling machine, the sachets were filled with 1500 mg of granules to obtain 600 mg of N-acetylcysteine in each sachet.
    Characteristics of the effervescent granule
    Appearance of granules White to yellow granules without foreign bodies
    Particle size 90% to less than 530 pm 50% to less than 250 pm
    Apparent density 0,87
    Density after settlement 0.96
    Ability to flow as a 34 ° angle of repose
    Example 3
    Preparation of a non-effervescent granulate
    In an Aeromatic S6 fluid bed granulator, 60 kg of N-acetylcysteine, 66 kg of maltodextrin, 66 kg of DC mannitol, 400 kg of orange flavor, 1.8 kg of sucralose were placed, 0.2 kg Aerosyl 200.
    The mixture was granulated with 6 kg of purified water and then dried at 60 ° C until the relative humidity (RH) of the granule was below 0.5%.
    At the end of the process, the granulate was mixed for 15 minutes in a cubic mixer such as a Zanchetta silo mixer.
    Using industrial equipment such as a Marchesini RC 600 filling machine, the sachets were filled with 2000 mg of granules to obtain 600 mg of N-acetylcysteine in each sachet.
    Characteristics of the non-effervescent granule
    Appearance of granules White to yellow granules without foreign bodies
    Particle size 90% to less than 530 pm 50% to less than 250 pm
    Apparent density 0,70
    Density after settlement 0.8
    Ability to flow as a 35 ° angle of repose
    Example 4
    Comparison of the CV (coefficient of variation) of the weight of the granule filling the sachets
    权利要求:
    Claims (10)
    [1]

    Example 1, despite the reduced weight of the bags and the presence of more than 40% of N-acetylcysteine in the composition, has a similar weight regularity or greater than the other compositions. Example 5 Comparison of the stability between Example 1, Comparative Example 2 and Example 3

    As can be appreciated from the results reported above, the non-effervescent granules of the present invention (Examples 1 and 3) have: - a lower bulk density compared to the effervescent granule of the comparative example 2; lower packing density compared to the effervescent granule of Comparative Example 2; - a coefficient of variation (in particular example 1) lower compared to the effervescent granule of Comparative Example 2; a better stability (N-acetylcysteine assay) in comparison with the effervescent granule of Comparative Example 2. Claims
    1. Non-effervescent granulate comprising: at least 30% by weight of N-acetylcysteine, at least 30% by weight of maltodextrin, a slip, a flavoring agent, a sweetener, in which the ratio by weight of N acetylcysteine and maltodextrin is from about 0.8 to about 1.2.
    [2]
    The non-effervescent granulate of claim 1 comprising N-acetylcysteine in an amount of about 30 to 45% by weight and maltodextrin in an amount of about 33 to 50% by weight.
    [3]
    3. Non-effervescent granulate according to claim 1 or 2, comprising - 30 to 45% by weight of N-acetylcysteine, - 33 to 50% by weight of maltodextrin, - 0.1 to 0.5% by weight of a slipping agent. 2 to 6% by weight of a flavoring agent, 0.7 to 2% by weight of a sweetener.
    [4]
    The non-effervescent granulate according to claims 1 to 3, wherein the slipper is fumed colloidal silicon dioxide or precipitated silica or talc, preferably the slipper is fumed colloidal silicon dioxide.
    [5]
    5. Non-effervescent granulate according to claims 1 to 4, wherein the flavoring agent is an orange aroma, a lemon aroma, a peppermint aroma, an anise aroma, apricot aroma, aroma. strawberry, preferably the flavoring agent is an orange flavor.
    [6]
    6. non-effervescent granulate according to claims 1 to 5, wherein the sweetener is an artificial or natural sweetener selected from aspartame, saccharin, acesulfame potassium, sucralose, stevia, advantame, neotame, preferably the sweetener is sucralose.
    [7]
    7. Non-effervescent granulate according to claims 1 to 6, further comprising a polyhydric alcohol.
    [8]
    8. Non-effervescent granulate according to claim 7, wherein the polyalcohol is selected from sorbitol, xylitol, mannitol, maltitol, lactitol, preferably the polyhydric alcohol is mannitol.
    [9]
    The non-effervescent granulate of claim 1 having the following quantitative composition: N-acetylcysteine 600 mg Maltodextrin 660 mg Orange flavor 60 mg Sucralose 18 mg Colloidal silicon dioxide 2 mg Total weight 1340 mg.
    [10]
    10. Non-effervescent granulate according to claim 1, having the following quantitative composition: N-acetylcysteine 600 mg Maltodextrin 660 mg Mannitol 660 mg Orange flavor 60 mg Sucralose 18 mg Colloidal silicon dioxide 2 mg Total weight 2000 mg.
    类似技术:
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    同族专利:
    公开号 | 公开日
    CH712181B1|2020-09-30|
    FR3047898B1|2020-09-18|
    GB201701787D0|2017-03-22|
    DE102017103033A1|2017-08-24|
    GB2552728B|2019-11-20|
    GB2552728A|2018-02-07|
    FR3047898A1|2017-08-25|
    GB2552728A9|2019-07-17|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE19931708A1|1999-07-08|2001-01-18|Bayer Ag|Process for the preparation of rapidly disintegrating solid pharmaceutical preparations|
    EP1449525A1|2003-02-20|2004-08-25|Cross Chem Llc|chewing gum in the form of multi-layer tablets|
    TR200900882A2|2009-02-05|2010-08-23|Bi̇lgi̇ç Mahmut|Pharmaceutical compositions with high bioavailability, masked by taste and odor.|
    IT1399492B1|2010-04-13|2013-04-19|Alpex Pharma Sa|EFFERVESCENT PHARMACEUTICAL COMPOSITIONS CONTAINING N-ACETYLCISTEIN.|
    EP2571499A1|2010-05-18|2013-03-27|Mahmut Bilgic|Pharmaceutical composition comprising n- acetylcysteine and a xanthine|
    US8747894B2|2012-05-08|2014-06-10|Alpex Pharma S.A.|Effervescent compositions containing N-acetylcysteine|
    法律状态:
    2020-02-14| NV| New agent|Representative=s name: IPWAY SAGL, CH |
    2020-04-15| PCAR| Change of the address of the representative|Free format text: NEW ADDRESS: VIA FRANCESCO SOMAINI 9, 6900 LUGANO (CH) |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1651458A|FR3047898B1|2016-02-23|2016-02-23|NON-EFFERVESCENT GRANULES CONTAINING N-ACETYLCYSTEINE.|
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