• 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:
    L'invention concerne la préparation de nouveaux couples effervescents et de compositions les contenant par réaction d'acide citrique avec un carbonate ou bicarbonate alcalin, le milieu étant amené à réagir avec dégagement d'anhydride carbonique jusqu'à ce que l'acide soit transformé en citrate mono- ou di-alcalin. …<??>Les couples comprennent un mélange de citrates mono- et di-alcalin dans un rapport pondéral compris entre 8/1 et 1/10. …<??>Suivant une réalisation particulière de l'invention, ces compositions pharmaceutiques contiennent également un antacide pour le traitement simultané d'hyperacidité stomacale et d'hypersécrétion d'histamine au niveau des récepteurs H2.
    公开号:SU1605913A3
    申请号:SU874028841
    申请日:1987-01-21
    公开日:1990-11-07
    发明作者:Мансьон Жаки；Тарраль Рене
    申请人:Лаборатуар Смит Клайн Э Френч (Фирма)；
    IPC主号:
    专利说明:

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    This invention relates to the chemical and pharmaceutical industry and relates to a process for the preparation of effervescent antacid tablets.
    The aim of the invention is to increase stability.
    Example 1. A drying granulating mixer consisting of a vessel thermostatted by a jacket and connected to a vacuum pump, having an opening for feeding solid products, an opening for introducing liquids in dispersed form, a mixing device ensuring complete homogeneity, and an opening with a device for applying pressure to atmospheric, at 100 s (± 5 ° C) is fed through a mesh sieve with openings. in 1 mm 43.25 kg of powdered anhydrous citric acid and 5.75 kg
    sodium bicarbonate. The mixture is heated with stirring intensity. When the temperature of the products reaches 40 C (+1 C), the temperature in the thermostatted jacket is set to 75 C (+ 1 ° C).
    When the temperature of the mixture reaches 45 C (+1 s) under reduced pressure (600 mm Hg), water (160 ml) is fed in and at the same time the opening with a device for bringing the pressure to atmospheric is opened. The mixture was allowed to react for 40 minutes with vigorous stirring. Then, the stirring speed is reduced and the reaction is stopped by drying with an intensive and continuous method, which allows a decrease in the residual pressure and temperature (approximately 5-10 seconds), the latter again rising after the mass is dried.
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    cm
    Then the vacuum is removed and the mass is sieved through a sieve with openings of 2 mm.
    The result is a stoichiometric two-component mixture (78.5 kg having the ability to gasify in 64.2% (expressed in percent of the initial potential of carbon dioxide) and the corresponding composition containing 32.2% sodium dihydrate citrate, 31.4% disodium hydrate, rocitrate and 36.4% sodium bicarbonate.
    The carbon dioxide content is determined volumetric based on standardization carried out on known amounts of citric acid and sodium bicarbonate.
    Example 2. At a controlled temperature of 20 ° C (i2 c) and a relative humidity of 20% (+ 1%), 1 kg of cimetidine, 15 kg of the mixture obtained in example 1, and, are thoroughly mixed. 700 g of sodium benzoate crushed into dust,
    The mixture is pressed using a press equipped with flat round dies with a diameter of 20 mm and a weight of 1670 g, to obtain tablets with a dosage of cimetidine 100 mg „
    Tablets are packaged in sacks formed by sealing of complex sheets from Kraft-cardboard-polyethylene (12.5 g) aluminum (300 mm) - polyethylene (25 g),
    In order to determine the stability of the tablets, the bags are filled for 7 days in a drying cabinet at 70 ° C (+1 ° C) and 10 days in a drying cabinet at 60 ° C (+ 1 ° C) and using high performance liquid chromatography (HPLC)
    on a PARTI-SII / - 10-SCX column using as the mobile phase a mixture of ammonium sulphate (0.075 M, 65 vol.), methanol for spectral analysis (35 vol.) and ammonia with a total pH value of 7, determine possible decomposition products cimetidine, namely: N-carbamal N-methyl- (5-methyl 4-imidazolyl-11-thio) ethyl Tguanidine and K-methyl-M - (5-methyl-4-imidazol-sctiethyl) ethyl guanidine. Under these conditions, no trace of the presence of cimetidine debris was detected, indicating that the tablets are completely stable. At the same time, the manufacture of tablets from a simple mixture of cimetidine (1 kg), sodium benzoate (700 g) and


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    mixtures with a gas-generating ability "(63.2%), identical to the capacity of the mixture obtained in Example 1 and containing sodium d} hydrocitrate (4.575 kg), disodium hydrogen citrate (5.050 kg), and sodium bicarbonate (5.385 kg), in those the same pressing and holding conditions give 5.8% of the content of M-carbonyl-K-methyl-N -p- (5-methyl-4-imidazolylmethylthio) ethyl guanidine and 0.5% of the content of N-methyl- - N (5 -methyl-4-imidazole-1-methyl-thio-ethyl guanidine after 7 days at 70 ° C, and after 10 days at 60 C gives the content of N-carbamyl-N-methyl-N--G2- (5-methyl-4-imide, azolylmethylthio) i
    U-h
    ethyl 1 guanidine in 8.5% and N-methyl-N - -r- (5-methyl-4-imidazolylmethylthio) ethyl-guanidine in 0.6%.
    Example Z. In a drying granulating mixer, which is a vessel with a thermostatic jacket, connected to a vacuum pump and having openings for the introduction of solid products, an opening for feeding liquid in dispersed form, a mixing device ensuring complete homogeneity, and an opening with a device for applying pressure to atmospheric, at 100 ° C (± 5 ° C), 33.56 kg of powdered anhydrous citric acid and 44.04 kg of sodium bicarbonate are loaded through a sieve with openings of 1 mm. The mixture is heated with vigorous stirring. When the temperature of the products reaches 43 C (), the temperature of the thermostatic jacket is set at 65 C.
    When the temperature of the mixture reaches 51 ° C (+ 1 ° C) under reduced pressure (600 mm Hg), water (165 mm) is supplied and at the same time the opening is opened with a device to bring the pressure to atmospheric. The mixture was reacted with vigorous stirring for 35 minutes. Stirring is then slowed down and the reaction is stopped by drying with constant and vigorous suction.
    After the mass is dried, the vacuum is removed and the mass is sifted through a sieve with openings of 2 mm.
    Stoichiometric mixture (61.2 kg)
    with a gas-generating ability of 67.8% (expressed as a percentage of the initial potential of carbon dioxide) cof (4iep; v-; iiiien
    90
    i.jTBeTCTjjyp t Knmiiviiiru; 38.6% naTpniv4i7n; ipoiurir ii i 5 22.9% disodium hydrogen iprocitrate and 38.5% sodium bicarbonate. Carbon dioxide dosage is carried out by volumetric method / ohm based on standardization carried out on a certain Kojni ecTBe citric acid and nltri bicarbonate.
    Example 4. Using the method described in example 2, tablets of cimetidine were prepared containing the mixture as described in example 3, and stability tests were carried out in bags.
    After 7 days of incubation at 70 ° C (+1 s) using high performance liquid chromatography (HPLC), even traces of cimetidine decomposition products were not found: N-carba-n-methyl-N-2- (5-methyl-4- imidazolylmethylthio) ethyl guanidine; and N-mEl TIL-N | 2- (5-methyl-4-imidazolylmethylthio) ethyl guanidine.
    Example 5. In the dry FPC, a granulating mixer, which is a vessel with a total volume of 130 liters (useful volume 90 liters), which is equipped with a circulating warm water jacket and connected to a vacuum pump, has an opening for loading solid products, an opening for supplying liquid in dispersed the form, a mixing device that provides complete homogeneity, a high-speed circular knife and a hole with a device for bringing the pressure to atmospheric, at 65 ° C are fed under vigorous stirring through a sieve with 1 mm thick coats of 20.975 kg of powdered anhydrous citric acid, 27.525 kg of sodium bicarbonate and 1.5 kg of polyethylene glycol (mol.m.6000). The mixture is crushed with a disk knife and then heated with vigorous stirring. When the temperature of the mixture reached 51 ° C, water (300 ml) was added in six equal portions at intervals of 3 minutes and the mixture was left for 31 minutes after adding the first portion of water to react with vigorous stirring.
    The reaction is stopped by drying with intensive and constant suction, and the mass uniformity is ensured by using a mixing device at a reduced speed and in a batch mode.
     OS4 | one
    I 39.2
    ten
    15
    20
    25
    rezu.i1, .t; pch pysu-iipani 1g.puch, kg stokhis meter 1ch (: 1 (5) gmegp. The emitted mixture has a glucose-fighting method of 70.3% (expressed, -, in percent of the initial potential) - a lnuoksni carbongO, h its composition corresponds to 42.4% natrig dihydrocitrate, 15.5% of dinatropgyhydroggrate, 38.65% sodium bicarbonate and 3.26%
    nQJlH3 thilol glycol. The dosage of carbon nnvoKncn was carried out using the volumetric method based on standardization carried out on known amounts of citric acid and sodium bicarbonate,
    Example 6. According to the method described in example 2, obtained tablets cimetidine, containing a pair of example 3, and determined their stability in the bags.
    After 20 days. According to high performance liquid chromatography data, out, erb1van11 at 40 ° C (+ 1 ° C) was not detected: even traces of decomposition products of cimetidine, namely M-carbamyl-N -methyl-N-2- (5-methyl-4-imidazolylmethylthio) ethyl guanidine and N-MeTitn-N G2- (5-methyl-4-imidazolyl 1
    30 methylthio) ethyl / gnadipa.
    Example 7. In order to determine the limits: the acceptability of effervescent compositions containing cimetidine, a mixture with a gas-forming
    2J ability higher than in the previous examples. In this case, the method of Example 1 was used, but the reaction time was reduced from 40 to 25 minutes.
    40 As a result, a stoichiometric mixture (85 kg) with a gas-forming capacity of 78% was obtained, and this mixture was used to prepare C1 methidine tablets according to the procedure of Example 2.
    The stability test showed significant destruction of cimetidine on N-Kap6aMiin-N -methyl-N (5-methyl-4-imidazolylmethylthio) ethyl guanidine (0.89%) at the end of the process.
    6%
    a week later, 70 C ().
    popping and vani
    Moreover, testing the stability of tablets prepared according to the method of example 2 from cimetidia (1 kg), sodium benzoate (700 g) and a mixture of sodium dihydrocitrate (8.405 kg) and sodium bicarbonate (6.595 kg) and around 71 605913
    adherents. the same gas-generating aptitude as the described mixture of 78% showed, after 7 days of sweating at 70%, the presence of decomposition in the products (38 38% N-carbamyl-N-methyl-M-2) (5-methyl 4-imidazo - ylmethylthio) ethylZguan- dinne, 4% N-methyl-N- .- (5-methyl-4 imidazolylmetnl-yo) ethyl guanidine, and after 10 days at 50 ° C - the presence of 4% N-carb of CL-N -methyl-N (5-methyl-4-imidazolylmethylthio) ethyl guanidine.
    Example 8. 15 of the procedure of Example 4 was reproduced, but instead of the sodium benzoate of Example 2, the same amount of siliconized sodium benzoate with the addition of silicone oil was used (50 cSt). As a result, 20 tablets were obtained, showing no breakage after 7 days of aging at 70 s or 10 days at 60 ° C.
    Example 9. The limited protective effect of siliconized sodium benzoate was studied using the example of tablets prepared from sodium dihydrocitrate sodium bicarbonate mixture of Example 7.
    In this case, according to the method of Example 2, but replacing the mixture and the sodium bentoate of the corresponding amount of sodium dihydrogen citrate – bicarbonate sodium and siliconized sodium benzoate with the addition of 10% silicone oil (50 cSt) were obtained with dimetidine-based tablets, the stability of which was tested during the 7-day run, held at 40–70 ° C. Under these conditions, the content of N-carbamyl-N-methyl-N - p- (5-methyl-4-imidazolylmethyl-Thio) ethyl guanidine is reduced from 38 to 12%, and
    N-methyl-H - 2- (5-methyl-4-imidazolyl-45 methylthio) this guanidine snih from the
    4 to 1.2%.
    The limited protective effect of siliconized sodium benzoate was also studied on tablets prepared by the procedure of Example 2 using the mixture specified in Example 2: sodium dihydro citrate, disodium hydroxy citrate, sodium bicarbonate. It was noted that after 10 days incubation at 60 ° C, the content of N-carba-mil-K -methyl-H-C2- (5-methyl-4-imidazolylmethylthio) ethyl Zguanicidin and N-me- (5 -methyl-4-imidazolyl,

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    methylthio-5-guanidine is reduced, respectively, from 8.5 to 6.3% and from 0.6 to 0.2%.
    Example 10. A drying granulating mixer, which is a vessel, temperature-controlled by a jacket and connected to a vacuum pump, having an opening for loading solid products, an opening for introducing liquids in dispersed form, a mixing device that ensures complete homogeneity, and an opening for pressure reduction to atmospheric, when loaded with vigorous stirring through a sieve with openings in 1 mm, 33.56 kg of powdered anhydrous citric acid, and 44.04 kg of bicarbonate Atri. When the temperature of the mixture reaches 43 ° C (+ 1 ° C), the temperature in the jacket. set to 65 C (+1 C).
    When the temperature of the mixture reaches 51 ° C (+ 1 ° C) in water form, water is added to two porpes of 155 ml at an interval of 5 minutes with vigorous stirring, the reaction is carried out for 50 minutes from the moment of adding the first
    portions of water
    Then, the stirring speed is reduced and the reaction is stopped with intensive suction, which ensures a drop in residual pressure and temperature (approximately 5-10 ° C), the latter increasing again by the time the mass is dried.
    The result was a stoichiometric mixture (57.7 kg) with a gas-forming capacity of 59%, whose composition corresponds to 23.2% sodium dihydrogen citrate, 43.4% disodium hydrate, rocitrate and 33.5% sodium bicarbonate.
    Example 11. Under normal room conditions (26 ° C and relative humidity of 55-55%), carefully displace 2.5 kg of cimetidine and 25 kg of the mixture obtained at the end of Example 10, after which the resulting mixture is sealed in bags of complex Kraft sheets cardboard (50 g), polyethylene (12.5, g aluminum (300 mm) and polyethylene (25 g).
    In order to improve the stability of the powder packaged in this way, the bags are stored for 6 weeks in a drying cupboard, when used at (+ 1 ° C). After this trans-rhode by means of highly efficient
    916
    liquid chromatography did not detect decomposition products of cimetidine, while, as a result of hardening, under the conditions of a packed in bags of methyl acetate (2.5 kg), powdered anhydrous citric acid (10.815 kg), and sodium bicarbonate (14.185 kg) 0.5% N-methyl-H - 2- (5-methy-1-4-imidazolylmethylthio) ethane guanidine is formed.
    Under the same storage conditions, a mixture of cimetidine (2.5 kg), sodium dihydrogen citrate (12.058 kg) and sodium bicarbonate (9.456 kg) produces 2.3% M-carbamyl-M-methyl-K (5-methyl- - 4-imidazolylmethylthio) ethylJ guanidine and 0.02% M-methyl-k-2- (5-methyl-4-imidazolylmethylthio) methyl guanidine
    Example 12. In a drying granulation mixer, which is a vessel, thermostated by a jacket and connected to a vacuum pump, having an opening for supplying dispersed liquids, a mixing device that ensures complete homogeneity, and an opening with a device for reducing pressure to atmospheric, 100 ° C and vigorous stirring, 36.75 kg of powdered anhydrous citric acid and 63.25 kg of sodium bicarbonate are loaded through a 1 mm sieve. After the temperature of the mixture reaches 40 ° C, the temperature in the thermostatic jacket is set to 75 ° C. When the temperature reached 45–46 ° C, with vigorous stirring, water (160 ml) was added in a spray form. The mixture was allowed to react for 30 minutes (+3 minutes).
    Then, the stirring rate is reduced and the reaction is stopped by drying with intensive suction, providing a drop in residual pressure and temperature (approximately 5-10 ° C), with the latter increasing again as the mass is dried.
    By this time, the vacuum is removed and the mass is sieved by passing through a sieve with openings of 2 mm.
    As a result, a mixture (78.4 kg) with an excess of bicarbonate and a gas-forming capacity of 60.5% was obtained, whose composition corresponds to 24.45% sodium dihydrocitrate, 28.05% disodium hydrohydrate and 47.5% sodium bicarbonate.
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    Example 13. According to the method of example 2, tablets were prepared containing the mixture of example 12, and their stability was tested during storage in bags.
    After 13 days of storage at () by high performance liquid chromatography, 0.3% H-carbamyl-H-methyl-N - (5-methyl-4-imvdazolylmethyl) thio-ethyl-guanidine was detected.
    On the other hand, in the same storage conditions, tablets prepared by mixing c of shetidine (1 kg) and sodium benzoate (700 g) with a mixture having the same gas-generating capacity as the preceding vapor, and consisting of sodium dihydrocitrate (3.74 kg ), disodium hydrogen citrate (4.12 kg) and sodium bicarbonate (7.14 kg), form upon decomposition 10.1% of K-carbamyl-N-methyl-N - (5-methyl-4-imidazolylthio) ethyl guanidine and 1.38% N-methyl-N - 2- (5-methyl-4-imide, azolylmethylthio) ethyl guanidine.
    Example 14. A solid granulating mixer consisting of a vessel, equipped with a thermostatic jacket and connected to a vacuum pump, having an opening for loading solid products, an opening for supplying liquids in dispersed form, a mixing device ensuring complete homogeneity, and an opening with a device to bring ggls to atm spherical, with () through a sieve with openings of 1 mm. 43.25 kg of powdered anhydrous citric acid and 56.75 kg of sodium bicarbonate are harvested. The mixture is heated with vigorous stirring, and when the temperature of the products reaches 0 ° C, the temperature in the thermostatic head is set to 75 ° C. When the temperature of the mixture reaches 45-46 ° C, at the temperature of the jacket, sprayed water (160 mp) is added with vigorous stirring. The mixture is left to react for 40 minutes. Then, the stirring speed is reduced and the reaction is stopped by drying. With intensive suction, providing a drop in residual pressure and temperature (about 5-10 seconds), the latter is again shed as it dries.
    i160
    masses. At this point, the vacuum is removed and the mass sieved Circassian lattice
    a sieve with 2 mm openings,
    As a result, a stoichiometric mixture (78.6 kg) with a gas-forming capacity of 62%, whose composition corresponds to 28.8% sodium hydroxide, 35.8% sodium disodium hydroxide and 35.4% sodium carbonate, was obtained.
    Example 15. At room conditions and at a relative humidity of 20% cimetidine hydrochloride h.) Are thoroughly mixed with 15 parts of the pair obtained in Example 14, and the mixture is packaged in bags formed by sealing of complex Kraft cardboard sheets (50 g), polyethylene (12.5 g), aluminum (30 mm.) and polyethylene (25 g).
    To test the powder packaged in this way, the bags were stored for a week, after which no high-performance chromatography of the decomposition products was detected.
    Under the same storage conditions, a mixture of 1.1455 parts of hydrochloride dimethidine, 6.4875 parts of powdered anhydrous citric acid, and 8.5125 parts of sodium bicarbonate formed 59.6% of N-carbamate-N-methyl-N ( 5-methyl-4-imidazolylmethylthio) ethylDgua.nidine and 3.5% K-methyl-S - 2- (5-methyl-4-imidazolylmethylthio) ethyl guanidine. Under the same storage conditions (1 week at 60 ° C) in a mixture of 1.1455 parts of cimetidine hydrochloride, 8.41 parts of sodium-dihydroditrate and 6.59 parts of sodium bicarbonate, 3.6% of N-carbamate-N-methyl-N is formed: - 2 - (5-metesh-6-imida-zolylmethylthio) ethyl jgianidine,
    Under the same storage conditions in a mixture of 1.1445 parts of cimetidine chlorohydrate, 4.32 hours, sodium dihydrocitrate, 5.38 parts of disodium hydrocitrate, 5.300 parts of sodium bicarbonate with the same gas-forming capacity (62%, as mixtures, obtained in Example 14., 3.2% of N-carbamate-N-methyl 1 2- (5-methyl-4-imidazoylmethylthio ethylLguanide is formed.
    EXAMPLE 16 A drying granulation mixer, which is a vessel equipped with a thermostatic jacket and connected to a vacuum pump, having an opening for feeding solid products, an opening for feeding liquids into the dispersion.

    five
    ABOUT
    5 50
    55
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    Iio eMtniinn; iioiui (- ug -) - roystvo, obesinichnaya polluk odtsm affinity, and the hole with the structure of the atmosphere, to reduce the pressure to atmospheric, at 100 ° C through a lattice sieve with openings of 1 mm serves 36, 76 kg of powdered anhydrous citric acid and 63.25 kg of sodium bicarbonate. The mixture is heated with vigorous stirring, and when the temperature of the products reaches 40 C (+ l c), the temperature in the thermostating jacket is set to 75 C
    (ti c).
    When the temperature of the mixture reaches 45-46 ° C and a jacket temperature of 75 ° C, sprayed water (160 ml) is added with vigorous stirring. The mixture is left to react for 28 minutes and 30 seconds. Then, the stirring speed is reduced and the reaction is stopped by drying with an intense and continuous suction, providing a drop in residual pressure and temperature (approximately), and the latter rises again as the mass dries.
    The vacuum is then removed and the mass is sieved through a two-millimeter sieve.
    As a result, a mixture (78.52 kg) was obtained with an excess of bicarbonate with respect to the stoichiometric amount and gas-forming ability of 61.9%, whose composition corresponds to 26.3% sodium dihydrocyterate, 25.7% disodium hydrocite and 25.7% sodium bicarbonate.
    Example 17. At room conditions, corresponding to a temperature in and a relative humidity of 20%, cimetidine hydrochloride (h) is thoroughly mixed with 15 parts of the mixture obtained in Example 16, and the mixture is poured into bags formed by sealing of complex sheets of Kraft cardboard (50 g), polyethylene (12.5 g), aluminum (30 mm) and polyethylene (25 g).
    To reveal the stability of the powder packaged in this way, the bags were stored at 60 ° C for a week, and no decomposition products were detected using high performance liquid chromatography.
    Under the same storage conditions (one week at) in a mixture of 1.1445 hours. cimetidine hydrochloride, 9.4875 parts of sodium bicarbonate and 5.5125 parts of powdered anhydrous citric acid form 40.9% of N-Kap6aMHn-N - methyl-M -12- (5-methyl-4-imidazolylthio) ethyl guanidine and .O., 8% N-methyl-2- (5-methyl-4-imidazolylmethylthio) ethylTguanidine
    Under the same storage conditions (one week at 70 s) in a mixture of 1.1445 h of cimetidine hydrochloride, 6.97 parts of sodium dihydrocitrate and 8.03 h, sodium bicarbonate forms 5.4% of N-carbamyl -N - 2- (5-methyl-4-imidazolylmethyl) ethyl guanidine.
    Under the same storage conditions (one week at 60 ° C) in a mixture of 1.1445 h of cimetidine hydrochloride, 3.94 parts of sodium dihydrocitrate, 3.86 parts of disodium hydrocitrate and 7.2 parts of sodium bicarbonate j the same gas-forming ability (61.9%) as the mixture obtained in Example 16 yields 4.9% H-carbamyl-H-methyl--N-2- (5-methyl-4-imidazo-1-methyl-thio) guanidine .
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    After the check, the effervescent tablets are more stable in the proposed method and their destruction was not detected in comparison with the tablets obtained by a known method, while 38% destruction was observed during a week at 70 ° C.
    权利要求:
    Claims (1)
    [1]
    The invention of the method of obtaining effervescent tablets by mixing citric acid FJ with an at least stoichiometric amount of alkali metal bicarbonate and granulating, characterized in that, with a mixture of stability of sodium bicarbonate, the mixture is left to react at that moment, when 23–54% of carbon dioxide is released, and a double mixture of 5 containing mono- and disodium citrate is obtained in a ratio of 8: 1 to 1:10 by weight, the reaction is stopped by drying and mixed with cimetide after granulation.
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    GR3001150T3|1992-06-25|
    AU6789987A|1987-07-23|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8600839A|FR2593065B1|1986-01-22|1986-01-22|EFFERVESCENT COUPLES, EFFERVESCENT COMPOSITIONS OF HISTAMINE H2 ANTAGONISTS CONTAINING THEM AND THEIR PREPARATION.|
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