• 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:
    Improved pharmaceutical salts of amlodipine, particularly the besylate salt, and pharmaceutical compositions thereof. These salts find utility as anti-ischaemic and anti-hypertensive agents.
    公开号:SU1498388A3
    申请号:SU874202353
    申请日:1987-04-03
    公开日:1989-07-30
    发明作者:Дэвисон Эдвард；Инграм Веллс Джеймс
    申请人:Пфайзер Лимитед (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the preparation of a novel 1,4-dihydropyridine-3,5-carboxylic acid derivative, in particular, to a process for the preparation of the benzosulfonate salt of 3-methyl 2-methyl ester 2- (2-aminoethoxymethyl) -4 - (2-chlorophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid-amlodipine, is an anti-ischemic and anti-hypertensive agent.
    The purpose of the invention is to create, on the basis of known methods, a method of obtaining a new compound possessing a number of valuable pharmacological and physiological properties.
    The invention is illustrated by the following;
    Example 1. Preparation of the ester-free ester (benzenesulfonate salt) of amlodipine (3-ethyl-5-methyl 3-ether 2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -6-methyl-1,4-dihydro - pyridine-3,5 dicarboxylic acid).
    Amdodipine (base) (65.6 g, 0.16 mol) is stirred in industrial methylated alcohol (ethanol, methanol-depaturated) (326.4 ml) and oh-pdzhd to. Benzenesulfonic acid (26.2 g. O, 168 mol) is dissolved in industrial methylated alcohol (65.6 ° ml) at 5 ° C and added) sweat to the base sludge, the resulting slurry is then granulated, filtered and washed with two volumes of oil. } 1npgo methylated-
    four
    about 00 with
    00 00

    Sl1
    alcohol (65.6 ml). (Ibipoe solid is stirred for 1 hour in industrial methylated alcohol (327.6 ml), filtered off, rinsed with two volumes of industrial methylated alcohol (65.6 ml) and sutate in vacuum at 55 ° C for 24 hours. Yield 76.5 g (83.8%) of T. pl. 201.0 C.
    Calculated,%: C 55.07; H 5.51; N 4.94.
    Found,%: C 54.91; H 5.46; N 4.93.
    Example 2. Ammonium benzene sulfoate (0.943 g) is added to the pads of amlodipine base (2 g) in industrial methylated alcohol (10 ml) and the resulting solution is heated under reflux for 10 minutes. The reaction mixture is cooled and granulated at 5 ° C for 1 h, Amlodipine benzene sulphonate is filtered, washed with industrial methylated alcohol (ml) and dried in vacuum o The yield is 1.9 g (70% of the theoretical). T. pl. 201.0 C.
    Calculated,%: C 55.07; H 5.51; N 4.95.
    Found,%: C 54.98; H 5.46; N 4.90.
    Pharmacological and physicochemical tests
    Determination of solubility. Water solubility is required for bio-mixing. It is preferable to obtain a solubility of 1 mg / ml at pH 1-7.5. Among additive acid salts, those with a pH close to the blood pH level (7.4) are preferred because they are biocompatible and easily stabilized with buffer to the required pH level without changing their solubility.
    In tab. I is given the solubility of a besylate salt.
    As can be seen from the table. 1 besylat- amlodipine salt is characterized by good solubility compared with other salts.
    Definition of stability. Solid stability is important for tablets and capsules. To determine chemical stability, each of the salts was mixed with a porous carrier and molded into tablets or capsules. The carrier in the tablets is microcrystalline cel
    0
    5 0 5
    0
    50
    0
    five
    a 50:50 vine with an anhydrous calcium phosphate containing two bases, a carrier in capsules is mannitol in a ratio of 54: 1 with dry corn starch. Then, tablets and capsules were stored in sealed ampoules at 50 and 75 ° C for up to three weeks. The drug and broken rock were extracted with a methanol: chloroform mixture (50:50) and separated on a thin layer chromatography column with silica gel plates using the I-dissolving systems.
    Salts were evaluated according to the number and amount of degraded products. After comparing the results, the following order of location of the salts was determined, with the besylate being the most stable salt and the hydrochloride being the least stable salt:
    Besylate most stable
    Mesilate
    Tosylate
    Succinate
    Salicylate
    Maleat
    Acetate
    Hydrochloride Unstable
    Determination of hygroscopicity. In order to obtain stable forms, one needs to have a non-hygroscopic salt. The hygroscopicity of the drug or its salt leads to the absorption of free moisture, which usually causes instability.
    Only salts such as maleate, tosylate and besylate do not absorb moisture at a relative humidity of 75% at 37 ° C for 24 hours. Even at a relative humidity of 95% and for 3 days both the besylate and maleate remain anhydrous. Therefore, it can be considered that besylate salt is non-hygroscopic and therefore it forms stable forms, minimizing the possibility of internal chemical decomposition.
    Determination of adhesion properties. The last characteristic of acceptable salt is considered the possibility of its processing, i.e. the ability to be pressed pressed} and also the ability to adhere and adhere to a tablet manufacturing plant.
    Compatibility is very important for release forms that contain a large dose, since sticking of the drug to the stamps should be avoided.
    tablet making machines. When the compound sticks to the surface of the punch, it causes spoilage of the surface of the tablets, which become ng. PG-anodic. The drug is priggyping when:: dit is increased, then the effort spent on removing the tablet from the device. Thus, the selection of salt with good anti-adhesive properties reduces these problems to a minimum.
    In order to compare the degree of adherence of the various salts of amlodipine, the following procedures were performed using known tablet manufacturing facilities: half fifty tablets containing calcium sulfate dihydrate, microcrystalline cellulose, and amlodipine bezalt (47.5: 47.5: 5 ), the material sticking to the stamp was then extracted using methanol, and the amount was determined by spectrometric methods. This procedure was repeated for 100, 150, 200, 250 and 300 tablets. After each procedure, the amount of adhering material on the die was determined to compress the tablets after extraction with methanol. Values are presented in the form of a graph and calculated the average value based on the slope of the obtained curve.
    The same procedure was then repeated for each amlodipine salt. The measured amount of amlodipine adhering to the tablet process is shown in Table. 2 for each salt and for the maleate salt.
    Thus, besylate possesses higher anti-adhesive properties compared to maleate.
    A three-month oral test of amlodipine besylate for rat toxicity. Amlodipine besylate is prescribed for oral forced feeding to Sprague-Dyuli rats (16 each sex per level) at daily doses of 30, 10, 3 mg / kg for 3 months, followed by 6 rats of each group followed a one-month recovery period.
    ten
    15
    4983886
    At no dose level would there be any deaths associated with the drug. At the highest dose of 30 mg / kg, salivation and growth suppression were observed, there was an increase in urinary volume, accompanied by increased electrolyte secretion and decrease in tertiary electrolytes with a slight increase in BUN, the small intestine was slightly enlarged in the absence of any morphological damage. Histopathology revealed a generally moderate proliferation of the glomerular zone of the adrenal gland, and urine excretion of electrolytes was impaired at 10 mg / kg.
    After 3 months, the intake of the drug was discontinued and in a subsequent study of rats after months of c, the indicated changes in the experimental group turned out to be comparable with the changes in the control animals, which shows the complete reversibility of the changes caused by the medication.
    Thus, amlodiline besylate salt is characterized by good solubility, stability, non-hygroscopicity and good compressibility, which makes it suitable for the preparation of pharmaceutical forms of amlodiline.
    20
    25
    thirty
    权利要求:
    Claims (2)
    [1]
    Claim 1 o Method for the preparation of 3- (2-amino-ethoxymethyl) -4- (2-chlorophenyl) -6-methyl-1,4-dihydropyridine-3,5- benzene sulphate salt of the 3-ethyl-5-methyl-2-amino-ethoxymethyl benzene sulphate salt. dicarboxylic acid, characterized in that 3-ethyl-5-methyl ester. 2- (2-aminoethoxymethyl) -4- (2-chlorophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid is reacted with a solution of benzenesulfonic acid or its ammonium salt in an inert solvent o
    [2]
    2. The method according to PI 1, characterized in that ethanol denatured by methyl alcohol is used as an inert solvent.
    1498388
    Table 1
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    同族专利:
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    申请号 | 申请日 | 专利标题
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