• 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:
    The invention relates to a new antibiotic compound, acetyl erythromycin stearate having formula I <IMAGE> The compound according to the invention is absorbed readily from the alimentary tract. Gastric acid does not convert the compound according to the invention to an uneffective form as is the case with some other erythromycin antibiotics. Absorbing is good also when the patient eats when taking the new medicine. The compound according to the invention is prepared by reacting erythromycin base with acetyl halide in an organic solvent in the presence of an acid acceptor. The stearate salt is prepared from the obtained ester without in between isolating the ester.
    公开号:SU1410866A3
    申请号:SU853836820
    申请日:1985-01-04
    公开日:1988-07-15
    发明作者:Лауриантеро Марвола Мартти；Вейкко Марттила Эско；Антеро Уотила Яакко；Килликки Пиппури Айно；Юхани Кайрисало Пекка；Юхани Хонканен Эркки
    申请人:Орион-Ихтюмя Ой (Фирма)；
    IPC主号:
    专利说明:

    00
    about
    Od
     sn

    This invention relates to the preparation of a new antibiotic acetylerythromycin.
    SNS SNZ
     oHLxOH
    0 lHO., CH3bHj


    (I)
    C, gH3602
    15
    20
    CHs H
    has antimicrobial activity.
    The aim of the invention is to develop a method for the preparation of a new erythromycin prizvodnogo, which has a better absorbability compared with erythromycin stearate, less toxic to the liver than erythromycin-estolate (erythromycin lauryl sulfate 1p).
    Receiving a compound.
    200 g (2.38 mol) of sodium bicarbonate are added to the solution, which contains 400 g (0.545 mol) of erythromycin base in 3.6 liters of ethylendelate. The resulting suspension is heated to and 46.4 MP (0.65 mol) of acetyl chloride in 400 ml of ethyl acetate are added to it for 2-3 hours. Stirring at 40 ° C. is continued for another 2 hours, after which the mixture is added at 40 ° C. 1 l water. Stirring is continued for a while, after which the ethyl acetate layer is separated, concentrated to 2.5 liters and 155 g (0.545 mol) of stearic acid is added to it, Ethyl acetate is distilled off under normal pressure and 2 liters of petroleum ether are added to the residue. (bp). The mixture is slowly cooled to room temperature and then to 0 ° C. The required stearin salt is filtered from the solution, washed with petroleum ether and dried. The yield of 520 g of the product (90% of theoretical).
    Calculated: C 64.56 FI 9.98; N 1.32.
    .j (mol. weight 1060,42) Found: C 64.74; H 10.21; N 1.28.
    Preparation of pills. Example 1. Using the compound (I), tablets are prepared having the following composition, m Erythromycin acetyl stearate, corresponding to 230 mg of erythromycin393 PolyvinylpyrroleIdone 6 Purified water 54 Microcrystalline cellulose 80 Modified cellulose resin
    (Ac-gu-Sol). 10 Stemmy mgni 2 Water is evaporated during the process, and the modified cellulose resin is croscarmellose sodium.
    The active ingredient is granulated with an aqueous solution of polyvinylpyrrolidone. The granules are dried and sieved, after which the remaining ingredients are mixed with the granules and tablets are compressed from the resulting mass. Tablets are coated with a conventional coating in the form of a cellulose pigment film.
    Example 2. Using the ingredients in an amount according to example 1, excluding polyvinylpyrrolidone and water, prepare the tablets as follows. The active ingredient and microcrystalline cellulose, as well as the modified cellulose gum, are mixed. The mixture in the form of a powder is granulated in a dry form by pressing and sieving, after which magnesium stearate is added and the mixture is pressed into tablets. Also use the usual film coating.
    Preparation of spherical granules Granules contain, mg: Acetyl-erythromycin stearate, corresponding
    125 mg of erythromycin 196.5 Cornstarch 30 Granulated sugar 50
    Polyvinylpyrrole. Id15
    Water is evaporated during the process.
    Spherical granules are prepared using a Frund CF-360 granulator.
    Erythromycin preparations currently available include the erythromycin state, erythromycin lactobionic, erythromycin stearate (salt), and erythromycin-estolate, which is an erythromycin lauryl sulfate salt of erythromycin. Stearate salt is absorbed easily. Absorption is reduced further if the patient takes a meal shortly before taking the medicine or eats while taking it.
    The biggest disadvantage of the preparation in base form is that gastric acids neutralize efficacy. Transformations can be avoided by making tablets that would not dissolve until they enter the intestine. However, these so-called entero tablets are more expensive to manufacture than conventional tablets, and it is also difficult to obtain preparations that would always dissolve in the same way. This results in a variation in the concentration of active ingredient in the blood.
    Erythromycin-estol is toxic to the liver, therefore its use is limited.
    The proposed erythromycin derivative is a product that does not need to be processed to obtain enterotables or enterocapsules. In addition, good absorption allows a smaller amount of the active ingredient to obtain the necessary concentration in the blood. For this reason, tablets made from acetyl tromycin stearate are smaller in size and, therefore, less unpleasant to take. Large tablets, for example, had the disadvantage that they relatively often stuck to esophagus and could cause localized damage.
    Experiments on the absorption of erythromycin acetate.
    Absorbance Stearate Absorbtion was compared in Absorption tests.
    erythromycin absorption of erythromycin-stearate salt in humans after fasting after eating. Figure 1 shows the results of a comparative experience in people after fasting; figure 2 - the corresponding result in people who have had a normal breakfast.
    As shown in Figures 1 and 2, the absorption of acetylerythromycin stearate is better than that of erythromycin stearate after starvation. The difference is even greater when patients simultaneously with the medication took food. Serum drug concentrations increased faster when compound (I) was used than when acetylrythromycin or erythromycin stearate was used. The magnification was three times higher than with acetylerythromycin. In addition, it can be seen that the concentration in the remaining serum is higher than the concentration, which was in the case of erythromycin stearate, even after 8 hours.
    When taking Compound (I), consuming food with a drug also reduces the maximum serum concentration, and when taking Erythromycin Stearate, the reduction is so large that the resulting concentration is not sufficient to constitute a therapeutic dose.
    Thus, it was clearly shown that the compound is effectively absorbed regardless of the conditions.
    Experiments on toxicity for the liver.
    In order to determine the toxicity to the liver of acetyryrythromycin stearate salt, its effect on the enzyme Cg characterizing the functions of the liver was compared with the effect on those. the same enzymes erythromycin stearate salt and estol and erythromycin. Experimental animals were dogs in which enzymes characterizing liver function were determined both before and after a test period of 5 days. The results are shown in the table.
    It can be seen from the table that erythromycin estolate is the most toxic of the compounds tested. Increasing ASAT and
    AI.AT, caused by him, the highest. In addition, it is the only compound tested that also caused an increase in the APHOS and y-GT values.
    Pharmacological studies.
    Bacterial culture experienced.
    Experiments were performed on Dip-lococcus pneumoniae type 3 culture. Bacteria were transferred from a medium of anaerobic culture to vessels with a blood culture with a capacity of 50 ml using a metal loop. Bacteria were incubated at 37 ° C for 24 hours, yielding about 10 bacteria / ml.
    Test animals are white NMRI mice of both sexes weighing 20-25 g.
    Test procedure.
    Experimental groups were divided into 12 groups, each of which consisted of 10 smaller ones. The animals were given erythromycin stearate and acetyl-erythromycin stearate, and 100 μl of bacterial culture (about 10 bacteria / ml) was peritoneally subcutaneously injected. The doses of each of the tested compounds were as follows, mg / kg: 1.5; five; 15; 50; 150. Compounds were not administered to two control groups.
    The drugs were suspended in 0.125% carboxymethylcellulose lulose, the pH was adjusted to 6, the solution was kept on ice to minimize the degree of hydrolysis. Drugs were injected subcutaneously with an interval of a - m at 12 h.
    All animals from the control group died within 48 hours of the onset of infection. Treatment with erythromycin stearate and acetylerythromycin stearate gave results depending on the dose. None of the animals died when he was treated with acetylerythromycin stearate at a dose of 150 mg / kg of body weight per day, while in the treatment with erythromycin stearate at the same dose 1/10 of the animals died.
    Pharmacological studies show that acetylerythromycin stearate is at least as good when administered by subcutaneous route.
    activity, like erythromycin stearate.
    权利要求:
    Claims (1)
    [1]
    1. A method for preparing acetylerythromycin stearate of the formula CH3 CH2
    I on1 .on
    0 Jk JC n 0
    n c
     Cfflhseor
    CHj N
    characterized in that
    the erythromycin base is treated with an acetyl halide in an organic solvent at 20–70 ° C in the presence of an alkali or alkaline earth metal bicarbonate or carbonate, followed by treatment of the reaction mixture with water, at least an equivalent amount of stearic acid is added to the resulting solution, the solution is concentrated, a suitable solvent is added boiling point above 100 ° C, for example, petroleum ether (120 s), is cooled to a temperature below 10 ° C, followed by isolation of the desired product.
    2, The method according to claim 1, characterized in that the acetylation. is carried out in ethyl acetate with sodium bicarbonate.
    Control
    Erythromycin stearate, 278 mg / kg-2
    Before trial
    After trial
    Before trial
    After trial
    30.5 ± 7.832.8 ± 7.0 227 ± 52.4 3,, 9 15.0 ± 10.4
    30.0 ± 7.824.8 ± 1.7, 1 2.5 ± 1.7 7.5 ± 2.7
    27.3ir6.85 25.5 ± 8.5 214 ± 48.3 3,; 82 13.3 ± 5.7
    102.0 ± 48.0 33.3i13.9 178 ± 38.7 3.3tt, 3 12, Ct4.1
    Estol t Do Probe- erythromitin
    24.0 ± 7.027.3 ± 6.4 218140.6 2.8 ± 1.3 10, C ± 1.8
    qina,
    144 mg / kg 2
    After the test 285.8 ± 218.1 274,, 8 610 ± 582.4 8.0 ± 5.7 11.5i2.1
    Stearate Prior to testing acetyltinin erythromycin, 145 mg / kg 2
    After trial
    25.3 ± 3.0.0.0 ± 7.0. 209 ± 39.7 2.5 ± 1.0 7.3 ± 1.0
    90.25 ± 51.15 24.5 ± 4.4 189 ± 40.6 3.3 ± 1.5 10.3 ± 3.4
    Stearate Prior to testing acetyltinine erythromycin, 290 mg / kg-2
    After trial
    26.5t7.327.8 ± 9.2 180 ± 70.6 30.0 ± 0.0 13.0 ± 5.7
    177,01192.5 28.0ir50.9 197i96.3 5.5 ± 4.4 8.814.4
    -.- Acetyl spectrotic Acid Stearate Erythromycin
    -five
    AT
    1
    t / H / j iH d) iijuodogi90 g buYiodujHd nno)
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    同族专利:
    公开号 | 公开日
    FI77249B|1988-10-31|
    ATA985A|1988-01-15|
    DK149776C|1987-04-21|
    FI850023L|1985-07-07|
    ZA8410143B|1985-08-28|
    PT79777A|1985-01-01|
    PL251457A1|1985-11-05|
    IS2968A7|1985-04-03|
    NO160263C|1989-03-29|
    AU3705984A|1985-07-11|
    NO850007L|1985-07-08|
    BG43189A3|1988-04-15|
    JPS60158197A|1985-08-19|
    AU565688B2|1987-09-24|
    HK11590A|1990-02-23|
    AT386414B|1988-08-25|
    RO91262B|1987-07-01|
    NL8403979A|1985-08-01|
    PT79777B|1986-10-21|
    FI77249C|1989-02-10|
    HUT37628A|1986-01-23|
    IT1184304B|1987-10-28|
    HU196221B|1988-10-28|
    GB8432368D0|1985-02-06|
    NZ210606A|1987-08-31|
    FR2557878B1|1988-01-15|
    FR2557878A1|1985-07-12|
    IL73885D0|1985-03-31|
    YU44485B|1990-08-31|
    US4599326A|1986-07-08|
    CS247191B2|1986-12-18|
    KR900006237B1|1990-08-27|
    DE3500179C2|1989-08-24|
    DK5884A|1985-07-07|
    JPH029040B2|1990-02-28|
    IT8519012D0|1985-01-04|
    IL73885A|1988-10-31|
    BE901411A|1985-04-16|
    SE8406671D0|1984-12-28|
    FI850023A0|1985-01-03|
    GB2152502A|1985-08-07|
    IE850022L|1985-07-06|
    KE3841A|1989-04-07|
    RO91262A|1987-06-30|
    MX156277A|1988-08-04|
    KR850005452A|1985-08-26|
    YU2085A|1987-12-31|
    CA1224461A|1987-07-21|
    ES8605818A1|1986-04-01|
    IE57967B1|1993-06-02|
    DK5884D0|1984-01-06|
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    GB2152502B|1987-10-07|
    SE461854B|1990-04-02|
    NO160263B|1988-12-19|
    PL144349B1|1988-05-31|
    MA20316A1|1985-10-01|
    DE3500179A1|1985-07-18|
    LU85721A1|1985-07-24|
    CY1462A|1989-07-21|
    CH666275A5|1988-07-15|
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    PH22471A|1988-09-12|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR1179208A|1953-11-16|1959-05-21|Abbott Lab|Process for preparing erythromycin salts|
    DE1011117B|1953-11-16|1957-06-27|Abbott Lab|Process for the preparation of pure, stable erythromycin acid addition salts|
    GB834397A|1958-07-29|1960-05-04|Lilly Co Eli|Therapeutic compositions comprising erythromycin esters|
    US4150220A|1977-02-04|1979-04-17|Pfizer Inc.|Semi-synthetic 4"-erythromycin A derivatives|
    FR2473525B1|1980-01-11|1983-04-15|Roussel Uclaf|US4863741A|1985-03-25|1989-09-05|Abbott Laboratories|Tablet composition for drug combinations|
    US4874614A|1985-03-25|1989-10-17|Abbott Laboratories|Pharmaceutical tableting method|
    JP3382159B2|1998-08-05|2003-03-04|株式会社東芝|Information recording medium, reproducing method and recording method thereof|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DK5884A|DK149776C|1984-01-06|1984-01-06|ANTIBIOTIC EFFECT OF ERYTHROMYCIN COMPOUND AND PREPARATION CONTAINING THE COMPOUND|
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