• 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 present invention relates to the preparation of sterile and stable freeze-dried forms of Cisplatinum containing from 10 to 50 mg of active ingredient, which can be obtained on an industrial scale and which have particular characteristics of facility and rapidity of dissolution which permit them to be used in a more advantageous and rational manner in antitumor chemotherapy, as compared with the freeze-dried forms of Cisplatinum presently on the market. These particular characteristics are achieved as the result of employing special ingredients in respect of formulation (concentration of the solution to be freeze-dried, introduction of alcohols, adjustment of the pH of the solution to an appropriate value), and as the result of using a manufacturing technique having as its final stage the freeze-drying of Cisplatinum in a water-alcoholic medium. The manufacturing method, and in particular the freeze-drying process, have shown themselves to be economically advantageous, and have made it possible to overcome the very considerable problems connected with the freeze-drying of Cisplatinum in aqueous medium (breakage of containers, very low yields), as well as to obtain preparations perfectly adapted to be used therapeutically by intravenous administration.
    公开号:SU1424722A3
    申请号:SU833643499
    申请日:1983-09-15
    公开日:1988-09-15
    发明作者:Баттелли Гаетано；Олдани Диего；Ригамонти Александро
    申请人:Фармиталия Карло Эрба С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    SP
    The invention relates to the chemical and pharmaceutical industry and relates to the preparation of a medicament having an anti-wound effect.
    The purpose of the invention is to increase the solubility.
    Example 1. Use 0 mg of the preparation of platinum cisisomer, dried at a temperature below 5 C, having a composition per ampoule, g:
    Diamine dichloride
    platinum (P)
    Cis isomer 0,010
    Sodium chloride 0.045 mannitol
    Take 1 n. hydrochloric acid to bring the pH to 3.5; isopropyl alcohol, 0.015 ml; water for injection in an amount sufficient to bring the volume to 7.500 ml.
    1. In 90% of water for injection, deaerated by blowing nitrogen, sodium chloride is dissolved with stirring.
    2. The solution obtained is heated to 45-AO with, while purging with nitrogen, the Platinum (P) Diamine Dichloride is dissolved in the cis-isomer with vigorous stirring. The implementation of this procedure is carried out in the absence of light. Subsequent procedures are also performed, protecting the solution from light.
    3. Slowly cool the solution to and dissolve the mannitol.
    4.1 N hydrochloric acid adjusted the pH of the solution to 3.5.
    5. While stirring, add isopropyl alcohol and bring to final volume.
    6. Under aseptic conditions, filter the solution through a membrane filter with a pore size of 0.22 oi.
    7.B aseptic conditions distribute the solution in colorless sterile glass ampoules with a capacity of 20 mp.
    7.5 ml per vial.
    8. Cool ampoules to -45 C.
    9. Prispunda to drying at a temperature below 0 C, heat the shelves of the apparatus in which the drying is carried out at. temperature below 0 ° C to 40 ° C. Limit the time required for the final drying of the product at 25-35 C (preferably 30 C), up to 3-6 hours, and preferably up to 4 hours,
    10. Capsules dried at temperatures below О С with sterile stoppers made of elasto
    ABOUT
    0
    e
    0
    five
    dimensional material, preferably halide butyl rubber, and sealed with sterile aluminum caps.
    The drying time at a temperature below 0 ° C (excluding the freezing time) is 18 hours. The dissolution time of the preparation dried at a temperature below 0 ° C in 10 ml of sterile water for injection is 30 seconds.
    PRI mme R 2. Use 25 mg of the cis-isomer of platinum of the following composition, dried at a temperature below О С per ampoule, g: Diamine-dichloride plate (P)
    cis isomer 0,025 Sodium chloride 0,200 Mannit 0,600
    Take 1 n. sufficient hydrochloric acid to bring the pH to 3.2; 96% ethyl alcohol 0.375 ml; water for injection in an amount necessary to bring the volume to 18.750 ml.
    The substance is prepared according to example 1 with the exception of paragraphs 4.5 and 7, which were modified as follows.
    4. Adjust the pH of the solution to 3.2 by adding 1 n. hydrochloric acid.
    5. With stirring, add 96% ethyl alcohol and bring the volume to a final value.
    7. Aseptically distribute the solution in sterile colorless glass ampoules (type 1) with a capacity of 50 mp in the amount of 18.75 ml per vial.
    The drying time at a temperature below (excluding the freezing time) is 25 hours. The time of dissolution of the preparation dried at a temperature below 0 ° C in 25 ml of sterile water for injection is 1 minute.
    Example 3. Use 50 mg of the drug dried at a temperature below 0 ° C, having the following composition per astulla, g:
    Diamine dichloride
    platinum (P)
    cis isomer 0,050
    Sodium chloride 0,225
    Mannitol 1,500

    Use 1 n. sufficient hydrochloric acid to bring the pH to 4; tert-butyl alcohol 0.375 ml; water for injection in an amount necessary to bring the volume to 37,500 ml.
    The substance is obtained according to example 1 with the exception of paragraphs 4.5 and 7, which were modified as follows.
    4. To bring the pH of the solution to 4 by adding 1 n hydrochloric acid.
    5. With stirring, add tert-butyl alcohol and bring the volume to a final value.
    7. Aseptically distribute the solution in sterile colorless glass ampoules (type 1) with a capacity of 100 ml in an amount of 37.5 ml per vial.
    Drying time at a temperature below 0 ° C (excluding the freezing time) is 33 h.
    The dissolution time of the 50-MP drug, dried at a temperature below О С, of sterile water for injection is 30 s.
    PRI me R 4. Use 10 mg of the cis-isomer of platinum dried at a temperature below О С, having a composition per ampoule, g:
    Diamine dichloride

    0.010 0.090 0.130
    Take 1 n. sufficient hydrochloric acid to bring the pH to 3.5; 96% ethyl alcohol 0.025 ml; water for injection in an amount necessary to bring the volume up to 5,000 kp.
    Receiving the solution is similar to example 1 except for paragraphs 5 and 7.
    5. With stirring, add 96% ethyl alcohol and bring the volume to a final value.
    7. Aseptically distribute the solution in sterile yellow glass ampoules (type I) with a capacity of 20 mp in an amount of 5 ml per ampoule.
    Drying time at a temperature below 0 s (excluding freezing time) is 15 hours. The dissolution time of the dried at a temperature below the preparation in 10 ml of sterile water for injection is 1 minute.
    Example 5. Use 25 mg of the cis-isomer of platinum dried at a temperature below О С, having a composition per ampoule, g:
    Diamine dichloride
    platinum (P)
    cis isomer 0.025 sodium chloride 0.120 mannitol 0.750
    Take 1 n. a sufficient amount of hydrochloric acid to adjust the pH to 3.5, 96% ethyl alcohol 0.125 ml; water for injection in an amount necessary to bring the volume up to 12,500 ml.
    The preparation of the solution was carried out according to Example 1 with the exception of paragraphs 5.7 and 10.
    5. With stirring, add 96% ethyl alcohol and bring the volume to a final value.
    7. Aseptically distribute the solution in sterile colorless glass ampoules (type I) with a capacity of 50 ml in the amount of 12.5 ml per vial and close with a stopper made of chlorinated rubber, then freeze.
    10. Shut dried at a temperature below the ampoule and directly in the chamber using an internal blocking device. Unload ampoules and seal with sterile aluminum caps. Drying time at a temperature below 0 ° C (excluding freezing time) is 20 hours. The time of dissolution of the preparation dried at a temperature below 0 ° C in 25 ml of sterile water for injection is 1 minute.
    PRI me R 6. Use 50 mg
    Cis-isomer of platinum dried at a temperature below О С, having a composition per ampoule, g: Platinum (II) diamine dichloride
    cis isomer 0,050 sodium chloride 0,450 cannitol 0,500
    Take 1 n. sufficient hydrochloric acid to bring the pH to 3.2; isopropyl alcohol 0.187 ml; water for injection in an amount necessary to bring the volume to 37,500 ml.
    Receipt was carried out according to example 1 with the exception of points 4 7 ..
    4. Adjust the pH of the solution to 3.2 by adding 1 n. hydrochloric acid.
    7. Aseptically distribute the solution in colorless sterile glass ampoules (type I) with a capacity of 100 ml in an amount of 37.5 mp per vial.
    Drying time, at a temperature below O C (excluding the freezing time T
    147U.722 j-o
    It is 32 hours. The dissolution time, with solid substances, distinguished by drying at a temperature below 0 ° C (: y and with the fact that, with the aim of increasing the preparation in 50 ml of sterile water, the solubility in an aqueous plant for injection is 30 seq.gp containing chloride ions, with
    权利要求:
    Claims (1)
    [1]
    The proposed method allows 35-45 ° C to be added to cisplatin in the amount of cis-platinum solubility ranging from 1.2-2 mg / ml, mannitol 100-30 seconds to 1 minute, according to the well-known method 1500 mg, then The pH of the solution was adjusted to a dissolution time of 2-3 minutes. up to 3,2-D, 0 1 and. with a solution of hydrochloric acid Formula Yu, added alcohol, mainly ethanol, isopropanol, tert. A method of producing cisplatin, puutanol in an amount of 0.2-0.5 ob.h. Mix it with water and auxiliary, and freeze dry it.
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    同族专利:
    公开号 | 公开日
    FR2533439B1|1986-08-14|
    SE8304920D0|1983-09-13|
    JPS5978117A|1984-05-04|
    NL8303211A|1984-04-16|
    FI78236B|1989-03-31|
    CA1211372A|1986-09-16|
    GB2127291B|1986-01-15|
    US4670262A|1987-06-02|
    DK424383A|1984-03-24|
    FR2533439A1|1984-03-30|
    SE8304920L|1984-03-24|
    SE464061B|1991-03-04|
    FI78236C|1989-07-10|
    IE832172L|1984-03-23|
    CH655852A5|1986-05-30|
    GB2127291A|1984-04-11|
    BE897761A|1984-01-02|
    IL69752D0|1983-12-30|
    AU1908983A|1984-03-29|
    ZA836904B|1984-10-31|
    ATA326283A|1986-06-15|
    IE56173B1|1991-05-08|
    DK157168B|1989-11-20|
    IT8223396D0|1982-09-23|
    FI833300A0|1983-09-15|
    DK157168C|1990-04-09|
    GB8324380D0|1983-10-12|
    IT1153974B|1987-01-21|
    FI833300A|1984-03-24|
    AU559499B2|1987-03-12|
    GR79055B|1984-10-02|
    IL69752A|1986-07-31|
    AT382077B|1987-01-12|
    DK424383D0|1983-09-16|
    DE3333024A1|1984-03-29|
    引用文献:
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    GB1432562A|1972-04-10|1976-04-22|Rustenburg Platinum Mines Ltd|Platinum co-ordination compounds|
    US4053587A|1973-04-13|1977-10-11|Research Corporation|Method of treating viral infections|
    US4255417A|1976-08-04|1981-03-10|Johnson Matthey, Inc.|Platinum compounds for the irradication of skin blemishes|
    SE445172B|1978-05-30|1986-06-09|Bristol Myers Co|STABLE, STERILE WATER DISPOSAL OF CISPLATIN IN UNIT DOSAGE FORM|
    US4273755A|1979-08-16|1981-06-16|Mpd Technology Corporation|Preparation of platinum complexes|
    US4302446A|1979-10-02|1981-11-24|Bristol-Myers Company|Pharmaceutical compositions|
    US4451447A|1980-03-31|1984-05-29|Bristol-Myers Company|Pharmaceutical formulations|
    CA1162479A|1980-03-31|1984-02-21|Murray A. Kaplan|Pharmaceutical formulations containing cisplatin|NL8303657A|1983-10-24|1985-05-17|Pharmachemie Bv|SOLUTION, STABLE, AQUEOUS, AQUEOUS, CONTAINING SOLUTION OF CISPLATINE, AND METHOD OF PREPARING THEREOF.|
    IL76889D0|1984-11-02|1986-02-28|Johnson Matthey Plc|Solubilised platinum compound,method for the production thereof and pharmaceutical compositions containing the same|
    JPH0665648B2|1985-09-25|1994-08-24|塩野義製薬株式会社|Stable freeze-drying formulation of platinum anticancer substance|
    JP2524217B2|1988-04-18|1996-08-14|マルハ株式会社|Brain function improving composition, learning ability enhancing agent, memory enhancing agent, dementia preventive agent or dementia therapeutic agent|
    FI895340A0|1988-11-14|1989-11-09|Squibb Bristol Myers Co|HYPERTONISK CISPLATIN-LOESNING.|
    US20030148933A1|1990-10-01|2003-08-07|Pharma Mar S.A.|Derivatives of dehydrodidemnin B|
    WO1994005299A1|1992-09-04|1994-03-17|Fuji Kagaku Kogyo Kabushiki Kaisha|Medicinal composition|
    FR2759293B1|1997-02-11|1999-04-30|Ethypharm Lab Prod Ethiques|CISPLATIN-CONTAINING MICROGRANULES, MANUFACTURING METHOD, PHARMACEUTICAL PREPARATION AND USE IN POLYCHEMOTHERAPY OR IN ASSOCIATION WITH RADIOTHERAPY|
    GB9803448D0|1998-02-18|1998-04-15|Pharma Mar Sa|Pharmaceutical formulation|
    IL155273D0|2000-10-12|2003-11-23|Pharma Mar Sa|Pharmaceutical compositions comprising an aplidine compound|
    IL149488D0|1999-11-15|2002-11-10|Pharma Mar Sa|Pharmaceutical compositions containing aplidine|
    DE60133817T2|2000-06-30|2009-05-20|Pharma Mar, S.A., Tres Cantos|PROCESS FOR PREPARING APLIDINE AND NEW ANTITUMOROUS DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE|
    US6699835B2|2001-01-25|2004-03-02|The United States Of America As Represented By The Department Of Health And Human Services|Formulation of boronic acid compounds|
    EP1447084B1|2001-09-21|2012-11-28|Dainippon Sumitomo Pharma Co., Ltd.|Freeze-dried pharmaceutical preparation|
    AT411036T|2001-10-19|2008-10-15|Pharma Mar Sa|USE OF APLIDINE IN THE TREATMENT OF PANCREATIC CANCER|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    IT23396/82A|IT1153974B|1982-09-23|1982-09-23|PHARMACOLOGICAL COMPOSITIONS BASED ON CISPLATIN AND METHOD FOR THEIR OBTAINMENT|
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