• 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:
    Stabilised pharmaceutical formulations of prostacyclin or certain analogues thereof comprising an amino acid buffer, optionally containing a base, and the preparation of such formulations.
    公开号:SU978715A3
    申请号:SU792772851
    申请日:1979-05-16
    公开日:1982-11-30
    发明作者:Сеймур Воттс Ян；Хью Марсден Питер
    申请人:Дзе Велкам Фаундейшн Лимитед (Фирма)；
    IPC主号:
    专利说明:

    I The invention relates to chemical-pharmaceutical industry and pharmaceuticals: the production of pharmaceuticals. A method is known for preparing an aqueous solution of prostacyclic or a salt thereof by mixing with a pharmaceutically acceptable buffer C1. However, the known method does not allow to obtain a stable target product. The purpose of the invention is to increase the stability of the target product. This goal is achieved according to the method of obtaining an aqueous solution of prostacyclin or its salt by mixing with a pharmaceutically acceptable buffer, in which non-alkaline O1-amino acid is used as a buffer with an amino acid concentration of 0.02-0.03 M and the pH of the composition is 9.0-11.6. The amino acid used as a buffer should be free of sulfur, glycine is most preferred, but other amino acids such as valine, alanine and arginine can be used. The total concentration of the amino acid should be lower - 0.020, 03 N, preferably O, 025 M. The amino acid must be sufficiently dilute to provide the necessary buffer capacity. Sodium chloride may be present in the buffer solution, but its amount should not be such that the solution becomes pharmaceutically unacceptable. The molar concentration of sodium chloride should be the same as the amino acid concentration. A large amount of sodium chloride increases the ionic strength of the solution, the bound active compound and the buffer, which is undesirable for the stability of the compound, and potassium chloride may be present in the buffer. The pH of the buffer should be between 10.2 and 11.6, preferably 10.5. The method is carried out as follows. A solution of glycine in water is prepared containing some sodium chloride. To this solution, sodium hydroxide is added first as a base in order to raise the pH to the required level, and then prostacyclin. Any base that is strong enough to make a buffer solution with the required pH can be used as a base. The base must be such that it results in a pharmaceutically acceptable solution, i.e. a solution that is not harmful to the recipient. The amount of amino acid used, for example glycine, and a base, for example sodium hydroxide, should be minimally necessary to stabilize the active compound for the required time. The use of an excess of an amino acid or base, or both, of these components results in the retention of water in the drying product upon freezing, which causes the destruction of the active compound. In determining pharmaceutical acceptability, pH of the solution is an important factor. If a prostacyclin solution has to be introduced into the device, for example, an artificial kidney, then the pH can be as high as 12 or even more, but if the solution is to be introduced into a large volume in a vein, for example, into a cardiopulmonary artificial system, the pH at The vein should be predominantly 8.4-9.0. For this, the pH of the solution can be lowered immediately before use. Other agents may be present in the buffer solution, but their number should not significantly reduce the stability of the active compound in the solution. For example, some carbonates associated with prostacyclin may be present, for example, sodium simple cyclin may contain up to 5 wt. sodium carbonate. When the active compound is pharmacologically very active, the required amount is very small; For example, only a few miligrams are required for a one-hour infusion into a patient weighing 70 kg. The amount of active compound present in this buffer solution prior to freeze drying depends on the use of this material after reconstitution. Recovery can be done with a buffer solution free of the active compound, so that. the ratio of active compound to buffer components may be greater than that used for administration. If the solution containing only buffering agents, the active compound and sodium chloride is freeze-dried, then the physical strength and appearance of the freeze-dried sample obtained are not particularly satisfactory. Therefore, before drying, it is preferable to include in the buffer solution an indifferent part of the drug. The preferred indifferent component of the drug is mannitol, which concentrates 25-50 mg / ml buffer solution. ; If less than 25 mg / ml / mannitol is used, the strength and appearance of the drug are not good enough. If more than 50 mg / ml is used, the improvement is insignificant or not at all observed and the stability of the active compound is low. The indifferent component provides in the freeze-dried sample a supporting matrix and improves the physical strength and appearance of the sample. Not all indifferent constituents can be used, for example, those substances that exhibit excessive foaming of the recovered material, such as polyvinylpyrrolidone, should be avoided. Also, substances that affect the pH of the buffer solution, such as glycine, cannot be used. The buffer solution may contain, besides the active compound, other therapeutic components. The freeze-dried product may also contain other therapeutic substances or these substances may be added to the reconstituted buffer solution. Such therapeutic substances can partially or completely replace the indifferent parts of the drug. The solvent used to prepare the buffer solution.
    is preferably water for injection (Eurapeun pharmacopelce) or other water suitable for use in infusions or injections. When the freeze-dried substance is reconstituted for use, it can be redissolved in water for injection, having a pH of 5.5-7, preferably 7, or in an amino acid buffer solution, having a pH of 9, preferably 10.5, or some amount of buffer. the solution can be added to the solution in water for injection. The reduction of the freeze-dried material can also be carried out by dissolving it in a physiological solution suitable for infusion. For this purpose use glucose. .
    Freeze-drying of the buffer solution can be carried out using any known method, and the water content should be reduced, since this is necessary for the subsequent stability of the active compound.
    The amount of prostacyclin required for therapeutic effect is dependent on the mode of administration. The dose for mammals is in the range of 0.01-200 mg per 1 kg of live weight, better than 0.01-10 mg per 1 kg of live weight, preferably 0.2-0.5 mg / kg.
    The amount of prostacyclin present in the ampoule for infusion is in the range of 0.11, 5 mg / kg, preferably 0.51; 0 mg / kg. Active compound, when 025 M amino acid, 0.25 chloride
    Amino acid buffer: sodium and yatri hydroxide at pH 10.5; mg / l sodium bicarbonate and 161 mg / l Carbonate buffer: sodium carbonate; 605 mg / l Tris base and 2.5 ml Tris buffer: 0.1 sodium hydroxide per liter.
    The 5 ml portions of each of these i Column Parameters 25 cm x 2 mm.
    The solutions are then dried in a freeze-column. They are packed using waving at -40 ° C under the base of the Akbeum and Webbera and Mekerrbla methods; the first stage of drying at 0 ° C is applied to the willow of the liquid medium at 4 ° C. Sealing bubble-jQ carbon chloride.
    Covers are carried out under a nitrogen atmosphere. Next, the column phase is prepared followed by dried products are subjected to storage testing. After the test, it is analyzed for the content of prostacyclin by liquid chromatography.
    Yes, it is applied to humans, it may be several times more potent than other mammals.
    For humans and for veterinary use, at least measures are taken from two vessels (for example, in the form of multi-component packaging, one of which is a vial or ampoule and contains a freeze-dried sample (lyrphilized) from the active compound with a buffer, and the other a vial or ampoule, and contains an additional amount of buffer in an aqueous solution or freeze-dried, which does not contain the active compound. Freeze-dried product can be further reconstituted with an aqueous solution of buffer or solution from the second vessel. The recovered material can be further diluted, and the target dose should be provided immediately prior to administration. Thus, the dried preparation, for example, 0.5 mg of prostacyclin at pH 11.5 can be diluted with 50 or 500 ml of an aqueous dextrose solution or saline solution having a pH such as to obtain a solution with a pH of 10.010, 5.
    Example 1 Sterile solutions containing prostacyclin (0.2 and O, it mg / ml) and mannitol (50 mg / ml) are prepared in the following buffers: glycine, arginine, valine, alanine, carbonate, and tris buffer. The concentrations of the buffer components are:
    in a way.
    10 g of the packing is dried under vacuum for two and a half hours in a 250 ml rotary evaporation flask. 10 ml of octadecyltrichlorosilane and 100 ml of: toluene are added and the solution is heated under reflux for three hours with stirring using a paddle stirrer and using a reflux condenser equipped with a calcium chloride protection tube; The mixture is cooled and then filtered through a 0.5 micron filter. The oxide of the cream on the filter is washed with 250 ml of hot acetone and dried under vacuum for two hours. The product (11 g) is treated with trimethylchlorosilane (10 ml) as above, boiling under reflux for 5 minutes leads to the formation of the desired product. Water (1200 ml) is used as the mobile phase, in which 5 g of boric acid and 7.6 g of binatrium tetraborate are dissolved and then methanol (8800 ml) is added. The temperature of the column is room temperature (about 25-30 ° C), the flow of the mobile phase is 3.6 ml / min at a pressure of 20 MPa. Product detection was performed using Ruy Unichem IZ at a wavelength of 205 n with a full scale of 0.16 absorption units for 0-100 mg / ml solution. The amount of simple cyclin present is calculated by measuring the peak height and comparison with a reference sample of known concentration. . Example 2. Freeze-dried injection of prostacyclin contains the following ingredients, mg: Prostacyclin Mannitol Sodium chloride (0, M) Glycine (0.025 M) Sodium hydroxide Quantity corresponding to 1 pH 10, as in Example 1, 1 ml of prostacyclin injection is freeze-dried to obtain a substance containing up to 5 wt.% of water. Example 3. Stirred solution of β-prostaglandin PLF / ioL-methyl ester (50 mg) in ether (1 ml is treated with sodium bicarbonate and then an aqueous solution of potassium triiodide is added dropwise over 2 hours. After stirring overnight, the reaction the mixture is shaken with ether and an aqueous solution of sodium thiosulfate. The ether phase is separated, washed with water, dried over magnesium sulfate and evaporated to give a yellow gum with 5 f-iodo-3-deoxy-6, Eot-epoxyprostaglandin Fi methyl fir. Solution of 5-iodo-9-deoxy-6 |, 9p-epoxy prostaglandin P methyl cl The aqueous ester in a methanolic solution of sodium methoxide obtained from atri and dry methanol is left under dry nitrogen for 5 hours and then the solvent is distilled off in a BbicoKOM vacuum.The remaining solid amorphous substance is washed with benzene, left in an air atmosphere overnight and then stirred with an aqueous solution of sodium hydroxide to form a suspension of thin, colorless needles. The crystals are removed, washed with several drops of an aqueous solution of sodium hydroxide and air dried to obtain the 9-deoxy-6.91-epoxy sodium salt -prostaglandina. Inhibition of arachidonic acid induced by human platelet aggregation at a concentration of 0.2 ng / ml of this salt, and its instability at an acidic pH, together with subsequent evidence, suggest that it is consistent with the configuration (52) -5,5-DIdehydro-3 -deoxy-b. Eob-.epoxy-prostaglandin F / it ,. NMR specimens of high resolution C of a solution of crystals in dimethyl sulfoxide-d showed the corresponding 20 radicals, the chemical shifts of which fully correspond to the chemical structure established for prostacyclin. No impurity peaks detected. Example k. 5 | -Iodo-9-deoxy-6f, 9-epoxy prostaglandin F / fj-t methyl ester is mixed with a methanol solution of sodium methoxide prepared from sodium under nitrogen at room temperature overnight; A 1N aqueous solution of sodium hydroxide was added to the yellow reaction solution to hydrolyze the ether portion, and after 2 hours, the methanol was evaporated under vacuum at room temperature. In the residual aqueous solution, colorless fine needles of the sodium salt crystallize spontaneously, which is cooled (until). taken, washed carefully with 1N. , aqueous solution of sodium hydroxide, dried in air and xpahmT in a closed tube. This salt has a Vmax (CVH disk). CM 1b9 2 () and twenty (resonances C are observed at 182.7
    权利要求:
    Claims (1)
    [1]
    Claim
    A method of obtaining an aqueous solution of prostacyclin or its salt by mixing with a pharmaceutically acceptable buffer, characterized in that, in order to increase the stability of the target product, a non-sulfur containing ct amino acid with an amino acid concentration of 0.02-0.03 M and a pH of composition 9 is used as a buffer 0-11.6.
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    同族专利:
    公开号 | 公开日
    DK156004B|1989-06-12|
    PH15850A|1983-04-13|
    IT7949064D0|1979-05-16|
    CS214798B2|1982-05-28|
    MC1265A1|1980-03-28|
    NL7903871A|1979-11-20|
    PL134004B1|1985-07-31|
    FI68359C|1985-09-10|
    AT4411T|1983-08-15|
    DK156004C|1989-11-06|
    DK201879A|1979-11-18|
    FI68359B|1985-05-31|
    KR830000527B1|1983-03-12|
    AU4704279A|1979-11-22|
    DE2966046D1|1983-09-15|
    ES480597A1|1980-08-16|
    GR68452B|1981-12-30|
    SE7904284L|1979-11-18|
    CH641044A5|1984-02-15|
    IT1116840B|1986-02-10|
    BE876296A|1979-11-16|
    ATA363479A|1981-07-15|
    EP0005768B1|1983-08-10|
    HU182746B|1984-03-28|
    AT365926B|1982-02-25|
    EP0005768A1|1979-12-12|
    FI791565A|1979-11-18|
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    IL57298A|1983-09-30|
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    US4335139A|1982-06-15|
    DE2920020A1|1979-11-29|
    FR2425856B1|1982-06-25|
    FR2425856A1|1979-12-14|
    PL215627A1|1981-08-07|
    JPS6358810B2|1988-11-17|
    LU81272A1|1979-12-07|
    NZ190462A|1982-05-31|
    AU525695B2|1982-11-25|
    ZA787353B|1980-08-27|
    CA1141661A|1983-02-22|
    引用文献:
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    US4036954A|1973-11-02|1977-07-19|Yamanouchi Pharmaceutical Co., Ltd.|Stable prostaglandin E group-containing formulation|
    GB1504437A|1974-03-08|1978-03-22|Dunlop Ltd|Rubberplastics composites|
    DE2515001C2|1975-04-04|1986-10-02|Schering AG, 1000 Berlin und 4709 Bergkamen|Freeze-dried powders containing prostaglandin|
    US3997587A|1975-06-26|1976-12-14|Syntex Inc.|D1- and 8R-9-fluoro-prostadienoic acid derivatives|
    US4005133A|1975-10-14|1977-01-25|The Upjohn Company|PGF2.sub.α, L-Arginine salt|
    FR2351112B1|1975-10-21|1981-05-29|Wellcome Found|
    US4062964A|1975-12-03|1977-12-13|Ciba-Geigy Corporation|Antifertility-combinations|
    GB1583961A|1976-05-11|1981-02-04|Wellcome Found|Prostacyclin and derivatives thereof|
    FR2390964B1|1977-05-20|1980-07-11|Wellcome Found|DE3010002A1|1980-03-15|1981-10-01|Hoechst Ag, 6000 Frankfurt|PROSTAGLANDINE CONTAINING PHARMACEUTICAL PREPARATION|
    AU623147B2|1988-06-17|1992-05-07|Wellcome Foundation Limited, The|Compounds for use in medicine|
    GB8814438D0|1988-06-17|1988-07-20|Wellcome Found|Compounds for use in medicine|
    JP3421330B2|2000-11-02|2003-06-30|持田製薬株式会社|Vidarabine dry preparation for injection|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB2017578|1978-05-17|
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