• 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:
    A process for preparing a liquid pharmaceutical preparation containing a complex of DOTA and gadolinium and a base such as L-lysine or meglumine comprises the following steps: a) An aqueous solution containing free DOTA, free gadolinium and a base such as L is obtained Lysine or meglumine produced. b) The content of free DOTA and free gadolinium in the solution obtained after step a) is determined. c) Free gadolinium and / or free DOTA are added to adjust a stoichiometric excess of free DOTA in the solution. d) The complexation is carried out at elevated temperature. e) Additional base such as L-lysine or meglumine is added to adjust the pH. f) The final volume of the preparation is discontinued.
    公开号:AT516104A1
    申请号:T608/2014
    申请日:2014-07-31
    公开日:2016-02-15
    发明作者:Beate Dr Kälz；Stefan Dr Welzig；Klaus Dr Gerdes；Roswitha Dr Braunrath；József Mag Gungl；Raffael Dr Schuecker
    申请人:Sanochemia Pharmazeutika Ag；
    IPC主号:
    专利说明:

    The invention relates to a method for producing a liquid pharmaceutical preparation comprising a complex of the macrocyclic chelate DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) with gadolinium and additionally as base L-lysine or meglumine.
    The preparation preparable according to the invention can be used as a contrast agent.
    From EP 2 242 515 Bl a method of the generic type is known, which serves for example for the production of gadoteric meglumine salt.
    The process known from EP 2 242 515 Bl for preparing a liquid pharmaceutical formulation which contains a complex of macrocyclic chelate with a lanthanide comprises the following steps:
    Preparing a liquid pharmaceutical composition comprising the complex of macrocyclic chelate with a lanthanide and free macrocyclic chelate which is not in the form of an adjuvant X [X ', L], where L is the macrocyclic chelate and X and X' are a metal ion , and containing free lanthanide, by mixing a solution of free macrocyclic chelate and free lanthanide so as to obtain complexation of the lanthanide by the macrocyclic chelate, wherein the amounts of free macrocyclic chelate and free lanthanide are such that not all of the lanthanide complexes becomes;
    Measuring the concentration of free lanthanide in the pharmaceutical formulation thus obtained, wherein the concentration of the free macrocyclic chelate is 0;
    Adjust the levels of free chelate and free
    Lanthanide by adding the amount of free macrocyclic chelate to the resulting formulation necessary to complete, firstly, the complexation of the free lanthanide so as not to obtain a free lanthanide; and second, to determine the target concentration of the free macrocyclic chelate in the final liquid pharmaceutical To achieve formulation wherein the amount of free macrocyclic chelate in the final liquid pharmaceutical formulation corresponds to the proportion of free macrocyclic chelate based on the amount of complexed macrocyclic chelate in the final liquid pharmaceutical formulation.
    The method known from EP 2 242 515 B1 is comparatively complicated and difficult to apply on a commercial scale, since numerous readjustment steps are necessary.
    A reworking of the process described in Example 2 of EP 2 242 515 Bl, moreover, does not yield any product described in EP 2 242 515 Bl, since the complexation takes place only by about 88% if the process steps from Example 2 are strictly followed. Residual gadolinium and DOTA thus remain uncomplexed and the specification given in claim 1 under Ic to Cchi equal to zero (concentration of free macrocyclic chelate equal to zero) is not reached. See the comparative example.
    Since the complex-forming components are in complexed and free form, it is not possible to adjust excess chelate as set forth in point ld of claim 1 of EP 2 242 515 B1.
    The invention has for its object to provide a method of the type mentioned is available, which is easier to perform and leads to the desired pharmaceutical preparation, such as gadoteric meglumine salt.
    According to the invention the object is achieved by a method of the type mentioned above, which comprises the following steps: a) Preparation of an aqueous solution containing free DOTA, free gadolinium and as base L-lysine or meglumine. b) Determining the contents of the obtained after step a) solution of free DOTA and free gadolinium. c) Add free gadolinium or free DOTA to adjust a stoichiometric excess of free DOTA in the solution. d) carrying out the complexation at elevated temperature. e) Addition of further base to adjust the pH. f) adjusting the final volume of the preparation.
    It can be seen that the method according to the invention is simple to carry out because of the special guidance of the method and surprisingly leads to a preparation which can be used as a contrast agent without the risk that free gadolinium is contained in the contrast agent.
    A feature of the process according to the invention is the reaction of DOTA with gadolinium in the presence of a base. In the invention, prior to first measuring the free DOTA and free gadolinium content, the three components DOTA, gadolinium and L-lysine or meglumine (in the reactor) are reacted together. In fact, it is only through the presence of a base that an environment is obtained which completes the complexation reaction and leads to the complete complexation of the complex-forming component (gadolinium) present in the deficit
    Free gadolinium content is zero. By measuring the excess of free DOTA, gadolinium can be replenished such that the content of free DOTA can be adjusted to a range of 200-1500 ppm based on the complex.
    In one embodiment of the method according to the invention, it is possible to proceed in such a way that, for the preparation of the solution according to step a), firstly DOTA is dissolved in water at elevated temperature and then gadolinium is added.
    In one embodiment of the method according to the invention, it is possible to proceed in such a way that the addition of free DOTA and of free gadolinium takes place in such a way that no free gadolinium is present in the preparation.
    In one embodiment of the method according to the invention, it is possible to proceed such that the complexing is completed by further adding a base such as L-lysine or meglumine.
    In one embodiment of the method according to the invention, it is possible to proceed in such a way that step a) is carried out at a temperature between 60 ° C. and 95 ° C.
    In one embodiment of the method according to the invention, it is possible to proceed in such a way that the solution is stirred when carrying out steps a) and / or d). In one embodiment of the method according to the invention, it is possible to proceed by using meglumine or L-lysine as the base.
    In one embodiment of the method according to the invention, it is possible to proceed in such a way that in step c) the addition of gadolinium takes place in two or more than two subsets.
    In one embodiment of the method according to the invention, it is possible to proceed by adding free DOTA in the form of a solution and / or free gadolinium in the form of a solution.
    In one embodiment of the method according to the invention, it is possible to proceed in such a way that the gadolinium is added as oxide (Gd203). In this case, gadolinium exists as a trivalent cation.
    In one embodiment of the method according to the invention, the procedure can be such that the concentration of free DOTA in the preparation is 180-2000 ppm, preferably 200-1500 ppm.
    In one embodiment of the method according to the invention, it is possible to proceed in such a way that the concentration of free gadolinium in the preparation is below 10 ppm.
    In one embodiment of the method according to the invention, it is possible to proceed in such a way that the pH in step e), in particular at room temperature, is adjusted to a value between 7.0 and 7.2.
    In the figure, the basic procedure of the method according to the invention is reproduced.
    In carrying out the method according to the invention for producing a liquid, pharmaceutical preparation by complexing DOTA with gadolinium, the following steps can be carried out, for example:
    In water for injections, DOTA is dissolved at an elevated temperature.
    In a further step, a previously calculated amount of gadolinium is added, taking care that the calculated amount of gadolinium must be sub-derechoimetric, i. DOTA is in stoichiometric excess.
    Complexing occurs at high temperatures for a time sufficient to complex the gadolinium and DOTA.
    The reaction of the substances (DOTA and gadolinium) is completed by addition of a required base (for example meglumine or L-lysine).
    Subsequently, the concentration of free DOTA and free gadolinium is determined to ensure that there is a sub-choiometric amount of gadolinium and a higher concentration of DOTA.
    By further adjusting the concentrations of the above free fractions (gadolinium and DOTA), the concentration is controlled so that the concentration of free gadolinium in the finished preparation is zero and the concentration of free DOTA is between 200 and 1500 ppm calculated on the complex , is present.
    The formation of the complex can be carried out at a temperature in the range between 60 ° C and 95 ° C.
    The reaction times for the formation of the complex depend on the process run. For example, it is stirred for two hours and then allowed to stand for ten hours.
    Adjustment of free DOTA content and free gadolinium content can be made not only with the aid of solid substances but also with previously prepared solutions of the two substances.
    Hereinafter, the comparative example in which the operation of Example 2 of EP 2 242 515 B1 was applied is shown.
    The batch from Example 2 was reduced by a factor of 500, which corresponds to a laboratory batch size of 200 ml total volume. The ratio of raw material weights has not changed.
    After mixing DOTA and gadolinium oxide in water at 80 ° C, a solution was obtained. Within 48 hours several samples were taken and the content of free DOTA and complex determined. On the one hand, at no time was the content of complex greater than 88%, and on the other hand correlated with the content of free DOTA was below 11% (see Table 1). From the batch calculation results an excess of gadolinium oxide, which is why with complete complexation a content of free DOTA would be expected to be zero. However, since a significant proportion of uncomplexed DOTA was present in the batch, the complexation was not complete. An adjustment of the free DOTA was therefore not possible at this time, as described in EP 2 242 515 Bl Example 2 Step 3. Only by the addition of meglumine was a medium generated, which completed the complexation and significantly increased the content of complex (see Table 1).
    Much more important, however, is that generally after the addition of meglumine a free DOTA content adjustment within the desired limits is possible, since the addition of meglumine completely dusts the free DOTA already present in solution (free DOTA <50 ppm).
    The results of this comparative example thus contradict the teaching of EP 2 242 515 Bl.
    Table 1. Measured values of the comparative example.
    The process developed according to the invention solves this problem by adding meglumine to the reaction mixture even before the first free DOTA and complex content determination. A stoichiometric excess of DOTA is used, ensuring complete conversion of gadolinium to the complex and zero free gadolinium content in the first assay. It can be clearly seen from the measured values from Table 2 that only the addition of meglumine produces a medium which completes the complexation. A salary adjustment of free DOTA by
    Addition of gadolinium is then easily possible (see Table 2).
    Table 2. Measured values of the method according to the invention. Hereinafter, embodiments of the method according to the invention are reproduced.
    Example 1:
    In 150 ml of water at a temperature of 75 ° C, 40.5 g of DOTA were suspended. 17.8 g of gadolinium oxide were added and the batch was stirred at 75 ° C. for 2 hours. The resulting solution was added with 19.5 g of meglumine and stirred at 75 ° C for one hour. Thereafter, the content of free DOTA, free
    Gadolinium and complex determined and adjusted the final content of excess free DOTA. The concentration of free gadolinium was zero and the concentration of excess free DOTA was adjusted to between 200 and 1500 ppm calculated on the complex. The reaction mixture was made up to a total volume of 200 ml and filtered.
    Example 2:
    In 150 ml of water at a temperature of 75 ° C, 7.8 g of gadolinium oxide were suspended. 40.5 g of DOTA was added and the reaction was stirred at 75 ° C. for 2 hours. Another 10.0 g of gadolinium oxide was added and stirred again at 75 ° C for 15 minutes. The resulting solution was added with 19.5 g of meglumine and stirred at 75 ° C for one hour. Thereafter, the content of free DOTA, free gadolinium and complex was determined and the final content of excess free DOTA was adjusted. The concentration of free gadolinium was zero and the concentration of excess free DOTA was adjusted to between 200 and 1500 ppm calculated on the complex. The reaction mixture was made up to a total volume of 200 ml and filtered.
    Example 3:
    In 150 ml of water at a temperature of 75 ° C, 13.5 g of DOTA were suspended. 5.9 g of gadolinium oxide were added and the batch was stirred at 75 ° C. for 30 minutes. Furthermore, 13.5 g DOTA and 5.9 g gadolinium oxide were added and at 75 ° C for 30
    Stirred for minutes. Once again, 13.5 g of DOTA and 6.0 g of gadolinium oxide were added and stirred at 75 ° C for 30 minutes. The resulting solution was added with 19.5 g of meglumine and stirred at 75 ° C for one hour. Thereafter, the content of free DOTA, free gadolinium and complex was determined and the final content of excess free DOTA was adjusted. The concentration of free gadolinium was zero and the concentration of excess free DOTA was adjusted to between 200 and 1500 ppm calculated on the complex. The reaction mixture was made up to a total volume of 200 ml and filtered.
    As shown in the examples, in the process of the present invention, the final content of excess DOTA can be adjusted to 200-1500 ppm.
    The content of free gadolinium is always zero when carrying out the process according to the invention, since an excess of DOTA is used. In the method according to the invention, gadolinium is added in order to adjust the proportion of DOTA to the stated range.
    In carrying out the method according to the invention, the substances gadolinium and DOTA can be added alternately. For example, one-third of the nominal quantity is added every half hour.
    Gadolinium can be initially introduced at the beginning of the process according to the invention. Subsequently, a part, e.g. a quarter of the target amount of DOTA added. The solution thus obtained is stirred, for example at 80 ° C, e.g. For 2 hours, and then to the solution the remaining amount of DOTA added.
    In summary, an embodiment of the invention can be described as follows:
    A process for preparing a liquid pharmaceutical preparation containing a complex of gadolinium and DOTA and a base such as L-lysine or meglumine comprises, for example, the following steps: a) an aqueous solution consisting of DOTA,
    Gadolinium and a base such as meglumine or L-lysine. b) The content of free DOTA and free gadolinium in the solution obtained after step a) is determined. c) Free gadolinium and / or free DOTA is added to adjust the content of free DOTA to 200 - 1500 ppm, based on the complex. d) The complexation can be carried out at elevated temperature. e) Additional base is added to adjust the final pH. f) The final volume of the preparation is discontinued.
    权利要求:
    Claims (12)
    [1]
    Claims 1. A process for preparing a liquid pharmaceutical preparation containing a complex of DOTA and gadolinium and a base such as L-lysine or meglumine characterized by the following steps: a) An aqueous solution of DOTA, gadolinium and a base such as meglumine or L-lysine. b) In the solution obtained according to step a) the content of free DOTA and free gadolinium is determined. c) Free gadolinium and / or free DOTA is added in order to set in the solution a free DOTA content of 200-1500 ppm, based on the complex. d) The complexation is carried out at elevated temperature. e) Additional base is added to adjust the pH. f) The final volume is set.
    [2]
    2. The method according to claim 1, characterized in that for preparing the solution according to step a) first DOTA is dissolved in water at elevated temperature and then gadolinium is added.
    [3]
    3. The method according to claim 1 or 2, characterized in that the addition of free DOTA and free gadolinium takes place in such a way that there is no free gadolinium in the preparation.
    [4]
    4. The method according to any one of claims 1 to 3, characterized in that the complexing is completed by further adding a base such as L-lysine or meglumine.
    [5]
    5. The method according to any one of claims 1 to 4, characterized in that step a) is carried out at a temperature between 60 ° C and 95 ° C.
    [6]
    6. The method according to any one of claims 1 to 5, characterized in that the solution during the execution of steps a) and / or d) is stirred.
    [7]
    7. The method according to any one of claims 1 to 6, characterized in that in step c) the addition of free gadolinium and / or free DOTA takes place in two or more than two subsets.
    [8]
    8. The method according to any one of claims 1 to 7, characterized in that free DOTA is added in the form of a solution and / or free gadolinium in the form of a solution.
    [9]
    9. The method according to any one of claims 1 to 8, characterized in that the gadolinium is added as oxide (Gd203) and in the oxidation state + III.
    [10]
    10. The method according to any one of claims 1 to 9, characterized in that the concentration of free DOTA in the preparation is 180 - 2000 ppm, preferably 200 to 1500 ppm, based on the complex.
    [11]
    11. The method according to any one of claims 1 to 10, characterized in that the concentration of free gadolinium in the preparation is below 10 ppm.
    [12]
    12. The method according to any one of claims 1 to 11, characterized in that the pH in step e), in particular at room temperature, is adjusted to a value between 7.0 and 7.2.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    EP2242515B1|2008-02-19|2014-04-02|Guerbet|Process for preparing a pharmaceutical formulation of contrast agents|
    US5560903A|1981-07-24|1996-10-01|Schering Aktiengesellschaft|Method of enhancing paramagnetism in chelates for MRI|
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    WO2019020662A1|2017-07-27|2019-01-31|Sanochemia Pharmazeutika Ag|Preparation containing a contrast agent, and method for the production thereof|
    法律状态:
    2020-03-15| MM01| Lapse because of not paying annual fees|Effective date: 20190731 |
    优先权:
    申请号 | 申请日 | 专利标题
    ATA608/2014A|AT516104B1|2014-07-31|2014-07-31|Process for preparing a liquid pharmaceutical preparation|ATA608/2014A| AT516104B1|2014-07-31|2014-07-31|Process for preparing a liquid pharmaceutical preparation|
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