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    • 专利摘要:
    Fig. 1a Fig. 1b Verder voorziet de uitvinding in een injectie flacon of een ampul omvattende genoemde tranexaminezuur oplossing en een werkwijze voor het bekomen van genoemde tranexaminezuur oplossing. The present invention relates to a tranexamic acid solution suitable for intravenous administration. The tranexamic acid solution has a pH value of 6.5 to 8.0 and an oxygen content below 2.0 ppm. FIG. 1a FIG. 1b Further, the invention provides an injection vial or an ampoule comprising said tranexamic acid solution and a method for obtaining said tranexamic acid solution.
    公开号:BE1022999B1
    申请号:E2015/5373
    申请日:2015-06-18
    公开日:2016-10-31
    发明作者:Thomas Jacobsen
    申请人:Neogen N.V.；
    IPC主号:
    专利说明:

    TRANEXAMIC ACID SOLUTION, AMPULA AND INJECTION FLACON INCLUDING MENTIONED SOLUTION
    TECHNICAL DOMAIN
    The invention relates to the technical domain of tranexamic acid solutions and methods for making said solutions. The object of the invention is to provide a longer storage stability than for the current known tranexamic acid solutions.
    BACKGROUND ART
    Tranexamic acid is a synthetic derivative of the amino acid lysine, the structure of tranexamic acid is shown in formula I. It is often used as a medicine in the treatment and prevention of excessive blood loss during operations and other medical conditions.
    (I)
    Currently, the medicine is formulated on the market as tablets or as an intravenous solution. The intravenous solution usually comprises 100 mg of tranexamic acid per ml of preparation.
    A problem with the known intravenous tranexamic acid formulations in the form of an intravenously administrable solution is the low storage stability and the formation of impurities during storage. A number of impurities are known and have been included in the European Pharmacopoeia. If the number of impurities rises too high according to the same European Pharmacopoea, the solution is unsuitable for administration.
    It is an object of the present invention to find a solution to at least some of the aforementioned problems.
    SUMMARY OF THE INVENTION
    In a first aspect, the invention relates to a method for making an intravenously administrable tranexamic acid solution, in a non-aseptic manner, comprising the following steps: a) provided with an aqueous solution for injection; b) reducing the oxygen content of said aqueous solution to obtain a low-oxygen aqueous solution; c) adding tranexamic acid to said oxygen-depleted aqueous solution to obtain a tranexamic acid solution; d) adjusting the pH of said tranexamic acid solution; e) filtering said tranexamic acid solution to obtain a filtered tranexamic acid solution; f) filling said filtered tranexamic acid solution in vials; g) sterilization of said filled vials, wherein the pH of the filtered tranexamic acid solution is 6.5 to 8.0 and the oxygen content of the filtered tranexamic acid solution is less than 2.0 ppm.
    A non-aseptic method for preparing an intravenously administrable solution has the advantage that less stringent requirements are imposed on the environment in which the method is carried out and the machines used during the method compared to an aseptic method. The requirements for an aseptic method are so high that it is more economically interesting to work non-aseptically.
    In a second aspect, the invention relates to a sterile intravenously administered tranexamic acid solution, comprising: - 100 mg of tranexamic acid per ml of solution; - aqueous solution for injection, wherein the pH of the tranexamic acid solution is 6.5 to 8.0 and the oxygen content of the tranexamic acid solution is less than 2.0 ppm.
    A pH value of 6.5 to 8.0 and preferably 7.0 to 7.5 provides the least amount of impurities during manufacture and during storage of the tranexamic acid solution. In particular, the impurities C and D described and known in the Pharmacopoeia are formed less.
    In a further aspect, the invention relates to an ampoule comprising a sterile intravenously administrable tranexamic acid solution according to an embodiment of the invention.
    In a final aspect, the invention relates to a vial comprising a sterile intravenously administrable tranexamic acid solution according to an embodiment of the invention.
    DESCRIPTION OF THE FIGURES
    Figure 1a shows the stopper of a vial according to an embodiment of the invention.
    Figure 1b shows a cross-section of a stopper vial according to an embodiment of the invention.
    DETAILED DESCRIPTION
    The invention relates to a non-aseptic method for making a tranexamic acid solution suitable for intravenous injection.
    In a first aspect, the invention relates to a method for making an intravenously administrable tranexamic acid solution, in a non-aseptic manner, comprising the following steps: a) provided with an aqueous solution for injection; b) reducing the oxygen content of said aqueous solution to obtain a low-oxygen aqueous solution; c) adding tranexamic acid to said oxygen-depleted aqueous solution to obtain a tranexamic acid solution; d) adjusting the pH of said tranexamic acid solution; e) filtering said tranexamic acid solution to obtain a filtered tranexamic acid solution; f) filling said filtered tranexamic acid solution in vials; g) sterilization of said filled vials, wherein the pH of the filtered tranexamic acid solution is 6.5 to 8.0 and the oxygen content of the filtered tranexamic acid solution is less than 2.0 ppm.
    A non-aseptic method for preparing an intravenously administrable solution has the advantage that less stringent requirements are imposed on the environment in which the method is carried out and the machines used during the method compared to an aseptic method. The requirements for an aseptic method are so high that it is more economically interesting to work non-aseptically.
    A non-aseptic method, however, requires a sterilization step at the end that makes the solution suitable for intravenous administration. During sterilization, the formulated tranexamic acid solution is warmed up and brought under elevated pressure for a certain time, preferably a temperature of at least 100 ° C for at least 15 minutes, more preferably at least 115 ° C, for at least 20 minutes, and most preferably at least 122 ° C, for at least 30 minutes. Decomposition reactions are accelerated during sterilization. Decomposition can occur both from the active, in this case tranexamic acid, and from excipients in the solution. As a result, the retention period can be reduced and the impurities formed can possibly react further with components of the solution, whereby more impurities are formed in the long run than if the solution were not subjected to sterilization. It is therefore important to avoid the causes of decomposition as much as possible before performing the sterilization process. The inventor found that especially the pH and the oxygen content in the solution can have adverse effects on the stability of the solution. He found that a pH value of 6.5 to 8.0 and preferably 7.0 to 7.5 provides the least amount of impurities. The inventor also found that an oxygen content of the solution less than 2.0 ppm, preferably less than 1.5 ppm, more preferably 1.0 ppm, even more preferably less than 0.5 ppm and most preferably less than 0.2 ppm gave a significant reduction in oxidation products and other impurities. In particular, the known impurity C (RS) -4- (aminomethyl) cyclohex-1-enecarboxylic acid, formula (II) and its enantiomer, and known impurity D 4-aminomethylbenzoic acid, formula (III) were greatly reduced by adjusting the pH and the oxygen content to the stated values. Preferably, the amounts of impurity C and D are reduced by at least 30%, more preferably by at least 50% and most preferably by at least 70%, relative to a formulation where the pH and the oxygen content are not adjusted for sterilization.
    The reduction of the oxygen content is preferably done before adding tranexamic acid to the aqueous solution. Tranexamic acid is particularly susceptible to oxidation in solution. By first reducing the oxygen content in the aqueous solution, tranexamic acid is avoided in oxygen-rich water during the process.
    In a preferred embodiment of the method, the oxygen content is reduced by bubbling said aqueous solution with an inert gas, preferably nitrogen gas. Preferably nitrogen gas that has been filtered, more preferably filtered through a 0.2 µm filter, and most preferably through a 0.2 µm polytetrafluoroethylene (PTFE) membrane.
    The oxygen gas present in the aqueous solution dissolves in the nitrogen gas bubbles and is entrained by the nitrogen gas and removed from the aqueous solution. This has the advantage that the inert nitrogen gas does not cause any side reactions and does not drastically change the pH value of the aqueous solution.
    In a preferred embodiment of the method, the bioburden is less than 10 cfu / 100 ml of solution just prior to sterilization. Cfu or cfu stands for bacterial count or colony forming units. The germ count is the number of bacteria germs that are present in or on a product.
    The term "bioburden" refers to the amount of biological contamination. It is a measure of the number of germs and the type of microbiological contamination that remains for sterilization after cleaning and disinfection.
    A bioburden below 10 cfu / 100 ml ensures that after sterilization it can be assumed that the sterilization can effectively kill the germs.
    In a preferred embodiment of the method, steps a), b), c) and d) are performed under class C GMP conditions.
    The term "GMP" stands for Good Manufacturing Practice or good production method and is an internationally recognized quality assurance system for the human and veterinary pharmaceutical industry, the cosmetic industry and the food industry. It sets out the requirements that different clean rooms distinguish between themselves in 4 classes, A to D. The requirements of the different classes are summarized in Table 1.
    Table 1: maximum number of particles per GMP class
    Performing steps a), b), c) and d) under class C GMP conditions has the advantage that it is possible to work under less stringent conditions during this work step than during the final filling of the tranexamic acid solution. A clean room class C is more available and is less economical to maintain. Filtering the solution in the next step, step e) makes it possible to use less strict conditions in the previous steps.
    In a preferred embodiment of the method, steps e) and f) are performed under class A GMP conditions.
    A method in which only steps e) and f) must be carried out under class A conditions is economically more advantageous, setting up class A conditions requires specialized equipment and is more expensive to maintain.
    In a preferred embodiment of the method, said tranexamic acid solution moves from class C conditions to class A through a sterile conduit.
    Preferably class A conditions and class C conditions are physically separated from each other. More preferably, class A conditions and class C conditions are accommodated in a different room. When these spaces are next to each other or close to each other, a sterile pipeline can be provided between these two spaces with which the solution can be moved from one space to another without having to move objects from one space to another which may cause contamination or disruption of a class.
    In a preferred embodiment of the method, said vial is a vial.
    This has the advantage that the tranexamic acid solution contained in the vial is sealed from the environment by means of a stopper through which an injection needle can be applied. The tranexamic acid solution can be drawn into a syringe through the injection needle and then administered intravenously to a patient. This has the advantage that the tranexamic acid solution is never exposed to the environment at any time.
    In a preferred embodiment of the method, said vial is an ampoule.
    An ampoule has the advantage that the content, here the tranexamic acid solution, is hermetically sealed from the environment. Gases from the environment cannot penetrate the ampoule and cause side reactions there. The use of an ampoule mainly benefits the storage stability.
    In a second aspect, the invention relates to a sterile intravenous administrable tranexamic acid solution, comprising: - 100 mg tranexamic acid per ml of solution; - aqueous solution for injection, wherein the pH of the tranexamic acid solution is 6.5 to 8.0 and the oxygen content of the tranexamic acid solution is less than 2.0 ppm.
    A pH value of 6.5 to 8.0 and preferably 7.0 to 7.5 provides the least amount of impurities during manufacture and during storage of the tranexamic acid solution. Known impurities C and D in particular are formed less.
    The inventor found that an oxygen content of the tranexamic acid solution of less than 2.0 ppm, preferably less than 1.5 ppm, more preferably 1.0 ppm, even more preferably less than 0.5 ppm and most preferably less than 0.2 ppm gave a significant reduction in oxidation products and other impurities during production and during storage of the tranexamic acid solution.
    In a preferred embodiment of the sterile tranexamic acid solution, this solution is obtained according to an embodiment of a method according to the invention.
    This has the advantage that the pH conditions and the oxygen content of the solution were optimized before the sterilization took place and therefore there was less decomposition during the sterilization. Therefore, there are fewer impurities in the sterile tranexamic acid solution.
    In a preferred embodiment of the sterile tranexamic acid solution, the solution has a sodium content of less than 0.000006 mg of sodium per ml of tranexamic acid solution.
    This has the advantage that when administering the tranexamic acid solution only very few sodium ions are administered to the patient. As a result, the patient will not increase his blood pressure due to the influence of sodium ions.
    Preferably a solution according to an embodiment of the invention is used as a medicament.
    More preferably, a solution according to an embodiment of the invention is used as a medicament for the treatment or prevention of bleeding. Bleeding may be caused by fibrinolysis or fibrinogenolysis, drug-induced fibrinolysis, general fibrinolysis (in prostate cancer and pancreatic cancer) and local fibrinolysis such as occurs under the following conditions: prostatectomy and bladder surgery, menorrhagia, epistaxis, cervical cervix, trauma (trauma) hyphemia, hereditary angioneurotic edema, dental extraction in haemophilia patients, hip or knee prosthesis surgery and heart surgery ie.
    In a preferred form of the invention, a 100 mg / ml intravenously administered tranexamic acid solution is administered by intravenous injection at a rate of 1 ml / min.
    In a further aspect, the invention relates to an ampoule comprising a sterile intravenous administrable tranexamic acid solution according to an embodiment of the invention.
    In a final aspect, the invention relates to a vial comprising a sterile intravenously administrable tranexamic acid solution according to an embodiment of the invention.
    A vial has the advantage that the tranexamic acid solution contained in the vial 1 is sealed off from the environment by means of a stopper 2 through which an injection needle can be applied. The tranexamic acid solution can be drawn into a syringe through the injection needle and then administered intravenously to a patient. This has the advantage that the tranexamic acid solution is never exposed to the environment during administration.
    In a preferred embodiment, said vial 1 is provided with an elastomeric plug 2, the part of which is on the exterior side of said vial has a concave curvature, the size of the curvature being determined by the ratio between the height H of the curvature and the diameter D of the stopper 2 on the exterior side of said vial 1 is a maximum of 0.25. The elastomeric plug is preferably a butyl rubber plug, more preferably a bromobutyl rubber plug.
    This has the advantage that the stopper 2 closes the vial properly at these values. In this way, the stopper fits well with the vial and ensures a good seal between vial 1 and the stopper. When the ratio is higher than 0.25, the contact angle between the vial and the stopper changes, so that the seal becomes less and gases can be exchanged more easily with the environment. A higher ratio indicates that the stopper has been pushed too deep into the vial.
    In a preferred embodiment, said plug 2 comprises a disc-shaped part 3 and a cylindrical part 4, the disc-shaped part 3 of which is located on the exterior side of said vial 1.
    Both the cylindrical part 4 and the disc-shaped part 3 ensure a closure of the vial 1. It is mainly the closure of the disc-shaped part that is lost if said ratio is higher than 0.25.
    Vials preferably have a volume of 5, 10, 20 or 50 ml.
    In a preferred embodiment, the vial, preferably an ampoule according to an embodiment of the invention or a vial according to a preferred embodiment of the invention, comprises 5.3 to 5.5 ml or 10.5 to 10.6 ml of a sterile intravenous administrable tranexamic acid solution preferably according to an embodiment of the invention.
    This has the advantage that exactly 5 or 10 ml can be administered to the patient. The surplus volume solution remains in the bottle. This surplus ensures that no air is drawn in when the solution is removed from the vial by means of a syringe.
    Products according to an embodiment of the invention have a storage period of at least six months, preferably at least twelve months, more preferably eighteen months and most preferably twenty-four months.
    In the following, the invention is described on the basis of non-limiting examples illustrating the invention, which are not intended or may be interpreted to limit the scope of the invention. EXAMPLE 1:
    Table 2 shows an overview of different ampoules and vials according to embodiments of the invention.
    Table 2: different facets according to an embodiment of the invention. EXAMPLE 2
    Figure 1a shows a stopper 2 used to close a vial 1 according to an embodiment of the invention. The plug 2 is made of an elastomer and comprises a disc-shaped part 3 and a cylindrical part 4.
    Figure 1b shows a cross-section of the same stopper 2 as in Figure 1a, when it closes a vial 1. The concave curvature is also shown, which is located on the exterior side of the vial. The height H of the curvature and diameter D of the stopper 2 are indicated in the figure. EXAMPLE 3
    In a GMP class C environment, an amount of water suitable for injection was provided in a stainless steel vessel fitted with a stirrer. Nitrogen gas was bubbled through the water. This nitrogen gas was first filtered through a double hydrophobic polytetrafluoroethylene (PTFE) membrane that retains particles from 0.2 µm.
    Once the oxygen content of the water for injection had fallen below the desired value, below 2 ppm, the amount of tranexamic acid was added and stirred until a clear solution was obtained. After this, the pH was adjusted with either 1 M hydrochloric acid or 1 M sodium hydroxide to the desired pH 6.5-8.0.
    This solution was then pumped through a sterile tube to the filtration chamber. GMP class A conditions applied in the filtration chamber. The solution was filtered with a 0.22 µm polyethersulfone filter using an overpressure nitrogen gas that was also filtered through a double hydrophobic polytetrafluoroethylene (PTFE) membrane that retains particles from 0.2 µm. The filtrate was collected in a stainless steel vessel that was completely sealed off from the environment.
    The latter stainless steel vessel which contained the filtrate was then sterilized in an autoclave at a temperature of 122 ° C for 30 minutes.
    After this, the sterilized filtrate was filled into the flasks by means of a filling machine and this under a nitrogen atmosphere. The filled vials were then sterilized again in an autoclave at 122 ° C for 30 minutes.
    权利要求:
    Claims (15)
    [1]
    CONCLUSIONS
    A method for making an intravenously administrable tranexamic acid solution, in a non-aseptic manner, comprising the steps of: a) providing an aqueous solution for injection; b) reducing the oxygen content of said aqueous solution to obtain a low-oxygen aqueous solution; c) adding tranexamic acid to said oxygen-depleted aqueous solution to obtain a tranexamic acid solution; d) adjusting the pH of said tranexamic acid solution; e) filtering said tranexamic acid solution to obtain a filtered tranexamic acid solution; f) filling said filtered tranexamic acid solution in vials; g) sterilization of said filled vials, characterized in that the pH of the filtered tranexamic acid solution is 6.5 to 8.0 and that the oxygen content of the filtered tranexamic acid solution is lower than 2.0 ppm.
    [2]
    A method according to claim 1, wherein the lowering of the oxygen content is effected by bubbling said aqueous solution with nitrogen gas.
    [3]
    A method according to at least one of the preceding claims, wherein the bioburden just before sterilization is less than 10 cfu / 100 ml.
    [4]
    Method according to at least one of the preceding claims, wherein steps a), b), c) and d) are carried out under class C GMP conditions.
    [5]
    Method according to at least one of the preceding claims, wherein steps e) and f) are carried out under class A GMP conditions.
    [6]
    The method of at least one of the preceding claims, wherein said tranexamic acid solution moves from class C conditions to class A through a sterile conduit.
    [7]
    The method of at least one of the preceding claims, wherein said vial is a vial or an ampoule.
    [8]
    Sterile intravenously administrable tranexamic acid solution, comprising: - 100 mg tranexamic acid per ml of solution; - aqueous solution for injection, characterized in that the pH of the tranexamic acid solution is 6.5 to 8.0 and the oxygen content of the tranexamic acid solution is less than 2.0 ppm.
    [9]
    The sterile intravenously administrable tranexamic acid solution according to claim 8, obtained by a method according to at least one of claims 1 to 5.
    [10]
    Sterile intravenously administrable tranexamic acid solution according to at least one of claims 8-9, with a sodium content of less than 0.000006 mg of sodium per ml of tranexamic acid solution.
    [11]
    Ampoule comprising a sterile intravenously administrable tranexamic acid solution according to at least one of claims 8-10.
    [12]
    A vial comprising a sterile intravenously administrable tranexamic acid solution according to at least one of claims 8-10.
    [13]
    The vial (1) according to claim 12, provided with an elastomeric plug (2), the part of which is located on the exterior side of said vial (1) has a concave curvature, the size of the curvature being determined by the ratio between the height H of the curvature and the diameter D of the stopper (2) on the exterior side of said vial (1) and amounts to a maximum of 0.25.
    [14]
    The vial according to claim 12 or 13, wherein said stopper (2) comprises a disc-shaped part (3) and a cylindrical part (4), the disc-shaped part (3) of which is located on the exterior side of said injection vial (1).
    [15]
    Ampoule according to claim 11 or injection vial according to at least one of claims 12-14 comprising 5.3 to 5.5 ml or 10.5 to 10.6 ml of a sterile intravenously administrable tranexamic acid solution according to at least one of claims 810.
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