• 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 provides intravenous stable aqueous compositions of tranexamic acid, ready for use.
    公开号:BE1026546B1
    申请号:E20195387
    申请日:2019-06-17
    公开日:2020-09-28
    发明作者:Eric Dubois；Thomas Jacobsen
    申请人:RTU Pharma SA；
    IPC主号:
    专利说明:

    [0001] The present application claims the advantage of US provisional patent application No. 62/727,939, filed Thursday, September 6, 2018, the description of which is incorporated here by reference in its entirety. DESCRIPTION OF RELATED ART
    [0002] [0002] Tranexamic acid, trans-4- (aminomethyl) cyclohexanecarboxylic acid, is an antifibrinolytic agent. It produces an antifibrinolytic effect by competitively inhibiting the activation of plasminogen to plasmin. It is also a weak, uncompetitive plasmin inhibitor. These properties make possible its clinical use as an antifibrinolytic in the treatment of both general and local fibrinolytic hemorrhages.
    [0003] [0003] The injectable solution of tranexamic acid is indicated in patients with hemophilia for short-term use (two to eight days) to reduce or prevent bleeding and to reduce the need for replacement therapy. during and after tooth extraction. Other indications may include hereditary angioneurotic edema, hyperfibrinolysis, epistaxis, hyphema, and menorrhagia. Tranexamic acid has also been shown to decrease all-cause mortality and death from bleeding in trauma patients. McCluskey et al, Int J Pharm Compounding 2014, 18 (5), 432-487.
    [0004] [0004] Tranexamic acid is commercially available in tablet form and in injectable intravenous form under the name CYKLOKAPRON®.
    [0005] [0005] The generic product on the market, the 100 mg / ml solution for injection of tranexamic acid, is supplied in ampoules or vials for dilution with, for example, a 0.9% sodium chloride solution, a solution. 5% glucose, or Ringer's solution (made up of sodium chloride). The required volume of generic concentrate is added to the chosen infusion solution to achieve final concentrations of 1% or 2% (i.e. 1 gram or 2 grams in 100 ml). The mixture should be used immediately after preparation, according to the label. If storage is required, the mixture should be stored at 2 ° C to 8 ° C for up to 24 hours. Mixture not used within 24 hours of preparation should be discarded. The physicochemical stability of reconstituted solutions of the marketed generic product of tranexamic acid at 100 mg / ml in the solvent solutions of the above diluents, packaged in glass and plastic containers, has been demonstrated for 24 hours, stored at a temperature between 2 ° Cet8 ° C.
    [0006] [0006] The need to dilute CYKLOKAPRON® or generic 100 mg / ml tranexamic acid injection solution before use has a number of disadvantages. A disadvantage is that the diluted solution is only stable for 24 hours at 2-8 ° C and only stable for 4 hours at room temperature before administration to the patient. Another drawback is that the pH of the diluted formulation varies depending on the choice of diluent. The dilution step has other drawbacks, in particular the risk of contamination and dosing errors.
    [0007] The document Yang et al., CN 106109401 A, proposes formulations for BE2019 / 5387 injection of tranexamic acid using water for injection, the conductivity of which is not greater than 0.6u4S / cm at 20 ° C and whose total organic carbon (TOC) is less than 0.4 mg / L or less than 0.35 mg / L. A complex method of pretreating water is described.
    [0008] [0008] Ready-to-use, stable injectable solutions of tranexamic acid are desirable due to their improved convenience and safety over concentrated solutions of tranexamic acid.
    [0009] The pharmaceutical compositions and methods described herein overcome these drawbacks. In particular, the ready-to-use injectable formulations described herein are stable, allow medical personnel to use commercially prepared containers containing an injectable formulation without additional preparation, avoid potential contamination problems, and eliminate contamination. dosing errors. SUMMARY OF THE INVENTION
    [0010] The present invention relates to ready-to-use pharmaceutical compositions of tranexamic acid or its pharmaceutically acceptable salts, which are suitable for intravenous administration. By providing ready-to-use pharmaceutical compositions at a specific pH, these pharmaceutical compositions are stable at room temperature for at least one year. When stored at room temperature, pharmaceutical compositions exhibit between 0% and about 5% drug loss and between 0% and about 3% (w / w) total impurity formation over a period of eighteen. at twenty-four months.
    [0011] [0011] Ready-to-use injectable pharmaceutical compositions have the following additional advantages: convenience and ease of use compared to concentrated formulations, increased safety for patients by eliminating dosing errors and contamination of the solution, reduction of medical waste, and ease of administration in emergency situations.
    [0012] [0012] The present invention relates to ready-to-use pharmaceutical compositions comprising tranexamic acid or its pharmaceutically acceptable salts, water, and one or more tonicity agents, and a dupH adjusting agent. In certain embodiments, the compositions optionally comprise a BE2019 / 5387 or more cosolvents. Tranexamic acid can be present in concentrations from about 0.05 mg / ml to about 15 mg / ml. Typically, the concentration range for tranexamic acid is from about 3 mg / ml to about 12 mg / ml. The pharmaceutical compositions can optionally comprise pH adjustment agents chosen from acids and bases.
    [0013] The pharmaceutical compositions described herein do not require any dilution prior to administration and typically have a pH of between about 6.0 and about 8.0 and a tonicity of between about 270 and about 340 mOsm / kg. The compositions can be administered to a patient parenterally, including by continuous subcutaneous, intramuscular, intravenous, intra-auricular, or intra-arterial infusion. The compositions are suitable for use in patients with hemophilia for short term use (two to eight days) to reduce or prevent bleeding and to reduce the need for replacement therapy during and after tooth extraction when treatment orally is not feasible or desirable.
    [0014] An aqueous pharmaceutical composition for parenteral administration is provided, comprising tranexamic acid or a pharmaceutically acceptable salt thereof, and a tonicity agent, the composition requiring no dilution before administration and having a pH of 6, 0 to 8.0, 7.0 to 8.0 or 7.2 to 7.4. In some embodiments, aqueous pharmaceutical compositions are provided in which tranexamic acid is present at a concentration of 3 to 12 mg per ml. Aqueous pharmaceutical compositions are provided wherein the tranexamic acid is present at a concentration of 3-7 mg per ml, or 4-6 mg per ml, or 8-12 mg per ml or 9-11 mg per ml. ml. The aqueous pharmaceutical compositions use water for injection (WFT) having a conductivity at 25 ° C <1.5 uS / cm, or 0.6 to 1.5 uS / cm, or 0.65 to 1, 4 uS / cm per USP <645>. Aqueous pharmaceutical compositions use WFI having a Total Organic Carbon (TOC) <500 ppb, 5 to 250 ppb or 10 to 150 ppb according to USP <643>.
    [0015] [0015] The tonicity agent can be chosen from the group comprising sodium chloride, dextrose, sucrose, xylitol, fructose, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride and magnesium chloride. In some embodiments, the tonicity agent is in a concentration BE2019 / 5387 effective to impart osmolality ranging from 270 to 340 mOsm / kg. In some embodiments, the tonicity agent is sodium chloride. In some embodiments, sodium chloride is present at a concentration of 5 to 10 mg / ml or 6 to 8.5 mg / ml.
    [0016] [0016] The tonicity agent can be mannitol, optionally at a concentration of 35 to 45 mg per ml.
    [0017] [0017] The ready-to-use solutions of tranexamic acid in aqueous sodium chloride remain stable at a pH chosen in the range from pH 4.0 to pH 11.0 and exhibit more than 97% of tranexamic acid not degraded compared to the initial concentration after at least 6 months of storage at 25 ° C + 2 ° C and 60% RH + 5% or 40 ° C + 2 ° C and 75% RH + 5%.
    [0018] [0018] The ready-to-use solutions of tranexamic acid in aqueous sodium chloride remain stable at a pH chosen in the range from pH 6.0 to pH 8.0 and exhibit more than 98% by HPLC of tranexamic acid not degraded compared to the initial concentration after at least 6 months of storage at 25 ° C + 2 ° C and 60% RH + 5% or 40 ° C + 2 ° C and 75% RH + 5%.
    [0019] Ready-to-use tranexamic acid compositions are capable of maintaining at least about 90%, 95%, 97% or 98% of the tranexamic acid in an undegraded form after storage of at least 90%. days, 120 days, 180 days, 360 days, or 540 days, or 730 days at room temperature.
    [0020] In some embodiments, there is provided an aqueous pharmaceutical composition for parenteral administration comprising: tranexamic acid or a pharmaceutically acceptable salt thereof, water for injection, a tonicity agent, and at minus one pH adjusting agent, optionally selected from the group consisting of hydrochloric acid, sodium hydroxide and a mixture thereof.
    [0021] In certain embodiments, there is provided a pharmaceutical composition for intravenous administration comprising a ready-to-use aqueous solution with a pH of from about 6.0 to about 8.0 comprising: from about 3 mg / ml to about 12 mg / ml of tranexamic acid or a pharmaceutically acceptable salt of BE2019 / 5387 thereof; a tonicity agent selected from (1) about 35 mg / ml to about 45 mg / ml mannitol or (ii) about 6.8 to 8.2 mg / ml sodium chloride; and a pH adjusting agent in an amount to obtain an initial pH of about 6.0 to about 8.0, 7.0 to 8.0, or 7.3 to 7.5. In some embodiments, the aqueous solution is contained in a pharmaceutically acceptable container. In some embodiments, the aqueous solution of tranexamic acid, when stored in the container for at least one year at room temperature, exhibits (1) a decrease in the concentration of tranexamic acid of less than 10% over at manufacturing concentration, and (11) total impurity formation of less than about 3%. BRIEF DESCRIPTION OF THE DRAWINGS
    [0022] [0022] FIG. Figure 1 shows the chemical structures of tranexamic acid (1) and impurities A, B, C and D bound to tranexamic acid. DETAILED DESCRIPTION OF THE INVENTION
    [0023] [0023] | Definitions
    [0024] The singular forms "un", "une" and "le" or "la" are intended to also include plural forms, unless the context clearly indicates otherwise.
    [0025] [0025] The term "and / or" designates and encompasses all possible combinations of one or more of the associated listed elements.
    [0026] [0026] The term "about", as used herein when referring to a measurable value such as an amount of a compound, a dose, a time, a temperature, etc., is intended to encompass variations in the measurement error for the specified quantity.
    [0027] [0027] Unless otherwise indicated, all the “%” percentage values are expressed as a percentage by weight relative to the total weight of the composition.
    [0028] The terms "comprises" and / or "comprising", when used in the present specification, specify the presence of characteristics, of integers,
    [0029] The term "therapeutically effective amount" denotes the amount of a compound which, when administered to a subject to treat a disease or pathology, is sufficient to effect such treatment in order to completely or substantially relieve the symptoms. symptoms of disease or pathology. The "therapeutically effective amount" may vary depending on the compound, the disease and its severity, as well as condition, age, weight, sex, etc. of the subject to be treated. In some embodiments, the effective amount of tranexamic acid is the amount sufficient to prevent or alleviate bleeding during and after dental procedures. In some embodiments, the effective amount of tranexamic acid is an amount sufficient to avoid reducing, interrupting, or stopping anticoagulant, fibrinolytic, or thrombolytic therapy in a patient in need thereof during and after dental procedures. In some embodiments, the effective amount of tranexamic acid is an amount sufficient to reduce the need for factor replacement therapy in the patient during and after dental procedures. In some embodiments, the effective amount of tranexamic acid is an amount sufficient to reduce the need for antifibrinolytic treatment in the patient during and after dental procedures.
    [0030] [0030] The terms "treating" and "treating" a pathological condition or disease include: (1) preventing the pathological condition or disease, i.e. preventing the clinical symptoms of the disease. '' disease state or disease to develop in a subject who is likely to be exposed or predisposed to the disease state or disease, but who is not yet experiencing or exhibiting symptoms of the disease state or disease (ii) inhibit the pathological condition or disease, i.e. arrest the development of the pathological condition of the disease or its clinical symptoms, or (iii) relieve the pathological condition or disease, c that is to say to cause a temporary or permanent regression of the pathological state or of the disease or of its clinical symptoms BE2019 / 5387. In some embodiments, the terms "treat" or "treatment" refer to the prevention or alleviation of bleeding during and after dental procedures.
    [0031] The terms "patient", "subject" or "subjects" include, but are not limited to humans, the term can also include other mammals, or domestic or exotic animals, for example, dogs. , cats, ferrets, rabbits, pigs, horses, cattle, birds or reptiles.
    [0032] [0032] The term "solution" denotes a clear and homogeneous liquid dosage form containing at least one active pharmaceutical chemical substance dissolved in a solvent or a mixture of solvents miscible with one another.
    [0033] The term "room temperature" designates a controlled room temperature between 20 ° C and 25 ° C.
    [0034] The terms "compound A bound to tranexamic acid" or "impurity A" denote the acid = trans, trans-4,4'-iminodimethylenedi (cyclohexanecarboxylic), also known under the name of tranexamic acid dimer , bearing CAS number 93940-19-3. The chemical structure of impurity A is shown in Fig. 1 (A).
    [0035] The terms "compound B linked to tranexamic acid" or "impurity B" denote cis-4- (aminomethyl) cyclohexanecarboxylic acid, also known under the name of cis-tranexamic acid, bearing the CAS number. : 1197-17-7. The chemical structure of impurity B is shown in Fig. 1 (B).
    [0036] The terms "compound C bonded to tranexamic acid" or "impurity C" denote (RS) -4- (aminomethyl) cyclohex-1-enecarboxylic acid, also known under the name of 1,2 acid. -dehydro tranexamic, bearing the CAS number: 330838-52-3. The chemical structure of the impurity C is shown in Fig. 1 C).
    [0037] The terms "compound D linked to tranexamic acid" or "impurity D" denote 4- (aminomethyl) benzoic acid, also known under the name of benzylamine-4-carboxylic acid, bearing the CAS number : 56-91-7. The chemical structure of impurity D is shown in Fig. 1 (D).
    [0038] [0038] Tranexamic acid, also known as trans-4- BE2019 / 5387 (ammomethyl) cyclohexanecarboxylic acid, also called TXA, for example, having the CAS number: 1197-18-8, is an agent hemostatic antifibrinolytic drug used to prevent or treat severe bleeding. The chemical structure of tranexamic acid is illustrated in Fig. 1 (1). Tranexamic acid is useful for topical antifibrinolytic therapy in patients with inherited bleeding disorders during dental procedures. After being administered 36 to 48 hours before surgery in four doses of to 20 mg per kg of body weight, an antifibrinolytically active concentration (10 μg / ml) of tranexamic acid remained for up to 17 hours in the tissues studied and up to 10 7-8 hours in serum.
    [0039] [0039] Ready-to-use stable pharmaceutical compositions comprising tranexamic acid and water for injection are described herein and are suitable for intravenous administration. The ready-to-use pharmaceutical compositions described herein comprise tranexamic acid or a pharmaceutically acceptable salt thereof as an active ingredient, water, at least one tonicity agent and a pH adjusting agent.
    [0040] [0040] As used herein, the term "ready to use" refers to a premixed pharmaceutical composition which does not require reconstitution or dilution prior to administration to a patient. Unlike ampoule formulations comprising tranexamic acid which must be diluted before use in a diluent and container selected by hospital staff, the ready-to-use pharmaceutical compositions described herein are stable at room temperature for 6 months or more. In some embodiments, suitable buffers and / or co-solvents can be added to the pharmaceutical compositions. In some embodiments, no buffer - and / or no co-solvent is used.
    [0041] All patents, patent applications and publications referred to in 1c1 are incorporated in their entirety by reference.
    [0042] [0042] Compositions
    [0043] Pharmaceutical compositions in the form of ready-to-use intravemnous solutions comprising tranexamic acid are described herein.
    [0044] [0044] In certain embodiments, the pharmaceutical compositions BE2019 / 5387 ready for use comprise one or more tonicity agents. Typically, tonicity agents are used to adjust the osmolality of ready-to-use pharmaceutical compositions to approximate the osmotic pressure of body fluids, such as blood or plasma. In some embodiments, the tonicity of the ready-to-use formulation can be altered by adjusting the concentration of other components present in the ready-to-use formulation. Provided that the compositions are physiologically compatible, the compositions do not require any particular osmolality. Thus, the compositions can be hypotonic, isotonic or hypertonic. In some preferred embodiments, the compositions are isotonic with blood in the range of 270-340 mOsmol / kg. Typically, ready-to-use pharmaceutical compositions have a tonicity of between about 270 and about 340 mOsm / kg, between about 280 and about 330 mOsm / kg, and between about 290 and about 310 mOsm / kg.
    [0045] Toning agents suitable for use in ready-to-use pharmaceutical compositions include, but are not limited to, anhydrous or hydrated forms of sodium chloride, dextrose, sucrose, xylitol, fructose , glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride, magnesium chloride, and other inorganic salts. The amount of the tonicity agent in the formulation can be expressed in mg / ml or in g / l. In typical embodiments, the tonicity agent (s) is present at from about 1 mg / ml to about 90 mg / ml. Thus, ready-to-use pharmaceutical compositions may comprise one or more tonicity agents at about 1 to 5 mg / ml, to about 5 to 10 mg / ml, to about 10 to 15 mg / ml, to about 15 to 25 mg / ml, to about 25 to 50 mg / ml, to about 50 to 60 mg / ml, to about 60 to 70 mg / ml, to about 70 to 80 mg / ml, and to about 80 to 90 mg / ml, as well as combinations of the aforementioned ranges.
    [0046] [0046] In some embodiments, the tonicity agent is sodium chloride. The ready-to-use pharmaceutical composition may comprise sodium chloride at a concentration of from about 0.68 to about 0.82% w / v, from about 0.79 to about 0.82%, or from about 0.68 to about 0.74% w / v. The ready-to-use pharmaceutical composition may comprise sodium chloride at a concentration of from about 5 mg / ml to about 9 mg / ml or from about 6 to about
    [0047] In certain embodiments, the tonicity agent is mannitol. The ready-to-use pharmaceutical composition may comprise mannitol at a concentration of about 30 to about 50 mg / ml, about 35 to about 45 mg per ml, or about 38 to about 43 mg / ml.
    [0048] [0048] In some embodiments, ready-to-use pharmaceutical compositions further comprise a pH adjusting agent. Suitable pH adjusting agents typically include at least one acid or a salt thereof, and / or a base or a salt thereof. Acids and bases are added as needed to achieve the desired pH. For example, if the pH is higher than the desired pH, an acid is used to lower the pH to the desired pH. Acids suitable for use in ready to use pharmaceutical compositions include, but are not limited to hydrochloric acid, phosphoric acid, citric acid, ascorbic acid, acetic acid, l sulfuric acid, carbonic acid and nitric acid. In some embodiments, hydrochloric acid is used to adjust the pH. As a further example, if the pH is below the desired pH, a base is used to adjust the pH to the desired pH. Bases suitable for use in ready-to-use pharmaceutical compositions include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, citrate. of sodium, sodium acetate and magnesium hydroxide. In some embodiments, sodium hydroxide is used to adjust the pH.
    [0049] [0049] In certain embodiments, the pH adjusting agent is any pharmaceutically acceptable pH adjusting agent known in the art. In some embodiments, the pH adjusting agent is selected from phosphoric acid, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, citric acid, malic acid , adipic acid, ascorbic acid, BE2019 / 5387 tartaric acid, lactic acid, phosphoric acid, and their combinations. In some embodiments, the pH adjusting agent is hydrochloric acid. The pH adjusting agent can be used in the composition in an amount in the range of about 0.1 wt% to 1 wt% or about 0.2 to 0.5 wt% or d. About 0.3-0.4% by weight to adjust the pH range as specified.
    [0050] [0050] Tranexamic acid in a ready-to-use intravenous solution can be supplied with or without a pH adjusting agent in a range of pH 4.0 to 11.0, pH 4.5 to 10.0, pH 5.0 to 9.0, pH 5.5 to 8.5, pH 6.0 to 8.0, pH 7.0 to 8.0, or pH 7.3 to 7.5, or approximately pH 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7 , 2, 7.3, 7.4, 7, 5, 7.6, 7.7, 7.8, 7.9 or 8.0, or any intermediate pH value. In a specific embodiment, the pH is about 7.3. In another specific embodiment, the pH is about 7.4. In some embodiments, a pH adjusting agent is used in the aqueous tranexamic formulations to adjust the pH.
    [0051] [0051] In some embodiments, ready-to-use pharmaceutical compositions further comprise a buffer. In some embodiments, no buffer is used.
    [0052] [0052] Suitable buffers for use in the pharmaceutical compositions described herein include, without limitation, the pharmaceutically acceptable salts and acids of acetate, glutamate, citrate, tartrate, benzoate, lactate, d histidine or other amino acids, gluconate, phosphate, malate, succinate, formate, propionate and carbonate. The term "pharmaceutically acceptable" is used herein in the sense of being compatible with the other ingredients of the formulation and not harmful to its recipient. Accordingly, the term "pharmaceutically acceptable salt" refers to salt forms of the active compounds which are prepared with counterions which are not toxic under the conditions of use and which are compatible with a stable formulation. The concentration of the buffer in the formulation can be expressed in mg / ml, g / L or as a molar concentration. Optionally, the composition may comprise from about 0.0001 mg / ml to about 100 mg / ml of a suitable buffer present in the pharmaceutical compositions. Thus, ready-to-use pharmaceutical compositions may comprise from about 0.0001 to about 0.001 mg / ml of a suitable buffer, from about
    [0053] [0053] As a variant, the concentration of buffer can be expressed in molar concentrations. In typical embodiments, about 0.1 to 100 mM of a suitable buffer is present in the pharmaceutical compositions. Thus, ready-to-use pharmaceutical compositions may comprise a suitable buffer having a concentration of about 0.1 to about 100 mM, about 0.1 to about 0.5 mM, about 0.5 to about. 1.0 mM, about 1.0 to about 5 mM, about 5 to about 10 mM, about 10 to about 15 mM, about 15 to about 25 mM, about 25 to about 50 mM, about 50 to about 75 mM, and about 75 to about 100 mM.
    [0054] The ready-to-use compositions of tranexamic acid at 5 mg / ml or 10 mg / ml can be autoclaved in their final container.
    [0055] In some embodiments, the compositions provided herein are capable of maintaining at least about 90%, 95%, 97.5%, 98%, 99%, 99.5% or 99.7% of the amount of release, or "as made" of tranexamic acid in an undegraded form after storage for at least 6 months at 25 ° C and 40% relative humidity, measured by liquid chromatography, e.g. HPLC according to at USP <621>. In some embodiments, the compositions provided herein are capable of maintaining at least about 90%, 95%, 97.5%, 98%, 99%, or 99.5% of the amount of release, or "as manufactured. »Tranexamic acid in undegraded form after storage for at least 12 months at 25 ° C and 40% relative humidity, measured by liquid chromatography. In some embodiments, the compositions provided herein are capable of maintaining at least about 90%, 95%, 97.5%, 98%, 99%, 99.5% of the amount of release, or "as made" of tranexamic acid in an undegraded form after storage for at least 18 months at 25 ° C and relative humidity of 40%, measured by liquid chromatography. In certain embodiments of BE2019 / 5387, the compositions provided herein are capable of maintaining at least about 90%, 95%, 97.5%, 98%, 99%, of the amount of release, or "as manufactured". Tranexamic acid in an undegraded form after storage for at least 24 months at 25 ° C and 40% relative humidity, measured by liquid chromatography. In some embodiments, the compositions provided herein are capable of maintaining at least about 90%, 95%, 97.5%, 98%, 99%, of the amount of release, or "as made" of tranexamic acid. in undegraded form after storage for at least 36 months at 25 ° C and 40% relative humidity, measured by liquid chromatography. In certain embodiments, the compositions provided herein are capable of maintaining at least about 90%, 95%, 97.5%, 98%, of the amount of release, or "as made" of tranexamic acid in a form. not degraded after storage for at least 48 months at 25 ° C and 40% relative humidity, measured by liquid chromatography.
    [0056] In certain embodiments, the compositions provided herein are capable of maintaining at least about 90%, 95%, 97.5%, 98%, 99%, 99.5% or 99.7% of the amount of release, or "as manufactured" of tranexamic acid in an undegraded form after storage for at least 6 months at 40 ° C and 25% relative humidity, measured by liquid chromatography. In some embodiments, the compositions provided 1c1 are capable of maintaining at least about 90%, 95%, 97.5%, 98%, 99%, 99.5%, 99.7%, or 99.8% of the amount of release, or “as made” of tranexamic acid in undegraded form after storage for at least 12 months at 40 ° C and 25% relative humidity, - measured by liquid chromatography. In some embodiments, the compositions provided herein are capable of maintaining at least about 90%, 95%, 97%, 97.5%, 98%, 99%, 99.5%, 99.7%, or 99, 8% of the release amount, or "as made" of tranexamic acid in undegraded form after storage for at least 18 months at 40 ° C and 25% relative humidity, measured by liquid chromatography .
    [0057] [0057] Ready-to-use compositions can be packaged for use in a variety of pharmaceutically acceptable containers. The compositions are preferably packaged in an acceptable BE2019 / 5387 pharmaceutically acceptable container chosen from a vial, bag or bottle for intravenous. In some embodiments, packages can be used which reduce the amount of light that can reach the composition. For example, in some embodiments, the container may optionally further include a light barrier, such as an aluminum overwrap or carton.
    [0058] [0058] In some embodiments, ready-to-use pharmaceutical compositions are dispensed in a pharmaceutically acceptable container such as plastic intravenous bags, comprising premixed bags and mix bags or bottles. Intravenous bags are well known in the art and commercially available. Examples of commercially available intravenous bags include, but are not limited to: ADDEASE®, ADD-VANTAGE®, BFSTM, DUPLEXTM, EXCEL®, FIRST CHOICETM, GALAXY®, INTRAVIA®, PROPYFLEXTM SOLOMIX®, STEDIM® 71 , STEDIM®100, VIAFLEX®, VIAFLOTM, and VISIV®. In some embodiments, the pharmaceutical compositions are provided in intravenous containers comprising a polymeric contact surface comprising a copolymer of ethylene and propylene (eg EXCEL), polyethylene (eg GALAXY), a blend of polyolefins ( eg VISIV and VIAFLO), PVC (VIAFLEX and INTRAVIA), or ethylene vinyl acetate (EVA) (eg STEDIM®71).
    [0059] In another embodiment, the pharmaceutical compositions are packaged in plastic containers made of ethylene / propylene copolymer (EXCEL®).
    [0060] [0060] In some embodiments, the components of the bag which come into contact with the pharmaceutical compositions should not contain polar polymers, such as polyvinyl chloride (PVC) and ethylene vinyl acetate (EVA) . Examples of bags which do not contain polar polymers and are therefore suitable for use in these embodiments include, but are not limited to, GALAXY®, EXCEL®, VISIV® and VIAFLO "M,
    [0061] In some embodiments, the pharmaceutical compositions are BE2019 / 5387 packaged in a glass container. In some embodiments, the pharmaceutical compositions are packaged in USP Type I borosilicate glass vials or USP Type II soda lime silica glass vials. Glass vials can be clear or amber. Glass vials can be 50ml, 100ml or 200ml in size.
    [0062] [0062] Glass vials may include an elastomeric USP closure for injections with an elastomeric stopper <381>. The stopper can be selected from a material of butyl, EPDM, natural rubber, nitrile or silicone. The butyl stopper can be chosen from a chlorobutyl or bromobutyl stopper. The stopper or cap may be coated with a silicone, B2 cross-linked coating, Flurotec coating, Teflon coating, Westar RS treatment, RTS treatment or a product. thermoplastic elastomer (TPE). In some embodiments, the glass vial is closed with a bromobutyl stopper and sealed with aluminum caps.
    [0063] [0063] Procedures for filling pharmaceutical compositions into pharmaceutically acceptable containers and their subsequent processing are known in the art. These procedures can be used to produce sterile pharmaceutical drugs often required for health care. See, for example, the document from the Center for Drug Evaluation and Research (CDER) and the Center for Veterinary Medicine (CVM) titled “Guidance for Industry for Submission Documentation for Validation of the Sterilization Process in applications of pharmaceuticals for human and veterinary use ”(November 1994). Examples of suitable procedures for the production of sterile pharmaceuticals include, but are not limited to, terminal moist heat sterilization, ethylene oxide, radiation (i.e. gamma beams and electronic) and aseptic processing techniques. Any of these sterilization methods can be used to produce the sterile pharmaceutical compositions described herein.
    [0064] [0064] In certain embodiments, sterile pharmaceutical compositions can be prepared using aseptic processing techniques. Sterility is maintained using sterile materials and a controlled working environment.
    [0065] In some embodiments, the compositions are terminally sterilized using moist heat. Terminal sterilization can be used to destroy any viable microorganisms in the final sealed container containing the pharmaceutical composition. An autoclave is typically used to perform final heat sterilization of drug products in their final packaging. Typical autoclave cycles in the pharmaceutical industry to achieve final sterilization of the final product are at 121 ° C for at least 10 minutes.
    [0066] The ready-to-use isotonic composition comprising tranexamic acid can be supplied at a concentration of 5 mg / ml in water for injection comprising a tonicity agent and a pH adjusting agent in a volume of 100 ml. This will provide a dose of 500 mg of tranexamic acid.
    [0067] [0067] The ready-to-use isotonic composition comprising tranexamic acid can be provided at a concentration of 5 mg / ml in water for injection comprising a tonicity agent and a pH adjusting agent in a volume of 200 ml. This will provide a dose of 1000 mg of tranexamic acid.
    [0068] The ready-to-use isotonic composition comprising tranexamic acid can be provided at a concentration of 10 mg / ml in water for injection comprising a tonicity agent and a pH adjusting agent in a volume of 50 ml. This will make it possible to obtain a dose of 500 g of tranexamic acid.
    [0069] The ready-to-use isotonic composition comprising tranexamic acid can be provided at a concentration of 10 mg / ml in water for injection comprising a tonicity agent and a pH adjusting agent in a volume of 100 ml. This will give a dose of 1000 g of tranexamic acid.
    [0070] [0070] The ready-to-use isotonic composition comprising BE2019 / 5387 tranexamic acid can be provided at a concentration of 10 mg / ml in water for injection comprising a tonicity agent and a tone adjusting agent. pH in a volume of 200 ml. This will provide a dose of 2000 mg of tranexamic acid.
    [0071] [0071] Analytical procedures
    [0072] In some embodiments, ready-to-use tranexamic compositions are provided which pass the particulate matter test according to USP <788> when stored at room temperature for at least 3 months, 6 months, 12 months, 18 months or more.
    [0073] [0073] In certain embodiments, ready-to-use tranexamic compositions are provided which satisfy the pH test according to USP <791> with a variation of + 0.5 pH unit from the initial pH when 'they are stored at room temperature for at least 3 months, 6 months, 12 months, 18 months or more.
    [0074] [0074] In certain embodiments, ready-to-use tranexamic compositions are provided which pass the test for completeness of solution according to USP <641>, in the form of a clear solution when they are stored at room temperature for at least 3 months, 6 months, 12 months, 18 months or more.
    [0075] In certain embodiments, ready-to-use tranexamic compositions are provided which pass the visible particles test according to 1 USP <790>, exhibiting an absence of visible particles when stored at room temperature for at least less 3 months, 6 months, 12 months, 18 months or more.
    [0076] In certain embodiments, ready-to-use tranexamic compositions are proposed which satisfy the test for the coloration of the solution or the degree of coloration according to Ph. Eur 2.2.2., In the form of d a colorless solution when stored at room temperature for at least 3 months, 6 months, 12 months, 18 months or more.
    [0077] In some embodiments, ready-to-use tranexamic compositions are provided which exhibit tranexamic acid by HPLC at 95.0-105.0% of the initial value according to USP <621> when they are stored at BE2019 / 5387 room temperature for at least 3 months, 6 months, 12 months, 18 months or more.
    [0078] [0078] In certain embodiments, ready-to-use tranexamic compositions are provided which do not exhibit more than 0.1% of impurity λ bound to tranexamic acid by HPLC according to USP <621> when 'they are stored at room temperature for at least 3 months, 6 months, 12 months, 18 months or more.
    [0079] [0079] In certain embodiments, ready-to-use tranexamic compositions are provided which do not exhibit more than 0.2% of impurity B bound to tranexamic acid by HPLC according to USP <621> when they are stored at room temperature for at least 3 months, 6 months, 12 months, 18 months or more.
    [0080] [0080] In some embodiments, ready-to-use tranexamic compositions are provided which do not exhibit more than 0.1% of impurity C bound to tranexamic acid by HPLC according to USP <621> when they are stored at room temperature for at least 3 months, 6 months, 12 months, 18 months or more.
    [0081] [0081] In some embodiments, ready-to-use tranexamic compositions are provided which do not exhibit more than 0.1% of impurity D bound to tranexamic acid by HPLC according to USP <621> when they are stored at room temperature for at least 3 months, 6 months, 12 months, 18 months or more.
    [0082] In some embodiments, ready-to-use tranexamic compositions are provided which exhibit no more than 0.1% of any impurity not identified by HPLC according to USP <621> when stored at temperature. ambient for at least 3 months, 6 months, 12 months, 18 months or more.
    [0083] [0083] In some embodiments, ready-to-use tranexamic compositions are provided which do not exhibit more than 0.4% of total impurities by HPLC according to USP <621> when stored at temperature. ambient for at least 3 months, 6 months, 12 months, 18 months or more.
    [0084] [0084] In certain embodiments, ready-to-use tranexamic compositions are provided which do not exhibit more than the aerobic total microbial count (TAMC) of <10 cfu / 100 ml according to the USP <61> when they are are stored BE2019 / 5387 at room temperature for at least 3 months and 6 months, 12 months, 18 months or more.
    [0085] In some embodiments, ready-to-use tranexamic compositions are provided which do not exhibit more than the total number of yeasts and molds (TYMC) of <10 cfu / 100 ml according to USP <61 > when stored at room temperature for at least 3 months, 6 months, 12 months, 18 months or more.
    [0086] [0086] In certain embodiments, ready-to-use tranexamic compositions are provided which exhibit endotoxins <35 IU / ml according to USP <85>, during manufacture and when stored at room temperature for at less 3 months, 6 months, 12 months, 18 months or more.
    [0087] [0087] In certain embodiments, ready-to-use tranexamic compositions are provided which are sterile according to USP <71> during manufacture and when stored at room temperature for at least 3 months, 6 months, 12 months, 18 months or more.
    [0088] In some embodiments, ready-to-use tranexamic compositions are provided, the pH of which is between 6.0 and 8.0 according to USP <791>, during manufacture and when stored at room temperature for at least 3 months, 6 months, 12 months, 18 months or more.
    [0089] [0089] Manufacturing
    [0090] [0090] In some embodiments, the process for making ready-to-use compositions is a non-aseptic process with terminal sterilization. The facilities, equipment, procedures and processing staff comply with European and GMP rules for non-aseptic processes. The filter of the solution may be a 0.22 µm hydrophilic filter, for example, suitable for substances readily soluble in water. Tranexamic acid is sensitive to oxidation and to light. Therefore, in some embodiments, the active ingredient, the main solution and the filled vials are shielded as much as possible from light. The amount of tranexamic acid in the compositional formula is adjusted depending on the desired final concentration.
    [0091] For the preparation of the ready-to-use solution, the process comprises BE2019 / 5387 to introduce approximately 90% of water for injection of the composition formula into the preparation vessel; introduce 0.22 µm filtered nitrogen into the water for injection until the dissolved oxygen level is <0.5 ppm: add tranexamic acid in divided portions until complete dissolution; add sodium chloride and stir under N2 until complete dissolution; adjust the pH by adding a pH adjusting agent; and stir with nitrogen bubbling until dissolved oxygen is <0.5 ppm. In some embodiments, the pH is adjusted with 0.1-1M sodium hydroxide or 0.1-1M 1M hydrochloric acid to 7.4. (limit: 7.3 - 7.5). Oxygen level: <0.5 ppm. Appearance of the solution by visual inspection: clear and free of particles. pH: 7.3 - 7.5. Tranexamic acid content: 97 - 103 mg / ml (97 - 103%). Microbial load of main solution: bacteria: 10 cfu / 100 ml. Mushrooms: 10 cfu / 100 ml. The solution is filtered through a 0.22 µm filter under 0.22 µm filtered nitrogen pressure into the mixing vessel.
    [0092] The bottles are washed, rinsed, sterilized and the endotoxins are inactivated. The caps are purchased ready for use from the supplier. The solution is introduced into the vials which are closed by the stopper and sealed with aluminum stoppers. The vials are sterilized at 121 ° C for 20 minutes.
    [0093] The controls during manufacture include the biological load of pre-sterilization of the solution in the vials. Bacteria: 10 cfu / 100 ml. Mushrooms: 10 cfu / 100 ml, verification of the conformity of the sterilization cycle and control of the integrity of the closure. The product is analyzed according to the analytical procedures in Table 1A.
    [0094] [0094] Table 1 To. Analytical procedures for testing: Appearance of solution (USP <641>) Identification of tranexamic acid by HPLC (USP
    [0095] The specifications of the finished product are presented in Table 1B.
    [0096] [0096] Table 1B. Specifications for intravenous ready-to-use tranexamic acid
    [0097] [0097] In addition, identification of tranexamic acid by UV can be performed according to USP <857>. Prepare the test solutions and standards at 0.05 mg / ml of tranexamic acid. Make zero with WFI. Perform UV spectra from 200 to 400 nm. The two spectra must be similar.
    [0098] [0098] Administration
    [0099] Ready-to-use tranexamic compositions are intended for intravenous administration. Intravenous administration can be chosen from one or more of the following solutions: intravenous injection and infusion. Intravenous injection can be chosen from one, two, three, four times a day or more. Ready-to-use compositions can be administered without dilution at 2.5 to 5 ml / min to 10 mg / ml or can be administered at about 5 ml / min.
    [00100] [00100] In some embodiments, the composition is administered intravenously at a rate of from about 2 mg / kg to about 30 mg / kg or from about 10 mg / kg to about 15 mg / kg of body weight. In some embodiments, the dose is from about 200 mg to about 2000 mg, or from about 500 mg to about 1000 mg of tranexamic acid.
    [00101] Ready-to-use tranexamic compositions can be used in patients with coagulopathy, such as hemophilia, for short-term use (two to eight days) to reduce or prevent hemorrhage and to prevent bleeding. reduce the need for replacement therapy during and after tooth extraction. Specifically, immediately prior to tooth extraction in patients with coagulopathy, the composition can be administered at about 10 mg / kg body weight intravenously, for example in conjunction with replacement therapy. After tooth extraction, intravenous therapy at a dose of 10 mg / kg body weight three to four times a day can be used for 2 to 8 days.
    [00102] [00102] Other indications may include cardiac surgery in adults, total knee arthroplasty in adults, total hip arthroplasty in adults, hereditary angioneurotic edema, hyperfibrinolysis, epistaxis, hyphema. , and menorrhagia. The ready-to-use tranexamic compositions can BE2019 / 5387 be used in trauma patients with severe bleeding.
    [00103] The osmolality of the solutions of tranexamic acid at 5 mg / ml and at 10 mg / ml was measured in order to verify whether the formulations could only be made by dissolving the tranexamic acid in water for injection as solvent. The objective was to prepare ready-to-use isotonic compositions containing tranexamic acid with an osmolality in the range of 270 to 340 mOsmol / kg. Three solutions of 100 ml each of 5 mg / ml of tranexamic acid and three more of 10 mg / ml were prepared by dissolving the tranexamic acid in water for injection. The prepared solutions were placed in 100 ml glass vials and were autoclaved at 121 ° C for 20 minutes. The osmolality of the solutions was measured. The results are shown in Table IC.
    [00104] [00104] Table 1C. Osmolality of tranexamic acid in water for injection 32 mOsmol / Kg 65 mOsmol / Kg 31 mOsmol / Kg 64 mOsmol / Kg 33 mOsmol / Kg 63 mOsmol / Kg 32 mOsmol / Kg 64 mOsmol / Kg Conclusion:
    [00105] The objective is a tranexamic injection which is isotonic with blood in a range of 270 to 340 mOsmol / Kg. Therefore, the formulations cannot be obtained by dissolving tranexamic acid in the water for injection solvent alone, given the strongly hypotonic results. Therefore, an isotonic agent was required in the formulation.
    [00106] First of all, calculations were carried out on the amounts of sodium chloride and mannitol necessary for the isotonic preparation in the presence of tranexamic acid. An isotonic preparation range is 270-340 mOsmol / Kg in Water for Injection (WFT).
    [00107] To calculate the amount of sodium chloride necessary to prepare an isotonic solution of tranexamic acid at 5 mg / ml, a calculation was made on the basis of an osmolality of 32 mOsmol / kg of tranexamic acid at 5 mg / ml. For 900 mg / 100 ml of sodium chloride (0.9%), the osmolality is 308 mOsmol / kg. 900/308 X (308-32) = 806.49. Therefore, 806 mg of sodium chloride was used to prepare 100 ml of a 5 mg / ml solution of tranexamic acid.
    [00108] To calculate the amount of sodium chloride required to prepare an isotonic solution of tranexamic acid at 10 mg / ml, a calculation was made on the basis of an osmolality of 64 mOsmol / kg of tranexamic acid at 10 mg / ml. For 900 mg / 100 ml of sodium chloride (0.9%), the osmolality is 308 mOsmol / kg. 900/308 X (308 - 64) = 714.98. Therefore, 715 mg of sodium chloride was used to prepare 100 ml of a 10 mg / ml solution of tranexamic acid.
    [00109] To calculate the amount of mannitol needed to prepare an isotonic solution of tranexamic acid at 5 mg / ml, a calculation was carried out on the basis of an osmolality of 32 mOsmol / kg of tranexamic acid at 5 mg / ml. For 5000 mg / 100 ml of mannitol (5%), the osmolality is 296 mOsmol / kg. 5000/296 X (296 - 32) = 4459.46. Therefore, 4460 mg of mannitol was used to prepare 100 ml of a 5 mg / ml solution of tranexamic acid.
    [00110] To calculate the amount of sodium chloride necessary to prepare an isotonic solution of tranexamic acid at 10 mg / ml, a calculation was made on the basis of an osmolality of 64 mOsmol / kg of tranexamic acid at 10 mg / ml. 5000 mg / 100 ml of mannitol (5%): the osmolality is 296 mOsmol / Kg. 5000/296 X (296 - 64) = 3918.92. Therefore, 3919 mg of mannitol was used to prepare 100 ml of a 10 mg / ml solution of tranexamic acid.
    [00111] The osmolality of the formulations of tranexamic acid at 5 mg / ml and 10 mg / ml BE2019 / 5387 with the calculated amount of isotonic agent, sodium chloride and mannitol, was measured experimentally and verified in the next step in formulation development studies. Adjustment was made as needed to achieve target osmolality.
    [00112] [00112] 1. A solution of 100 ml of 5 mg / ml tranexamic acid was prepared as follows.
    [00113] [00113] Dissolution of the tranexamic acid did not occur immediately upon addition in the WFI, but took some time. Even when it appeared that dissolution had been achieved, a detailed visual observation showed that some grains of the powder were still not completely solubilized. Therefore, the dissolution of tranexamic acid in water was achieved by adding tranexamic acid in WFI in portions, with the addition of one portion after the dissolution of the previous one. At the end of the addition of tranexamic acid, stirring was continued for 15 minutes to ensure complete dissolution. Tranexamic acid was added first, followed by the other ingredients in the formulation.
    [00114] 2. A solution of 100 ml of 10 mg / ml tranexamic acid was prepared as follows.
    [00115] 1000 mg of tranexamic acid were added with stirring to 100 ml of water for injection (WFT) until complete dissolution. A WFI dissolution profile had the same observation as above for 5 mg / ml, except that pH stabilization was faster than for 5 mg / ml and required about 2-3 minutes. The 10 mg / ml solution of tranexamic acid had a pH of 5.6.
    [00116] 5 mg / ml and 10 mg / ml tranexamic acid formulations in isotonic sodium chloride and mannitol were prepared as follows.
    [00117] 3. A 5 mg / ml formulation of tranexamic acid with sodium chloride as an isotonic agent was prepared according to Table 2.
    [00118] [00118] Table 2. Tranexamic acid at 5 mg / ml with BE2019 / 5387 sodium chloride as isotonic agent Ingredient Formulation for 1 ml | Formulation for 100 ml Sodium chloride 8.06 mg 806 mg
    [00119] 100 ml of a 5 mg / ml solution of tranexamic acid were prepared by first dissolving tranexamic acid, then sodium chloride according to the above techniques. The pH of the preparation quickly stabilized at 7.2.
    [00120] [00120] Table 3. Tranexamic acid at 10 mg / ml with sodium chloride as isotonic agent Ingredient Formulation for 1 ml | Formulation for 100 ml Sodium chloride 7.15 mg 715 mg
    [00121] 100 ml of a 10 mg / ml solution of tranexamic acid were prepared by first dissolving tranexamic acid, then sodium chloride according to the above techniques. The pH of the preparation quickly stabilized at 7.3.
    [00122] 5. A 5 mg / ml formulation of tranexamic acid with mannitol as an isotonic agent was prepared according to Table 4.
    [00123] [00123] Table 4. Tranexamic acid at 5 mg / ml with mannitol as isotonic agent BE2019 / 5387 Ingredient Formulation for 1 ml | Formulation for 100 ml Tranexamic acid 500 mg Water for injection ad 100 ml
    [00124] 100 ml of a 5 mg / ml solution of tranexamic acid were prepared by first dissolving tranexamic acid, then mannitol according to the above techniques. The pH of the preparation stabilized relatively quickly at 5.8.
    [00125] 6. A 10 mg / ml formulation of tranexamic acid with mannitol as an isotonic agent was prepared according to Table 5.
    [00126] [00126] Table 5. Tranexamic acid at 10 mg / ml with mannitol as isotonic agent Formulation for 1 ml Formulation for 100 ml
    [00127] 100 ml of a 10 mg / ml solution of tranexamic acid were prepared by first dissolving tranexamic acid, then mannitol according to the above techniques. The pH of the preparation stabilized relatively quickly at 5.8.
    [00128] Each of the above preparations was placed in 25 ml vials and autoclaved at 121 ° C for 20 minutes. Multipurpose vials that had been washed and sterilized several times were used to ensure that no significant release from the glass vial would enter the preparation. The stability of the preparation was monitored for up to 5 weeks for appearance, particles by visual inspection, and pH. Results: Appearance and particles by visual inspection: compliant. BE2019 / 5387 No change is observed. Table 6 shows the pH stability for up to 5 weeks.
    [00129] [00129] Table 6. Preliminary test for pH stability Solution Start After 1 3 4 5 acid sterilization | week | weeks | weeks | weeks tranexamic mg / ml, 7.2 7.1 7.0 6.9 7.0 6.8 NaCl mg / ml, 7.3 7.5 7.6 7.2 7.3 7.1 NaCl 5 mg / ml, 5.8 7.8 7.8 6.8 7.1 6.8 Mannitol 10 mg / ml, 5.8 6.9 7.0 6.8 7.1 6.8 Mannitol 5 [00130] In the preliminary pH stability test, minor variations in pH were generally observed, possibly due to the fact that tranexamic acid is an amino acid with acidic and basic functions. However, the formulations containing sodium chloride exhibited significantly less pH variability than the formulations containing mannitol, mainly after sterilization, but also over time. The initial pH of the formulations with sodium chloride was about 7 without pH adjustment, which is close to the blood pH of 7.4. Sodium chloride was chosen as the tonicity agent for the further development of the formulation.
    [00131] [00131] After the development of formulations of tranexamic acid at 5 mg / ml and 10 mg / ml, a stability study lasting 3 months at the laboratory level was carried out as a preliminary study in order to verify the suitability of the formulations developed.
    [00132] 500 ml of each formulation of Tables 7 and 8 were prepared as described above, and pH adjusting agents, 1M sodium hydroxide solution and 1M hydrochloric solution were used to adjust the pH. pH 7.4, as shown in Table 7 and Table 8.
    [00133] Table 7. Tranexamic acid at 5 mg / ml with sodium chloride as isotonic agent, pH 7.4
    [00134] [00134] Table 8. Tranexamic acid at 10 mg / ml with sodium chloride as isotonic agent, pH 7.4
    [00135] Each formulation was introduced into a 50 ml type I glass vial, BE2019 / 5387 closed with a bromobutyl stopper and sealed with aluminum caps. Tranexamic acid RTU 5 mg / ml: 10 vials. Tranexamic acid RTU 10 mg / ml: 10 vials. All vials were sterilized by steam autoclave at 121 ° C for 20 minutes. The vials were stored at 25 ° C + 2 ° C / 60% RH + 5% and were analyzed at baseline, after 2 weeks, and 1, 2 and 3 months. Analyzes were performed in duplicate, with one analysis performed on one vial. The average result of the analysis of two vials is reported. The results for the formulation of Table 7 are shown in Table 9 and the results for the formulation of Table 8 are shown in Table
    [00136] [00136] Table 9. Stability of tranexamic acid RTU 5 mg / ml Tranexamic acid RTU 5 mg / ml test Method | Criteria Start 2 1 2 3 analytical | week acceptance | month month month € n Ss Completeness | USP Solution Cp * Cp Cp Cp Cp of the <641>; solution and clear visible particles USP Particles Absence Cp Cp Cp Cp Cp <790> visible Color of Visual Colorless Cp Cp Cp Cp Cp solution pH USP 6.0 - 8.0 725 | 724 | 723 | 724 | 723 <791> posse de | USP 95.0- 999 | 100.1% [99.8 | 999 | 100.1 <621> tranexamiqu 105.0%%%%% e by HPLC
    [00137] [00137] Table 10. Stability Tranexamic acid RTU Tranexamic acid RTU 10 mg / ml test Method | Criteria Start 2 1 2 3 analytical | week acceptance | months months months in s Completeness | USP Solution Cp * Cp Cp Cp Cp of the <641>; solution and clear visible particles USP Particles Absence Cp Cp Cp Cp Cp <790> visible Visual Color | Colorless Cp Cp Cp Cp Cp solution pH USP 60-80 | 732 | 733 | 733 | 728 | 730 <791> Dosage of | USP 95.0- 100.2 | 99.8% | 999 [1001 | 100.0 acid <621> 105.0%%%%%
    [00138] [00138] All the results were found to be within the acceptance criteria without significant variation. No change in the physicochemical parameters is observed. No impurity is observed. No significant change in pH is observed. The formulations developed were found to be suitable according to preliminary experimental data on stability.
    [00139] Stability studies are performed on validation batches using specifications from Table 1B and analytical procedures from Table 1A, as described here for the finished product. Stability studies are carried out at 25 ° C + 2 ° C / 60% RH + 5%: 48 months; 30 ° C + 2 ° C / 75% RH + 5%: 48 months and / or 40 ° C + 2 ° C / 75% RH + 5%: 48 months. Example 4. Characterization of water for injection
    [00140] [00140] The European Pharmacopoeia (Ph Eur) contains standards for the qualities of water for pharmaceutical use, including water for injections (WFT). Water for Injections (WFT) is water intended for the preparation of medicaments for parenteral administration when water is used as a vehicle and for dissolving or diluting substances or preparations for parenteral administration before use. One of the problems is to ensure constant microbiological quality with regard to BE2019 / 5387 removal of bacteria and bacterial endotoxins, for example by distillation. The WFI complies with the tests for purified water with additional requirements for bacterial endotoxins of up to (nmt) 0.25 IU endotoxin per ml). The biological load limit of WFI is nmt 10 cfu / 100 ml, the conductivity is 0.6 to 1.5 uS / cm and the total organic carbon is 0.5 mg / L (= 500 ppb). The European monograph for water for injections is the Ph. Eur. 0169, the monograph for purified water is the Ph. Eur. 0008, the monograph for highly purified water is the Ph. Eur.
    [00141] [00141] Table 11A. Specifications of water for injection Total Organic Carbon | USP <643> <0.5 mg / L (TOC) Total microbial load | USP <61> <10 cfu / 100 ml * internal specifications
    [00142] [00142] Table 11B. Water for Injection Analysis Aspect * Clear and | Claire and | Claire and | Clear and colorless colorless colorless colorless a
    [00143] [00143] The WFI used in the compositions of the description exhibited a conductivity range of 0.68 to 1.36uS / cm, with an average conductivity at 25 ° C of 1.05 uS / cm +0.34 d ' standard deviation. The WFI used in the compositions of the description exhibited a TOC ranging from 13.0 to 128 ppb, with an average TOC of 60 ppb + 60 standard deviation. Example 5. pH stability of tranexamic acid at 5 mg / ml and at 10 mg / ml in sodium chloride
    [00144] A study of the optimum pH for the stability of tranexamic acid RTU at 5 mg / ml and at 10 mg / ml in sodium chloride solution was carried out. Formulations of 5 mg / ml and 10 mg / ml tranexamic acid in sodium chloride were prepared as shown in Example 3, except that the initial pH was adjusted to pH 4.0, 5.0, 6.0, 6.5, 7.0, 7.4, 7.8, 8.0, 9.0 and 11.0 using pH adjusting agents, hydrochloric acid or sodium hydroxide. The solutions were stored either at 25 ° C = 25 ° C + 2 ° C / 60% RH + 5%, or at 40 ° C = 40 ° C + 2 ° C / 75% RH + 5%. The solutions were characterized at the initial time, after one, two, three, four, five or six months for each storage condition, by the methods given in Table 12A for the completeness of the solution, visible particles and color of. the solution.
    [00145] [00145] Table 12A. PH stability tests BE2019 / 5387 Completeness of the solution USP <641> Visible particles USP <790> Color of the solution Ph Eur 2.2.2
    [00146] The results of the tests for the completeness of the solution, the visible particles and the color of the solution are presented in Tables 12B to 12E, where C = is in conformity.
    [00147] [00147] Table 12B. Tranexamic acid 5 mg / ml OL | [9 PTE | wc (PE [we 6/4 I I I I I I I | 8 Js I I I I I I Jc | 9 loo I I I I I I I |
    [00148] [00148] Table 12C. Tranexamic acid 5 mg / ml [BE [ee [ee [we [we [we
    [00149] [00149] Table 12D. Tranexamic acid 10 mg / ml OLO | C | C (PE | wc (PC [wo | 6 [74 I I I I the I | ss | 85 I I I I the I |> oo I the the the the I |
    [00150] [00150] Table 12E. Tranexamic acid at 6 months 10 mg / ml EE qe 5th EEE EEC CUT EE EE IEEE PU EEE EEE PO PR EEE ES
    [00151] Surprisingly, each composition of tranexamic acid at 5 mg / ml or at 10 mg / ml from pH 4 to pH 11 met the requirements for completeness of the solution, visible particles and color of the solution. , stored for 6 months at 25 ° C = 25 ° C + 2 ° C / 60% RH + 5% or 40 ° C = 40 ° C + 2 ° C / 75% RH + 5%.
    [00152] [00152] Particulate matter test
    [00153] [00153] The pH solutions were also evaluated for particulate matter. In this test, 5 and 10 mg / ml solutions of tranexamic acid were prepared and adjusted to an initial pH of 4.0, 5.0, 6.0, 6.5, 7.0, 7, 4, 7.8, 8.0, 9.0 or 11.0 in aqueous sodium chloride, and stored under two different conditions; either 25 ° C = 25 ° C + 2 ° C / 60% RH + 5%, or 40 ° C = 40 ° C + 2 ° C / 75% RH + 5%. Solutions were characterized at the initial time, after one, three, four, five and six months, by the method shown in Table 13A for particulate matter according to USP <788>. The results are shown in Tables 13B to 13E. The 5 mg / ml and 10 mg / ml tranexamic acid RTU solutions met USP <788> particulate matter specifications after 6 months at each pH 4.0-11.0 at 25 ° C + 2 ° C / 60% RH + 5% and / or 40 ° C + 2 ° C / 75% RH + 5%.
    [00154] [00154] Table 13A. Particulate matter test Specification Method reference Particulate matter> 10 um: 3000 / unit USP <788>> 25 um: 300 / unit
    [00155] [00155] The results of the evaluation for particulate matter are shown in Tables 13B and 13C.
    [00156] [00156] Table 13B. PH stability of tranexamic acid at 5 mg / ml at 3 months - BE2019 / 5387 Particulate matter LL | | | C [bc | wc (PE [we | EE [na [an 64 Qi Ir [na 8 | 80 [ns | 203 [m4 | | 1 [is ie | 9 Voo [191 [128 167 oe ss Jie |
    [00157] [00157] Table 13C. PH stability of tranexamic acid at 5 mg / ml at 6 months - Particulate matter pre [we | we [we | s € [we
    [00158] [00158] Table 13D. PH stability of tranexamic acid at 10 mg / ml at 3 months - BE2019 / 5387 Particulate matter | | [st [we [st [oe [are [we 6 | 74 214 [an [ie | s oe ass 154 | 8 | 80 [mm [as [me [| [19 166 | 9 | oo | [mas Jia | s [is im |
    [00159] [00159] Table 13E. PH stability of tranexamic acid at 10 mg / ml at 6 months - Particulate matter [| mw pre [re [re | [SE Ea [a [5 (A | [a [a 5e [5 [6 | 18 1m 1e [a | [a | [| [a
    [00160] [00160] A study of the optimum pH for the stability of tranexamic acid RTU at BE2019 / 5387 mg / ml and at 10 mg / ml in sodium chloride solution was carried out. Formulations of 5 mg / ml and 10 mg / ml tranexamic acid in sodium chloride were prepared as shown in Example 3, except that the initial pH was adjusted to pH 4.0, 5.0 , 6.0, 6.5, 7.0, 7.4, 7.8, 8.0, 9.0 and 11.0 using pH adjusting agents, hydrochloric acid or l 'sodium hydroxide. The solutions were stored either at 25 ° C = 25 ° C + 2 ° C / 60% RH + 5%, or at 40 ° C = 40 ° C + 2 ° C / 75% RH + 5%.
    [00161] [00161] Table 14A. PH stability test Specification Method reference Variation + 0.5 pH unit | USP <791>
    [00162] [00162] Table 14B. PH stability of tranexamic acid at 5 mg / ml in aqueous sodium chloride LL | (PE (PE (BC | wc (PE [WC | 6/74 [74 [73 [74 [74 [74 [75 [75 _ 8 | 80 [79 [78 [79 [so | 80 | 78 so | 9 loo | o0 | 89 | s9 | oo | s9 [89 | n / a
    [00163] [00163] Table 14C. PH stability of tranexamic acid at 5 mg / ml over 6 months BE2019 / 5387 in aqueous sodium chloride | (PSC (80 ° C | 25 ° C | 40 ° C | 25 ° C | 40 ° C PA (75 | 15 15 1e [a [a [ea [a [ea p 5 15 [90 EE 15
    [00164] [00164] Table 14D. PH stability of tranexamic acid at 10 mg / ml in aqueous sodium chloride | | (PSE (PTE | C | wc (BTE [MC | 6 [4 [74 [74 [15 [75 [74 [74 [74 _ 8 [so | 80 (79 [79 (81 | 80 [79 80 | 9 | oo | oo [89 | s9 | 89 | oo | s9 89 | io [mo [mo [105 [109 [u [m1 [os | |
    [00165] [00165] Table 14E. PH stability of tranexamic acid at 10 mg / ml over 6 months BE2019 / 5387 in aqueous sodium chloride
    [00166] [00166] The pH stability samples were evaluated by HPLC to determine the content of tranexamic acid at the start, one, two, three, four, five and six months after storage at 25 ° C = 25 ° C + 2 ° C / 60% RH + 5% or 40 ° C = 40 ° C + 2 ° C / 75% RH + 5% according to the method in table 15A. The results are shown in Tables 15B-15E for 5 mg / ml or 10 mg / ml tranexamic acid in aqueous sodium chloride prepared as shown in Example 3 at the indicated pH value.
    [00167] [00167] Table 15A. HPLC assay for tranexamic acid Assay (HPLC content) | 95.0-105.5% HPLC USP <621>
    [00168] [00168] Table 15B. PH stability of tranexamic acid at 5 mg / ml in aqueous content of sodium chloride and tranexamic acid, HPLC%
    [00169] [00169] Table 15C. PH stability of tranexamic acid at 5 mg / ml in aqueous contents of sodium chloride and tranexamic acid, HPLC% | F0 ne 5th re 5 € re pu (A pres [aan omas [weapon [03% [1005 EE pros [res ose Poe fees (os java [re ons [ro
    [00170] [00170] Table 15D. PH stability of tranexamic acid at 10 mg / ml in aqueous content of sodium chloride and tranexamic acid, HPLC%
    [00171] [00171] Table 15E. PH stability of tranexamic acid at 10 mg / ml in aqueous content of sodium chloride and tranexamic acid, HPLC%
    [00172] Each ready-to-use solution of tranexamic acid at 5 mg / ml and at mg / ml in aqueous sodium chloride from pH 4.0 to pH 11.0 remained stable and presented more than 97% acid tranexamic not degraded compared to the initial BE2019 / 5387 concentration, when stored for at least 6 months at 25 ° C + 2 ° C / 60% RH +% or 40 ° C = 40 ° C + 2 ° C / 75% RH + 5%.
    [00173] Each ready-to-use solution of 5 mg / ml and 10 mg / ml tranexamic acid in aqueous sodium chloride from pH 6.0 to pH 8.0 remained stable and showed more than 98 % undegraded tranexamic acid from the initial concentration, when stored for at least 6 months at 25 ° C + 2 ° C / 60% RH + 5% or 40 ° C = 40 ° C + 2 ° C / 75% RH + 5%.
    [00174] [00174] HPLC impurity profiles for each of the pH stability samples were also obtained, as shown in Table 15A. The HPLC method for the assay and impurities was developed with the reference standards USP Tranexamic acid RS and USP Compound bound to tranexamic acid C RS.
    [00175] The chromatic conditions were: Column: octadecylsilyl silica gel (C18) for chromatography. 25 cm x 4.6 mm (5 µm) (USP L1 column); Mobile phase: dissolve 11.0 g of anhydrous sodium dihydrogenphosphate in 500 ml of water and add 5 ml of triethylamine and 1.4 g of sodium laurilsulfate. Adjust to pH 2.5 with dilute phosphoric acid and dilute to 600 ml with water. Add 400 ml of methanol and mix. Column temperature: ambient. Flow rate: 0.9 ml / min; Detection: spectrophotometer at 220nm; Injection volume: 20ul; Running time: 40 minutes. The test solution was diluted in water to 0.5 mg / ml. The standard solution was prepared with 0.5 mg / ml Tranexamic Acid RS USP in water.
    [00176] [00176] The adequacy of the system was achieved as follows. Resolution: 0.2 mg / ml RS USP Tranexamic Acid and 0.002 mg / ml RS USP Tranexamic Acid C Bound Compound in water. The resolution is not less than 2.0 between tranexamic acid - and tranexamic acid related compound C.
    [00177] [00177] Asymmetry: The asymmetry of the peak of tranexamic acid RS USP is at most 2.0. Accuracy: The standard deviation of six injections of Tranexamic Acid RS USP is a maximum of 2.0%. Calculation: Area of tranexamic acid in the test solution relative to the area of tranexamic acid RS USP in the standard solution, taking into account the working weight and declared potency of the standard.
    [00178] [00178] The determination of the impurities by HPLC used the same column, mobile phase, BE2019 / 5387 column temperature, flow rate, detection, and execution time as in the test presented above. The injection volume was 90 µl. Test solution, for tranexamic acid at 5 mg / ml, the assay was performed without dilution. For 10 mg / ml tranexamic acid, the sample was diluted in 5 mg / ml water. The standard solution was prepared with 2.5 µg / ml RS USP Tranexamic Acid in water. The mobile phase is injected at the same injection volume of 90 µl. For suitability of the system: Resolution: Same as assay. Asymmetry: The peak asymmetry of RS USP tranexamic acid is at most 2.5. Accuracy: The standard deviation of six injections of Tranexamic Acid RS USP is a maximum of 10.0%.
    [00179] [00179] The following peaks are eliminated in the chromatograms of the test solutions: the peaks present in the mobile phase chromatogram are eliminated. Exclusion limit: 0.05 times the area of the main peak in the chromatogram obtained with the standard solution for the determination of impurities: 0.025% (according to USP). The known impurities A, B, C and D are identified by the relative retention time of the peak of each impurity, if any in the test solution, in relation to the peak of tranexamic acid according to Table 16A, which corresponds to the impurity table 1 of the USP:
    [00180] [00180] Table 16A. Table of impurities 1 Name Retention time | Response factor | Relative relative acceptance criteria NMT (%) Compound bound to aa | 2.1l 1 0.1 tranexamic acid A Compound bound to | 1.5 1.2 0.2 tranexamic acid B °
    [00181] [00181] The declaration limit is 0.05%. This means 0.05% of the analytical concentration of the test solution. The analytical concentration of the test solution is 5 mg / ml; the declaration limit is therefore 2.5 µg / ml. Only results above the reporting limit are reported. The HPLC impurity limits are shown in Table 16B.
    [00182] [00182] Table 16B. PH stability-HPLC determination of impurities Determination of impurities The HPLC <621> LE |
    [00183] The results of the impurities over 6 months of the study are presented in Tables 16C to 16F.
    [00184] [00184] Table 16C. PH stability Tranexamic acid 5 mg / ml HPLC impurities | | (OT PE (PT PE [VT | 40 | A, B, | Absence | Absence | Absence | Absence | Absence | Absence | Absence unknown C, | BRL BRL BRL BRL BRL BRL BRL D, Total 5.0 | A, B , | Absence | Absence | Absence | Absence | Absence | Absence | Absence unknown C, | BRL BRL BRL BRL BRL BRL BRL D, Total 60 | A, B, | Absence | Absence | Absence | Absence | Absence | Absence | Absence unknown C, | BRL BRL BRL BRL BRL BRL BRL D, Total 6,5 | A, B, | Absence | Absence | Absence | Absence | Absence | Absence | Absence unknown C, | BRL BRL BRL BRL BRL BRL BRL D, Total 7 , 0 | A, B, | Absence | Absence | Absence | Absence | Absence | Absence | Absence unknown C, | BRL BRL BRL BRL BRL BRL BRL D, Total
    [00185] [00185] Table 16D. PH stability over 6 months Tranexamic acid 5 mg / ml Impurities HPLC PU (re are [wep ae | se] ae 4,0 A, B, | Absenc | Absence | Absenc | Absence | Absenc | Absence unknown e BRL € BRL € BRL C, D, Total BRL BRL BRL 5.0 A, B, | Absenc | Absence | Absenc | Absence | Absenc | Absence unknown € BRL € BRL € BRL C, D, Total BRL BRL BRL 6.0 A, B, | Absenc | Absence | Absenc | Absence | Absenc | Absence unknown C, € BRL € BRL € BRL D, Total BRL BRL BRL 6.5 A, B, unknown | Absence | Absence | Absence | Absence | Absence | Absence C, D , Total € BRL € BRL € BRL
    [00186] [00186] Table 16E. PH stability Tranexamic acid 10 mg / ml HPLC impurities | | (PE (PT BE (PT IPC (PT | 40 | A, B, | Absence | Absence | Absence | Absence | Absence | Absence | Absence unknown C, | BRL BRL BRL BRL BRL BRL BRL 5.0 | A, B, | Absence | Absence | Absence | Absence | Absence | Absence | Absence unknown C, | BRL BRL BRL BRL BRL BRL BRL 6,0 | A, B, | Absence | Absence | Absence | Absence | Absence | Absence | Absence unknown C, | BRL BRL BRL BRL BRL BRL BRL
    [00187] [00187] Table 16F. PH stability over 6 months Tranexamic acid 10 mg / ml Impurities HPLC PU re Tee | se 1 ae | se] ue.
    [00188] As shown in Tables 16C to 16F, surprisingly, for each of the pH values of 4.0 to 11.0 for both 5 mg / ml and 10 mg / ml of tranexamic acid in chloride sodium aqueous, A, B and unknown impurities were not detected, while C, D and total impurities were below the reporting limit in Table 16B when stored for at least six months at 25 ° C = ° C + 2 ° C / 60% RH + 5% or 40 ° C = 40 ° C + 2 ° C / 75% RH + 5%.
    权利要求:
    Claims (24)
    [1]
    1. An aqueous pharmaceutical composition for parenteral administration comprising: tranexamic acid or a pharmaceutically acceptable salt thereof; and a tonicity agent, wherein the composition does not require any dilution before administration and has a pH of 6.0 to 8.0.
    [2]
    2. The aqueous pharmaceutical composition according to claim 1, comprising from 0.05 to 15 mg / ml of tranexamic acid.
    [3]
    3. The aqueous pharmaceutical composition according to claim 1 comprising 5 mg / ml of tranexamic acid.
    [4]
    4. The aqueous pharmaceutical composition according to claim 1 comprising 10 mg / ml of tranexamic acid.
    [5]
    5. The aqueous pharmaceutical composition according to claim 1, wherein the tonicity agent is selected from the group consisting of sodium chloride, dextrose, sucrose, xylitol, fructose, glycerol, sorbitol, mannitol, potassium chloride, mannose, calcium chloride and magnesium chloride.
    [6]
    6. The aqueous pharmaceutical composition according to claim 1, comprising the tonicity agent at a concentration effective to impart osmolality ranging from 270 to 340 mOsm / kg.
    [7]
    7. The aqueous pharmaceutical composition according to claim 1, wherein the tonicity agent is sodium chloride.
    [8]
    8. The aqueous pharmaceutical composition according to claim 7, comprising from 5 to 10 mg / ml of sodium chloride.
    [9]
    9. The aqueous pharmaceutical composition according to claim 1, wherein the tonicity agent is mannitol.
    [10]
    10. The aqueous pharmaceutical composition according to claim 9, comprising from 45 mg / ml of mannitol.
    [11]
    11. The aqueous pharmaceutical composition of claim 1, wherein BE2019 / 5387 the composition maintains at least about 95% of the tranexamic acid in undegraded form after storage for 180 days at 25 ° C.
    [12]
    12. The aqueous pharmaceutical composition of claim 1, wherein the composition maintains at least about 98% of the tranexamic acid in undegraded form after storage for 180 days at 25 ° C.
    [13]
    13. The aqueous pharmaceutical composition according to claim 1, further comprising at least one pH adjusting agent selected from the group consisting of hydrochloric acid, sodium hydroxide and a mixture thereof.
    [14]
    The aqueous pharmaceutical composition according to claim 1 further comprising water for injection having a conductivity at 25 ° C of 0.6 to 1.5 mS / em.
    [15]
    15. A pharmaceutical composition for parenteral administration comprising a ready-to-use aqueous solution with a pH of from about 6.0 to about 8.0 comprising: from 0.05 to about 15 mg / ml of tranexamic acid or of. one of its pharmaceutically acceptable salts; a tonicity agent selected from (1) about 35 mg / ml to about 45 mg / ml mannitol or (ii) about 6.8-8.2 mg / ml sodium chloride; and a pH adjusting agent in an amount to provide an initial pH of from about 6.0 to about 8.0.
    [16]
    16. The aqueous pharmaceutical composition according to claim 15, further comprising water for injection having a conductivity at 25 ° C of 0.6 to 1.5 mS / em.
    [17]
    17. The pharmaceutical composition of claim 15, wherein the aqueous solution is contained in a pharmaceutically acceptable container.
    [18]
    18. The pharmaceutical composition of claim 15, wherein the aqueous solution, when stored in the container for at least one year at room temperature, exhibits (1) a decrease of less than 10% in the concentration of tranexamic acid. and (ii) formation of total impurities of less than about 3%.
    [19]
    19. The aqueous pharmaceutical composition according to claim 15 comprising 5 mg / ml of tranexamic acid.
    [20]
    20. The aqueous pharmaceutical composition according to claim 15, comprising BE2019 / 5387 10 mg / ml of tranexamic acid.
    [21]
    21. A method of reducing or preventing hemorrhage associated with tooth extraction in a coagulopathic patient, comprising the steps of: (a) administering the composition of claim 1 to the patient immediately prior to tooth extraction; and (b) administering the composition of claim 1 to the patient for 2 to 8 days after tooth extraction.
    [22]
    22. The method of claim 21, wherein step (a) further comprises the concomitant administration of a replacement therapy.
    [23]
    23. The method of claim 21, wherein step (a) comprises intravenous administration of the composition at a dose of 10 mg of tranexamic acid per kg of body weight of the patient.
    [24]
    24. The method of claim 21, wherein step (b) comprises intravenous administration of the composition at a dose of 10 mg of tranexamic acid per kg of body weight of the patient three to four times per day.
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    法律状态:
    2020-10-23| FG| Patent granted|Effective date: 20200928 |
    优先权:
    申请号 | 申请日 | 专利标题
    US201862727939P| true| 2018-09-06|2018-09-06|
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