Stable pharmaceutical composition containing blood coagulation factor x

Abstract

There has been demand for a pharmaceutical composition containing blood coagulation factor X in which the amount of FXa is suppressed. Provided is a pharmaceutical composition containing blood coagulation factor X, the pharmaceutical composition furthermore containing antithrombin III.

Description

Stable pharmaceutical composition containing blood coagulation factor X

[0001] RELATED APPLICATIONS This application claims the benefit of priority from Application No. 2024-148637, filed with the Japan Patent Office on August 30, 2024. The priority application is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to stable pharmaceutical compositions comprising blood clotting factor X.

[0003] Blood coagulation factor X (FX) is an enzyme that plays an important role in the blood coagulation cascade. It is a precursor of serine proteases and is a vitamin K-dependent coagulation factor with a gamma-carboxyglutamic acid (Gla) residue at its N-terminal region. Like other vitamin K-dependent coagulation factors, it is synthesized in the liver and is present in plasma at a concentration of 5-10 μg / mL. Physiologically, activation of factor X occurs via activation of factor IX by activated factor VII / tissue factor complex, and the blood coagulation cascade progresses. Furthermore, activated factor X (factor Xa) further activates factor VII (Non-Patent Document 1).

[0004] Blood coagulation factor X deficiency and abnormality are autosomal recessive inherited disorders. They are caused by decreased synthesis of blood coagulation factor X, production of impaired blood coagulation factor X function, or a combination of both. Symptoms include mucocutaneous bleeding (subcutaneous, epistaxis, and gingival bleeding), excessive bleeding after trauma, menorrhagia, intracranial hemorrhage, and intra-articular bleeding. The severity of bleeding correlates with blood coagulation factor X activity, and patients with blood coagulation factor X activity below 1% experience severe bleeding within joints, soft tissues, and mucous membranes. Mild to moderate blood coagulation factor X deficiency predisposes to bleeding after trauma or surgery. Heterozygotes have blood coagulation factor X levels that are approximately 50% of normal, do not usually exhibit bleeding symptoms, and are often discovered incidentally through screening tests (Non-Patent Document 2).

[0005] The incidence of this disease is reported to be 1 in 1 million. In Japan, a nationwide survey of blood coagulation disorders in 2023 (a project commissioned by the Ministry of Health, Labor and Welfare) reported a total of 28 cases, 14 men and 14 women.

[0006] PPSB-HT "Takeda," a prothrombin complex concentrate (PCC), is a plasma-derived preparation containing 200 international units (IU) of its active ingredient, blood coagulation factor IX, per 10 mL, or 20 IU / mL (Non-Patent Document 3). It also contains 26.5 units / mL of blood coagulation factor X, making it used in Japan to treat blood coagulation factor X deficiency and abnormalities. While the minimum required amount for hemostasis is 10-20%, replacement therapy should be tailored to the severity of bleeding. For soft tissue, mucosal, and joint bleeding, replacement therapy is recommended to achieve blood coagulation factor X activity at 30% of normal, while for more severe bleeding, replacement therapy is recommended to achieve blood coagulation factor X activity at 50-100%. Because the half-life of blood coagulation factor X is approximately 30 hours, maintenance therapy should be administered every 24 hours, taking into consideration bleeding symptoms (Non-Patent Document 2).

[0007] Overseas, Coagadex (Bio Products Laboratory), a blood coagulation factor X preparation, is available as a therapeutic agent for blood coagulation factor X deficiency and abnormalities (Non-Patent Document 4). The formulation is disclosed to contain citric acid, sodium hydroxide, disodium phosphate dihydrate, and sucrose, but the amounts of each ingredient added are not disclosed.

[0008] As mentioned above, there are no single-ingredient preparations of blood coagulation factor X commercially available in Japan as a treatment for blood coagulation factor X deficiency and abnormalities.

[0009] Hemostasis, Thrombosis, Fibrinolysis Chugai Igakusha (1994) p. 120 Factor X Deficiency and Abnormalities | Glossary of the Japanese Society on Thrombosis and Hemostasis (medical-words.jp), URL: https: / / jsth.medical-words.jp / words / word-304 / PPSB-HT "Takeda" Package Insert: PPSB-HT Intravenous Injection 200 / 500 Units "Takeda" | [Official] Takeda Pharmaceutical Information for Medical Professionals, Takeda Medical Site, URL: https: / / www.takedamed.com / medicine / detail?medicine_id=588 BPL Group Official Website, Product Page (URL: https: / / www.bplgroup.com / therapy-areas-and-products / bpl-products / ) Journal of Thrombosis and Haemostasis, Volume 18, Issue 1, p. 255-257 (URL: https: / / onlinelibrary.wiley.com / doi / 10.1111 / jth.14623) National Institute for Biological Standards and Control (NIBSC), "WHO Reference Reagent, Activated Blood Coagulation Factor X (FXa), Human, NIBSC code: 15 / 102, Instructions for use, Version 1.0, Dated 23 / 11 / 2017," (URL: https: / / nibsc.org / documents / ifu / 15-102.pdf)

[0010] When hemostatic compositions and preparations containing blood coagulation factor X purified from donated plasma as an active ingredient are left in solution, the amount of activated blood coagulation factor X (FXa) increases over time (Example 1). Furthermore, even when a very small amount of FXa is present, the amount of FXa increases over time (Example 2). Since an increase in the amount of FXa promotes the blood coagulation reaction and increases the risk of thrombosis, it is necessary to suppress unnecessary amounts of FXa in blood coagulation factor X preparations.

[0011] The objective of the present disclosure is to suppress the amount of FXa by specifically inhibiting the produced FXa or factors that activate FXa, for example, by adding antithrombin III (AT-III), or by optimizing the pH of the buffer.

[0012] [Item 1] A pharmaceutical composition comprising blood coagulation factor X (FX), further comprising antithrombin III. [Item 2] The pharmaceutical composition according to Item 1, wherein the pH of the solution when the pharmaceutical composition is dissolved in a solvent is in the range of 6.4 to 7.5. [Item 3] The pharmaceutical composition according to Item 1 or 2, wherein the solvent is water. [Item 4] The pharmaceutical composition according to any one of Items 1 to 3, which does not contain at least one blood coagulation factor or blood-derived substance selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin. [Item 5] The pharmaceutical composition according to any one of Items 1 to 3, which does not contain at least two or more blood coagulation factors or blood-derived substances selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin. [Item 6] The pharmaceutical composition according to any one of Items 1 to 3, which does not contain at least three or more blood coagulation factors or blood-derived substances selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin. [Item 7] The pharmaceutical composition according to any one of Items 1 to 6, comprising FX at a final concentration of 50 to 1000 IU / mL, preferably 100 to 800 IU / mL, more preferably 150 to 600 IU / mL, even more preferably 200 to 500 IU / mL, even more preferably 250 to 550 IU / mL, and most preferably about 400 IU / mL.[Item 8] The pharmaceutical composition according to any one of Items 1 to 7, comprising antithrombin III at a final concentration of 0.1 to 2.0 IU / mL, preferably 0.2 to 1.5 IU / mL, more preferably 0.25 to 1.0 IU / mL, even more preferably 0.3 to 0.8 IU / mL, even more preferably 0.35 to 0.45 IU / mL, and most preferably about 0.4 IU / mL. [Item 9] A method for stabilizing a pharmaceutical composition containing FX, using antithrombin III. [Item 10] The method according to Item 9, wherein the solution of the pharmaceutical composition dissolved in a solvent has a pH in the range of 6.4 to 7.5. [Item 11] The method according to Item 9 or 10, wherein the solvent is water. [Item 12] The method according to any one of Items 9 to 11, which does not contain at least one blood coagulation factor or blood-derived substance selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin. [Item 13] The method according to any one of Items 9 to 11, which does not contain at least two or more blood coagulation factors or blood-derived substances selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin. [Item 14] The method according to any one of Items 9 to 11, which does not contain at least three or more blood coagulation factors or blood-derived substances selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin.[Item 15] The method of any one of Items 9 to 14, wherein the pharmaceutical composition contains FX at a final concentration of 50 to 1000 IU / mL, preferably 100 to 800 IU / mL, more preferably 150 to 600 IU / mL, even more preferably 200 to 500 IU / mL, even more preferably 250 to 550 IU / mL, and most preferably about 400 IU / mL. [Item 16] The method of any one of Items 9 to 15, wherein the pharmaceutical composition contains antithrombin III at a final concentration of 0.1 to 2.0 IU / mL, preferably 0.2 to 1.5 IU / mL, more preferably 0.25 to 1.0 IU / mL, even more preferably 0.3 to 0.8 IU / mL, even more preferably 0.35 to 0.45 IU / mL, and most preferably about 0.4 IU / mL.

[0013] Fig. 1 is a graph confirming the FXa inhibitory effect of a composition containing FX in the presence of AT-III. Fig. 2 is a graph confirming the FXa inhibitory effect of a composition containing FX in the presence of FXa and AT-III. Fig. 3 is a graph confirming the FXa inhibitory effect of a composition containing FX as a function of pH in the presence of FXa and AT-III.

[0014] As used herein, "blood clotting factor," "(blood) clotting factor," or simply the abbreviated form "F" preceding each blood clotting factor number (e.g., FVII, FX, etc.) are used synonymously and refer to each blood clotting factor of the coagulation system. Activated clotting factors are abbreviated, for example, as Factor VIIa, Factor Xa. Unactivated clotting factors are abbreviated, for example, as Factor VII, Factor X, etc. As used herein, antithrombin III is sometimes abbreviated as AT-III or AT.

[0015] FX is an enzyme that plays an important role in the blood coagulation cascade. It is a precursor of serine protease and a vitamin K-dependent coagulation factor with a gamma-carboxyglutamic acid (Gla) residue in the N-terminal region. Like other vitamin K-dependent coagulation factors, it is synthesized in the liver and is found in plasma at 5-10 μg / mL. Physiologically, FX activation occurs via activation of FIX by the FVII / tissue factor complex, and the blood coagulation cascade progresses. Furthermore, activated FX (FXa) further activates FVII.

[0016] The method for producing FX used in the present invention is not particularly limited, but examples of methods for producing blood-derived FX include a method in which fresh frozen human plasma is cold-thawed and centrifuged to remove cryoprecipitate, resulting in cryo-depleted plasma, which is then crudely purified by anion exchange chromatography, and FX is then purified by affinity chromatography using an anti-FX monoclonal antibody-immobilized column.

[0017] In one embodiment, the pharmaceutical composition of the present disclosure enables hemostasis management in a subject patient. The subject patient includes, for example, a patient with FX deficiency or abnormality, preferably a patient with FX deficiency or abnormality. The subject patient has congenital or acquired FX deficiency, and the subject patient of the present disclosure has, for example, an FX activity of about 1, 2.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80% or less of normal, preferably about 1, 2.5, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60% or less, more preferably about 1, 2.5, 5, 10, 15, 20, 25, 30, 35, 40% or less, and even more preferably about 1, 2.5, 5, 10, 15, 20, 25, 30, 35, 40% or less, and even more preferably about 1, 2.5, 5, 10% or less.

[0018] In one aspect, a pharmaceutical composition comprising FX is provided, wherein the pharmaceutical composition further comprises antithrombin III. In another aspect, a method of treatment is provided in which a pharmaceutical composition comprising FX is administered, wherein the pharmaceutical composition further comprises antithrombin III. In another aspect, a use of a pharmaceutical composition comprising FX is provided, wherein the pharmaceutical composition further comprises antithrombin III. In yet another aspect, a use of FX and / or antithrombin III in the manufacture of a medicament, wherein the medicament comprises FX and antithrombin III. In yet another embodiment, a method of stabilizing a pharmaceutical composition comprising FX using antithrombin III is provided. In yet another aspect, a pharmaceutical composition comprising FX is provided, wherein the pharmaceutical composition is manufactured by a method of stabilizing a pharmaceutical composition comprising FX using antithrombin III.

[0019] In one embodiment, the pharmaceutical composition of the present disclosure does not comprise at least one, two, or three or more blood coagulation factors or blood-derived substances selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin. For example, the pharmaceutical composition of the present disclosure does not contain FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, or heparin. In another embodiment, the pharmaceutical composition of the present disclosure consists essentially of FX as a blood coagulation factor or consists essentially of FX as a blood coagulation factor. The pharmaceutical composition of the present disclosure does not substantially contain FXa.

[0020] In one embodiment, the pharmaceutical composition of the present disclosure comprises FX at a final concentration of about 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000 international units (IU) / mL or more. In one embodiment, the pharmaceutical composition of the present disclosure may comprise FX at a final concentration of 50 to 1000 IU / mL, preferably 100 to 800 IU / mL, more preferably 150 to 600 IU / mL, even more preferably 200 to 500 IU / mL, even more preferably 250 to 550 IU / mL, and most preferably about 400 IU / mL.

[0021] In one embodiment, the pharmaceutical composition of the present disclosure comprises antithrombin III at a final concentration of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 IU / mL or more. In one embodiment, the pharmaceutical composition of the present disclosure may comprise antithrombin III at a final concentration of 0.1 to 2.0 IU / mL, preferably 0.2 to 1.5 IU / mL, more preferably 0.25 to 1.0 IU / mL, even more preferably 0.3 to 0.8 IU / mL, even more preferably 0.35 to 0.45 IU / mL, and most preferably about 0.4 IU / mL.

[0022] In one embodiment, the pharmaceutical composition of the present disclosure may contain suitable substances as additives at suitable concentrations that can be appropriately determined by a person skilled in the art. For example, the final concentrations may be about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 mg / mL albumin, about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 mg / mL refined sucrose, about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 mg / mL ... These may be contained to give additives such as 0, 60, 70, 80, 90, or 100 ppm polysorbate 80, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mM sodium citrate, or about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 mM NaCl. For example, the pharmaceutical composition of the present disclosure contains additives such as albumin, sucrose, 50 ppm polysorbate 80, 10 mM sodium citrate, and 120 mM NaCl at final concentrations of about 20 mg / mL.

[0023] In one embodiment, the pharmaceutical composition of the present disclosure, when dissolved in a solvent, has a solution pH of about 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. Preferably, the pharmaceutical composition of the present disclosure, when dissolved in a solvent, has a solution pH in the range of 6.4-7.5, more preferably 6.8-7.5. While there are no particular limitations on the buffer as long as it can be controlled to a predetermined pH, preferred buffers include sodium citrate buffer. The pharmaceutical composition of the present disclosure may contain a pH adjuster. The pH adjuster can be selected as appropriate by those skilled in the art, and examples include hydrochloric acid. The solvent of the present disclosure can be selected as appropriate by those skilled in the art, and examples include water or water for injection.

[0024] The pharmaceutical composition of the present disclosure is advantageous because, when a composition containing FX is dissolved in a solvent, the increase in FXa over time is smaller than in pharmaceutical compositions containing FX that have antithrombin III and / or pH configurations different from those of the pharmaceutical composition of the present disclosure. In the present disclosure, "stabilizing a pharmaceutical composition containing FX" includes suppressing the amount of FXa produced. In one embodiment, when a composition containing FX of the present disclosure is dissolved in a solvent, the amount of FXa is suppressed by about 10, 20, 30, 40, 50, 60, 70, 80, 90% or more when left at room temperature for 72 hours, compared to a pharmaceutical composition containing FX with antithrombin III and / or a different pH configuration from the pharmaceutical composition of the present disclosure, preferably the amount of FXa is suppressed by about 10, 20, 30, 40, 50, 60, 70, 80, 90% or more after being left at room temperature for 48 hours, and more preferably the amount of FXa is suppressed by about 10, 20, 30, 40, 50, 60, 70, 80, 90% or more after being left at room temperature for 24 hours. Specifically, when the composition containing FX of the present disclosure is dissolved in a solvent, the amount of FXa after being left at room temperature for 72 hours is about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 mU / mL or less, preferably after being left at room temperature for 48 hours. , 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 mU / mL or less, and more preferably, the amount of FXa after standing at room temperature for 24 hours is about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10 mU / mL or less. Note that the unit of FXa depends on the unit of the reference material of the National Institute for Biological Standards and Control (NIBSC) used for quantification, and the unit of FXa in this example is "U (Unit)" (Non-Patent Documents 5 and 6).

[0025] In this disclosure, the term "treatment" is meant to encompass alleviating, suppressing, or preventing a disorder, disease, or condition, or one or more symptoms associated with that disorder, disease, or condition; or reducing or eradicating the cause of the disorder, disease, or condition itself. For example, as used herein, treatment also includes improving bleeding conditions in patients who are unable, slow to, or have difficulty in achieving hemostasis.

[0026] The administration interval and number of administrations can be appropriately determined by those skilled in the art. The pharmaceutical composition containing FX of the present disclosure contains a lower amount of FXa, exhibits high stability, and can reduce the risk of thrombosis, compared to pharmaceutical compositions containing FX that have antithrombin III and / or pH configurations different from those of the pharmaceutical composition of the present disclosure.

[0027] Pharmaceutical compositions containing FX of the present disclosure can be administered by any suitable means, including parenteral, pulmonary, and nasal administration, and, if desired for localized treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Pharmaceutical compositions containing FX of the present disclosure are preferably administered intravenously. Dosing can be by any suitable route, for example, by injection, e.g., intravenous or subcutaneous injection, depending in part on whether administration is short-term or chronic. Various dosing schedules include, but are not limited to, single or repeated doses over various time periods, bolus administration, and pulse infusion. Preferably, bolus intravenous administration or continuous intravenous administration is desired.

[0028] The blood coagulation factors or blood coagulation-related substances used in the present disclosure may be natural proteins derived from living organisms or recombinant proteins. When derived from living organisms, they may be derived from humans, pigs, etc., or from plasma. The plasma is preferably human plasma.

[0029] As used herein, "pharmaceutical composition" includes, for example, a pharmaceutical composition. As used herein, a "pharmaceutical composition" is a preparation in a form that allows the biological activity of the active ingredient contained therein to be effective. A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical composition other than the active ingredient that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives, and the substance or concentration thereof can be appropriately determined by one skilled in the art.

[0030] In one embodiment of the present disclosure, blood coagulation activity is improved by using a pharmaceutical composition containing FX. For example, blood coagulation activity can be examined by measuring prothrombin time (PT) and activated partial thromboplastin time (APTT). In the present disclosure, for example, a shortening of the prothrombin time (PT) and / or activated partial thromboplastin time (APTT) indicates improved blood coagulation activity. In another embodiment of the present disclosure, the amount of FXa is reduced, and therefore the risk of thrombosis tendency is reduced compared to an FX composition that also contains FXa. The risk of thrombosis tendency can be examined, for example, by measuring fibrinogen, fibrinogen degradation product (FDP), and D-dimer.

[0031] As used herein, "about" means within a range of ±10%, preferably ±5%, and more preferably ±2.5%.

[0032] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples in any way.

[0033] Example 1: FXa suppression effect by addition of AT-III To examine the liquid stability of FX preparations, FX was added to a buffer solution (20 mg / mL albumin, 30 mg / mL refined sucrose, 50 ppm polysorbate 80, 10 mM sodium citrate, 120 mM NaCl, pH 6.8) to a final concentration of 400 International Units (IU) / mL (=2.4 mg / mL). Samples were prepared with or without AT-III added to a final concentration of 0.4 IU / mL, and then incubated at room temperature for 24, 48, and 72 hours. The FXa activity in the samples after each incubation period was calculated from the hydrolysis activity of a synthetic substrate (S2765), and the results are shown in Figure 1. As is clear from Figure 1, the increase in FXa after 72 hours was suppressed to less than half in the presence of AT-III compared to the absence of AT-III.

[0034] Example 2: FXa suppression effect of AT-III addition in FXa-added samples Samples were prepared by adding 0.3 or 3 U / mL of FXa to an FX formulation, and the effect of AT-III was confirmed using the increase in FXa as an index, as in Example 1 (Figure 2). As shown in Figure 2, for the sample with 3 U / mL of FXa added, the increase in FXa after 72 hours at room temperature was suppressed to less than half in the presence of AT-III compared to the sample without AT-III. Note that for the sample with 0.3 U / mL of FXa added, the increase in FXa after 72 hours at room temperature was also slightly suppressed in the presence of AT-III compared to the sample without AT-III.

[0035] Example 3: FXa suppression effect by addition of AT-III For an FX formulation containing 3 U / mL of FXa and 0.4 IU / mL of AT-III, samples were prepared in which the pH of the formulation buffer was changed to pH 6.3, pH 6.8, and pH 7.5 in the neutral range, and the increase in FXa was confirmed in the same manner as in Example 2 (Figure 3). As shown in Figure 3, it was found that the increase in FXa after leaving it at room temperature for 72 hours was suppressed to one-third at relatively higher pH values, even within the neutral range.

[0036] According to the present disclosure, a stable pharmaceutical composition of a blood coagulation factor X preparation can be provided.

Claims

1. A pharmaceutical composition comprising blood coagulation factor X (FX), said pharmaceutical composition further comprising antithrombin III.

2. The pharmaceutical composition according to claim 1, wherein the pH of the solution when the pharmaceutical composition is dissolved in a solvent is in the range of 6.4 to 7.

5.

3. The pharmaceutical composition according to claim 1 or 2, wherein the solvent is water.

4. The pharmaceutical composition according to any one of claims 1 to 3, which does not contain at least one blood coagulation factor or blood-derived substance selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin.

5. The pharmaceutical composition according to any one of claims 1 to 3, which does not contain at least two or more blood coagulation factors or blood-derived substances selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin.

6. The pharmaceutical composition according to any one of claims 1 to 3, which does not contain at least three or more blood coagulation factors or blood-derived substances selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin.

7. A method for stabilizing a pharmaceutical composition containing FX using antithrombin III.

8. The method of claim 7, wherein the pharmaceutical composition has a solution having a pH in the range of 6.4 to 7.5 when dissolved in a solvent.

9. The method of claim 7 or 8, wherein the solvent is water.

10. The method according to any one of claims 7 to 9, which does not contain at least one blood coagulation factor or blood-derived substance selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin.

11. The method according to any one of claims 7 to 9, which does not contain at least two or more blood coagulation factors or blood-derived substances selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin.

12. The method according to any one of claims 7 to 9, which does not contain at least three or more blood coagulation factors or blood-derived substances selected from the group consisting of FI, FII, FIII, FIV, FV, FVII, FVIII, FIX, FXI, FXII, FXIII, FIa, FIIa, FIIIa, FVa, FVIIa, FVIIIa, FIXa, FXIa, FXIIa, FXIIIa, protein C, protein S, red blood cells, platelets, immunoglobulins, albumin, and heparin.

Images