CN117338937A - Coagulation factor X activator composition - Google Patents

Coagulation factor X activator composition Download PDF

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Publication number
CN117338937A
CN117338937A CN202311569302.6A CN202311569302A CN117338937A CN 117338937 A CN117338937 A CN 117338937A CN 202311569302 A CN202311569302 A CN 202311569302A CN 117338937 A CN117338937 A CN 117338937A
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activator
coagulation factor
factor
composition
mass volume
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王炳璋
谭剑平
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Beijing Nvk Pharm Technologies Co ltd
Staidson Beijing Biopharmaceutical Co Ltd
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Beijing Nvk Pharm Technologies Co ltd
Staidson Beijing Biopharmaceutical Co Ltd
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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Abstract

The invention discloses a blood coagulation factor X activator composition, which comprises a blood coagulation factor X activator, a stabilizer, a buffer, a surfactant and an excipient, wherein the stabilizer is at least one of sucrose or trehalose; the buffer is at least one of histidine and arginine. The invention adopts disaccharide (sucrose or/and trehalose) as a stabilizer and is combined with an amino acid buffer (arginine or/and histidine), so that the stability of the product is greatly improved, the aggregation of protein and the content of insoluble particles are reduced, and the composition product does not contain human serum albumin, and has higher safety.

Description

Coagulation factor X activator composition
Technical Field
The invention relates to the field of biological medicine, in particular to a coagulation factor X activator composition.
Background
Factor X (coagulation factor X, FX) is a vitamin K dependent serine protease zymogen whose active form (FXa) is the only physiological activator of prothrombin (prothrombin) in the body and plays a key role in the co-coagulation pathway. The blood coagulation factor X activator (Coagulation factor X activator) can specifically activate FX, so that FXa is fully exposed at an active site to generate FXa, and FXa further forms a prothrombin complex with platelets activated at a damaged site, FVa and calcium ions, thereby increasing thrombin generation, and the thrombin activates platelets and V and VIII at the damaged site and forms a hemostatic plug through conversion of fibrinogen to fibrin, thereby achieving the purpose of hemostasis of bleeding patients. Has potential great application value in the aspects of surgical wound surface bleeding, internal hemorrhagic diseases, coagulation system diseases, such as hemophilia and the like.
The earliest found that the most active factor X activator was extracted from the venom of viper (Vipera russeli), called RVV-X. It is a metalloprotease with a relative molecular weight of 92880D, composed of a heavy chain with a molecular weight of 57600D and two light chains with molecular weights of 16400D and 19400D respectively, through disulfide bonds.
Since the first discovery of factor X activator RVV-X in the venom of the viper, mcFarlane, activators of factor X have also been found in many other venom types. Factor X activators are commonly found in viper and rattlesnake venom, and substances that activate factor X are also found in a few cobra venom. In addition, the blood coagulation factor X activator can also be obtained by expressing cells of the recombinant human blood coagulation factor X activator by a biological engineering technology and separating and purifying the cells from a cell culture solution.
In the prior art, thrombin and a coagulation factor X activator are commonly prepared into a composition to be used as hemostatic medicines. For example, patent CN1520880a discloses a hemostatic containing serum albumin and RVV-X and a synergistic agent type thrombin as active ingredients; patent CN1727002a discloses a compound biological component comprising thrombin-like enzyme and thromboplastin; CN108785665a discloses a pharmaceutical composition of snake venom thrombin, which is prepared from 0.00005% -0.0005% of thrombin composition and the balance of acceptable carrier for the pharmaceutical composition, wherein the thrombin pharmaceutical composition comprises coagulation factor X activator and thrombin-like enzyme; CN1810258A discloses a compound hemostatic with main active ingredients of thrombin-like enzyme with purity more than 97% and coagulation factor X activator, the main active ingredients are thrombin-like enzyme, and the coagulation factor X activator is a synergistic agent.
If the blood coagulation factor X activator is used as a single pharmacodynamic active ingredient to prepare the blood coagulation factor X activator pharmaceutical composition, the blood coagulation factor X activator is macromolecular protein, and is easy to denature after long-term placement, thus being unfavorable for long-term storage. Human serum albumin is a commonly used protective agent, has been widely used in biological products as a stabilizer for proteins, but is gradually eliminated due to the susceptibility to allergic reactions and potential risk of virus contamination.
At present, how to prepare a stable single active ingredient coagulation factor X activator composition is a problem to be solved.
Disclosure of Invention
The object of the present invention is to provide a stable, safe single active ingredient coagulation factor X activator composition. The composition of the invention does not contain human serum albumin and has higher stability and safety.
The invention provides a blood coagulation factor X activator composition, which comprises a blood coagulation factor X activator, a stabilizer, a buffer, a surfactant and an excipient, wherein the stabilizer is at least one of sucrose or trehalose; the buffer is at least one of histidine or arginine.
The invention adopts disaccharide (i.e. sucrose or/and trehalose) as the stabilizer and combines with amino acid buffer (i.e. arginine or/and histidine), in the composition taking the coagulation factor X activator as a single active ingredient, the invention not only can greatly improve the stability of the product and reduce the aggregation of protein and the content of insoluble particles, but also avoids anaphylactic reaction and potential virus pollution risks caused by using human serum albumin as the stabilizer in the prior art. In the freeze-drying process of the blood coagulation factor X activator, sucrose or/and trehalose is used as a stabilizer, so that the high-grade structure of the blood coagulation factor X activator is more stable, the deformation of the blood coagulation factor X activator caused by freeze-drying is prevented, the structure and the function of the blood coagulation factor X activator are kept intact even under the conditions of low-temperature freezing and drying and water loss, and the stability of the blood coagulation factor X activator is obviously improved.
Since the concentration of the factor X activator gradually increases during the lyophilization of the factor X activator solution, the pH of the solution may change at high concentrations, which may cause denaturation of the factor X activator in severe cases, resulting in inactivation. In order to ensure that the active ingredient factor X activator has the maximum biological activity, the proper pH range needs to be controlled. The invention adopts histidine or/and arginine as buffering agent, which not only has good buffering capacity and can keep the relative stability of the pH value of the product within a certain range, but also can ensure the activity of the coagulation factor X activator and further improve the stability of the composition when the amino acid buffering agent (arginine or/and histidine) is combined with disaccharide (namely, sucrose or/and trehalose) as a stabilizer.
In the above-described factor X activator compositions, the sources of factor X activators are well known to those skilled in the art and include, but are not limited to, factor X activators extracted from snake venom, factor X activators prepared by genetic engineering; preferably, the blood coagulation factor X activator is blood coagulation factor X activator (RVV-X) extracted from viper venom or prepared by genetic engineering.
In some embodiments of the compositions of the invention, the active concentration of factor X activator is from 1U/ml to 100U/ml, more preferably from 5U/ml to 100U/ml, still more preferably from 5U/ml to 50U/ml, still more preferably 5U/ml, 10U/ml, 20U/ml, 30U/ml, 40U/ml or 50U/ml.
In other embodiments of the compositions of the present invention, the stabilizer is present in a mass volume concentration of 15mg/ml to 60mg/ml, more preferably 30mg/ml to 50mg/ml, still more preferably 30mg/ml, 40mg/ml or 50mg/ml.
In other embodiments of the compositions of the present invention, the buffer is present in a mass volume concentration of from 2mg/ml to 15mg/ml, more preferably from 3mg/ml to 5mg/ml, still more preferably 3mg/ml, 4mg/ml, 5mg/ml.
In other embodiments of the compositions of the present invention, the surfactant is present in a mass volume concentration of from 0.05mg/ml to 0.5mg/ml, more preferably from 0.1mg/ml to 0.3mg/ml, still more preferably from 0.1mg/ml, 0.2mg/ml or 0.3mg/ml.
In other embodiments of the compositions of the present invention, the excipient is present in a mass volume concentration of 10mg/ml to 60mg/ml, more preferably 30mg/ml to 60mg/ml, still more preferably 30mg/ml, 40mg/ml, 50mg/ml or 60mg/ml.
In other embodiments of the compositions of the present invention, the pH is from 6.0 to 8.0, more preferably from 6.3 to 7.3, and even more preferably from 6.8 to 7.0.
Specifically, the invention provides a blood coagulation factor X activator composition, wherein the active concentration of the blood coagulation factor X activator is 1U/ml-100U/ml; the mass volume concentration of the stabilizer is 15mg/ml-60mg/ml; the mass volume concentration of the buffer is 2mg/ml-15mg/ml; the mass volume concentration of the surfactant is 0.05mg/ml-0.5mg/ml; the mass volume concentration of the excipient is 10mg/ml-60mg/ml; the pH of the composition is 6.0-8.0.
Further more preferably, in the above blood coagulation factor X activator composition, the active concentration of the blood coagulation factor X activator is 5U/ml to 100U/ml; the mass volume concentration of the stabilizer is 30mg/ml-50mg/ml; the mass volume concentration of the buffer is 2mg/ml-15mg/ml; the mass volume concentration of the surfactant is 0.1mg/ml-0.5mg/ml; the mass volume concentration of the excipient is 30mg/ml-60mg/ml; the pH of the composition is 6.3-7.3.
Further, particularly preferably, in the above-mentioned blood coagulation factor X activator composition, the active concentration of the blood coagulation factor X activator is 5U/ml to 50U/ml; the mass volume concentration of the stabilizer is 30mg/ml-50mg/ml; the mass volume concentration of the buffer is 3mg/ml-5mg/ml; the mass volume concentration of the surfactant is 0.1mg/ml-0.3mg/ml; the mass volume concentration of the excipient is 30mg/ml-60mg/ml; the pH of the composition is 6.8-7.0.
In the coagulation factor X activator composition, the surfactant is at least one of polysorbate 20, polysorbate 80 and poloxamer 188.
In the freeze-drying process of the coagulation factor X activator composition, the surfactant can reduce freezing and dehydration deformation caused by ice water interfacial tension in the freezing and dehydration process, and can play roles of a wetting agent and a heavy wrinkling agent on active components in the rehydration process. At least one of polysorbate 20, polysorbate 80 and poloxamer 188 is selected as the surfactant, so that the composition has low toxicity, can effectively inhibit the surface adsorption and aggregation of the coagulation factor X activator under various conditions, and improves the stability of the composition.
In the blood coagulation factor X activator composition, the preparation can also comprise an antioxidant, wherein the mass volume concentration of the antioxidant is 0-1mg/ml; preferably, the antioxidant is methionine.
In the blood coagulation factor X activator composition, the preparation can also comprise divalent calcium salt, and the mass volume concentration of the divalent calcium salt is 0-10mg/ml; preferably, the divalent calcium salt is calcium chloride.
More specifically, in the above-described coagulation factor X activator composition, the concentration of each component may be any one of the following 1) to 5) or a combination thereof:
1) The active concentration of the coagulation factor X activator is 5U/ml, 10U/ml, 20U/ml, 30U/ml, 40U/ml or 50U/ml, and the mass volume concentration of the stabilizer is 30mg/ml-50mg/ml; the mass volume concentration of the buffer is 3mg/ml-5mg/ml; the mass volume concentration of the surfactant is 0.1mg/ml-0.3mg/ml, and the mass volume concentration of the excipient is 30mg/ml-60mg/ml;
2) The active concentration of the coagulation factor X activator is 5U/ml-50U/ml, the mass volume concentration of the stabilizer is 30mg/ml, 40mg/ml or 50mg/ml, and the mass volume concentration of the buffer is 3mg/ml-5mg/ml; the mass volume concentration of the surfactant is 0.1mg/ml-0.3mg/ml, and the mass volume concentration of the excipient is 30mg/ml-60mg/ml;
3) The active concentration of the coagulation factor X activator is 5U/ml-50U/ml, the mass volume concentration of the stabilizer is 30mg/ml-50mg/ml, the mass volume concentration of the buffer is 3mg/ml, 4mg/ml and 5mg/ml, the mass volume concentration of the surfactant is 0.1mg/ml-0.3mg/ml, and the mass volume concentration of the excipient is 30mg/ml-60mg/ml;
4) The active concentration of the coagulation factor X activator is 5U/ml-50U/ml, the mass volume concentration of the stabilizer is 30mg/ml-50mg/ml, the mass volume concentration of the buffer is 3mg/ml-5mg/ml, the mass volume concentration of the surfactant is 0.1mg/ml, 0.2mg/ml or 0.3mg/ml, and the mass volume concentration of the excipient is 30mg/ml-60mg/ml;
5) The active concentration of the coagulation factor X activator is 5U/ml-50U/ml, the mass volume concentration of the stabilizer is 30mg/ml-50mg/ml, the mass volume concentration of the buffer is 3mg/ml-5mg/ml, the mass volume concentration of the surfactant is 0.1mg/ml-0.3mg/ml, and the mass volume concentration of the excipient is 30mg/ml, 40mg/ml, 50mg/ml or 60mg/ml.
On the other hand, the invention also discloses a preparation method of the coagulation factor X activator composition injection powder, and the coagulation factor X activator composition injection powder is obtained after freeze drying of the coagulation factor X activator composition.
On the other hand, the invention also discloses the injection powder of the coagulation factor X activator composition obtained by the preparation method.
On the other hand, the invention also discloses the application of the blood coagulation factor X activator composition and the injection powder of the blood coagulation factor X activator composition in preparing medicines with procoagulant or hemostatic functions; preferably, drugs having procoagulant or hemostatic functions include, but are not limited to: a medicament for treating surgical wound bleeding, internal hemorrhagic diseases and coagulation system diseases.
Further, the invention discloses application of the coagulation factor X activator composition in preparation of a medicament for treating hemophilia.
Further, the invention discloses application of the coagulation factor X activator composition in preparing medicines for treating hemophilia A or B accompanied with inhibitors.
The blood coagulation factor X activator composition and the injection powder have the following beneficial effects:
(1) The blood coagulation factor X activator composition provided by the invention is particularly aimed at a composition with only a single active component of the blood coagulation factor X activator, and the stability of a blood coagulation factor X activator composition product is obviously improved and the potential risk caused by carrying viruses or other unknown components by albumin can be avoided by using sucrose or/and trehalose as a stabilizer instead of albumin and combining with arginine or/and histidine as a buffering agent.
(2) The blood coagulation factor X activator composition takes the blood coagulation factor X activator as a single active ingredient, the active ingredient and the content are definite, the purity of the used stabilizer sucrose or/and trehalose is high, the source is wide, the long-term mass production is easy to carry out, the cost is convenient to control, and the product quality is improved.
(3) The blood coagulation factor X activator composition can ensure that the blood coagulation factor X activator has good stability in the preparation, transportation and storage processes, has low insoluble particle content, and has better clinical medication safety and quality controllability.
(4) The coagulation factor X activator composition disclosed by the invention does not contain albumin, and is higher in stability; after compatibility with 0.9% sodium chloride injection, the product can be kept stable for at least 8 hours at room temperature.
Drawings
FIG. 1 number of insoluble particles for each example, 0 month.
FIG. 2. Various examples accelerate the number of insoluble particles for 6 months.
Detailed Description
The following examples are presented to illustrate the present invention and to aid one skilled in the art in making and using it. These examples are not intended to limit the scope of the invention in any way.
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
The clotting factor X activator stock solution used in the following examples is viper venom, which is prepared by the method of example 6 in the publication of patent application publication No. CN109943554A, and the rest of the auxiliary materials are injection grade unless specified.
Examples 1 to 10, preparation of coagulation factor X activator injection powder
Weighing the stabilizer, buffer, excipient, surfactant, antioxidant and divalent calcium salt according to the prescription in table 1, adding appropriate amount of water for injection, stirring until completely dissolving (when the surfactant is liquid, other components can be dissolved firstly, then the liquid surfactant is added, stirring uniformly), adding the blood coagulation factor X activator stock solution according to the prescription, regulating pH with HCl or NaOH, finally adding water for injection to volume to scale, mixing uniformly, filtering with 0.22 μm filter membrane into a sterile container, and preparing into semi-finished product solution (example 1 is comparative example).
TABLE 1 amounts of the components in examples 1-10
The feed liquid of each embodiment is subpackaged into medium borosilicate glass injection bottles according to 0.53+/-0.03 ml/bottle, half-tamponade is carried out, and freeze drying is carried out, thus obtaining the coagulation factor X activator injection powder.
Example 11 coagulation factor X activator composition physical Properties test
1. Appearance, moisture, reconstitution time, pH, biological Activity detection
The appearance, the moisture content, the reconstitution time, the pH value and the biological activity of the coagulation factor X activator injection powder prepared in examples 1 to 10 were tested, and the biological activity was tested by a coagulometer, and the results are shown in the following table:
table 2 results of the various examples
Note that: for more visual description of the appearance, the appearance is classified into the following 4 grades
Stage 1: fine, full and white loose body
2 stages: slightly atrophy, slightly rough surface, particulate matter, slightly wall separation
3 stages: moderate atrophy, wall separation, slight shrinkage of the cake
4 stages: severely atrophy, obvious shrinkage of the lumps and severely wall separation
The results in Table 2 show that the appearance, moisture content, reconstitution time, pH and biological activity of the products of each example all meet the corresponding product standards. Except for example 3, the appearance of each example was fine, full and white loose, and after 2ml of the complex solvent was added, the mixture was rapidly dissolved to form colorless clear liquid. Example 3 has slightly shrunken appearance due to the higher amount of trehalose, less amount of mannitol, and slightly longer reconstitution time than other examples, but within 30s, and is colorless clear liquid after dissolution. The pH and activity of each example were not significantly different before and after lyophilization.
2. Stability test under high temperature, high humidity and illumination conditions
Because the samples can deviate from preset conditions in the storage process, the influence factor test is utilized to examine the influence on key indexes of the samples under the conditions of high temperature (40+/-2 ℃), high humidity (2-8 ℃ and RH 92.5% +/-5%) and illumination (2-8 ℃ and 4500+/-500 LX) in a short period. The test results are shown in tables 3 and 4.
TABLE 3 partial index results under influence of factors
The results in Table 3 show that under high temperature conditions, the corresponding product standards are met with the prolonged standing time. The products of examples 3, 10 showed a tendency to shrink in appearance and slightly prolonged reconstitution time. Under other conditions, examples 2, 4-9 showed no significant change in appearance, moisture, pH compared to day 0, and in particular examples 2, 4, 6 and 8 remained in a grade 1 state in appearance at all times.
TABLE 4 Activity results under influencing factors
The results in Table 4 show that examples 3, 4, and 10 show a slight decrease in activity between 3.41% and 9.45% after 14 days of high temperature and light irradiation, but are still better than the comparative examples; examples 2 and 5-9 were substantially stable under the influence of factors, and the activity decrease rate was only less than 1.60% after 14 days of high temperature and light irradiation. The activity of the factor X activator is significantly reduced in the comparative example (example 1) compared to the technical solutions of the invention (examples 2 to 10). The result shows that under the high temperature and illumination condition, the human serum albumin has insufficient stabilization and protection effects on active ingredients, and the technical scheme of the invention can provide more effective stabilization and protection effects.
The results show that the technical scheme of the invention can obviously and effectively stabilize and protect the activity of the blood coagulation factor X activator under the conditions of high temperature, high humidity and illumination.
3. Accelerated and long term stability test
Stability studies were performed on samples of each example to examine the activity and insoluble particle changes.
1) Activity detection
The samples of each example were subjected to stability studies under accelerated (25.+ -. 2 ℃ C., RH 65.+ -. 5%) and long-term (2-8 ℃ C.) conditions to detect changes in activity.
TABLE 5 results of Activity under accelerated and Long term conditions
The results of the accelerated and long-term activity for 6 months show that the preparation prepared by freeze-drying after being prepared by adopting the technical scheme of the invention (examples 2-10) has the long-term stability obviously superior to that of the comparative example (example 1), and particularly the activity reduction rate of examples 2 and 5-9 after the accelerated and long-term activity for 6 months is only lower than 1.60 percent. The results show that the technical scheme of the invention can ensure that the blood coagulation factor X activator can be stored more stably under the accelerated and long-term conditions.
2) Insoluble particle detection
Since the diameter of human capillary is 7-12 μm, insoluble particles may cause vascular embolism, phlebitis, granuloma, pulmonary hypertension and heat-induced reaction during intravenous administration, and the content of insoluble particles should be avoided and reduced for intravenous administration. Therefore, detection of insoluble particles is required during the relevant drug manufacturing process. The insoluble particles mainly originate from the production process, the compatibility process and the administration process of the medicine, and in addition, the protein medicine can be aggregated during stirring, freeze-drying and storage, and the insoluble particles can be generated.
The invention adoptsThe sub-visible particle imaging analysis system shoots particles flowing through the flow cell dynamically through the electronic imaging system, then analyzes parameters such as size, shape, refraction and the like of insoluble particles through software, and further distinguishes all images, such as protein particles, silicone oil, bubbles, fibers and the like, and the particle size range of the detectable particles is 2-100 mu m. Not only can the insoluble particles be classified and counted according to the particle size, but also has certain prompting effect on particle sources and formation mechanisms.
After dissolving the samples of each example after 0 month and 6 months of acceleration with 2ml of physiological saline, the insoluble particles were detected according to the method for detecting insoluble particles by the rule 0903 of four-part of the "Chinese pharmacopoeia" 2015, and the results are shown in tables 6 and 7 (the data in the tables are subtracted from background particles).
Table 60 month insoluble microparticle results
The results in table 6 show that the number of insoluble particles after lyophilization is in accordance with the pharmacopoeia requirements for the samples of each example, but the number of insoluble particles in the comparative example (example 1) is significantly higher than that in the other examples, but the number of insoluble particles in the examples of the present invention is at a lower level, especially examples 2, 5 to 10, and the total amount of insoluble particles is even lower than 260, which indicates that the technical scheme of the present invention has a significant improvement in reducing insoluble particles, as shown in fig. 1.
Table 7 results of accelerating insoluble particles for 6 months
The results in Table 7 show that the insoluble particles in the comparative example (example 1) increased significantly after 6 months of standing, wherein the number of particles in the range of 2 to 10 μm was the largest, as shown in FIG. 2, probably due to the fact that the human serum albumin added in the prescription was partially aggregated during its own storage, resulting in an increase in the content of insoluble particles. Although the amount of insoluble particles in the comparative example was still within the acceptable range, it was much higher than in the other examples, and the total amount of insoluble particles in the examples of the present invention was at a lower level, especially examples 2, 5 to 10, even below 2000. The above results again show that compared with the comparative example, the technical scheme of the invention can obviously and effectively improve the content of insoluble particles, thereby further reducing the risk brought by the insoluble particles and improving the clinical use safety.
Example 12 compatibility stability test
The product of the invention can be prepared into sterile powder for injection, the product of the dosage form is required to be dissolved by a proper amount of solvent before use and then is administrated by intravenous injection, and according to a clinically common compatibility administration method, sterilized water for injection, 0.9% sodium chloride injection and 5% glucose injection are selected as solvents, and compatibility stability research is carried out on samples at the starting time point and the end time point (shelf life or reporting time point) so as to provide basis for clinical medication.
The sample selected from example 6 was used as an exemplary sample, and 2ml of sterilized water for injection, 0.9% sodium chloride injection, and 5% glucose injection were dissolved again, and gently shaken to obtain a uniform solution, and the diluted solution was left at room temperature (25 ℃) for 0, 2, 4, 6, and 8 hours, and the appearance of the solution was observed, and pH, osmotic pressure, activity, insoluble particles, endotoxin, and sterility were measured, and the results were recorded in the following table.
TABLE 8 compatibility stability test results
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As can be seen from the results in Table 8, the samples were reconstituted with 3 different solvents and left at room temperature for 8 hours, all of which were colorless clear liquids in appearance and did not change significantly in pH.
The normal osmotic pressure of human blood plasma is 280-320 mOsm/kg, and the osmotic pressure of a sample solution after redissolving with 2ml of water for injection is about 85mOsm/kg and lower than the normal osmotic pressure of blood plasma; the osmotic pressure of the sample solution after being reconstituted by 2ml of 0.9% sodium chloride injection and 5% glucose injection is between 360 and 400mOsm/kg, which is higher than the normal osmotic pressure of blood plasma. Although the liquid medicine is not isotonic after the 3 solvents are redissolved, the product is intravenous injection, the administration volume is small, and the human blood plasma has certain buffer capacity, so the osmotic pressure of the blood plasma is not adversely affected after the administration.
For activity stability, 2ml of 0.9% sodium chloride injection is used for redissolution and the activity is kept stable after being placed for 8 hours at room temperature; 2ml of sterilized water for injection or 5% glucose injection was reconstituted and the activity was substantially stable after 4 hours at room temperature.
While the invention has been described in detail with respect to the general description, specific embodiments and examples, those skilled in the art can make modifications and improvements on the basis of the invention without departing from the spirit of the invention, and these modifications or improvements fall within the scope of the invention as claimed.

Claims (13)

1. A factor X activator composition comprising a factor X activator, a stabilizer, a buffer, a surfactant, and an excipient, wherein the stabilizer is sucrose or trehalose, the buffer is histidine or arginine, and the excipient is mannitol; the active concentration of the coagulation factor X activator is 5-100U/ml, and the mass volume concentration of the stabilizer is 30-50 mg/ml; the mass volume concentration of the buffering agent is 2mg/ml-15mg/ml, the mass volume concentration of the surfactant is 0.1mg/ml-0.5mg/ml, the mass volume concentration of the excipient is 30mg/ml-60mg/ml, the pH value of the composition is 6.3-7.3, the composition takes a blood coagulation factor X activator as a single active ingredient, and the blood coagulation factor X activator is a blood coagulation factor X activator extracted from snake venom of viper, preferably a blood coagulation factor X activator extracted from snake venom of viper.
2. The factor X activator composition of claim 1, wherein the factor X activator has an active concentration of 5U/ml to 50U/ml; the mass volume concentration of the stabilizer is 30mg/ml-50mg/ml; the mass volume concentration of the buffer is 3mg/ml-5mg/ml; the mass volume concentration of the surfactant is 0.1mg/ml-0.3mg/ml; the excipient has a mass volume concentration of 30mg/ml to 60mg/ml, and the pH of the composition is 6.8 to 7.0.
3. The coagulation factor X activator composition of claim 1 or 2, wherein the surfactant is at least one of polysorbate 20, polysorbate 80, and poloxamer 188.
4. The coagulation factor X activator composition of claim 1 or 2, further comprising an antioxidant in a mass volume concentration of 0-1mg/ml.
5. The blood coagulation factor X activator composition of claim 4, wherein the antioxidant is methionine.
6. The coagulation factor X activator composition according to claim 1 or 2, characterized in that the composition further comprises a divalent calcium salt in a mass volume concentration of 0-10mg/ml.
7. The coagulation factor X activator composition of claim 6, wherein the divalent calcium salt is calcium chloride.
8. A method for preparing the coagulation factor X activator injection powder, which is characterized in that the coagulation factor X activator injection powder is obtained after freeze-drying the coagulation factor X activator composition according to any one of claims 1 to 7.
9. A clotting factor X activator composition injectable powder obtained by the preparation method of claim 8.
10. Use of a factor X activator composition according to any one of claims 1 to 7 or a factor X activator injection powder according to claim 9 for the preparation of a medicament having procoagulant or hemostatic function.
11. The use according to claim 10, wherein the medicament having procoagulant or hemostatic function comprises: a medicament for treating surgical wound bleeding, internal hemorrhagic diseases, coagulation system diseases and hereditary hemorrhagic diseases.
12. The use according to claim 10, wherein the medicament having procoagulant or haemostatic function is a medicament for the treatment of haemophilia.
13. The use according to claim 10, characterized in that the medicament with procoagulant or hemostatic function is a medicament for the treatment of hemophilia a or B with inhibitors.
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