TWI731108B - Hemostatic pharmaceutical composition - Google Patents

Abstract

The instant disclosure illustrates a hemostatic pharmaceutical composition including: (A) 23-26 wt% of double-layered protein spherical particles including human albumin spheres in the inner layer and fibrinogens covalently bonded to the surfaces of the human albumin spheres; (B) 2.3-2.7 wt% of a surfactant; (C) 7-9.5 wt% of a crosslinking agent; (D) 5-9.5 wt% of a biocompatible material; (E)1-10 wt% of an additive; and (F) 41.8-61.7 wt% of a solvent. The hemostatic pharmaceutical composition is suitable for intravenous injection, and the diameter of the double-layered protein spherical particles is between 0.1 μm and 3 μm. The ratio of the fibrinogens and the human albumins is between 1:10 and 1:18. The ratio of the surfactant and the crosslinking agent is between 1:3 and 1:4.2.

Description

Pharmaceutical composition with hemostatic function 【Related Application Cases】

The present invention claims the domestic priority of Taiwan Patent Application No. 105119927 (application date: June 24, 2016). The complete content of the application is incorporated into this invention patent specification for reference.

The invention relates to a surgical hemostatic material, in particular to a medical composition with hemostatic function suitable for intravenous injection.

Both surgical procedures and medical treatments can cause excessive bleeding and blood loss. Especially for patients with platelet deficiency, excessive blood loss can lead to life-threatening. At present, the fastest and most effective way is to carry out supportive and compensatory effects through external blood transfusion. However, for patients with internal bleeding, the urgent task is to find the bleeding point and stop the bleeding first, so as to minimize blood loss.

In the prior art, a coagulation-assisting substance for hemostasis has been developed. In addition to inducing the coagulation mechanism in the patient's body, it can also assist in replacing the function of platelets to form a thrombus at the bleeding site to shorten the hemostasis time. Such coagulation substances are usually administered to patients by injection, so the following requirements must be met: First, the diameter of the coagulation substance (such as particles) must be smaller than the average diameter of the human body: 7μm; Condensation in the blood can condense at the bleeding site, and this type of coagulation substance cannot cause blood cells to condense in the blood, but can promote the aggregation of platelets and other cells in the wound.

There is currently an article by K.I. Widder et al. in the literature "Development of Pharmacology and Chemotherapy (V0l.16.213-271)" "Magnetics in biophysical tracing of anticancer reagents" "Active Microspheres and Other Carriers" reveals the technical content of "using protein aqueous solution and oil and heating or polymerizing to obtain emulsion to synthesize protein microspheres"; however, protein microspheres synthesized through emulsion are prone to deterioration during the synthesis process. , So its half-life is shorter. Therefore, during the treatment process, protein microspheres staying in the blood vessel for more than one day will be prone to deterioration, which is not conducive to subsequent preservation or treatment.

In addition, Oppenhein et al. disclosed a method in the US Patent No. 4,107,288 "Effective Ultrafine Particles in Injection Composition and Its Production Method", which mainly uses an opposite solubilizer to adjust the concentration of the desolventizing agent to make The protein solution reaches a desolventizing limit. However, this method is extremely unstable at the beginning of the reaction, and the reaction is often accompanied by a large amount of polymerization that causes the formation of spheroids. The diameter of the aggregated spheres generated by polymerization is usually greater than 7 microns (larger than the diameter of human capillaries). It is easy to cause blood vessel blockage and cause life-threatening.

Therefore, in response to the aforementioned needs, it is bound to develop a pharmaceutical composition with hemostatic function, which can not only meet the aforementioned conditions, but also obtain a rapid hemostatic effect.

The technical problem to be solved by the present invention is to provide a pharmaceutical composition with hemostatic function in view of the shortcomings of the prior art, which can be used to treat patients with platelet deficiency, not only has no toxic side effects, fast hemostasis speed and good effect.

In order to solve the above technical problems, one of the technical solutions adopted by the present invention is to provide a pharmaceutical composition with hemostatic function, suitable for intravenous injection, based on the total weight, the pharmaceutical composition with hemostatic function includes: (A) Double-layer protein microspheres, the weight percentage of which is between 23wt% and 26wt%, and the double-layer protein microspheres are composed of albumin and fibrinogen; (B) Surfactant, its weight The percentage is between 2.3wt% and 2.7wt%; (C) the crosslinking agent is between 7wt% and 9.5wt%; (D) the biocompatible substance is between 5wt% (E) additives, the weight percentage of which is between 1 weight% and 10 weight%; and (F) the solvent, the weight percentage of which is between 41.8 weight% and 61.7 weight%. Wherein, the fibrinogen is covalently bound to the Described on the surface of albumin. Wherein, the ratio of the fibrinogen to the albumin of the double-layer protein microspheres is between 1:10 to 1:18, and the particle size of the double-layer protein microspheres is between 0.1 μm and Between 3μm. Wherein, the ratio of the surfactant to the crosslinking agent is between 1:3 and 1:4.2.

One of the beneficial effects of the present invention is that the pharmaceutical composition with hemostatic function provided by the present invention can pass through the "double-layer protein microspheres, the weight percentage of which is between 23wt% and 26wt%, and the double-layer Protein microspheres are composed of albumin and fibrinogen" and "the fibrinogen is bound to the surface of albumin through covalent bonds" are technical features, and will not affect the original in the solution during the manufacturing process. The number of albumin spheres causes any loss. In addition, the inside of the formed double-layer protein microspheres is albumin spheres, and the outside is covered by fibrinogen. Therefore, the albumin spheres will not aggregate with each other into larger spheres, which can combine the double-layer protein microspheres. The particle size is fixed in a specific range. Furthermore, the present invention uses a specific crosslinking agent to form a double-layer protein microsphere with a particle size ranging from 0.1 μm to 3 μm, and the coefficient of variation is very small, so that intravenous injection will not cause the patient’s blood vessels block.

Another beneficial effect of the present invention is that the fibrinogen of the present invention can be further combined with a marker to serve as a tracer molecule, which is used to carry the albumin spheres to the wound site and cause the albumin spheres to condense on Together, in order to achieve the effect of stopping bleeding or reducing the amount of bleeding.

Another beneficial effect of the present invention is that the pharmaceutical composition of the present invention can be used as a substitute for platelets. When it is used in patients with trauma, surgery or heavy bleeding, it will not produce autoimmune reactions and will not have insufficient blood supply. The problem of incompatibility with blood type, while reducing the risk of infection.

In order to further understand the features and technical content of the present invention, please refer to the following detailed description and drawings of the present invention. However, the drawings provided are only for reference and description, and are not used to limit the present invention.

Figure 1 is the flow of the method for manufacturing the pharmaceutical composition with hemostatic function of the present invention 程Schematic diagram.

The following are specific examples to illustrate the implementation of the "medical composition with hemostatic function" disclosed in the present invention. Those skilled in the art can understand the advantages and effects of the present invention from the contents disclosed in this specification. The present invention can be implemented or applied through other different specific embodiments, and various details in this specification can also be based on different viewpoints and applications, and various modifications and changes can be made without departing from the spirit of the present invention. In addition, the drawings of the present invention are merely schematic illustrations, and are not drawn according to actual dimensions, and are stated in advance. The following embodiments will further describe the related technical content of the present invention in detail, but the disclosed content is not intended to limit the protection scope of the present invention.

The purpose of the present invention is to provide a pharmaceutical composition and its manufacturing method and use. The pharmaceutical composition of the present invention is characterized in that it has double-layer protein microspheres, so that after the pharmaceutical composition of the present invention is intravenously injected into the patient's body, it can induce autologous fibrin to the bleeding point in the patient's body, and promote hemostasis Function, and will not self-aggregate in the blood during the circulation process, thereby avoiding thrombosis.

The pharmaceutical composition with hemostatic function provided by the present invention is suitable for intravenous injection administration. Among them, based on the total weight, the pharmaceutical composition with hemostatic function of the present invention includes: (A) double-layer protein microspheres, the weight percentage of which is between 23wt% and 26wt%, and the double-layer protein microspheres are made of white It is composed of protein and fibrinogen; (B) surfactant, whose weight percentage is between 2.3wt% and 2.7wt%; (C) crosslinking agent, whose weight percentage is between 7wt% and 9.5wt% (D) Biocompatible material, the weight percentage of which is between 5wt% and 10wt%; (E) the additive, the weight percentage of which is between 1wt% and 10wt%; and (F) the solvent, the weight percentage of Between 41.8wt% to 61.7wt%.

The following figures illustrate the manufacturing process and embodiments of the pharmaceutical composition with hemostatic function of the present invention.

Please refer to FIG. 1, which is a schematic flow chart of the manufacturing method of the pharmaceutical composition with hemostatic function of the present invention. The manufacturing method mainly includes:

Step S100: Dissolve albumin in a buffer to obtain an albumin solution.

Step S102: Add a surfactant, a cross-linking agent, and a solvent to the albumin solution in sequence to obtain an albumin sphere suspension.

Step S104: adding fibrinogen, a biocompatible substance and an additive to the albumin sphere suspension, wherein the fibrinogen is covalently bonded to the surface of the albumin sphere to form a double-layer protein microsphere.

Step S106: post-processing the suspension of double-layer protein globular particles.

The following is a detailed description of each step.

First, the albumin used in the present invention is preferably human albumin; and specific examples of the buffer include one or more of the following components: Tris, Tris-HCl, sodium acetate, HEPES, HEPES- Na, ACES, ADA, AMPSO, BES, Bicine, Bis-Tris, Bis-Tris Propane, CABS, CAPS, CAPSO, CHES, citric acid, DIPSO, EPPS, glycine, HEPBS, HEPPSO, imidazole, MES, MOBS, MOPS, MOPSO, PIPES, POPSO, Cacodylic acid sodium salt trihydrate, sodium citrate, TABS, TAPS, TAPSO, TEA, and TES. It is worth noting that the choice of buffer is not limited to a buffer with a specific composition, as long as the pH of the buffer is between 5 and 7.3, and its osmotic pressure is between 260 and 320 mOsm/Kg, it can be selected from the aforementioned The ingredients are optionally one or more or a combination thereof to form a buffer.

In this embodiment, the buffer is a Tris-HCl solution with a concentration of 45%. A specific weight of albumin powder is added to a 45% Tris-HCl solution to form an albumin solution, the albumin concentration of which is between 5wt% and 20wt%.

In order to make albumin form a polymer sphere shape for subsequent binding of fibrinogen, in this step, a surfactant is added to make the albumin evenly dispersed in the solution, and a cross-linking agent is added to induce albumin monomer The molecules of the para position of the above amino acid form a covalent bond with each other to polymerize together to form tiny albumin spheres. Accordingly, the average diameter of the formed albumin spheres can be less than 1 μm, and the albumin spheres can be uniformly dispersed in the suspension without agglomeration.

Then, a surfactant, a cross-linking agent and a solvent are sequentially added to the albumin solution. The surfactant can be selected from the group consisting of sodium n-decyl sulfate, sodium isodecyl sulfate, Triton ^TM X-151 and Tween 80. The crosslinking agent is a covalent molecule including glutaraldehyde. Furthermore, the solvent may include one or more of the following components: methanol, ethanol, n-propanol, isopropanol, butanol, ethyl acetate, water or a combination thereof; preferably ethanol and isopropanol.

The surfactant used in this example is Triton ^TM X-151 with a concentration of 0.1 to 10 mg/ml, and the cross-linking agent is glutaraldehyde with a concentration of 0.01 to 3.0 mg/ml, and the solvent has a concentration of 75% Of ethanol. It is worth mentioning that, in order to achieve the optimal particle size of the albumin spheres without excessively polymerizing together, the ratio of the surfactant and the crosslinking agent of the present invention is between 1:3 and 1:4.2.

Then, fibrinogen, a biocompatible substance and an additive are added to the albumin sphere suspension, wherein the fibrinogen is covalently bonded to the surface of the albumin sphere to form a double-layer protein microsphere.

In detail, the fibrinogen is first stored as a solution, and after step S102 is completed, 10 minutes to 1 hour later, it is added to the albumin sphere suspension. The weight ratio of fibrinogen to albumin used in this embodiment is between 1:10 and 1:18. Preferably it is 1:15.

At the same time, biocompatible substances are also added to the albumin sphere suspension. The biocompatible substance is selected from the group consisting of coagulation factor II, coagulation factor III, coagulation factor VII, coagulation factor VIII, plasminogen activator, cell growth factor, proteolytic enzyme inhibitor, and hemoglobin . The additives can be selected from the group consisting of glycine, proline, calcium ion, potassium ion, sodium ion, magnesium ion and phospholipid.

In this embodiment, the selected biocompatible substances include blood coagulation factors II, III, VII and hemoglobin. These biocompatible substances, especially hemoglobin, can promote the cross-linking of fibrinogen and albumin spheres, so that fibrinogen is covalently bound to the binding site of albumin, so that the outer layer is formed as fiber Proteinogen, The inner layer is a double-layer protein microsphere of albumin. The additives in this embodiment are calcium ions, magnesium ions and glycine. In this way, through the aforementioned manufacturing process, almost no loss will be caused to the number of albumin spheres in the suspension, so the yield of the double-layer protein microspheres can exceed 99%.

The suspension of the double-layer protein spherical particles is then subjected to post-processing, such as dilution, filtration, dialysis, re-filtration, centrifugal separation, electrophoresis separation, and column separation, and then passes through vacuum freeze-drying and frozen powder reconstitution. It is structured to prepare a freeze-dried pharmaceutical composition suitable for intravenous injection (that is, the pharmaceutical composition with hemostatic function of the present invention). In the process of reconstitution, it is necessary to add a buffer or change the buffer and preservatives and other biocompatibles. The types and dosages of such reagents are well known to those skilled in the art, so they will not be repeated here.

It is worth noting that the average diameter of the double-layer protein microspheres (that is, protein particles coated with fibrinogen on the surface) formed by reconstruction can be between 0.1 and 3 μm, which is much smaller than the diameter of human capillaries. Therefore, after intravenous injection, the blood vessel will not be blocked, and it can enter the bleeding site through the tiny blood vessels of the human body without hindrance to stop bleeding.

Within the range that does not impair the desired effect of the present invention, when step S106 is specifically implemented, an excipient may be added. The addition of excipients does not hinder the functional performance of the double-layer protein microspheres, and can increase the uniformity and stability of the pharmaceutical composition, while reducing the irritation and unpleasant odor of the pharmaceutical composition. Specific examples of excipients can be It is selected from the group consisting of lactose, sucrose, mannitol, xylitol, dextrin, cyclodextrin and colloid. The amount of addition and the manufacturing method can be understood by those skilled in the art based on common knowledge, and will not be repeated here.

The pharmaceutical composition with hemostatic effect obtained by the aforementioned method, which comprises (A) 23wt% to 26wt% double-layer protein spheres, (B) 2.3wt% to 2.7wt% surfactant, (C) 7wt% to 9.5wt% cross-linking agent, (D) 5wt% to 10wt% biocompatible material, (E) 1wt% to 10wt% additive and (F) 0.4wt% to 1.3wt% excipient , The rest is solvent. The pharmaceutical composition of this embodiment is In terms of weight percentages, the preferred proportions of the components are as follows: double-layer protein microspheres 24.5wt%; surfactants 2.65wt%; crosslinking agents 8wt%; biocompatible substances 5wt%; additives 5wt%; excipients 0.56 wt%, the rest is solvent. Among them, in the double-layer protein microspheres, the ratio of fibrinogen and albumin is 1:15.

Furthermore, the pharmaceutical composition with hemostatic function of the present invention may further include a marker, which may be combined with the double-layer protein microspheres to serve as a tracer function. The label is Fluorescein-5-isothiocyanate, iodine-123, iodine-125, iodine-131, nanoparticle, or a combination thereof. The label can be human albumin pre-labeled with the iodine isotope iodine-125 for subsequent preparation, or nanoparticle with a specific wavelength can be added after the double-layer protein microsphere is completed, so that the nanoparticle can be combined with the double-layer protein microsphere. In combination, a specific camera system is used to non-invasively visualize bleeding points that cannot be recognized by the naked eye in a living patient.

[Example 1]

Put human albumin powder into 0.9% sodium chloride solution, and add a surfactant with a concentration of 0.05mg/ml-15mg/ml, such as sodium tetradecyl sulfate, Tween-80 or TritonX-151 to form a concentration Protein solution in 5-20% weight by volume ratio. Then add 2ml of glutaraldehyde diluted with sodium chloride solution to a series of test tubes containing 2ml of the above-mentioned protein solution containing different concentrations of surfactants, with a concentration range of 0.01%-3.0%. After 10 minutes, add 10ml of ethanol [release to 80% (volume ratio) with water], and the solution immediately appears turbid. After another 10 minutes, dilute with 5 times the volume of sodium chloride solution to observe whether the suspension is clear. The result is negative. After that, the suspension was observed with a microscope at 1000 times, and it was found that the diameter of the particles in the suspension was less than 1 micron.

At the same time, it was also found that the combination of TritonX ^TM -151 with a concentration of 1mg/ml-2.5mg/ml and albumin with a concentration of 100mg/ml-200mg/ml had the best effect. In addition, it was also found that the mixture made of sodium tetradecyl sulfate with a concentration of 1mg/ml-12mg/ml had the smallest coefficient of variation of the particle diameter.

[Example 2]

Under the same conditions as in Example 1, human albumin labeled with iodine-125 was used. The spheres were precipitated by centrifugation, and the number of radioactive protein microspheres contained in the precipitation neutralization solution was measured, and it was found that 95% of the albumin particles formed spheres. If the pH value of the buffer solution is low, relatively more alcohol is required; if the pH value of the buffer solution is higher, the amount of alcohol required is relatively small. All in all, the pH of the buffer is between 5-7.3 and the highest yield of double-layer protein microspheres (<95%) can be obtained.

[Example 3]

Example 2 was repeated under the most preferred conditions. The difference was that human albumin was coated with fluorescent isothiocyanate. Using the optimal conditions of Example 1, the fibrin was removed in different time intervals after the turbidity appeared. The original was added to the ball suspension, and it was found that adding fibrinogen within fifteen minutes after the formation of the ball can stabilize the ball and obtain the best mixture. In addition, the sphere suspension must be further processed, including dilution, filtration, dialysis, re-filtration, centrifugal separation, electrophoresis separation, and column separation, which are completed after vacuum freeze-drying and refrigerated powder reconstitution. Need to add or change buffers or preservatives during the process.

[Beneficial effects of the embodiment]

In order to further prove the efficacy of the pharmaceutical composition with hemostatic function according to the present invention, the present invention is based on McGill et al.'s "Platelet mold cavity can reduce platelet deficiency" in J.Lab.Clin.Med.1987,109:127-133. In the article "Bleeding time of rabbits", a pharmacological test was performed on rabbits with platelet deficiency. The bleeding time of ten rabbits treated with 70mg/kg Busulfan method was 697 seconds, after injection of 1ml/kg fibrinogen-coated spheres (Use 0.9% sodium chloride solution to dissolve the frozen powder), the bleeding time is reduced to 115 seconds (standard deviation is 43 seconds). The wound of the rabbit ear was sectioned and moved to a fluorescent microscope for observation. It was found that there were fluorescent particles in the clotting blood. If a rabbit with platelet deficiency is injected with a fibrinogen-free spheroid suspension (1mg/ml), the bleeding time is not shortened, and no fluorescent particles are found in the ear clotting area, which shows that fibrinogen is used as a guiding molecule. The particles lead to the active area of coagulation, and lead to shortened bleeding time and reduced blood loss.

Furthermore, in order to further confirm that the pharmaceutical composition of the present invention can be used for patients with internal bleeding, the following experiments were carried out to prove the efficacy of this case.

First, 223 cases of platelet deficiency were obtained from the hospital. The platelet deficiency includes the platelet deficiency caused by the syndrome of abnormal thrombocytopenic hyperplasia and idiopathic thrombocytopenic purpura (idiopathic thrombocytopenic purpura). These patients were divided into a control group (N=111 cases) and an experimental group (N=112 cases), and they were given an albumin placebo and the pharmaceutical composition of the present invention (administered at a dose of 7.0 mg/kg). The fixed period of time, with bleeding symptoms and changes in bleeding time as the main evaluation indicators of efficacy.

Please refer to the table below for comparison of bleeding time after drug treatment.

It can be seen from the above table that after the administration of the pharmaceutical composition of the present invention, the bleeding time of the patient was significantly reduced by 700 seconds. Compared with the control group given only the albumin placebo, the bleeding time was significantly reduced. Obviously, the pharmaceutical composition with hemostatic function of the present invention, especially the double-layer protein microspheres combined by cross-linking, the fibrinogen can be used to guide the overall double-layer protein microspheres to move to the affected area, and can prevent platelet deficiency. Compensation supplement. Incidentally, after experimental tests, the pharmaceutical composition with hemostatic function of the present invention has no adverse reactions to patients at all.

At the same time, clinical efficacy tests were conducted for patients with platelet deficiency and active bleeding in the subcutaneous, mucosal, and liver. The pharmaceutical composition with hemostatic function of the present invention was administered to the aforementioned patients at a dose of 7.0 mg/kg/time. The results showed that after 2 hours of administration of the pharmaceutical composition, more than 60% of patients had started to stop bleeding. Obviously, the pharmaceutical composition of the present invention can effectively replace the original blood The function of the small plate promotes blood coagulation.

To reiterate, in the pharmaceutical composition of the present invention, fibrinogen is bound to the surface of the albumin spheres through a covalent bond, so during the manufacturing process, it will not cause any loss to the number of albumin spheres initially in the solution. In addition, the inside of the formed double-layer protein microspheres is albumin spheres, and the outside is covered by fibrinogen, so the albumin spheres will not aggregate with each other into larger spheres.

Furthermore, the present invention uses a specific crosslinking agent to form a double-layer protein microsphere with a particle size ranging from 0.1 μm to 3 μm, and the coefficient of variation is very small, so that intravenous injection will not cause the patient’s blood vessels block.

The fibrinogen of the present invention can be further combined with a marker to serve as a tracer, which is used to carry albumin spheres to the wound site and aggregate the double-layer protein microspheres together to achieve hemostasis or reduce bleeding The effect of the amount.

In summary, the pharmaceutical composition of the present invention can be used as a substitute for platelets. When it is used in patients with trauma, surgery or heavy bleeding, it will not produce autoimmune reactions, will not have the problems of insufficient blood source and blood type incompatibility, and at the same time It can also reduce the risk of infection.

The content disclosed above is only the preferred and feasible embodiments of the present invention, and does not limit the scope of the patent application of the present invention. Therefore, all equivalent technical changes made by using the content of the specification and drawings of the present invention are included in the application of the present invention. Within the scope of the patent.

The designated representative picture is a flow chart, so there is no symbol for simple explanation

Claims (9)

A pharmaceutical composition with hemostatic function, suitable for intravenous injection, based on the total weight, the pharmaceutical composition with hemostatic function comprises: (A) double-layer protein microspheres, the weight percentage of which is between 23wt% and 26wt% And the double-layer protein microspheres are composed of albumin and fibrinogen; (B) surfactant, the weight percentage of which is between 2.3wt% and 2.7wt%; (C) crosslinking agent , Its weight percentage is between 7wt% to 9.5wt%; (D) biocompatible material, its weight percentage is between 5wt% to 10wt%; (E) additive, its weight percentage is between 1wt% to 10wt%; (F) solvent, the weight percentage of which is between 41.8wt% to 61.7wt%; and (G) label, which is fluorescein-5-isothiocyanate (Fluorescein-5- isothiocyanate), iodine-123, iodine-125, iodine-131, nanoparticles or a combination thereof; wherein the fibrinogen is bound to the surface of the albumin through a covalent bond; wherein the double-layer protein The ratio of the fibrinogen to the albumin of the microspheres is between 1:10 to 1:18, and the particle size of the double-layer protein microspheres is between 0.1 μm and 3 μm; The ratio of the surfactant to the crosslinking agent is between 1:3 and 1:4.2. The pharmaceutical composition with hemostatic function according to claim 1, wherein the biocompatible substance is selected from the group consisting of coagulation factor II, coagulation factor III, coagulation factor VII, coagulation factor VIII, and plasma protein activator (plasminogen activator). activator), cell growth factors, proteolytic enzyme inhibitors, and hemoglobin. The pharmaceutical composition having a hemostatic function according to claim 1, wherein the additive The additive is selected from the group consisting of glycine, proline, calcium ion, potassium ion, sodium ion, magnesium ion and phospholipid. The pharmaceutical composition with hemostatic function according to claim 1, further comprising: an excipient whose weight percentage is between 0.4 wt% and 1.3 wt%, and the excipient is selected from lactose, sucrose, The group consisting of mannitol, xylitol, dextrin, cyclodextrin and colloids. The pharmaceutical composition with hemostatic function according to claim 1, wherein the surfactant is sodium n-decyl sulfate, sodium isodecyl sulfate, Triton ^TM X-151 or Tween 80. The pharmaceutical composition with hemostatic function according to claim 1, wherein the crosslinking agent is glutaraldehyde. The pharmaceutical composition with hemostatic function according to claim 1, wherein the solvent is methanol, ethanol, n-propanol, isopropanol, butanol, ethyl acetate, water or a combination thereof. The pharmaceutical composition with hemostatic function according to claim 1, wherein the fibrinogen is combined with the label as a tracer molecule for carrying the albumin and agglomerating the double-layer protein microspheres . The pharmaceutical composition having a hemostatic function according to claim 1, wherein the pharmaceutical composition is used as a substitute for platelets.

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