CN114177346B - Hemostatic composition and hemostatic patch and application thereof - Google Patents
Hemostatic composition and hemostatic patch and application thereof Download PDFInfo
- Publication number
- CN114177346B CN114177346B CN202111603820.6A CN202111603820A CN114177346B CN 114177346 B CN114177346 B CN 114177346B CN 202111603820 A CN202111603820 A CN 202111603820A CN 114177346 B CN114177346 B CN 114177346B
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- hemostatic
- collagen
- fibrinogen
- thrombin
- suspension
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- A61L2400/04—Materials for stopping bleeding
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Abstract
The invention discloses a hemostatic composition, a hemostatic patch and application thereof, wherein the hemostatic composition comprises 16-46 parts of fibrinogen, 38-42 parts of thrombin and 100-121 parts of calcium chloride. The hemostatic composition and the hemostatic patch have good hemostatic effect, good biocompatibility, complete degradation in vivo, no need of secondary debridement, and no secondary injury to wounded, can be applied to hemostasis (especially hemostasis of visceral hemorrhage) of wounded in various emergencies, natural disasters (especially strong earthquakes) and other conditions, and has good commercial value and wide application prospect.
Description
Technical Field
The invention relates to the technical field of medical hemostatic materials, in particular to a hemostatic composition, a hemostatic patch prepared from the hemostatic composition, and application of the hemostatic composition and the hemostatic patch.
Background
Bleeding is one of the most common and difficult problems to control in surgery and trauma, especially bleeding of important organs, such as liver, spleen, kidney rupture bleeding, is often directly life threatening. The traditional hemostasis mode (such as ligation and compression hemostasis) is only suitable for hemostasis of great vessel hemorrhage, and has limited hemostasis effect on diffuse hemorrhage and visceral hemorrhage. Wound bleeding is also a major lethal factor, and rapid and effective hemostasis after injury is the most important means of saving lives of sick and wounded.
However, when the body is subjected to a heavy wound, self-coagulation is not sufficient to quickly coagulate, and therefore, a hemostatic material needs to be applied to the wound to control bleeding. The ideal hemostatic material has the following requirements in performance: (1) rapid hemostasis (i.e., short clotting time); (2) Has good biocompatibility and no adverse effect of short term or long term; (3) Secondary debridement is not needed, and secondary injury to wounded persons is avoided; (4) The application is convenient, and the use is easy even for non-professional staff; (5) stable under various environmental conditions and long shelf life.
At present, various hemostatic materials can be used for surgery and wound treatment, such as fibrin, chitosan natural biological hemostatic materials, mineral hemostatic materials such as zeolite, kaolin, montmorillonite and the like, and artificial synthetic hemostatic materials such as gelatin-resorcinol-formaldehyde or propylene cyanide and the like, and the hemostatic mechanisms are different. The hemostatic materials have the respective defects that the conventional chitosan hemostatic materials have poor adhesiveness at wounds and are easy to wash away by blood, so that the hemostatic effect is greatly reduced; the mineral hemostatic material is not absorbable, needs secondary debridement, can cause secondary injury to wounded after being used for hemostasis of visceral hemorrhage, and has poor safety; the artificial hemostatic material has poor biocompatibility and degradability and many potential safety hazards.
In conclusion, compared with the materials, the hemostatic plaster product prepared from the fibrin hemostatic material has the advantages of strong adhesiveness, no need of secondary debridement, no secondary injury, degradability, low immunogenicity, convenient use and the like, can be used for bleeding with light and medium grade and no fixed bleeding point, and is particularly suitable for hemostasis of visceral bleeding.
In chinese patent application publication No. CN1507358A, a carrier having solid fibrinogen and solid thrombin is disclosed, on which solid fibrinogen and solid thrombin are uniformly dispersed and immobilized. The product has only two components of fibrinogen and thrombin which play a hemostatic role, and has overlong clotting time and unsatisfactory hemostatic effect. In addition, the liquid medicine layer (the liquid medicine layer is a layer containing solid fibrinogen and solid thrombin) of the product is easy to fall off in the use process (see figure 3), and the hemostatic effect of the liquid medicine layer cannot be ensured.
Disclosure of Invention
The object of the present invention is to address the technical drawbacks of the prior art by providing, in a first aspect, a hemostatic composition with a short clotting time comprising 16-46 parts (preferably 16-20 parts) fibrinogen, 38-42 parts thrombin and 100-121 parts calcium chloride, wherein fibrinogen is in mg, thrombin is in IU and calcium chloride is in μg.
Comprises 16-19 parts of fibrinogen, 39-41 parts of thrombin and 103-118 parts of calcium chloride; preferably, it comprises 17 parts fibrinogen, 40 parts thrombin, 115 parts calcium chloride (CaCl 2 )。
The hemostatic composition has a viscoelastic property value tan delta <1, preferably 0.13-0.31, of fibrin polymer formed by water.
In a second aspect, the present invention provides a hemostatic patch comprising a collagen carrier prepared from collagen and a liquid medicine layer uniformly dispersed and fixed on the collagen carrier, wherein the liquid medicine layer is prepared from the hemostatic composition; the collagen carrier is in the form of a sheet.
Each square centimeter of hemostatic patch contains 16-46mg of fibrinogen, 38-42IU of thrombin, 100-121 mug of calcium chloride and more than 0.5mg of collagen.
The liquid medicine layer is formed by dispersing the hemostatic composition in ethanol to prepare suspension and then spraying the suspension on a collagen carrier; optionally, dispersing the hemostatic composition in ethanol, homogenizing in a dispersing machine at (10-20) ×10 3 rpm, stirring times are 5-10 times, stirring is carried out for 2min each time, and stirring time is 10-20min.
When spraying, the liquid medicine amount sprayed on the collagen carrier per square centimeter is 0.049-0.563ml, and the thickness of the formed liquid medicine layer is 0.049-0.247mm.
The mean diameter of the particles of the suspension blood-stopping composition is 33-50 μm (preferably 37-42 μm), and/or the 5min sediment volume of the suspension is >90% (preferably ≡95%).
The collagen carrier is a glass body with smooth surface and compact internal structure, which is obtained by freezing collagen for 19-23 hours in the process of reducing the temperature to minus 50 ℃ at 20 ℃ before spraying; alternatively, the thickness is 0.3-0.5cm.
In a third aspect, the present invention provides the use of the hemostatic composition and hemostatic patch described above in the preparation of a hemostatic product, preferably a visceral hemorrhage hemostatic product.
The hemostatic composition provided by the invention comprises fibrinogen, thrombin and calcium chloride, and a great amount of experimental researches show that the fibrinogen, the thrombin and the calcium chloride can synergistically exert the hemostatic effect under a specific proportion to reduce the blood coagulation time, the specific proportion of the fibrinogen, the thrombin and the calcium chloride in the hemostatic composition is respectively 16-46 parts, 38-42 parts and 100-121 parts (the fibrinogen is in one part in mg, the thrombin is in one part in IU and the calcium chloride is in one part in mug), and experiments prove that the hemostatic composition under the specific proportion can achieve a good hemostatic effect.
The invention also provides a hemostatic patch, which comprises a collagen carrier and a liquid medicine layer formed by the hemostatic composition, wherein the liquid medicine layer is formed by uniformly dispersing and fixing a suspension containing the hemostatic composition on the collagen carrier. The hemostatic plaster can be used for hemostasis in visceral hemorrhage, and can be directly stuck to a non-fixed bleeding point on viscera in use, and has the advantages of simple operation, strong adhesiveness, good hemostatic effect, good biocompatibility, complete degradation in vivo, no need of secondary debridement, and no secondary injury to wounded. The hemostatic patch has stable performance, and the liquid medicine layer is not easy to fall off, can be applied to hemostasis (especially hemostasis of visceral hemorrhage) of wounded in various emergency, natural disasters (such as strong earthquake) and other conditions, and has good commercial value and wide application prospect.
Drawings
FIG. 1 is a side view of a hemostatic patch prepared from the hemostatic composition of example 1;
FIG. 2 is a top view of the hemostatic patch of FIG. 1;
FIG. 3 is a top view of a prior art carrier;
FIG. 4 is a schematic perspective view of an automatic spray device;
fig. 5 is a schematic structural view of the liquid ejecting mechanism 5.
Detailed Description
The invention provides a fibrin hemostatic composition, which comprises 16-46 parts of fibrinogen (from human, mammal or recombinant fibrinogen), 38-42 parts of thrombin (from human, mammal or recombinant thrombin) and 100-121 parts of calcium chloride, wherein the fibrinogen is in one part in mg, the thrombin is in one part in IU, and the calcium chloride is in one part in μg; preferably, it comprises 17 parts fibrinogen, 40 parts thrombin, 115 parts calcium chloride (CaCl 2 ). Wherein,,
fibrinogen (Fibrinogen), i.e. clotting factor i, is a macromolecular glycoprotein containing 2964 amino acids and having a relative molecular mass of 340kDa and consisting of two subunits (fibrinopeptides a and B) arranged in bilateral symmetry, each subunit containing three peptide chains α, β, γ, the middle of which is formed by 29 disulfide bonds (aαbβγ) 2. Fibrinogen is a precursor of fibrin, and adequate fibrinogen levels are a fundamental requirement for the formation of effective clotting. The hemostatic composition contains a sufficient amount of fibrinogen, can supplement additional fibrinogen to a blood loss part, and the fibrinogen is hydrolyzed into fibrin through thrombin, so that fibrin is polymerized to form fibrin polymers in solid blood coagulation blocks under the combined action of thrombin and blood coagulation factors XIII and XIIIa in blood, thereby blocking bleeding blood vessels or wound surfaces, preventing bleeding blood vessels or wounds from continuing bleeding, and achieving the purpose of hemostasis. The invention can use human fibrinogen, mammalian fibrinogen and recombinant fibrinogen, and can be purchased from Shanghai Yuan leaf technology Co., ltd, nanjing Seiyi Biotech Co., ltd; the human fibrinogen is white, off-white or pale yellow loose body, and can be pulverized into powder.
Thrombin (Thrombin) is a serine protease which has a main function of hydrolyzing water-soluble fibrinogen into water-insoluble fibrin, and thus plays an important role in hemostasis and coagulation, tissue repair, wound healing, and the like. Thrombin is produced by the activation of prothrombin (factor ii), which is converted mainly to alpha-thrombin in activated form (content > 97% in thrombin, the remainder being minor amounts of beta-and gamma-thrombin). The invention can use human thrombin, or mammalian thrombin and recombinant thrombin, which can be purchased from Hualan bioengineering Co., ltd, shanghai source leaf technology Co., nanjiahong Rui Biotechnology Co., ltd, and can be crushed into powder.
Calcium ion (Ca) 2+ ) I.e. coagulation factor iv. The Ca is generally provided by calcium chloride 2+ ，Ca 2+ Is essential in each coagulation pathway. As in the intrinsic coagulation pathway, ca 2+ Can assist in activating blood coagulation factor XI (existing in blood), which participates in other blood coagulationThe diameter further plays a role in coagulation; and at Ca 2+ And platelet phospholipids, factor x (present in blood) is also activated and thus plays a role in the common coagulation pathway. In the extrinsic pathway of coagulation, ca 2+ Factor III (present in the blood) and factor VII (present in the blood) together activate factor X and thus act in the common coagulation pathway. In the co-coagulation pathway, ca 2+ Binding thrombin, factor v (present in the blood) and activated factor x (activated in the intrinsic and extrinsic coagulation pathways) converts fibrinogen to fibrin monomers, which exert hemostatic and clotting effects. In addition, ca 2+ It may also assist in activating factor XIII (present in the blood) and thus factor XIIIa (present in the blood), which in turn acts on fibrin monomers to convert them into stable fibrin polymer blood clots. The calcium chloride used in the invention is purchased from Beijing red star chemical plant and is in white granular form.
The hemostatic composition provided by the invention takes fibrinogen, thrombin and calcium ions as main hemostatic components, and the hemostatic principle is to simulate the final stage of biological coagulation cascade reaction, namely: when the hemostatic composition is contacted with a bleeding site, fibrinogen is present in thrombin and Ca 2+ Forming fibrin monomers under the action of (a); the fibrin monomer is further polymerized under the action of the blood coagulation factor XIIIa to form fibrin polymer, and the fibrin polymer exists in the form of blood clots and is used as a barrier to block the bleeding blood vessel or the wound surface, so that the bleeding blood vessel or the wound surface can be effectively prevented from continuously bleeding. Meanwhile, thrombin can promote the adhesion, activation and aggregation of platelets, and the aggregated and activated platelets further release coagulation active substances such as Adenosine Diphosphate (ADP), adenosine Triphosphate (ATP), thromboxane A2, serotonin and the like; while Ca 2+ Can activate certain coagulation factors, and the coagulation active substances and the coagulation factors can increase the generation of thrombin, further increase and accelerate the formation of fibrin and polymers, thus positively accelerating the coagulation and hemostasis.
On the basis, the invention also providesA hemostatic patch comprises the hemostatic composition and a solid carrier. The solid carrier needs to be degradable, and common degradable solid carrier materials include oxidized regenerated cellulose, polylactic acid protein, collagen and the like. The present invention uses Collagen as a solid carrier for the hemostatic patch because Collagen (Collagen) has a developed quaternary structure, can form a scaffold-like structure, and can be used as a carrier. In addition, the collagen can play a role in stopping bleeding by promoting platelet aggregation, can promote the formation and growth of blood vessels, and has a repairing function on local tissues. Common collagens include bovine collagen, porcine collagen, equine collagen, etc., which are derived from mammals and have low immunogenicity. In the specific embodiment of the invention, bovine collagen is used as a solid carrier of the hemostatic patch, so that the solid carrier is also called as a collagen carrier. The oxcollagen solution is purchased from Tianjin century Kangtai biomedical engineering Co., ltd and is transparent gel. The hemostatic patch comprises the following raw materials: 16-46mg/cm 2 38-42IU/cm fibrinogen 2 100-121. Mu.g/cm of thrombin 2 More than or equal to 0.5mg/cm of calcium chloride 2 Is a collagen of the subject.
The process for preparing the hemostatic patch comprises the following steps:
(1) Placing a square mould (made of medical grade PVC) into a 316 stainless steel liquid medicine tray, taking a small amount of bovine collagen (transparent gel, which is not treated after purchase and is directly used) into the mould, and scraping the square mould with a collagen scraper (made of 316 stainless steel) to form a collagen layer with the thickness of 0.3-0.5cm on the mould; removing superfluous bovine collagen, sticking a laminated sheet (made of medical PVC) on the surface of the scraped collagen layer, avoiding large bubbles between the laminated sheet and the collagen layer in the sticking process, freezing for 19-23h at 20-50 ℃ in a gradient (namely, the temperature is reduced from 20 ℃ to-50 ℃), removing the laminated sheet, and taking the frozen collagen layer as a solid carrier of the hemostatic plaster, namely, a collagen carrier.
The gradient freezing can be specifically as follows: the temperature is reduced from 20 ℃ to 0 ℃ within 1h, then reduced to-50 ℃ within 18-22h, and the temperature is maintained for 2h.
(2) Mixing fibrinogen, thrombin, calcium chloride and low-temperature absolute ethanol (-20deg.C pre-cooling) to obtain medicinal liquid, homogenizing in a dispersing machine (IKA, T25 easy clean) at stirring speed of (10-20) x 10 3 The rpm is used for stirring the liquid medicine for 5-10 times, and the stirring time is 10-20min. Homogenizing to obtain suspension containing hemostatic composition, and placing in low temperature environment (-50 deg.C to-20 deg.C).
(3) Parameters for setting up an automatic spraying device (the structure of which is described in the patent with publication number CN 214021579U): the peristaltic pump has a flow rate of 50-80ml/min, the liquid spraying pipe swings for 1-6 times, and the sprayed liquid medicine amount is 0.049-0.563ml/cm 2 Y-axis single movement distance 3000-4500cm (1 cm (sudden meter) =1×10) -5 m); the total moving distance of the X axis is 3000-4500 cm.
(4) After the parameter setting in the step (3) is completed, a pump pipe (19 # and made of silica gel, with the inner diameter of 2.4mm and the outer diameter of 5.6mm, purchased from Baoding Lange constant flow pump Co., ltd.) is imported into the suspension obtained in the step (2), and the suspension is uniformly sprayed on the surface of the frozen collagen carrier by using an automatic spraying device, so that a liquid medicine layer with the thickness of 1-5mm is formed on the surface of the collagen carrier.
(5) After spraying, placing the stainless steel liquid medicine disc into a freeze dryer (CHRIST, epsilon 2-4 LSC plus) pre-cooled to-50 ℃ in advance, freeze-drying for 49-40 min-63h (the freeze-drying time is too short, the moisture content in the collagen carrier and the liquid medicine layer is too high, a sheet-shaped patch product cannot be formed, the freeze-drying time is too long, the moisture content in the collagen carrier and the liquid medicine layer is too low, the liquid medicine layer can be too dry and crack to affect the appearance of the product, the hemostatic effect is also affected), the liquid medicine layer is attached to the surface of the collagen carrier in the freeze-drying process, and forms an integrated hemostatic patch with the collagen carrier until the moisture content of the hemostatic patch is not higher than 10%, stopping freeze-drying, taking out, packaging and sterilizing to obtain the hemostatic patch product.
In this method, unlike the prior art, the collagen of step (1) is frozen (rather than lyophilized) to form a collagen carrier, which results in a collagen carrier that has no spongy structure, but rather is a glassy solid with a smooth surface and a dense interior. When the suspension in the step (4) is sprayed, the suspension does not permeate into the collagen carrier, but is positioned on the smooth surface of the collagen carrier. And finally, when the step (5) of freeze-drying is carried out, the water in the collagen carrier and the solvent in the liquid medicine layer volatilize together, and in the process, the collagen carrier and the substances left in the liquid medicine layer are mutually penetrated, so that the collagen carrier and the liquid medicine layer are tightly connected together, and the liquid medicine layer is not easy to fall off from the collagen carrier.
The automatic spraying apparatus used in the method was used to spray hemostatic composition onto each area of the square mold in the 316 stainless steel medical fluid tray to make a hemostatic patch. Fig. 4 is a structural example of the automatic spraying apparatus. The automatic spraying device comprises a reagent tray translation mechanism 3, a liquid spraying mechanism 5 and a nozzle traversing mechanism 6, wherein the reagent tray translation mechanism 3 is provided with a translation driving motor for driving the reagent tray arranged on the reagent tray translation mechanism 3 to move horizontally and reciprocally (namely left and right horizontally and an X-axis), the nozzle traversing mechanism 6 is provided with a traversing driving motor for driving the nozzle 65 arranged on the nozzle traversing mechanism 6 to move horizontally and reciprocally (namely front and back horizontally and a Y-axis), the nozzle is positioned above the reagent tray 4, and the liquid spraying mechanism 5 is provided with a peristaltic pump 51 (see figure 5) for pushing liquid medicine into the nozzle 65 through a spray pipe 52, so that the liquid medicine is quantitatively sprayed on each area of the reagent tray provided with a bottom plate. Wherein, the translation driving motor can rotate positively and negatively to make the reagent tray 4 mounted on the reagent tray translation mechanism 3 move horizontally and reciprocally, and the traversing driving motor can rotate positively and negatively to make the nozzle 65 mounted on the nozzle traversing mechanism 6 move linearly and reciprocally along the direction perpendicular to the translation direction of the reagent tray 4; the peristaltic pump of the liquid spraying mechanism 5 extracts a predetermined amount of liquid medicine for each area of the reagent tray 4, so that the liquid medicine is sprayed to each area of the reagent tray 4 quickly and uniformly according to a predetermined route, the activity of the medicine is maintained, the loss of the liquid medicine is reduced, and the uniformity of spraying is ensured.
The present invention will be described more specifically with reference to the following examples, which are not intended to limit the present invention in any way.
Example 1
The hemostatic composition of this example was prepared from 17mg fibrinogen, 40IU thrombin, 115 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Example 2
The hemostatic composition of this example was prepared from 16mg fibrinogen, 38IU thrombin, 100 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Example 3
The hemostatic composition of this example was prepared from 20mg fibrinogen, 42IU thrombin, 121 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Example 4
The hemostatic composition of this example is prepared from 18mg fibrinogen, 39IU thrombin, 110 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Example 5
The hemostatic composition of this example was prepared from 17mg fibrinogen, 40IU thrombin, 103 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Example 6
The hemostatic composition of this example was prepared from 46mg fibrinogen, 40IU thrombin, 115 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative example 1
The hemostatic composition of this comparative example consisted of 10.3mg fibrinogen, 28.6IU thrombin, 2500. Mu.g calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative example 2
The hemostatic composition of this comparative example consisted of 15mg fibrinogen, 37.5IU thrombin, 117 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative example 3
The hemostatic composition of this comparative example consisted of 13mg fibrinogen, 40IU thrombin, 115 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative example 4
The hemostatic composition of this comparative example consisted of 47mg fibrinogen, 40IU thrombin, 115 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative example 5
The hemostatic composition of this comparative example consisted of 17mg fibrinogen, 45IUThrombin, 115 μg of calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative example 6
The hemostatic composition of this comparative example consisted of 17mg fibrinogen, 30IU thrombin, 115 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative example 7
The hemostatic composition of this comparative example consisted of 17mg fibrinogen, 40IU thrombin, 80 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative example 8
The hemostatic composition of this comparative example consisted of 17mg fibrinogen, 40IU thrombin, 130 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Experiment one, detection of mechanical properties
The experiment aims at simulating that fibrin polymer blood clot is formed after the hemostatic composition is contacted with blood, and then the mechanical property of the hemostatic composition is detected. The mechanical performance indexes are as follows: the storage modulus (G '), loss modulus (G') and viscoelastic properties tan delta (G '/G') are used as detection indicators.
1. Preparation of samples
The fibrinogen in the hemostatic compositions of examples 1-6 is dissolved in 1ml of water to prepare an aqueous solution A, the thrombin and the calcium chloride in the hemostatic compositions of examples 1-6 are dissolved in 1ml of water to prepare an aqueous solution B, and finally the aqueous solution A and the aqueous solution B are mixed to form a clot sample, and the mechanical property indexes of the clot sample are detected. The water added during this process was used to simulate blood and the clot formed was used to simulate a fibrin polymer blood clot formed.
2. Detection of mechanical property index
A clot sample was placed on a test plate of a rheometer (An Dongpa, MCR 302), heated to 37 ℃, the diameter of the test rotor was 12mm and the distance between the test rotor and the test plate was 1mm. A dynamic method with small amplitude (1%) was used, namely: shearing the clot sample under small amplitude oscillation with the frequency of 0.1-10 Hz, then measuring the storage modulus (G ') and the loss modulus (G ") of the sample by frequency scanning, and calculating to obtain a viscoelastic characteristic value tan delta (G '/G '); tan delta <1, which indicates that the sample tends to gel and is not easy to deform, namely: the hemostatic composition is not easy to be broken by blood when in use, and can maintain the original shape; tan delta > 1, which indicates that the sample tends to fluid and is subject to deformation, i.e.: the hemostatic composition is easily broken by blood during use, and cannot maintain its original form. Taking example 1 and example 5 as examples, the results are shown in Table 1.
Table 1 results of mechanical property testing of hemostatic compositions of examples 1 and 5
| Examples | Storage modulus G' | Loss modulus G'. | Viscoelastic property value tan delta |
| Example 1 | 180.85-285.5 | 46.781-77.814 | 0.1396-0.3091 |
| Example 5 | 353.32-418.99 | 55.866-90.722 | 0.1581-0.2265 |
The results in Table 1 show that the example 1 and example 5 hemostatic compositions formed clot samples with tan delta <1, indicating that the formed clot samples tended to gel and were not prone to deformation, i.e.: the hemostatic composition of the invention is not easy to be broken by blood when in use, and can maintain the original shape.
Determination of experiment two, average particle size and precipitation volume ratio
The invention discovers that in the step (2) of the method for preparing the hemostatic plaster, the average diameter of particles in the obtained suspension and the volume ratio of precipitation of 5min (after the preparation of the suspension is completed, the suspension is kept stand for 5min, and the whole initial height (marked as H) of the particles in the suspension is measured before the standing 0 ) And the height of the particles in the suspension after standing (denoted H), 5min sediment volume ratio = H/H 0 ) The uniformity effect of the subsequent spraying can be affected: when the particle diameter is large, the sedimentation speed of particles in the suspension is high, and a pump pipe is easy to be blocked by deposition, so that the suspension cannot be sprayed or is unevenly sprayed. The experiment was thus carried out by adjusting the parameters of step (2) of the preparation process to obtain suspensions containing hemostatic compositions having different particle sizes and 5min sediment volume fractions. After the liquid medicine in the step (2) is homogenized by a dispersing machine, the temperature can change, and the too high temperature can influence the protein activities of fibrinogen and thrombin, so the experiment also detects the temperature of the suspension before and after homogenization.
The specific process of the experiment is as follows: the hemostatic compositions of examples 1-6 were each added with absolute ethanol previously cooled to-20℃and stirred to give a liquid medicine, wherein the final concentrations of the respective substances in the liquid medicine were 140.5mg/ml fibrinogen, 330.6IU/ml thrombin and 950.5. Mu.g/ml calcium chloride. Then homogenizing the medicinal solution with a dispersing machine (IKA, T25 easy clean) at a stirring speed of 15X10 3 rpm, stirring for 5-10 times, wherein the single stirring time is 2min (the subsequent spraying can block a pump pipe when the stirring time is 30 s), and the total time of the homogenizing process is 10-20min. Three samples were taken after each homogenization and the temperature before homogenization and at the time of stopping homogenization of the samples was recorded, as well as the sediment volume ratio of 5 min. Taking the hemostatic composition of example 1 as an example, two sets of experiments (experiment a and experiment B) were performed, differing only in the number of stirring times. The number of stirring times in experiment A was 5, and the results are shown in Table 2; the number of stirring times in experiment B was 10, and the results are shown in Table 3.
TABLE 2 temperatures before and after homogenization of experiment A, average diameter and precipitation volume fraction of 5min
As shown by the results in Table 2, the temperature difference between the suspension before and after homogenization in the step (2) is not more than 1.5 ℃, and the activity of the protein is not affected; the average diameter of the blood stopping composition particles of the suspension after homogenization is 37.78 mu m, the 5min precipitation volume ratio after each homogenization is higher than 90%, and the 5min precipitation volume ratio of the suspension obtained after the homogenization is over 95%, which indicates that the suspension obtained in the homogenization process can reach a higher 5min precipitation volume ratio.
TABLE 3 temperatures, average diameters and setting times before and after homogenization of experiment B
The results in Table 3 show that the mean diameter of the particles of the suspension-blood-stopping composition after homogenization is 41.63. Mu.m, and that the average of the 5min precipitation volume after each homogenization is higher than 90% (not shown in the table), indicating that the suspension obtained by the homogenization process can reach a higher 5min precipitation volume ratio. The temperature difference of the suspension before and after the homogenization in the step (2) is not more than 2.5 ℃, and the influence on the activity of the protein is low.
In addition, the effect of the homogenization procedure on the protein activity was characterized by the clotting time, and the results are shown in Table 3, taking fibrinogen clotting time as an example. The results in Table 3 show that the clotting time of fibrinogen after each homogenization is not more than 22s, and meets the requirement of the "Chinese pharmacopoeia (2020 edition)" for the clotting time of human fibrinogen activity standard of less than 60 s.
The results in tables 2 and 3 show that the average diameter of the suspension blood stopping composition particles obtained in the step (2) of the method for preparing the hemostatic plaster is 37.78-41.63 mu m, and the sedimentation volume ratio of 5min is higher than 90%, which indicates that the particle size of the obtained suspension particles is more concentrated, the span is small, the sedimentation speed of the particles is low, the pump pipe is not easy to be blocked by sedimentation, and the effect of uniform spraying can be achieved in the subsequent spraying. The temperature difference of the suspension before and after homogenization treatment is less than 10 ℃, the fibrinogen clotting time after homogenization is less than 60s, and meets the requirements of Chinese pharmacopoeia (2020 edition), which shows that the homogenization process can not influence the protein activities of fibrinogen and thrombin.
Since the content of each substance in the raw material is independent of the homogenization effect, the results of example 1 in this experiment indicate that other examples have the same results as those of example 1, and are not described in detail herein.
Measurement of clotting time in experiment three
Sample:
control sample 1: prepared according to the disclosure in the Chinese patent application with publication number CN1507358A, the hemostatic component is prepared from fibrinogen 5.5mg/cm 2 And thrombin 2.0IU/cm 2 Composition is prepared.
Control sample 2: the hemostatic component is prepared from fibrinogen 15mg/cm 2 Thrombin 37.5IU/cm 2 And calcium chloride 117. Mu.g/cm 2 Composition is prepared.
Experimental samples: hemostatic compositions of examples 1-6.
Comparison sample: hemostatic compositions of comparative examples 1 and 3 to 8.
The hemostatic composition/hemostatic component contained in a unit square centimeter was added to water for this experiment to simulate clotting in blood. According to the literature report, the amount of absorbed blood per unit area of control samples 1 and 2 is not more than 4ml. Therefore, in this experiment, fibrinogen in a hemostatic composition/hemostatic component contained in a unit square centimeter was added to 5ml of water to form a solution A, and then the remaining hemostatic component (thrombin or thrombin and calcium chloride) was added to 5ml of water to form a solution B, and 100. Mu.l of the solution A and 100. Mu.l of the solution B were sampled in a reaction cup of a coagulometer in equal volumes, and the time for the reaction of the solution A and the solution B to form a fibrin polymer clot was automatically detected by the coagulometer and recorded as the clotting time. The results are shown in Table 4, taking examples 1, 2, 5 and 6 as examples.
Table 4 setting time of samples
The results in table 5 show that at equal dilution ratios, the hemostatic compositions of examples 1, 2, 5, and 6 are all superior to control samples 1 and 2 in clotting time, and the difference is significant; the hemostatic composition of the present invention was shown to be significantly superior to control samples 1 and 2 in hemostatic effect. In addition, the hemostatic compositions of examples 1, 2, 5 and 6 are also superior to comparative examples 1-8 in clotting time and differ significantly; the hemostatic composition of the invention is shown to be significantly better than comparative examples 1-8 in hemostatic effect; in particular, comparative example 4 shows that the fibrinogen content is slightly higher than that of example 6, and the coagulation time is significantly improved, and the hemostatic composition provided by the invention can realize a more excellent hemostatic effect by adjusting the fibrinogen, thrombin and calcium chloride contents.
The foregoing is merely a preferred embodiment of the invention, and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended by the present invention.
Claims (12)
1. The hemostatic patch comprises a collagen carrier prepared from collagen and a liquid medicine layer uniformly dispersed and fixed on the collagen carrier, and is characterized in that the liquid medicine layer is prepared from a hemostatic composition, the hemostatic composition comprises 16-20 parts of fibrinogen, 38-42 parts of thrombin and 100-121 parts of calcium chloride, wherein the fibrinogen is in mg, the thrombin is in IU, and the calcium chloride is in μg;
the preparation method of the hemostatic patch comprises the following steps:
step one: placing a square mould into a 316 stainless steel liquid medicine tray, placing bovine collagen into the mould, and scraping with a collagen scraper to form a collagen layer with the thickness of 0.3-0.5cm on the mould; removing superfluous bovine collagen, then pasting a lamination sheet on the surface of the scraped collagen layer, avoiding large bubbles between the lamination sheet and the collagen layer in the pasting process, finally freezing for 19-23h at 20-50 ℃ in a gradient way, removing the lamination sheet, and taking the frozen collagen layer as a collagen carrier of the hemostatic plaster;
the gradient freezing is as follows: the temperature is reduced from 20 ℃ to 0 ℃ within 1h, then is reduced to-50 ℃ within 18-22h, and the temperature is maintained for 2h;
step two: mixing fibrinogen, thrombin, calcium chloride and anhydrous ethanol pre-cooled at-20deg.C to obtain medicinal liquid, homogenizing in a dispersing machine at stirring speed of (10-20) ×10 3 rpm, stirring the medicinal liquid for 5-10 times for 10-20min, homogenizing to obtain suspension containing hemostatic composition, and standing at-50deg.C to-20deg.C;
step three: setting parameters of an automatic spraying device: the peristaltic pump has a flow rate of 50-80ml/min, the liquid spraying pipe swings for 1-6 times, and the sprayed liquid medicine amount is 0.049-0.563ml/cm 2 The single movement distance of the Y axis is 3000-4500 cm; the total moving distance of the X axis is 3000-4500 cm;
step four: after the parameter setting of the third step is completed, the inlet of a pump pipe is put into the suspension obtained in the second step, the suspension is uniformly sprayed on the surface of the frozen collagen carrier by utilizing an automatic spraying device, and a liquid medicine layer with the thickness of 1-5mm is formed on the surface of the collagen carrier by the suspension;
step five: after spraying, placing the stainless steel liquid medicine disc into a freeze dryer pre-cooled to the temperature of minus 50 ℃ in advance, freeze-drying for 49.8-63h, attaching a liquid medicine layer on the surface of a collagen carrier in the freeze-drying process, forming an integrated hemostatic plaster with the collagen carrier until the water content of the hemostatic plaster is not higher than 10%, stopping freeze-drying, taking out, packaging and sterilizing to obtain a hemostatic plaster product.
2. The hemostatic patch of claim 1, wherein each square centimeter of hemostatic patch contains 16-46mg fibrinogen, 38-42IU thrombin, 100-121 μg calcium chloride, and > 0.5mg collagen.
3. The hemostatic patch of claim 1 wherein the medical fluid layer is formed by dispersing the hemostatic composition in ethanol to form a suspension, and then spraying the suspension onto a collagen carrier.
4. A hemostatic patch according to claim 3 wherein the amount of liquid drug sprayed per square centimeter of collagen carrier is 0.049-0.563ml and the thickness of the liquid drug layer is 0.049-0.247mm.
5. Hemostatic patch according to claim 1 wherein the mean diameter of particles of the suspension blood-stopping composition is 33-50 μm and/or the 5min sediment volume of the suspension is >90% of the mean value.
6. A hemostatic patch according to claim 5 wherein the mean diameter of particles of the suspension blood-stopping composition is from 37 to 42 μm and/or the 5min sediment volume of the suspension is greater than or equal to 95%.
7. The hemostatic patch according to claim 1 wherein the collagen carrier prior to spraying is a smooth surface, dense interior vitreous body obtained by freezing collagen for 19-23 hours at 20 ℃ down to-50 ℃.
8. The hemostatic patch according to claim 1 wherein the hemostatic composition comprises 16-19 parts fibrinogen, 39-41 parts thrombin and 103-118 parts calcium chloride.
9. The hemostatic patch of claim 8 wherein the hemostatic composition comprises 17 parts fibrinogen, 40 parts thrombin, 115 parts calcium chloride.
10. The hemostatic patch of claim 1 wherein the hemostatic composition has a viscoelastic property value tan δ <1 for fibrin polymers formed upon exposure to water.
11. The hemostatic patch according to claim 10 wherein the tan δ is from 0.13 to 0.31.
12. Use of a hemostatic patch according to any one of claims 1 to 11 in the preparation of a hemostatic product.
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