CN114246974B - Preparation method of hemostatic patch - Google Patents
Preparation method of hemostatic patch Download PDFInfo
- Publication number
- CN114246974B CN114246974B CN202111602011.3A CN202111602011A CN114246974B CN 114246974 B CN114246974 B CN 114246974B CN 202111602011 A CN202111602011 A CN 202111602011A CN 114246974 B CN114246974 B CN 114246974B
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- China
- Prior art keywords
- hemostatic
- liquid medicine
- collagen
- parts
- suspension
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Classifications
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Landscapes
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- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- Materials Engineering (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Wood Science & Technology (AREA)
- Materials For Medical Uses (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a preparation method of a hemostatic patch, which sequentially comprises the steps of preparing a collagen carrier, preparing suspension of a hemostatic composition, spraying the suspension on the surface of the collagen carrier to form a liquid medicine layer, forming the hemostatic patch by freeze-drying the liquid medicine layer and the collagen carrier, and the like; the mean diameter of the particles of the suspension bleeding-stopping composition is 33-50 μm (preferably 37-42 μm), and the volume of 5 minutes sediment is >90% (preferably > 95%). The hemostatic patch prepared by the method has good hemostatic effect and good biocompatibility, can be completely degraded in vivo, does not need secondary debridement, avoids secondary injury to wounded, can be applied to hemostasis (especially hemostasis of visceral hemorrhage) of wounded in various emergency, natural disasters (especially strong earthquake) and other conditions, and has good commercial value and wide application prospect.
Description
Technical Field
The invention relates to the technical field of preparation of medical hemostatic products, in particular to a preparation method of a 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. When the product is prepared, collagen is freeze-dried (the temperature is 2-10 ℃ and the pressure is lower than 1000 mbar), and the gel-like collagen becomes spongy in the freeze-drying process and is used as a carrier; and coating the liquid medicine containing solid fibrinogen and solid thrombin on the spongy collagen carrier, and finally vacuum drying the liquid medicine to obtain the carrier. Because the carrier is spongy, the liquid medicine can infiltrate into the spongy structure of the carrier when the liquid medicine is coated, the liquid volatilizes in the process of freeze-drying the liquid medicine, and the solid fibrinogen and the solid thrombin are remained in the spongy structure in the form of powder. When in use, the medicine powder is easy to fall off from the collagen carrier, and the hemostatic effect of the medicine powder cannot be ensured.
In chinese patent application publication No. CN1487843a, a suspension containing fibrinogen, thrombin and alcohol and a method of coating a carrier with the same are disclosed, wherein the average diameter of the fibrinogen and thrombin particles in the suspension is 25-100 μm, and the average diameter span of the particles is large, so that the particles in the suspension are unevenly distributed, resulting in uneven particle size when sprayed on the surface of the carrier; the sedimentation volume ratio of the suspension for 5min is more than 85%, namely particles are fast to sediment, the particles are easy to be deposited in a pipeline during coating, so that the waste of large-particle medicines is caused, the particle size is uneven when the particles are sprayed on the surface of a carrier, the distribution uniformity of hemostatic components on the carrier is poor, and the hemostatic performance of the product is further reduced. In addition, the method adopts a spraying mode, namely, a plurality of small holes are arranged on the side surface and the bottom of the tail end of the pipeline, and the suspension liquid is coated on the carrier through the small holes in a spraying mode. In order to ensure that the edges of the carrier are also coated with the suspension, some of the suspension is sprayed outside the carrier, resulting in a waste of the suspension.
Disclosure of Invention
The invention aims at overcoming the technical defects in the prior art, and in a first aspect, the invention provides a preparation method of a hemostatic patch, which can enable hemostatic composition to be uniformly sprayed on a carrier, and sequentially comprises the steps of preparing a collagen carrier by using collagen, preparing a suspension of the hemostatic composition, spraying the suspension on the surface of the collagen carrier to form a liquid medicine layer, forming a hemostatic patch by using a freeze-dried liquid medicine layer and the collagen carrier, and the like; the mean diameter of the particles of the suspension blood-stopping composition is 33-50 μm (preferably 37-42 μm), and/or the 5 minute sediment volume of the suspension is >90% (preferably ≡95%).
The hemostatic composition comprises 16-46 parts (preferably 16-20 parts) of fibrinogen, 38-42 parts of 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, the hemostatic composition comprises 16-19 parts fibrinogen, 39-41 parts thrombin and 103-118 parts calcium chloride; more preferably, the hemostatic composition 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.
The suspension for preparing the hemostatic composition comprises the following specific steps: dispersing the hemostatic composition in ethanol to form a liquid medicine, and homogenizing the liquid medicine in a dispersing machine to obtain a suspension; preferably, the liquid medicine is placed in a dispersing machine for homogenization, and the homogenization is specifically as follows: stirring the medicinal liquid for 5-10 times, each time stirring for 2 timesmin, stirring speed (10-20) ×10 3 rpm, stirring time is 10-20min.
The preparation of the collagen carrier comprises the following steps: and (3) taking collagen, putting the collagen into a mould, scraping the collagen with a scraper to form a collagen layer with the thickness of 0.3-0.5cm, cooling the collagen layer from 20 ℃ to-50 ℃ within 19-23h, and freezing the collagen layer to obtain the vitreous collagen carrier with smooth surface and compact internal structure.
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.
Spraying suspension on the surface of collagen carrier with peristaltic pump with flow rate of 50-80ml/min, swinging liquid spraying pipe for 1-6 times, and spraying suspension amount of 0.049-0.563ml/cm 2 。
Spraying suspension by using an automatic spraying device with a reagent tray translation mechanism and a nozzle traversing mechanism, wherein the single movement distance of the nozzle traversing mechanism in the vertical direction is 3000-4500cm, and the total movement distance of the reagent tray translation mechanism in the horizontal direction is 3000-4500 cm.
The thickness of the liquid medicine layer on the surface of the collagen carrier is 0.049-0.247mm per square centimeter.
The hemostatic patch formed by the lyophilized liquid medicine layer and the collagen carrier comprises the following components: and (3) freeze-drying the collagen carrier with the liquid medicine layer sprayed on the surface by using a freeze dryer at the temperature of minus 50 ℃ for 49 min to 63h until the water content is less than 10%, thus obtaining the hemostatic plaster.
The preparation method of the hemostatic patch provided by the invention comprises the steps of carrying out homogenization treatment on the liquid medicine before spraying, and enabling the hemostatic composition and ethanol to form uniform and stable suspension by adjusting parameters of the homogenization process; the mean diameter of the particles of the suspension blood stopping composition is 33-50 mu m (preferably 37-42 mu m), the diameter span is small, so that the particles are uniformly distributed in the suspension, the 5min precipitation volume ratio of the suspension is more than 90 percent (preferably more than 95 percent), namely, the particles are slower to settle, the particles are not easy to deposit in a nozzle and a pipeline in the subsequent spraying process, the nozzle and the pipeline are not blocked, the spraying is more uniform, the hemostatic composition is uniformly distributed on a carrier, and the hemostatic performance of a hemostatic patch product is further improved. The method adopts a freezing mode (rather than freeze-drying) to manufacture the collagen carrier, so that hemostatic components can be adhered to the collagen carrier after freeze-drying, and a liquid medicine layer which is not easy to fall off is formed.
In addition, when the spray coating is performed, a single spray nozzle is used for spraying a single collagen carrier, so that the loss of liquid medicine can be reduced compared with a common spray mode; compared with the common manual spraying mode, the automatic control of liquid medicine spraying can be realized by rapidly and uniformly spraying in each region of the collagen carrier.
The hemostatic patch prepared by the method disclosed by the invention has the advantages of uniform distribution of hemostatic compositions, shortened clotting time and improved hemostatic effect. 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 made from the hemostatic composition of example 2-1 and using the method of examples 1-4;
FIG. 2 is a top view of the hemostatic patch of FIG. 1;
FIG. 3 is a top view of a hemostatic patch prepared by the method of comparative examples 1-5;
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 preparation method of a hemostatic patch, which comprises the following steps:
(1) A small amount of bovine collagen is taken in a mould, and is scraped by a collagen scraper, so that the collagen forms a collagen layer with the thickness of 0.3-0.5cm on the mould; after removing the superfluous bovine collagen, sticking the laminated sheet on the surface of the scraped collagen layer, wherein large bubbles are avoided between the laminated sheet and the collagen layer in the sticking process, and finally, gradient freezing is carried out for 19-23h at 20-50 ℃, the laminated sheet is removed, and the frozen collagen layer is used as a solid carrier of the hemostatic plaster, also called as a collagen carrier.
(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), the suspension is uniformly sprayed on the surface of the frozen collagen carrier by using an automatic spraying device, a layer of liquid medicine layer is formed on the surface of the collagen carrier by the suspension, and the thickness of the liquid medicine layer on the collagen carrier per square centimeter is 0.049-0.247mm.
(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, the appearance of the product is influenced, the hemostatic effect is also influenced), the liquid medicine layer can be adhered to the surface of the collagen carrier in the freeze-drying process, and is adhered with the collagen carrier into an integrated hemostatic patch until the moisture content of the liquid medicine layer 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 adheres to 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 adhered together, and the liquid medicine layer is not easy to fall off from the collagen carrier.
The hemostatic composition used in the method of the invention is a fibrin comprising 16-46 parts (preferably 16-20 parts) fibrinogen (from human, mammalian or recombinant fibrinogen), 38-42 parts thrombin (from human, mammalian or recombinant thrombin) and 100-121 parts calcium chloride, wherein fibrinogen is in mg, thrombin is in IU, and calcium chloride is in μg; preferably, it comprises 17 parts fibrinogen, 40 parts thrombin, 115 parts calcium chloride (CaCl 2 ). Wherein, the liquid crystal display device comprises a liquid crystal display device,
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, mammalian thrombin and recombinant thrombin, can be purchased from Hualan bioengineering Co., shanghai source leaf technology Co., nanjiahong Rui Biotechnology Co., ltd, is white, off-white or light yellow loose body, 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 the blood coagulation factor XI (existing in blood), and the blood coagulation factor XI can participate in other blood coagulation pathways to perform blood 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+ Can also assist in activating coagulationFactor XIII (present in blood), in turn activated factor XIIIa (present in blood), which in turn acts on fibrin monomers, turning 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 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 provides a hemostatic patch which 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. Detailed description of the inventionIn the examples, bovine collagen is used as a solid carrier for the hemostatic patch, and thus the solid carrier is also referred to 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 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 preparation method of the hemostatic patch provided by the invention comprises the following steps:
(1) Placing square mould (made of medical grade PVC with size of 4.9cm×4.9cm×1 cm) into 316 stainless steel liquid medicine tray, taking small amount of bovine collagen (transparent gel, directly using without treatment after purchase), and scraping with collagen scraper (made of 316 stainless steel) to form collagen layer with 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 a speed of 15X10 × during homogenizing 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, and 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, the appearance of the product is influenced, the hemostatic effect is also influenced), the liquid medicine layer can be adhered to the surface of the collagen carrier in the freeze-drying process, the water content of the hemostatic patch is not higher than 10%, the freeze-drying is stopped, and the hemostatic patch product is obtained after taking out, packaging and sterilizing.
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.
A series of examples of hemostatic patches were prepared as described above (hemostatic compositions used in hemostatic patches were examples 2-1), except for the differences in the procedure and/or parameters of the preparation steps, as detailed in Table 1 below.
Table 1 parameters of each step in the method of preparing the hemostatic patch examples
Taking the hemostatic patch prepared by the methods of examples 1-4 in table 1 as an example, the top view and the side view of the hemostatic patch are shown in fig. 1 and 2, the collagen carrier is in a semitransparent state in the side view, and the white liquid medicine layer is formed; the liquid medicine layer in the hemostatic patch is completely and firmly adhered to the collagen carrier, and is not easy to fall off due to shaking and vibration.
Meanwhile, a series of comparative hemostatic patches were prepared as described above, except that the operations and/or parameters in the preparation steps were not within the scope of the method of the present invention, as specified in table 2 below.
Table 2 parameters of each step in the preparation method of comparative hemostatic patch
During spraying, it was found that when the parameters of the spraying liquid medicine of comparative examples 1-1 to 1-4 in Table 2 were not within the scope of the method of the present invention, or were sprayed outside the collagen carrier (examples 1-1, 1-3), resulting in waste of the liquid medicine; either the liquid medicine does not completely cover the collagen carrier (examples 1-4) or the particles of the hemostatic composition are unevenly sprayed due to the poor control of the spraying process (examples 1-2). Thus, these several comparative examples were not subjected to the subsequent lyophilization step. In this example, comparative examples 1 to 5 were also prepared, and the preparation process was the same as in examples 1 to 4, except that the collagen was lyophilized (but not frozen) in step (1), the temperature was lowered in a gradient manner at 20 to-50℃at a lyophilization pressure of not more than 1000mbar, the lyophilization time was 52h40min, and the collagen was prepared into a collagen sponge, which was used as a carrier and sprayed with a medicinal liquid, followed by lyophilization. As a result, it was found that the obtained sample (see fig. 3) had a powder-like liquid medicine layer, and the shaking was dropped, and the liquid medicine layer was cracked, indicating that the liquid medicine layer was easily dropped, and the hemostatic effect was lowered by dropping hemostatic components when used for hemostasis.
Example 2
The invention also prepares the following hemostatic composition examples, and experiments prove the influence of the content of each substance in the hemostatic composition examples on the hemostatic plaster.
Example 2-1
The hemostatic composition of this example was prepared from 17mg fibrinogen, 40IU thrombin, 115 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Example 2-2
The hemostatic composition of this example was prepared from 16mg fibrinogen, 38IU thrombin, 100 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Examples 2 to 3
The hemostatic composition of this example was prepared from 20mg fibrinogen, 42IU thrombin, 121 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Examples 2 to 4
The hemostatic composition of this example is prepared from 18mg fibrinogen, 39IU thrombin, 110 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Examples 2 to 5
The hemostatic composition of this example was prepared from 17mg fibrinogen, 40IU thrombin, 103 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Examples 2 to 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 2-1
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 2-2
The hemostatic composition of this comparative example consisted of 15mg fibrinogen, 37.5IU thrombin, 117 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative examples 2 to 3
The hemostatic composition of this comparative example consisted of 13mg fibrinogen, 40IU thrombin, 115 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative examples 2 to 4
The hemostatic composition of this comparative example consisted of 47mg fibrinogen, 40IU thrombin, 115 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative examples 2 to 5
The hemostatic composition of this comparative example consisted of 17mg fibrinogen, 45IU thrombin, 115 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative examples 2 to 6
The hemostatic composition of this comparative example consisted of 17mg fibrinogen, 30IU thrombin, 115 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative examples 2 to 7
The hemostatic composition of this comparative example consisted of 17mg fibrinogen, 40IU thrombin, 80 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Comparative examples 2 to 8
Hemostatic combination of this comparative exampleThe product consists of 17mg fibrinogen, 40IU thrombin, 130 μg calcium chloride (CaCl) 2 ) Composition is prepared.
Experiment one, determination of 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 2-1 to 2-6 were added with absolute ethanol, which had been cooled to-20℃in advance, and stirred to prepare 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 2-1 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 3; the number of stirring times in experiment B was 10, and the results are shown in Table 4.
TABLE 3 temperatures before and after homogenization of experiment A, average diameter and precipitation volume fraction of 5min
As shown by the results in Table 3, 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 4 temperature, average diameter and setting time before and after homogenization of experiment B
The results in Table 4 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 temperature change is less than 10 ℃ and does not influence the activity of the protein.
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 4, taking fibrinogen clotting time as an example. The results in Table 4 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 3 and 4 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 homogenizing effect, the results of example 2-1 in this experiment show that other examples have the same results as those of example 2-1, and are not described in detail herein.
Experiment two, 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
Dissolving fibrinogen in the hemostatic compositions of examples 2-1 to 2-6 in 1ml of water to prepare an aqueous solution A, dissolving thrombin and calcium chloride in the hemostatic compositions of examples 2-1 to 2-6 in 1ml of water to prepare an aqueous solution B, and finally mixing the aqueous solution A and the aqueous solution B to form a clot sample and detecting the mechanical property index of the clot sample. 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. The results are shown in Table 5, taking examples 2-1 and examples 2-5 as examples.
TABLE 5 mechanical test results for hemostatic compositions of examples 2-1 and 2-5
| Examples | Storage modulus G' | Loss modulus G'. | Viscoelastic property value tan delta |
| Example 2-1 | 180.85-285.5 | 46.781-77.814 | 0.1396-0.3091 |
| Examples 2 to 5 | 353.32-418.99 | 55.866-90.722 | 0.1581-0.2265 |
The results in Table 5 show that examples 2-1 and examples 2-5 provide clot samples with tan delta <1, indicating that the clot samples formed tend to gel and are less 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.
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 2-1 to 2-6.
Comparison sample: hemostatic compositions of comparative examples 2-1 and 2-3 to 2-8.
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 6, taking examples 2-1, 2-2, 2-5 and 2-6 as examples.
TABLE 6 setting time of samples
The results in Table 6 show that the hemostatic compositions of examples 2-1, 2-2, 2-5 and 2-6 are all superior to control samples 1 and 2 in clotting time at the same dilution ratio and differ significantly; 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 2-1, 2-2, 2-5 and 2-6 are also superior to comparative examples 2-1, 2-3 to 2-8 in setting time and differ significantly; the hemostatic composition of the invention is obviously superior to comparative examples 2-1 and 2-3 to 2-8 in hemostatic effect; in particular, comparative examples 2 to 4, in which the fibrinogen content was slightly higher than that of examples 2 to 6, showed a remarkable improvement in clotting time, and the hemostatic composition provided by the present invention was able to exert a superior hemostatic effect in cooperation with the three 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 (8)
1. The preparation method of the hemostatic patch is characterized by comprising the following steps of:
step 1: a small amount of bovine collagen is taken in a mould, and is scraped by a collagen scraper, so that a collagen layer with the thickness of 0.3-0.5cm is formed on the mould; removing superfluous bovine collagen, then pasting a lamination sheet on the surface of the scraped collagen layer, wherein large bubbles are avoided between the lamination sheet and the collagen layer in the pasting process, and finally, gradient freezing is carried out for 19-23h at 20-50 ℃, the lamination sheet is removed, the frozen collagen layer is used as a solid carrier of the hemostatic plaster, also called as a collagen carrier, and the collagen carrier is a glassy solid with smooth surface and compact interior;
gradient freezing for 19-23h at 20-50 ℃, wherein the freezing gradient is that the temperature is reduced from 20 ℃ to 0 ℃ in 1h, then the temperature is reduced to-50 ℃ in 18-22h, and the temperature is maintained for 2h at-50 ℃;
step 2: mixing fibrinogen, thrombin, calcium chloride and absolute ethanol precooled at-20 ℃ to form a liquid medicine, and placing the liquid medicine in a dispersing machine for homogenizing and stirring at the stirring speed of (10-20) multiplied by 10 in the homogenizing process 3 rpm, stirring the liquid medicine for 5-10 times, wherein the stirring time is 10-20min in total, homogenizing to obtain a suspension containing the hemostatic composition, and placing the suspension in an environment of-50 ℃ to-20 ℃ for later use;
step 3: setting parameters of an automatic spraying device: the peristaltic pump has the 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 X-axis moving distance is 3000-4500 cm;
the automatic spraying device comprises a reagent tray translation mechanism, a liquid spraying mechanism and a nozzle traversing mechanism, wherein the reagent tray translation mechanism is provided with a translation driving motor for driving the reagent tray arranged on the reagent tray translation mechanism to translate and reciprocate, the nozzle traversing mechanism is provided with a traversing driving motor for driving the nozzle arranged on the nozzle traversing mechanism to traverse and reciprocate, the nozzle is positioned above the reagent tray, and the liquid spraying mechanism is provided with a peristaltic pump for pushing liquid medicine into the nozzle through a spray pipe, so that the liquid medicine is quantitatively sprayed on each area of the reagent tray provided with a bottom plate;
step 4: after the parameter setting of the step 3 is completed, placing the inlet of the pump pipe into the suspension obtained in the step 2, and uniformly spraying the suspension on the surface of the frozen collagen carrier by using an automatic spraying device, wherein the suspension forms a liquid medicine layer on the surface of the collagen carrier, and the thickness of the liquid medicine layer on the collagen carrier per square centimeter is 0.049-0.247 mm;
step 5: 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 49h40min-63h, adhering the liquid medicine layer on the surface of a collagen carrier in the freeze-drying process, and adhering the liquid medicine layer and the collagen carrier into an integrated hemostatic plaster, stopping freeze-drying until the water content of the liquid medicine layer is not higher than 10%, taking out, packaging and sterilizing to obtain a hemostatic plaster product;
wherein the mean diameter of the particles of the suspension blood-stopping composition is 33-50 μm and/or the 5 minute sediment volume of the suspension is >90% of the mean value; 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.
2. The method of claim 1, wherein the particles of the suspension blood-stopping composition have an average diameter of 37-42 μm.
3. The method of claim 1 or 2, wherein the suspension has a 5 minute sediment volume of greater than or equal to 95% of the mean value.
4. The method of claim 1, wherein the hemostatic composition comprises 16-20 parts fibrinogen, 38-42 parts thrombin and 100-121 parts calcium chloride, wherein fibrinogen is in parts in mg, thrombin is in parts in IU, and calcium chloride is in parts in μg.
5. The method of claim 4, wherein the hemostatic composition comprises 16-19 parts fibrinogen, 39-41 parts thrombin and 103-118 parts calcium chloride, wherein fibrinogen is in parts in mg, thrombin is in parts in IU, and calcium chloride is in parts in μg.
6. The method of claim 5, wherein the hemostatic composition comprises 17 parts fibrinogen, 40 parts thrombin and 115 parts calcium chloride, wherein fibrinogen is in parts in mg, thrombin is in parts in IU and calcium chloride is in parts in μg.
7. The method of claim 1, wherein the hemostatic composition has a viscoelastic property value tan delta <1 of a fibrin polymer formed upon exposure to water.
8. The process according to claim 7, wherein tan delta is 0.13 to 0.31.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000038752A1 (en) * | 1998-12-23 | 2000-07-06 | Aventis Behring Gmbh | Fibrin-based glue granulate and corresponding production method |
| CN1507358A (en) * | 2001-01-25 | 2004-06-23 | �ο���ҽҩ����˾ | Carrier with solid fibrinogen and solid thrombin |
| CN2643866Y (en) * | 2003-06-13 | 2004-09-29 | 常春荣 | Quick-acting biological enclosing and hemostatic strip |
| CN112972755A (en) * | 2021-03-25 | 2021-06-18 | 哈尔滨瀚邦医疗科技有限公司 | Preparation method of biological hemostatic material based on porcine fibrinogen and thrombin |
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| DE102006020498A1 (en) * | 2006-04-20 | 2007-10-25 | Aesculap Ag & Co. Kg | Layered wound dressing |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000038752A1 (en) * | 1998-12-23 | 2000-07-06 | Aventis Behring Gmbh | Fibrin-based glue granulate and corresponding production method |
| CN1507358A (en) * | 2001-01-25 | 2004-06-23 | �ο���ҽҩ����˾ | Carrier with solid fibrinogen and solid thrombin |
| CN2643866Y (en) * | 2003-06-13 | 2004-09-29 | 常春荣 | Quick-acting biological enclosing and hemostatic strip |
| CN112972755A (en) * | 2021-03-25 | 2021-06-18 | 哈尔滨瀚邦医疗科技有限公司 | Preparation method of biological hemostatic material based on porcine fibrinogen and thrombin |
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