CN105030824A - Application of zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder - Google Patents
Application of zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder Download PDFInfo
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- CN105030824A CN105030824A CN201510514239.5A CN201510514239A CN105030824A CN 105030824 A CN105030824 A CN 105030824A CN 201510514239 A CN201510514239 A CN 201510514239A CN 105030824 A CN105030824 A CN 105030824A
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- based montmorillonite
- zinc
- calcium
- sterile
- montmorillonite
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Landscapes
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Abstract
The invention relates to an application of zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder in preparation of medicines for healing skin wounds. The zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is prepared from the following raw materials in parts by mass: 5-10 parts of zinc-based montmorillonite and 8-12 parts of calcium-based montmorillonite. According to the invention, zinc-based montmorillonite and calcium-based montmorillonite are used as effective ingredients of the medicament provided by the invention, and the effective ingredients are combined with pharmaceutical auxiliary materials to be prepared into the medicament through the processes of high-temperature dry heat sterilization, mixing, sterile sub-packaging and the like. Through skin external administration, the medicament can be used for quickly coagulating blood and arresting bleeding as well as preventing wound infection, has anti-bacterial and anti-inflammatory effects, and has converging and healing effects on the injured skin.
Description
Technical Field
The invention relates to application of styptic powder, in particular to application of zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder, and belongs to the technical field of medicines.
Background
Blood is a fluid tissue comprising plasma, which also contains water, acids, lipids, soluble electrolytes and proteins, and red blood cells, white blood cells, microparticles and platelets dispersed in the plasma. One particular protein suspended in plasma is fibrinogen, which in the case of bleeding can react with water and thrombin to form insoluble fibrin and further polymerize to form clots, preventing bleeding. Under normal conditions, when an animal body (including a human body) is injured to bleed, fibrinogen in blood can play the function of stopping bleeding.
In many cases, bleeding from smaller wounds can be inhibited by the coagulation function of the blood itself, plus some additional care. In other cases, if in the case of massive bleeding, special equipment and materials as well as medical professionals are necessary for the rescue. The bleeding and disability causing is always the main reason of battle injury paroxysmal death and peacetime trauma death, although military equipment is continuously upgraded in the recent war, the hemostasis technology is still more traditional, and the hemostasis is mostly performed by bundling and pressurizing a tourniquet. Although effective in stopping bleeding, the side effects are obvious, such as nerve paralysis caused by long time, limb injury caused by serious diseases, and even local tissue necrosis. The rapid hemostasis emergency equipment is a project which is currently and internationally accelerated to research, can help patients suffering from war injury or severe accidental injury to immediately stanch, and wins precious time for sending to hospitals for rescue.
With the improvement of the hemostatic performance requirements of the hemostatic materials in various medical communities, it is imperative to develop materials with better hemostatic effects. Firstly, the material used as the hemostatic dressing or the hemostatic agent has the advantages of good hemostatic performance, excellent biocompatibility, no toxicity, no side effect, no irritation, easy processing and molding, and the like. Therefore, from the existing conditions, it is an ideal choice to search for excellent biological materials in nature, process and improve the materials. Secondly, according to different performances of various hemostatic materials, a method of combining various hemostatic materials is adopted, so that the material can exert better hemostatic performance. In addition, research on hemostatic methods and hemostatic approaches of hemostatic materials is being further enhanced in order to develop hemostatic materials that are different from existing hemostatic approaches. Makes new contribution to human health.
Chinese patent document CN101677848A discloses the use of noncalcium zeolite with added calcium salt in hemostatic devices and products, which is the agent obtained by ion-exchanging zeolite with water-soluble calcium salt. As is well known, zeolite is a group of natural aluminosilicate minerals, 40 kinds of which are found at present, but less than 30 kinds of which are determined by structure, mainly comprising analcime, nepheloid zeolite, phillipsite, natrolite, mordenite, heulandite, clinoptilolite, chabazite, faujasite and the like, and the patent has the following defects; 1. the patent does not describe which zeolites are used, each having a different active site, the direction of application of which is greatly different; 2. the zeolite has strong water absorption, and the mineral generates higher temperature in the water absorption process and can cause thermal damage to a certain extent; 3. the natural zeolite contains more pathogenic bacteria, and the whole preparation process of the patent does not describe an aseptic preparation process; 4. since the mineral particles of zeolite are relatively coarse, there is no description in the patent that the particle size of zeolite is selected, and that it is likely to cause secondary damage to the skin and to cause adverse effects on wound healing when it is contained in the preparation of a hemostatic agent, such as a hemostatic agent containing relatively large particles. Chinese patent document CN101104080 discloses a zeolite hemostatic dressing and a preparation method and application thereof, the medicament is prepared from 4A zeolite, a binder, lignin and optional molecular sieve activated powder, and the zeolite hemostatic dressing is taken as a raw material, wherein the main components and contents of the zeolite hemostatic dressing are as follows: al (Al)2O3Between 25 and 35 percent of SiO2Between 30 and 40%, and CaOBetween 10 and 18 percent of Na2The content of O is less than 1%, and the particle diameter is in the range of more than 0.2 to less than 1 mm. The zeolite-containing hemostatic dressing has the advantages of high hemostatic speed, no bacteria, no pyrogen, no cytotoxicity, no allergic reaction, no skin irritation, convenient use and low cost. This patent suffers from the following drawbacks: however, the patent only has the function of hemostasis and has no function of convergence and healing on the wound surface.
At present, in the existing hemostatic materials, the hemostatic effect only on wound openings is achieved, the wound convergence and healing functions are not achieved, the hemostatic materials do not have antibacterial activity and the like, wound infection is easily caused, an environment beneficial to bacterial growth is possibly formed, repeated infection of the wound is caused, and healing is not easy. In summary, the above prior art treatments all suffer from various degrees of drawbacks, which greatly limit their clinical application. In order to meet the clinical requirements of patients, technicians in the field are always seeking to develop safe, efficient, quality-controllable and convenient hemostatic powder for years.
Montmorillonite is a mineral drug, is an aqueous phyllosilicate mineral, and its unit cell is composed of two layers of silicon-oxygen tetrahedral sheet and one layer of aluminum-oxygen octahedral sheet, and belongs to the typical Si in its tetrahedron4+Can be coated with AL3+Replacement of Si in octahedron4+、AL3+Is easy to be Mg2+、Fe2+、Fe3+、Zn2+、Mn2+And the like, so that the montmorillonite crystals generate interlayer negative charges. These characteristics of montmorillonite impart to it the characteristic swelling, adsorption, electrification and ion exchange properties that it possesses unique advantages for its use in pharmacy. The medicine is a common medicine for treating diarrhea and digestive tract ulcer and protecting gastrointestinal tract, and has better curative effect in clinic. At present, the montmorillonite preparation is mainly an oral preparation and is clinically used for acute and chronic diarrhea and the like of adults and children. So far, no report is found on the application of montmorillonite modified into zinc-based montmorillonite and calcium-based montmorillonite in preparing zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides application of zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder in preparation of a medicament for healing skin wounds.
Summary of The Invention
The invention adopts zinc-based montmorillonite and calcium-based montmorillonite as effective components of the medicine to prepare the medicine for healing skin wounds, and realizes the effects of stopping bleeding, resisting bacteria, promoting healing and relieving pain and good air permeability and liquid absorption performance.
The zinc-based montmorillonite and the calcium-based montmorillonite used in the invention can dissociate free zinc ions, calcium ions and montmorillonite; the medicament of the sterile styptic powder is scattered and applied to the skin wound, and can play the following roles: (1) the montmorillonite dissociated from the sterile styptic powder can form gel after meeting blood, and can oppressively prevent further outflow of the blood, so that the blood is quickly stopped; (2) the dissociated montmorillonite can also adsorb bacteria in the wound, prevent the propagation of the bacteria and prevent the infection of the wound, and the formed gel can be used as a protective layer on the surface and the periphery of the wound to prevent the invasion of the external bacteria; (3) zinc ions dissociated from the zinc-based montmorillonite have antibacterial and anti-inflammatory effects, and have astringent and healing effects on damaged skin; (4) calcium ion dissociated from calcium-based montmorillonite can shorten bleeding time and plasma recalcification time.
Detailed Description
Description of terms:
zinc-based montmorillonite (Zn-montmorillonite): after being acidified, montmorillonite is soaked in water-soluble zinc salt solution or is eluted and dried, and is crushed and sieved by a 500-mesh sieve to obtain the zinc-based montmorillonite zinc ion zinc-based montmorillonite with the labeled amount of 5.0-9.5%; can be purchased commercially or prepared according to the existing method.
Calcium-based montmorillonite (Ca-montmorillonite): after being acidified, montmorillonite is soaked in water-soluble calcium salt solution or is eluted and dried, and is crushed and sieved by a 500-mesh sieve to obtain the calcium-based montmorillonite calcium ion; can be purchased commercially or prepared according to the existing method.
Skin trauma: refers to the separation or defect of skin tissue caused by trauma or other injuries, including skin laceration, bleeding, scald, and traumatic injury.
Room temperature: the temperature of the environment where the experiment operation is carried out is controlled within the range of 15-30 ℃.
The technical scheme of the invention is as follows:
an application of sterile hemostatic powder of zinc-based montmorillonite and calcium-based montmorillonite in preparing medicine for healing skin wound is disclosed.
According to the invention, the application of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder in preparing the medicines for healing skin wounds is that the zinc-based montmorillonite and the calcium-based montmorillonite sterile styptic powder are applied independently or are used in combination with other medicines as medicaments.
According to the invention, the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is applied to preparation of a medicine for healing skin wounds, wherein the skin wounds comprise skin scratch bleeding, scald and traumatic injury.
According to the invention, the application of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder in preparing a medicament for healing skin wounds is disclosed, wherein the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is prepared from the following raw materials in parts by mass:
5-10 parts of zinc-based montmorillonite
8-12 parts of calcium-based montmorillonite;
according to the present invention, it is preferred;
the application of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder in preparing a medicament for healing skin wounds is disclosed, wherein the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is prepared from the following raw materials in parts by mass:
5-8 parts of zinc-based montmorillonite
8-10 parts of calcium-based montmorillonite;
according to the present invention, it is further preferred;
the application of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder in preparing a medicament for healing skin wounds is disclosed, wherein the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is prepared from the following raw materials in parts by mass:
8 parts of zinc-based montmorillonite
10 parts of calcium-based montmorillonite;
or,
zinc-base montmorillonite 7 parts
9 parts of calcium-based montmorillonite;
or,
5 parts of zinc-based montmorillonite
8 parts of calcium-based montmorillonite.
Wherein the zinc-based montmorillonite and the calcium-based montmorillonite are crushed and sieved by a 500-mesh sieve.
According to the invention, the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is applied to the preparation of the medicine for healing skin wounds, wherein the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is prepared by the following method:
(1) crushing zinc-based montmorillonite according to the formula amount, sieving with a 500-mesh sieve, placing into a dry heat sterilization cabinet, sterilizing at 170-180 ℃ for 180-240 min, and cooling to room temperature for later use;
(2) crushing the calcium-based montmorillonite according to the formula amount, sieving with a 500-mesh sieve, placing into a dry heat sterilization cabinet, sterilizing at 250-300 ℃ for 120min, and cooling to room temperature for later use;
(3) putting the materials obtained in the step (1) and the step (2) into a sterilized mixing tank; stirring and mixing uniformly; sterile subpackaging to obtain the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder.
The above is a preferred method of the present invention in terms of the preparation method, but is not limited thereto.
The preparation method of the above-mentioned zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is not particularly limited, and the prior art can be referred to. Those skilled in the art can appropriately adjust the conditions according to their knowledge.
In the preparation method, the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder has the following quality standard, but the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is not limited to the following standard.
Zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder
The zinc-based montmorillonite and calcium-based montmorillonite contained in the product are 97.0 to 105.0 percent of the marked amount; wherein the zinc ions are 3.5-5.5% of the labeled zinc-based montmorillonite and calcium-based montmorillonite, and the calcium ions are 3.5-5.5% of the labeled zinc-based montmorillonite and calcium-based montmorillonite.
[ PROPERTIES ] this product is similar to white powder.
[ IDENTIFICATION ] taking 0.5g of the product, placing the product in a bottle with a stopper, adding 50ml of purified water, and adding hydrochloric acid to adjust the pH value to 3.5-4.5; ultrasonic treatment for 20 minutes, centrifuging, filtering, drying a filter cake in an oven at 105 ℃ for 2 hours, placing the filter cake in a dryer for about 12 hours (sodium chloride saturated solution is filled in the dryer, and the relative humidity is about 78% at 20 ℃), measuring the sample according to an X-ray powder diffraction method (appendix IX F in the second part of 2010 edition of Chinese pharmacopoeia), and recording a spectrum, wherein the X-ray diffraction spectrum of the sample is consistent with that of a montmorillonite reference substance.
[ EXAMINATION ] sterility: the sterility test method is performed according to the Chinese pharmacopoeia 2010 edition (appendix XI H) and the requirements are met.
10g of test sample is taken, precisely weighed and placed on a No. seven sieve. The weight of the powder passing through the screen is precisely weighed and is not less than 95 percent according to the examination of a particle size and particle size distribution measuring method (an appendix IX E second method of 2010 edition of Chinese pharmacopoeia) by a single screening method.
Other should meet the regulations of powder.
[ contents ] of
The zinc content is measured and measured out from zinc standard solution, and diluted with water to obtain solutions containing about 0.05 μ g, 0.1 μ g, 0.2 μ g, 0.3 μ g, and 0.4 μ g zinc per 1ml, which are control solutions.
Precisely weighing 1.0g of the product containing zinc, precisely weighing, placing in a porcelain dish, respectively adding 6ml of sulfuric acid and 10ml of nitric acid, after the reaction is completed, placing on an electric furnace to be evaporated to dryness, cooling to room temperature, adding 40ml of 20% hydrochloric acid, uniformly stirring by using a glass rod, filtering by using filter paper, washing residues by using hot distilled water for 3 times, combining filtrates, placing in a 100ml volumetric flask, adding distilled water to dilute to a scale, and shaking uniformly. Precisely measuring 10ml of solution, placing the solution in a 100ml volumetric flask, adding distilled water to dilute the solution to a scale, shaking up, precisely measuring 10ml of solution, placing the solution in the 100ml volumetric flask, adding distilled water to dilute the solution to the scale, and shaking up to obtain a test solution. And (4) taking the reference substance solution and the test solution to respectively measure the absorbance, and calculating the zinc content in the sample.
Accurately weighing 0.5g of the product with calcium content; putting the mixture into a porcelain dish, respectively adding 98% (w/w) of concentrated sulfuric acid and 65% (w/w) of concentrated nitric acid, evaporating the mixture to dryness on an electric furnace after the reaction is completed, cooling the mixture to room temperature, adding 40ml of water, uniformly stirring the mixture by using a glass rod, filtering the mixture by using filter paper, washing residues by using hot distilled water for 3 times, combining the filtrates, putting the combined filtrates into a 100ml volumetric flask, adding distilled water to dilute the mixed filtrates to a scale, and shaking the mixed filtrates uniformly. Adding 15ml of sodium hydroxide test solution and 0.1g of calcium purpurin indicator, and titrating with disodium ethylene diamine tetraacetate titration solution (0.05mol/L) until the solution turns from purplish red to pure blue. Each 1ml of disodium EDTA titrant (0.05mol/L) corresponds to 25mg of calcium ions.
The present invention will be further described with reference to the following examples, but is not limited thereto.
Experimental example 1: sterilization experiment of zinc-based montmorillonite and calcium-based montmorillonite
In the application of the invention, the active ingredients of the preparation, namely the zinc-based montmorillonite and the calcium-based montmorillonite are layered minerals formed by modified montmorillonite and superfine hydrous aluminosilicate, and the research on sterilization methods of the zinc-based montmorillonite and the calcium-based montmorillonite ensures that the zinc-based montmorillonite and the calcium-based montmorillonite can be safely used on the premise of ensuring that the sterile styptic powder medicine meets the quality standard, so that the preparation has great innovation breakthrough.
1. Sterilization experiment of zinc-based montmorillonite
The dry heat sterilization effect of zinc-based montmorillonite is compared by different dry heat temperatures and dry heat times, and the comparison result is shown in a table 1:
TABLE 1 comparison of dry heat sterilization effect of zinc-based montmorillonite
From the analysis in table 1 it can be seen that:
(1) the dry heat temperature is 160-170 ℃, the drying time is 120-240 min, and the X-ray diffraction pattern of the zinc-based montmorillonite is consistent with that of a reference substance, which shows that the dry heat does not damage the zinc-based montmorillonite chemical structure under the condition, but the sterile inspection does not meet the regulation;
(2) the dry heat temperature is 170-180 ℃, the dry heat time is 120min, and the zinc-based montmorillonite X-ray diffraction pattern is consistent with the pattern of a reference substance, so that the zinc-based montmorillonite chemical structure is not damaged by the dry heat under the condition, but the sterile inspection is not in accordance with the regulation;
(3) the dry heat temperature is 170-180 ℃, the dry heat time is 180-240 min, and the zinc-based montmorillonite X-ray diffraction pattern is consistent with the pattern of a reference substance, so that the zinc-based montmorillonite chemical structure is not damaged by the dry heat under the condition, and the zinc-based montmorillonite chemical structure is subjected to aseptic inspection and meets the regulation; see figure 1 for details the X-ray diffraction pattern of zinc-based montmorillonite.
And result analysis shows that the sterilization temperature of the zinc-based montmorillonite is 170-180 ℃ and the time is 180-240 min.
2. Calcium-based montmorillonite sterilization experiment
The dry heat sterilization effect of calcium-based montmorillonite was compared between different dry heat temperatures and dry heat times, and is shown in Table 2:
TABLE 2 comparison of dry heat sterilization effect of calcium-based montmorillonite
From the analysis in table 1 it can be seen that:
(1) the dry heat temperature is 170-180 ℃, the drying time is 120-240 min, and the X-ray diffraction pattern of the calcium-based montmorillonite is consistent with the pattern of the standard substance, which shows that the dry heat does not damage the chemical structure of the calcium-based montmorillonite under the condition, but the aseptic inspection does not meet the regulation;
(2) the dry heat temperature is 250-300 ℃, the dry heat time is 120min, and the X-ray diffraction pattern of the calcium-based montmorillonite is consistent with the pattern of the standard substance, so that the dry heat does not damage the chemical structure of the calcium-based montmorillonite under the condition, and the detailed calcium-based montmorillonite X-ray diffraction pattern shown in figure 2 is subjected to sterile inspection and meets the regulation;
(3) the dry heat temperature is 250-300 ℃, the dry heat time is 180-240 min, and the comparison between the X-ray diffraction pattern of the calcium-based montmorillonite and the pattern of the standard substance shows that the dry heat destroys the chemical structure of the calcium-based montmorillonite under the condition, and the aseptic inspection is carried out to meet the regulations.
And result analysis shows that the sterilization temperature of the calcium-based montmorillonite is 250-300 ℃ and the time is 120 min.
Experimental example 2: skin irritation test of rabbit with zinc-based montmorillonite and calcium-based montmorillonite
1. Test materials
(1) Medicine preparation: the test was carried out using the sterile powders of Zn-based montmorillonite and Ca-based montmorillonite of example 1 as the test samples for further use.
(2) Animals: healthy Japanese big ear white rabbits, the body mass of which is 2.0-2.4 kg, and the sex is half of the body mass, are provided by the experimental animal center of Shandong university.
(3) Method of producing a composite material
The rabbits 6 were randomly divided into a complete skin group and a damaged skin group according to sex and weight, and each group had 3 rabbits. The rabbit was depilated symmetrically on both sides of the spine 24h before administration, the depilated area being 10% of the surface area of the rabbit (ranging about 50cm on each side). The left side is a zone A (blank control zone), a zone B (70% ethanol control zone) and the right side is a zone C (zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder administration experimental zone). After 24h of depilation, 0.5mL of distilled water is coated on the left area A of the intact skin group, 0.5mL of 70% ethanol is coated on the area B, and the sterile styptic powder of zinc-based montmorillonite and calcium-based montmorillonite is used on the right area C for 3 times in 1 day. Then covering the rabbit by a layer of plastic paper and two layers of gauze, and fixing the rabbit by a homemade rabbit sleeve. The damaged skin group was abraded on the skin of the depilatory area with a needle before administration, to the extent of abrasion of the epidermis, no damage to the dermis, and slight bleeding, and the administration method was the same as that of the intact skin group. After the administration was fixed for 6 hours, the cover was removed and the administration site was observed for erythema and edema. Applied 1 time daily for 7 days.
The evaluation method comprises the following steps: the stimulation responses and stimulation intensity scores were performed according to tables 3 and 4, respectively, and the stimulation intensity, recovery of stimulation response and time of multiple administrations on intact and damaged skin were evaluated and compared with the control group as shown in table 5. The mean response was calculated as the sum of the total erythema and edema formed divided by the total number of experimental animals in the same group.
TABLE 3 skin irritation response Scoring criteria
TABLE 4 skin irritation Strength scoring criteria
TABLE 5 Rabbit intact skin and broken skin irritation scores
2. Results
After 7 days of continuous skin administration of the zinc-based montmorillonite, the calcium-based montmorillonite sterile styptic powder and the excipient, no erythema and edema appear on the whole skin and the damaged skin, and the skin irritation reaction intensity is less than 0.5 minute. After the medicine is stopped, the medicine and the excipient part thereof are smeared for 1 week without the phenomena of pigmentation, thin and rough skin and the like. The result shows that the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder have no irritation to the intact skin and the damaged skin of the rabbits after multiple continuous administration, belong to non-irritant medicaments, and are safe in clinical application.
Experimental example 3: experiment of skin allergy of rabbit with zinc-based montmorillonite and calcium-based montmorillonite
1. Experimental Material
(1) Medicine preparation: the test was carried out using the sterile powders of Zn-based montmorillonite and Ca-based montmorillonite of example 1 as the test samples for further use.
(2) Animals, healthy male Wistar rats, weighing 250-300 g, were provided by the Experimental animals center of Shandong university.
2. Experimental methods
12 Wistar mice are divided into complete skin and damaged skin allergy test groups, and each group comprises 6 mice. Each rat was operated at a dose of 30mg/kg following intraperitoneal injection of pentobarbital sodium for anesthesia. Both sides of the back of each rat were depilated by a chemical method after shearing, and the depilating range was about 4cm × 6cm on each side. Broken skin groups each animal was scored with a sterile scalpel blade in the hair removal area "well" to the extent that bleeding occurred through the broken epidermis.
Sensitizing and contacting: the right hair-removing area is coated with 0.2g of test medicine, the left side is coated with 0.2mL of physiological saline as a control, the control is covered with sterile non-irritant medical gauze, the adhesive plaster is fixed, each animal is raised in a cage, the medicine is coated in the experiment for 6h, the experiment is repeated for 1 time on each of the 7 th day and the 14 th day, and the period is sensitization contact.
② contact excitation: on 14 days after the last drug application and sensitization, the test drug is applied for 0.2g1 times, the test drug is removed after the test drug is continuously applied for 6 hours, the test drug is immediately observed, and then the skin allergic reaction condition is observed again after 24 hours, 48 hours and 72 hours. This stage is the excitation contact. After the last application for 14 days, there were congestion, edema, induration, necrosis, etc. Local skin reactions (presence or absence of redness, erythema and edema) were observed throughout the experiment, as well as the presence or absence of specific events and the appearance of allergies. The appetite, behavior and activity of the animals and the presence or absence of abnormal reaction to the outside are observed. Allergic reaction scores are made according to the reaction conditions, the average score of each group of animals is calculated, and the difference between groups is evaluated by using a t test.
3. Results of the experiment
The diet and behavior activities of the two groups of rats are normal, no special condition or allergic reaction occurs, and the reaction to the outside is normal. The skin of rats in a test group and a control group has no erythema and edema, the skin reaction values of the rats in the test group and the control group are both 0, the sensitization rate is 0, and the anaphylactic reaction does not exist, and the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder has no sensitization to the skin of the rats.
4. Conclusion of the experiment
The zinc-based montmorillonite and calcium-based montmorillonite styptic powder has no anaphylactic reaction to the whole skin and the damaged skin of a rat, and shows that the toxicity is low, the side effect is small, and the medicine is safe and reliable.
Experimental example 4: experiment for researching antibacterial activity of zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder
1. Concentration of bacteriostasis
The zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder contains the zinc-based montmorillonite, the zinc-based montmorillonite can be combined with membrane protein of a bacterial cell membrane, and when the zinc-based montmorillonite is contacted with bacteria, zinc ions can be slowly released, so that the structure of the bacteria is damaged, the zinc ions enter cells of the bacteria to damage enzymes of an electron transfer system, and meanwhile, the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder reacts with DNA to play a role in sterilization. After killing bacteria, zinc ions are dissociated from cells, and the zinc-based montmorillonite has lasting bacteriostatic activity by repeating the sterilization process.
Table 6 lists various concentrations of Zn-based montmorillonite and Ca-based montmorillonite styptic powders (prepared in example 1) against (A) Staphylococcus aureus with tetracycline(s) as a control; (B) escherichia coli; (C) pseudomonas aeruginosa; (D) the bacteriostatic condition of salmonella is shown in table 6, wherein M is the mass concentration of zinc-based montmorillonite and calcium-based montmorillonite styptic powder, wherein M1 is 0.002g/mL, M2 is 0.006g/mL, M3 is 0.02g/mL, M4 is 0.2g/mL, and the diameter (mm) of a bacteriostatic circle represents the strength of bacteriostatic activity.
TABLE 6 Zinc-based montmorillonite bacteriostatic circle diameter (mm) of different concentrations
As can be seen from Table 6, the zinc-based montmorillonite with the mass concentration of 0.001 and 0.005g/mL has certain antibacterial activity, when the mass concentration of the zinc-based montmorillonite is 0.02 and 0.2g/mL, the antibacterial activity is basically the same, and no significant difference exists, which indicates that the antibacterial activity reaches a stable value along with the increase of the mass concentration of the zinc-based montmorillonite and the calcium-based montmorillonite sterile styptic powder, and the antibacterial effective concentration of the zinc-based montmorillonite and the calcium-based montmorillonite sterile styptic powder is 0.02 g/mL.
2. Bacteriostatic activity
The antibacterial activity of (1) calcium-based montmorillonite, (2) sodium-based montmorillonite, (3) zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder with a mass concentration of 0.02g/ml against 4 kinds of bacteria is shown in Table 7.
TABLE 7 the various montmorillonite zone diameters (mm)
As can be seen from Table 7, the zinc-based montmorillonite has significantly higher antibacterial activity, is significantly different from calcium-based montmorillonite and sodium-based montmorillonite, and has a wider antibacterial range than tetracycline for the four bacteria.
Experimental example 5: histological research experiment of influence of zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder on wound convergence and healing
Wound healing refers to a series of pathophysiological processes in which after skin and other tissues are separated or damaged due to trauma or other injuries, local tissues are repaired and restored through regeneration and reconstruction, and the process is one of the most basic problems in medicine and is an important clinical research subject which is researched for a long time in the surgical field. The invention selects the zinc-based montmorillonite and calcium-based montmorillonite powder which have the functions of stopping bleeding, resisting bacteria and promoting wound healing, applies a pathological experiment technology to observe the histological change of the wound tissue in the wound healing process and discuss the mechanism thereof, thereby exploring an effective way for promoting wound healing clinically and providing a reliable experimental basis for clinical research on skin wound healing.
1. Materials and methods
1.1 materials
Experimental animals: 24 healthy rabbits (purchased from non-clinical research center of Shandong university) with half male and female body weights of 2.5-3.0 kg;
medicine preparation: the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is prepared by the method of example 1;
1.2 Experimental methods
The animal model establishing method comprises the following steps: the operation cutting method is used for molding, and the backs of the rabbits are unhaired and preserved with 8 percent sodium sulfide one day before molding. Before operation, 2% pentobarbital sodium (30mg/kg) is injected into abdominal cavity, rabbits are in prone position, after conventional iodophor disinfection, skin full-thickness incisions are made at 2cm positions away from the middle of the spine, the area is about 2cm multiplied by 2cm, 6 are provided, the left and right are respectively 3, and the wound surface interval is about 2 cm. The wound is washed with normal saline and sterilized for later use.
Grouping experimental animals: rabbits were randomized into three groups: blank group (saline treated group), experimental group l (montmorillonite group), and experimental group 3 (zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder group), each group being 8, were administered physiological saline, montmorillonite, zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder treatments, respectively. Namely, post-operative day 3, 5, 7 and 10 groups and wound natural healing groups.
Material taking: four groups of rabbits were used to obtain full-thickness skin tissue at the wound about 0.2cm away from the edge on days 3, 5, 7, and 10 after operation. Part of the tissue was fixed with 4% paraformaldehyde in time, stored at 4 ℃ until paraffin sections were obtained and stained with HE and Masson.
Observation of wound healing time: the wound healing criteria were complete healing with wound area less than 5% of the total area or healing area greater than 95%.
Observation of wound healing rate: the wound area was measured on the 3 rd, 5 th, 7 th and 10 th days after injury by using 0.25cm × o.25cm transparent checkerboard paper, and the wound area was calculated by using asm.68k semi-automatic image analyzer from germany, and the wound healing rate was equal to the healing area/original wound area.
Statistical treatment: the various data were statistically processed using SAS6.12 statistical processing software.
2. Results of the experiment
2.1 general case: after anaesthesia, all animals revive about 2-4 h, start to move, eat freely and enter water. During feeding, the animals have good activity, good appetite and stable body weight.
2.2 wound healing rate: as can be seen from tables 1 and 2, on day 3 after surgery, the saline-treated group, montmorillonite, zinc-based montmorillonite were compared with the calcium-based montmorillonite sterile styptic powder group. On day 10 after surgery, the blank group (saline treatment group), montmorillonite group, zinc-based montmorillonite were compared with calcium-based montmorillonite sterile styptic powder groups, see tables 8, 9;
TABLE 8 comparison of wound healing rates on the third day after surgery(％)
Note: montmorillonite was compared to a blank (saline treated group),﹡p is less than 0.05; compared with montmorillonite, the p of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is less than 0.05; compared with the blank group (saline water treatment group), the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder,﹡﹡p＜0.01；
TABLE 9 comparison of wound healing Rate on day ten post-operative(％)
Note: montmorillonite was compared to a blank (saline treated group),﹡p is less than 0.05; compared with montmorillonite, the p of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is less than 0.05; compared with the blank group (saline water treatment group), the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder,﹡﹡p＜0.01；
the experiment shows that the following conclusions are obtained by observing the promoting effect of the zinc-based montmorillonite and the calcium-based montmorillonite sterile styptic powder on wound healing:
montmorillonite can promote wound healing, reduce tissue fluid exudation, dry wound surface, relieve local wound edema degree, accelerate granulation tissue generation, accelerate healing, achieve the purpose of astringing and promoting granulation, form a protective film on the wound surface, and prevent infection.
The zinc ions dissociated from the zinc-based montmorillonite can enhance the phagocytic function, chemotactic activity and sterilization function of phagocytes, maintain the level of free radicals in the phagocytes through superoxide dismutase, play a role in sterilization and accelerate the healing of wounds; in addition, zinc ions can precipitate proteins, and the external application has a convergence and anticorrosion effect to help granulation tissues to form; the quality of wound healing is improved; wherein calcium ion dissociated from calcium-based montmorillonite can shorten bleeding time and plasma recalcification time.
The zinc-based montmorillonite and the calcium-based montmorillonite are superior to single montmorillonite in the effect of accelerating wound healing by promoting the proliferation and differentiation of epidermal cells, vascular endothelial cells and fibroblasts, and the zinc-based montmorillonite slowly releases zinc ions in the epidermis, so that the montmorillonite can exert the effect to the maximum extent; the combination of the two is expected to be used as a new medicine for promoting wound healing to be applied to clinic, and has good clinical popularization and application prospect.
Experimental example 6: experiment of zinc ion release degree and calcium ion release degree in zinc-based montmorillonite and calcium-based montmorillonite powder
1. Reagent and apparatus
1.1 medicine: sterile powders of zinc-based montmorillonite and calcium-based montmorillonite prepared in examples 1, 2 and 3;
1.2 Instrument: an ultraviolet spectrophotometer and an intelligent dissolution tester;
2. determination of the degree of Release
Taking 1g of the product as the zinc ion release rate, sampling 5ml at time points of 1, 1.5, 2, 2.5 and 3h respectively according to a first method in an appendix XC of the second part of Chinese pharmacopoeia 2010, wherein the rotating speed is 100rpm, the release medium is phosphate buffer solution (pH6.8) of 1000ml, and the temperature is (37 +/-0.5) DEG C, and simultaneously supplementing 5ml of the release medium at the same temperature; the sample is taken out, filtered by a microporous filter membrane, placed in a 100ml volumetric flask, diluted to the scale by adding distilled water and shaken up. Then precisely measuring 10ml of solution, placing the solution in a 100ml volumetric flask, adding distilled water to dilute the solution to a scale, and shaking the solution uniformly to be used as a test solution. And (4) taking the reference substance solution and the test solution to respectively measure the absorbance, and calculating the zinc content in the sample. The results are shown in Table 10.
TABLE 10 cumulative zinc ion release (%)
The cumulative release profiles of the samples were obtained by plotting the cumulative amount (%) of zinc ions in three batches over time (h), and the results are shown in FIG. 3.
Taking 1g of the product as calcium ion release degree, sampling 5ml at time points of 1, 2, 3 and 4h respectively according to a first method in an appendix XC of the second part of Chinese pharmacopoeia 2010 edition at a rotating speed of 100rpm and a release medium of 1000ml of phosphate buffer (pH6.8) at a temperature of (37 +/-0.5) DEG C, and simultaneously supplementing 5ml of the release medium at the same temperature; the sample is taken out, filtered by a microporous filter membrane, placed in a 100ml volumetric flask, diluted to the scale by adding distilled water and shaken up. Then precisely measuring 10ml of solution, placing the solution in a 100ml volumetric flask, adding 15ml of sodium hydroxide test solution and 0.1g of calcium purpurin indicator, and titrating with disodium ethylene diamine tetraacetate titration solution (0.05mol/L) until the solution is converted from mauve to pure blue. Each 1ml of disodium EDTA titrant (0.05mol/L) corresponds to 25mg of calcium ions, and the results are shown in Table 11.
TABLE 11 cumulative release rate (%) -of calcium ion at various time points for the samples of examples
The cumulative release profiles of the samples were obtained by plotting the cumulative amount (%) of calcium ions in three batches over time (h), and the results are shown in FIG. 4.
And (4) analyzing results: the montmorillonite dissociated from the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is used as a slow release material and a damaged skin protective agent, so that zinc and calcium ions are slowly released, and the stimulation of the zinc and calcium ions to the skin is reduced; on the other hand, the skin protection agent has strong covering and protecting capability on damaged skin, and improves the defense capability of the skin barrier on attack factors and the local skin protection effect.
Experimental example 7: experiment of acute toxicity of zinc-based montmorillonite and calcium-based montmorillonite on animal skin
1. Medicine preparation: the sterile hemostatic powder of zinc-based montmorillonite and calcium-based montmorillonite is prepared in example 2, and is ground into fine powder in a mortar for later use.
2. Animals: healthy Japanese big ear white rabbits, the body mass of which is 2.0-2.4 kg, and the sex is half of the body mass, are provided by the experimental animal center of Shandong university.
(1) Method of producing a composite material
16 rabbits are randomly divided into a zinc-based montmorillonite and calcium-based montmorillonite complete skin group, a zinc-based montmorillonite and calcium-based montmorillonite damaged skin group, a solvent complete skin group and a solvent damaged skin group, and each group comprises 4 rabbits. Animals were backed with 6% Na 24h before testing2S unhairing area 80cm2. Before administration, whether the skin at the unhaired part is damaged due to unhairing is checked, and the injured skin is not suitable for toxicity test of the intact skin. The damaged skin was modeled before the experiment. After the skin of the rabbit is disinfected, the skin of the rabbit is cut into the shape of a Chinese character 'jing' by using a disinfection scalpel until slight blood seepage appears on the skin. The zinc-based montmorillonite and calcium-based montmorillonite are directly externally used, and the solvent is uniformly coated onThe dehaired skin of rabbit is about 70cm in area2After slightly drying, the coating was applied uniformly 1 more time (about 8mL in two times). The wet-proof gauze is fixed by non-irritant gauze, and then covered by polyethylene film, and then bandaged and fixed to prevent the liquid from volatilizing. After the test object is applied for 24 hours, the rabbit does not die after being poisoned, the test object remained on the skin is washed away by warm water and a cotton swab, and the observation is continued for 7 days continuously. The death condition and the general poisoning expression of the rabbits are observed, namely the reactions of the rabbits such as diet, activity, fur, excrement, oral secretion, ocular secretion, nasal secretion and the like are closely observed. After 7 days, the rabbits were sacrificed by air embolism and their internal organs such as liver, lung, kidney, stomach, intestine, etc. were visually observed.
(2) Results
In the course of skin acute toxicity test, the rabbit has no death, and has no abnormality in diet, activity, fur, excrement, oral secretion, eye secretion, nasal secretion and the like. Complete skin reaction: when the zinc-based montmorillonite and the calcium-based montmorillonite are administrated to rabbits with the area of 6cm multiplied by 6cm after cutting back hair for 24 hours, the rabbits have no abnormal appetite, spirit and excrement and have no death. No animal death and other abnormal manifestations were seen within 7 days after drug withdrawal.
Damaged skin reaction: the skin of the rabbits, on which back hair has been cut, is rubbed with abrasive paper until bleeding oozes, and zinc-based montmorillonite and calcium-based montmorillonite are used for 24 hours inside and outside, so that the rabbits have no abnormal appetite, spirit and feces within the administration time, have no diseased organs, and have no death. Namely, no abnormal reaction is found in diet, defecation, hair color, respiration, exercise, skin and test part within 7 days after the external application of the zinc-based montmorillonite and the calcium-based montmorillonite.
(3) Conclusion
The skin acute toxicity test shows that the zinc-based montmorillonite and the calcium-based montmorillonite do not cause local toxicity and systemic acute toxicity reaction of the rabbit skin, and the zinc-based montmorillonite and the calcium-based montmorillonite are not subjected to obvious toxicity reaction on the damaged rabbit skin.
Experimental example 8: experiment for researching prescription ratio of zinc-based montmorillonite and calcium-based montmorillonite
According to the invention, the blood coagulation time and the bleeding time of different proportions of the zinc-based montmorillonite and the calcium-based montmorillonite are compared through a blood coagulation time experiment, so that the proportion formula of the zinc-based montmorillonite and the calcium-based montmorillonite is examined.
Preparation of suspension of zinc-based montmorillonite and calcium-based montmorillonite: the method comprises the steps of adding mixtures of zinc-based montmorillonite and calcium-based montmorillonite in different proportions into beakers respectively, and carrying out ultrasonic treatment at room temperature according to the mass ratio of the mixture of zinc-based montmorillonite and calcium-based montmorillonite to purified water of 1:10 to prepare suspensions of zinc-based montmorillonite and calcium-based montmorillonite in different proportions for later use.
Taking 48 mice 18-22 g, keeping the male and female animals, and fasting and keeping water for 24 hours. Taking 1mL of blood from an eyeball, putting the blood into a centrifugal tube added with 0.1mL of sodium citrate solution (38mg/mL), uniformly mixing the blood and the blood, centrifuging the blood for 10min at 1000r/min, taking 1 test tube with the inner diameter of 8mm, adding 80mL of mixed plasma and physiological saline respectively, immediately putting the test tube into a water bath at 37 ℃ for warm bath for 2min, then adding 80mL of zinc-based montmorillonite and calcium-based montmorillonite suspension (2.8mg/mL) in different proportions, uniformly mixing the test tube and the blood, then putting the test tube into the water bath at 37 ℃, immediately timing, and recording the time required from the time of adding the medicine to the formation of fibrin and the immobility of the liquid level, namely the plasma recalcification time of the zinc-based montmorillonite and. The results are shown in Table 12.
TABLE 12 influence of different ratios of Zn-based montmorillonite and Ca-based montmorillonite on plasma recalcification time
Note: the results are shown in the table, but the plasma recalcification time in experiment 1 is 422s, and p is less than 0.05 compared with those in experiment examples 2, 3, 4, 5, 6 and 7. Experiment 7 plasma recalcification time was 312 s; compared with experimental examples 2, 3, 4, 5 and 6, p is more than 0.05. In consideration of economic benefit and clinical effect, according to the experimental results, the prescription of the invention is selected; zinc-based montmorillonite, namely calcium-based montmorillonite is 5:8, 7:9, 8:10, 9:11 and 10:12 (mass percent); the preferred prescription is as follows: the zinc-based montmorillonite is 5:8, 7:9 and 8:10 (mass percent).
Experimental example 9: experiment for in vitro coagulation research of zinc-based montmorillonite and calcium-based montmorillonite
1 materials and methods
1.1 drugs and reagents: sterile powders of zinc-based montmorillonite and calcium-based montmorillonite (prepared in example 1); yunnan Baiyao (Yunnan Baiyao group GmbH); starch (Hunan Erkang pharmaceuticals, Inc.);
1.2 Experimental animals: healthy adult New Zealand white rabbits weigh 2.0-2.5 kg, and are used for both male and female animals (provided by the Experimental animal center of Shandong university, common grade);
2 method
Determination of the in vitro clotting time: taking 32 test tubes, and dividing the test tubes into 4 groups according to experimental medicines: blank group, starch group, positive control Yunnan white drug group and zinc-based montmorillonite and calcium-based montmorillonite sterile hemostatic powder group, each group has 8 test tubes, blank group does not add any drug, and other groups respectively add different drugs each 100 mg. 8 healthy New Zealand white rabbits are selected, and the rabbits are female and male. The animals were acclimatized for 1 week and then tested by taking blood from the heart of the rabbits at 8m1 each after fixation. After blood is taken, the blood is quickly injected into a test tube, each test tube is 2ml, the test tube is immediately shaken up, timing is started simultaneously, the test tube is slightly inclined for 1 time every 15S, and whether blood coagulation appears or not is observed until the blood in the test tube does not flow any more, namely the time (S) for completely coagulating the blood. The results are shown in Table 13;
TABLE 13 Effect on coagulation time in vitro of New Zealand white rabbits (n＝8)
Evaluation of experimental results: the P of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder group is less than 0.01 compared with the blank group; p is less than 0.01 compared to the starch group; compared with Yunnan Baiyao group, P is less than 0.05.
3, results: compared with the blank group, the starch group has no significant difference (P is more than 0.05) although the coagulation time is shortened. Comparing the Yunnan Baiyao group with the blank group; the blood coagulation time is obviously shortened (P is less than 0. O1). The ratio of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder group to the starch group; the in vitro coagulation time is very obviously shortened (P < 0. O1). Compared with the positive Yunnan Baiyao, the hemostatic material of the zinc-based montmorillonite and the calcium-based montmorillonite sterile styptic powder has better in-vitro blood coagulation effect and has statistical significance (P is less than 0. O5). Test results show that the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder have better in-vitro coagulation effect.
Experimental example 10: research experiment of zinc-based montmorillonite and calcium-based montmorillonite sterile hemostatic powder hemostatic effect
1. Experimental Material
1.1 Bama miniature pig with the weight of 22-30 kg and dual purposes of male and female, wherein the common grade is provided by Huaru pig-raising factory in Shandong Dashan City;
1.2 sterile powders of zinc-based montmorillonite and calcium-based montmorillonite were prepared from example 1;
2. method and results
2.1 research on femoral vein and artery wound hemostasis effect of Bama miniature pigs, selecting 18 healthy Bama miniature pigs, dividing into 3 groups randomly with half male and female, and dividing each group into 6 groups, namely a negative control starch group, a positive control Yunnan white drug group, a zinc-based montmorillonite and calcium-based montmorillonite sterile hemostasis powder group.
Firstly, establishing a vascular wound model for a small experimental animal Bama pig, and performing ear vein anesthesia (30mg/kg) on phenobarbital sodium; fixing the upper part of the femoral vein on an operating table, disinfecting, fully exposing and dissociating about 6cm of the femoral vein, clamping the proximal femoral vein by using an artery clamp, pulling the other end of the femoral vein by using a rope, puncturing the exposed femoral vein by adopting a medical artery catheter puncture sheath (the diameter is 0.3cm) in the middle of the femoral vein, after a model is established, releasing the artery clamp, spraying blood out of a puncture hole, immediately pressing a hemostatic bag (each bleeding wound uses 30g of tested materials, namely negative control starch, positive control Yunnan white drug, test drugs, namely zinc-based montmorillonite and calcium-based montmorillonite sterile hemostatic powder), stopping bleeding, and observing and recording the hemostatic effect of the wound of each group of animals after pressing for 2 min.
Secondly, establishing a femoral artery bleeding model on the other side of the hind limb by the same method, starting timing while pressing, observing bleeding parts every 30s after pressing for 2min, and stopping timing when bleeding does not occur for 5s, namely bleeding time. The hemostatic effect of the wound surfaces of the animals in each group is observed and recorded. In the process of pressing a bleeding part, the arterial wound surface bleeding is absorbed in the hemostatic bag, the hemostatic bag is weighed by an electronic balance before being pressed, the weight is recorded, the wet weight of the hemostatic bag is weighed after hemostasis, and the weight before hemostasis is subtracted from the weight after hemostasis to represent the bleeding amount.
And thirdly, suturing the peritoneum, the muscles and the skin layer by layer after observation is finished, spraying povidone iodine on the suturing surface to prevent infection, and paying attention to aseptic operation in the experimental process. If femoral artery bleeding cannot be controlled, other intervention measures are not applied, the death number of the animals within 24h is recorded, and femoral artery wound surface tissues are taken down in time; survival of experimental animals, postoperative free drinking water and diet, anesthesia observation of femoral artery wound surface 24h after operation, taking down femoral artery wound surface tissue, fixing with 10% neutral formaldehyde, embedding in paraffin, making tissue section, and HE staining observation of wound surface tissue pathological change condition.
2.2 statistical treatment of the experimental data toShowing that SPSS13.0 software is used for statistical treatment by adopting one-way variance analysis, and counting data of abnormal distribution is tested. Significance level P < 0. O5.
2.3 Effect on the hemostatic Effect of Barma miniature pig femoral vein trauma
In a femoral vein wound hemostasis test of a small Bama pig, negative control starch cannot effectively stop bleeding after being pressed for 2min, and obvious bleeding oozes; after the positive control Yunnan white drug powder is pressed for 2min, bleeding occurs at the wound of one animal, and the effective hemostatic rate is 85.6%; the zinc-based montmorillonite and calcium-based montmorillonite sterile hemostatic powder can effectively stop bleeding after being pressed for 2 min. Compared with a starch control group, the positive control Yunnan white drug powder, zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder styptic bag has significant difference on the styptic effect of the femoral vein trauma bleeding of the small Bama pigs (P is less than 0.O5, P is less than 0. O1). See table 14.
Table 14 effect on hemostasis of bama mini pig femoral vein trauma (n ═ 6)
1P＜0.05，2P < 0.01, compared to the starch group.
2.4 Effect on the femoral artery wound hemostasis Effect of Bama miniature pigs
The wound hemostasis test result of the femoral artery of the small Bama pig shows that compared with a starch control group, the Yunnan white drug group and the sterile hemostatic powder group of zinc-based montmorillonite and calcium-based montmorillonite can obviously shorten the femoral artery bleeding time of the small Bama pig (P is less than 0.O1) and reduce the bleeding amount (P is less than 0.O5, P is less than 0. O1). The sterile hemostatic powder of the zinc-based montmorillonite and the calcium-based montmorillonite has obviously better hemostatic effect on the femoral artery trauma of the small Bama pigs than that of the Yunnan Baiyao, the bleeding time is obviously shortened (P is less than 0.O5), and the bleeding amount is also obviously reduced (P is less than 0. O5). The tested hemostatic materials of the zinc-based montmorillonite and the calcium-based montmorillonite can effectively stop bleeding after being pressed for about 5 min; no other measures were taken in the negative control starch group, and 2 of these Bama miniature pigs died in shock within 24h due to excessive blood loss. The results are shown in Table 15.
Table 15 influence on the femoral artery hemostatic effect of bama minipigs(n＝6)
1P＜0.05，2P < 0.01, compared to the starch group;3p is less than 0.05, compared with Yunnan Baiyao group.
Tests show that the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder styptic bag has a remarkable styptic effect on the fatal bleeding models of the femoral artery and vein of the small Bama pigs and reduces the death rate.
2.5 pathological observation tissue section HE staining of femoral artery hemostasis part, observing under microscope to see that tested hemostatic material starch group, Yunnan white drug group and zinc group montmorillonite and calcium group montmorillonite sterile hemostatic powder group, irregular thickening, ulcer, necrosis or aneurysm formation of vascular wall is not found at wound surface and nearby of each group of blood vessel, pathological examination of each group has no obvious abnormal change, but each group has thrombus adhesion of vascular cavity surface, and fresh thrombus formation is mainly shown under corresponding microscope. The pathological observation results are as follows;
A. the starch group femoral artery wound surface has no changes of irregular thickening, ulcer, necrosis or aneurysm formation and the like of the blood vessel wall;
B. thrombus is attached to the surface of the starch group femoral artery vessel cavity;
C. the Yunnan Baiyao femoral artery vascular wound does not show the changes of irregular thickening, ulcer, necrosis or aneurysm formation and the like of the vascular wall;
D. fresh thrombus is formed on the surface of the femoral artery blood vessel cavity of the Yunnan Baiyao;
E. the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder form femoral artery vascular wound surfaces, and changes such as irregular thickening, ulcer, necrosis or aneurysm formation of vascular walls are not found;
F. the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder group has thrombus adhesion on the femoral artery vessel cavity surface.
According to the experiment, the observation of in vitro blood coagulation of New Zealand white rabbits and the hemostasis experiment of fatal femoral artery and vein wounds of small Bama pigs proves that the zinc-based montmorillonite and calcium-based montmorillonite sterile hemostatic powder has a good hemostatic effect and can quickly and effectively stop bleeding; the animal experiment model is used for simulating wound bleeding, and the result shows that the emergency hemostasis effect of the zinc-based montmorillonite and calcium-based montmorillonite sterile hemostatic powder is very obvious, so that reliable experiment basis is provided for the application of the zinc-based montmorillonite and calcium-based montmorillonite sterile hemostatic powder in emergency. The traditional hemostasis methods such as pressurization, dressing filling, tourniquet and the like are hemostasis by pressure, and the tourniquet is used for hemostasis, so that the ischemia of a far-end tissue and metabolic abnormality can be caused to cause serious complications and the like. The hemostatic bag is an external first-aid hemostatic material, has the advantages of exact hemostatic effect, low price, portability, convenient use, safety, durability and the like, can effectively stop bleeding of large vessel trauma, meets the requirements of 'life protection and time delay' of serious injury first aid, and has the characteristics of portability, no fever and convenient debridement.
The invention has the following characteristics and beneficial effects:
1. the zinc-based montmorillonite and calcium-based montmorillonite are safe and nontoxic medicines, and after the medicine is used, the effective components of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder are not absorbed by skin and enter blood circulation, the montmorillonite locally forms electronegativity, layers are positively charged, and the charge distribution is in a polymorphic microphase separation structure. Thus, by means of electrostatic interaction, montmorillonite can interact with charged biomolecules, bacteria, viruses and toxins to fix and remove the charged biomolecules; so as to remove the putrefaction, promote tissue regeneration and promote ulcer healing.
2. The preparation applied in the invention is administrated by a skin external application way, and has the effects of bacteriostasis, dehydration and blood suppression. Montmorillonite separated from zinc-based montmorillonite and calcium-based montmorillonite has strong water absorption effect, reduces exudation of tissue fluid, dries wound surface, can relieve local wound edema degree, accelerates granulation tissue generation, accelerates healing, and can achieve the purpose of astringing and promoting granulation. Montmorillonite is directly introduced to the surface of bacteria to play a role in inhibiting bacteria for a long time, and is characterized by strong antibacterial power, no odor, stable performance, no irritation and no toxicity, can inhibit bacteria, viruses, fungi, spores, protozoa and the like, has no interference on wound healing, and is superior to any other wound care products in application.
3. In the preparation applied in the invention, zinc ions dissociated from the zinc-based montmorillonite can enhance phagocytic function, chemotactic activity and bactericidal function of phagocytes, and free radical level in the phagocytes is maintained through superoxide dismutase, so that bactericidal action is exerted, and healing of wounds and burns is accelerated; in addition, zinc ions can precipitate proteins, and the external application has a convergence and anticorrosion effect to help granulation tissues to form; zinc also has the effect of scavenging oxygen free radicals, and is a factor in the regulation of inflammatory cell activity. It also inhibits the growth of supraphysiological concentrations of bacteria in vitro; the montmorillonite has effects of stopping bleeding, relieving swelling, relieving inflammation, removing toxic substance, astringing, and promoting granulation.
4. The preparation in the application can shorten the bleeding time and the plasma recalcification time by calcium ions dissociated from the calcium-based montmorillonite.
In conclusion, the preparation adopts the zinc-based montmorillonite and the calcium-based montmorillonite as the effective components of the medicine, and is prepared into the medicine with pharmaceutic adjuvant by the processes of high-temperature dry heat sterilization, mixing, sterile subpackaging and the like. Administered by topical route to skin, can rapidly coagulate blood and stop bleeding, and prevent wound infection.
Drawings
FIG. 1 shows an X-ray diffraction pattern with abscissa of 2 theta (DEG) and ordinate of intensity (arbitrary unit) in which the dry heat temperature of zinc-based montmorillonite is 170-180 ℃, the dry heat time is 180-240 min;
FIG. 2 shows an X-ray diffraction pattern of calcium-based montmorillonite with abscissa of 2 θ (°) and ordinate of intensity (arbitrary unit) at dry heat temperature of 250-300 deg.C and dry heat time of 120 min;
FIG. 3 is a graph showing the cumulative amount (%) of zinc ions released from the samples of examples 1, 2 and 3, with time on the abscissa and the degree of release on the ordinate;
FIG. 4 is a graph showing the cumulative amount (%) of calcium ions released from the samples of examples 1, 2 and 3, with time on the abscissa and the degree of release on the ordinate.
Detailed Description
The present invention will be further described with reference to the following examples, but is not limited thereto.
Description of the raw and auxiliary materials in examples 1-3:
| name of raw and auxiliary materials | Manufacturing enterprise | Execution criteria |
| Zinc-based montmorillonite | SHANDONG SBOND PHARMACEUTICAL Co.,Ltd. | Enterprise standard |
| Calcium-based montmorillonite | SHANDONG SBOND PHARMACEUTICAL Co.,Ltd. | Chinese pharmacopoeia 2010 edition two additional edition |
The devices and equipment involved in the examples are all powder production universal equipment, and are commercially available. The description is as follows:
dry heat sterilization cabinet (model HDA500) available from Nanjing Changjiang medicine manufacturing Co.Ltd; the mixer (100L) is available from Nanjing Changjiang medicine manufacturing Co.
Example 1 Zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder and preparation method thereof
1. The raw and auxiliary materials are mixed according to the material feeding amount ratio (w/w):
8 parts of zinc-based montmorillonite
10 parts of calcium-based montmorillonite;
2. preparation of
(1) Putting the zinc-based montmorillonite with the formula amount into a dry heat sterilization cabinet, sterilizing at 170-180 ℃ for 180min, and cooling to room temperature for later use;
(2) placing the calcium-based montmorillonite with the formula amount into a dry heat sterilization cabinet, sterilizing at the temperature of 250-300 ℃ for 120min, and cooling to room temperature for later use;
(3) putting the materials obtained in the step (1) and the step (2) into a sterilized mixing tank; stirring and mixing uniformly; sterile subpackaging to obtain the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder.
Example 2 Zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder and preparation method thereof
1. The raw and auxiliary materials are mixed according to the material feeding amount ratio (w/w):
zinc-base montmorillonite 7 parts
9 parts of calcium-based montmorillonite;
2. preparation of
(1) Putting the zinc-based montmorillonite with the formula amount into a dry heat sterilization cabinet, sterilizing at 170-180 ℃ for 240min, and cooling to room temperature for later use;
(2) placing the calcium-based montmorillonite with the formula amount into a dry heat sterilization cabinet, sterilizing at the temperature of 250-300 ℃ for 120min, and cooling to room temperature for later use;
(3) putting the materials obtained in the step (1) and the step (2) into a sterilized mixing tank; stirring and mixing uniformly; sterile subpackaging to obtain the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder.
Example 3 Zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder and preparation method thereof
1. The raw and auxiliary materials are mixed according to the material feeding amount ratio (w/w):
5 parts of zinc-based montmorillonite
8 parts of calcium-based montmorillonite;
2. preparation of
(1) Putting the zinc-based montmorillonite with the formula amount into a dry heat sterilization cabinet, sterilizing at 170-180 ℃ for 210min, and cooling to room temperature for later use;
(2) placing the calcium-based montmorillonite with the formula amount into a dry heat sterilization cabinet, sterilizing at the temperature of 250-300 ℃ for 120min, and cooling to room temperature for later use;
(3) putting the materials obtained in the step (1) and the step (2) into a sterilized mixing tank; stirring and mixing uniformly; sterile subpackaging to obtain the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder.
Claims (10)
1. An application of sterile hemostatic powder of zinc-based montmorillonite and calcium-based montmorillonite in preparing medicine for healing skin wound is disclosed.
2. The use of the sterile zinc-based montmorillonite and calcium-based montmorillonite styptic powder according to claim 1 in the preparation of a medicament for healing skin wounds, wherein the use is the use of the sterile zinc-based montmorillonite and calcium-based montmorillonite styptic powder alone or in combination with other medicaments as a medicament.
3. The use of the sterile hemostatic powder of zinc-based montmorillonite and calcium-based montmorillonite as claimed in claim 1, for the preparation of a medicament for healing skin wounds, wherein the skin wounds include skin scratch bleeding, scalds, traumatic injuries.
4. The application of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder in preparing the medicine for healing skin wounds as claimed in claim 1, wherein the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is prepared from the following raw materials in parts by mass:
5-10 parts of zinc-based montmorillonite
8-12 parts of calcium-based montmorillonite.
5. The application of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder in preparing the medicine for healing skin wounds as claimed in claim 4, wherein the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is prepared from the following raw materials in parts by mass:
5-8 parts of zinc-based montmorillonite
8-10 parts of calcium-based montmorillonite.
6. The application of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder in preparing the medicine for healing skin wounds as claimed in claim 5, wherein the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is prepared from the following raw materials in parts by mass:
8 parts of zinc-based montmorillonite
10 parts of calcium-based montmorillonite.
7. The application of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder in preparing the medicine for healing skin wounds as claimed in claim 5, wherein the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is prepared from the following raw materials in parts by mass:
zinc-base montmorillonite 7 parts
9 parts of calcium-based montmorillonite.
8. The application of the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder in preparing the medicine for healing skin wounds as claimed in claim 5, wherein the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder is prepared from the following raw materials in parts by mass:
5 parts of zinc-based montmorillonite
8 parts of calcium-based montmorillonite.
9. The use of the sterile hemostatic powder of zinc-based montmorillonite and calcium-based montmorillonite as claimed in any one of claims 4 to 8 in the preparation of a medicament for healing skin wounds, wherein the zinc-based montmorillonite and the calcium-based montmorillonite are ground and sieved with a 500-mesh sieve.
10. The use of the sterile powder of zinc-based montmorillonite and calcium-based montmorillonite in the preparation of a medicament for healing skin wounds as claimed in any one of claims 4 to 8, wherein the sterile powder of zinc-based montmorillonite and calcium-based montmorillonite is prepared by the following method:
(1) crushing zinc-based montmorillonite according to the formula amount, sieving with a 500-mesh sieve, placing into a dry heat sterilization cabinet, sterilizing at 170-180 ℃ for 180-240 min, and cooling to room temperature for later use;
(2) crushing the calcium-based montmorillonite according to the formula amount, sieving with a 500-mesh sieve, placing into a dry heat sterilization cabinet, sterilizing at 250-300 ℃ for 120min, and cooling to room temperature for later use;
(3) putting the materials obtained in the step (1) and the step (2) into a sterilized mixing tank; stirring and mixing uniformly; sterile subpackaging to obtain the zinc-based montmorillonite and calcium-based montmorillonite sterile styptic powder.
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| US20120058165A1 (en) * | 2010-08-30 | 2012-03-08 | Thomas James Klofta | Opacifying Lotion |
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| CN1957948A (en) * | 2005-11-04 | 2007-05-09 | 浙江海力生制药有限公司 | Modified montmorillonite, preparation method and application |
| CN101773518A (en) * | 2010-02-24 | 2010-07-14 | 济南康众医药科技开发有限公司 | Medicine for treating infectious diseases |
| US20120058165A1 (en) * | 2010-08-30 | 2012-03-08 | Thomas James Klofta | Opacifying Lotion |
| CN102058898A (en) * | 2011-01-13 | 2011-05-18 | 深圳市源兴纳米医药科技有限公司 | Powder with antibacterial and haemostatic effects and preparation method and applications thereof |
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