WO2023173581A1 - New use of huatuo zaizao pill - Google Patents

Abstract

A Huatuo Zaizao pill for use in the preparation of a drug for treating aspirin resistance. The Huatuo Zaizao pill has a significant effect on aspirin resistance, and shows good functions in improving blood rheology and blood coagulation and an effect on reducing platelet aggregation, thereby providing a stable anti-platelet treatment.

Description

New applications of Huatuo Zaizao Pills

Cross-references to related applications

This application claims priority to the Chinese patent application filed with the China Patent Office on March 18, 2022, with the application number 202210269825.8 and the invention name "New Application of Huatuo Zaizao Pills", the entire content of which is incorporated into this application by reference. .

Technical field

The present invention relates to the field of medical technology, and in particular to a new application of Huatuo Zaizao Pills.

Background technique

According to international and domestic clinical guidelines or consensus, aspirin is the most commonly used drug in standard antiplatelet treatment regimens and is widely used to treat pan-vascular diseases. With the expansion of aspirin application, clinical findings have shown that aspirin sensitivity varies among individuals. Among them, 5% to 65% of stroke patients are insensitive to aspirin's antiplatelet therapy, which is aspirin resistance. Aspirin resistance may appear when you start taking aspirin, or it may appear after taking it for a period of time (effectiveness), and is closely related to an increased risk of recurrence of cardiovascular and cerebrovascular events.

Currently, there is a lack of effective intervention methods for aspirin resistance. Clinically, the main measures for aspirin-resistant patients are to add or switch to other antiplatelet drugs after recurrence of cardiovascular and cerebrovascular events (i.e., adjustment of antiplatelet medication regimen). Relevant guidelines/consensus point out that adjustments to the antiplatelet medication regimen may lead to an increased risk of secondary death, bleeding and other events. It is not recommended to adjust the antiplatelet medication regimen based on platelet function, and the stability of the antiplatelet medication regimen needs to be maintained. Therefore, it is necessary to explore effective intervention methods for aspirin resistance, reduce aspirin resistance, maintain a stable antiplatelet medication regimen, and reduce the disease burden on patients.

Contents of the invention

Based on this, the purpose of the present invention includes providing new applications of Huatuo Zaizao Pills, which mainly involve using Huatuo Zaizao Pills to prepare drugs for the treatment of aspirin resistance, and provide effective means for clinical aspirin resistance intervention.

The object of the present invention can be achieved through the following technical solutions:

Application of Huatuo Zaizao Pills in the preparation of drugs for the treatment of aspirin resistance.

In some embodiments of the present invention, the medicine includes the Huatuo Zaoxiao Pills and pharmaceutically acceptable excipients.

In some embodiments of the present invention, the auxiliary materials include diluents, wetting agents, binders, disintegrants, lubricants, color and flavor regulators, solvents, solubilizers, co-solvents, emulsifiers, antioxidants, One or more of a metal complexing agent, an inert gas, a preservative, a local analgesic, a pH adjuster, and an isotonic or isotonic adjuster.

In some embodiments of the present invention, the diluent is selected from at least one of starches, sugars, cellulose and inorganic salts.

In some embodiments of the present invention, the wetting agent is selected from at least one of water and ethanol.

In some embodiments of the present invention, the binder is selected from at least one of starch slurry, dextrin, sugar, cellulose derivatives, gelatin, povidone and polyethylene glycol.

In some embodiments of the invention, the disintegrant is selected from the group consisting of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, surface-active at least one of an agent and an effervescent disintegrant.

In some embodiments of the present invention, the lubricant is selected from at least one selected from the group consisting of talc, calcium stearate, magnesium stearate, magnesium lauryl sulfate, micronized silica gel, and polyethylene glycol.

In some embodiments of the present invention, the color and flavor modifier is selected from at least one selected from the group consisting of pigments, spices, sweeteners, glue agents and flavoring agents.

In some embodiments of the present invention, the solvent is selected from at least one of water, oil, ethanol, glycerin, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil and ethyl acetate.

In some embodiments of the present invention, the solubilizing agent is selected from at least one of Tweens, Zezes, polyoxyethylene fatty alcohol ethers, soaps, sulfates, and sulfonates.

In some embodiments of the present invention, the co-solvent is selected from at least one of organic acids and salts thereof, amides and amine compounds, inorganic salts, polyethylene glycol, povidone and glycerol.

In some embodiments of the present invention, the emulsifier is selected from the group consisting of spans, Tweens, benzene, glycerin fatty acid esters, higher fatty acid salts, sulfates, sulfonates, gum arabic , tragacanth, gelatin, pectin, phospholipid, agar, sodium alginate, at least one of hydroxide, silicon dioxide and bentonite.

In some embodiments of the invention, the suspending agent is selected from the group consisting of glycerol, syrup, gum arabic, tragacanth, agar, sodium alginate, cellulose derivatives, povidone, carbopol, polyvinyl alcohol and at least one type of thixotropic adhesive.

In some embodiments of the present invention, the antioxidant is selected from at least one of sulfite, metabisulfite, bisulfite, ascorbic acid, gallic acid and its esters.

In some embodiments of the present invention, the metal complexing agent is selected from one of disodium ethylenediaminetetraacetate and polycarboxylic acid compounds.

In some embodiments of the present invention, the inert gas is selected from one of nitrogen and carbon dioxide.

In some embodiments of the present invention, the preservative is selected from at least one of parabens, organic acids and their salts, quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols and volatile oils.

In some embodiments of the invention, the local analgesic is selected from at least one selected from the group consisting of benzyl alcohol, chlorobutanol, lidocaine and procaine.

In some embodiments of the invention, the pH adjuster selects hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphate, acetic acid At least one of salt and citrate.

In some embodiments of the present invention, the isotonic or isotonic regulator is selected from at least one selected from the group consisting of glucose, sodium chloride, sodium citrate, sorbitol and xylitol.

In some embodiments of the invention, the dosage form of the medicament is a tablet.

In some embodiments of the invention, the dosage form of the drug is granules.

In some embodiments of the invention, the dosage form of the medicament is a pill.

In some embodiments of the invention, the dosage form of the drug is powder.

In some embodiments of the invention, the dosage form of the medicament is a capsule.

In some embodiments of the invention, the dosage form of the drug is an injection.

In some embodiments of the invention, the dosage form of the drug is an enema.

In some embodiments of the invention, the dosage form of the drug is oral liquid.

In some embodiments of the invention, the dosage form of the drug is a tube feeding preparation.

In some embodiments of the invention, the administration route of the drug is oral administration.

In some embodiments of the present invention, the administration route of the drug is enema.

In some embodiments of the present invention, the administration route of the drug is injection.

Compared with traditional technology, the beneficial effects of this invention include:

The inventor found that Huatuo Zaizao Pills is effective in aspirin resistance, and the efficacy of Huatuo Zaizao Pills was verified on New Zealand rabbits that were insensitive to aspirin, showing good improvement in blood rheology and coagulation function, as well as reducing the The effect of platelet aggregation. The invention solves the problem of aspirin resistance in antiplatelet therapy and provides a stable antiplatelet therapy method.

Description of the drawings

In order to explain the technical solutions in the embodiments of the present application more clearly and to understand the present application and its beneficial effects more completely, the drawings needed to be used in the description of the embodiments will be briefly introduced below. Obviously, the drawings in the following description are only some embodiments of the present application. For those skilled in the art, other drawings can be obtained based on these drawings without exerting creative efforts.

Figure 1 shows the effect of Huatuo Zaizao Pills on the platelet aggregation rate of rabbits.

Result graph;

Figure 2 shows that aspirin has no significant effect on WBV at low shear rates.

Result graph;

Figure 3 shows that aspirin has no significant effect on WBV under high shear rate.

Result graph;

Figure 4 shows that aspirin has no significant effect on PV

Result graph;

Figure 5 shows that aspirin has no significant effect on APTT.

Result graph;

Figure 6 shows that aspirin has no significant effect on PT.

Result graph;

Figure 7 shows that aspirin has no significant effect on TT.

Result graph;

Figure 8 shows that Huatuo Zaozhao Pills significantly reduces WBV under low shear rate.

Result graph;

Figure 9 shows that Huatuo Zaozhao pills significantly reduce WBV under high shear rate.

Result graph;

Figure 10 shows that Huatuo Zaizao Pill significantly prolongs PV

Result graph;

Figure 11 shows that Huatuo Zaizao Pill significantly prolongs APTT.

Result graph;

Figure 12 shows that Huatuo Zaizao Pill significantly prolongs PT.

Result graph;

Figure 13 shows that Huatuo Zaizao Pill significantly prolongs TT.

Result graph.

Detailed ways

The present invention will be described in further detail below with reference to the drawings, implementation modes and examples. It should be understood that these embodiments and examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The purpose of providing these embodiments and examples is to make the disclosure of the present invention more thorough and comprehensive. It should also be understood that the present invention can be implemented in many different forms and is not limited to the implementation modes and examples described herein. Those skilled in the art can make various changes or modifications without violating the connotation of the present invention, and obtain The equivalent forms also fall within the protection scope of this application. Additionally, in the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention, and it is to be understood that the invention may be practiced without one or more of these details.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which the invention belongs. The terminology used herein in the description of the invention is for the purpose of describing embodiments and examples only and is not intended to limit the invention.

the term

Unless otherwise stated or contradictory, the terms or phrases used in this article have the following meanings:

The terms "and/or", "or/and" and "and/or" used in this article include any one of two or more related listed items, and also include any of the related listed items. and all combinations, including any two of the related listed items, any more of the related listed items, or a combination of all of the related listed items. It should be noted that when at least three items are connected in combination with at least two conjunctions selected from "and/or", "or/and", "and/or", it should be understood that in this application, the technical solution It undoubtedly includes technical solutions that are all connected by "logical AND", and it also undoubtedly includes technical solutions that are all connected by "logical OR". For example, "A and/or B" includes three parallel solutions: A, B and A+B. For another example, the technical solution of "A, and/or, B, and/or, C, and/or, D" includes any one of A, B, C, and D (that is, they are all connected with "logical OR" technical solution), also includes any and all combinations of A, B, C, and D, that is, including combinations of any two or any three of A, B, C, and D, and also includes A, B, C , four combinations of D (that is, technical solutions that are all connected by "logical AND").

The present invention refers to "multiple", "multiple", "multiple", "multiple", etc., and unless otherwise specified, it means that the number is greater than 2 or equal to 2. For example, "one or more" means one or more than two.

As used herein, "combinations thereof", "any combinations thereof", "any combinations thereof", etc. include all suitable combinations of any two or more of the listed items.

In this article, "suitable" in "appropriate combination", "appropriate way", "any suitable way", etc. are used to implement the technical solution of the present invention, solve the technical problems of the present invention, and realize the expectations of the present invention. The technical effect shall prevail.

In this article, "preferable", "better", "better" and "suitable" are only used to describe implementations or examples with better effects. It should be understood that they do not limit the scope of the present invention.

In the present invention, "further", "further", "especially", etc. are used for description purposes and indicate differences in content, but should not be understood as limiting the scope of the present invention.

In the present invention, "optionally", "optional" and "optional" mean that it is optional, that is, it refers to any one selected from the two parallel solutions of "with" or "without". If there are multiple "optionals" in a technical solution, each "optional" will be independent unless otherwise specified and there is no contradiction or mutual restriction.

In the present invention, in the "first aspect", "second aspect", "third aspect", "fourth aspect", etc., the terms "first", "second", "third" and "fourth" etc. are for descriptive purposes only and shall not be understood as indicating or implying relative importance or quantity, nor shall they be understood as implicitly indicating the importance or quantity of indicated technical features. Furthermore, “first”, “second”, “third”, “fourth”, etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation of quantity.

In the present invention, the technical features described in open terms include closed technical solutions composed of the listed features, and also include open technical solutions including the listed features.

In the present invention, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the optional numerical distribution is considered to be continuous within the above-mentioned numerical intervals, and includes the two numerical endpoints of the numerical range (i.e., the minimum value and the maximum value). value), and every value between the two numeric endpoints. Unless otherwise specified, when a numerical interval only points to integers within the numerical interval, including the two endpoint integers of the numerical range, and every integer between the two endpoints, in this article, it is equivalent to directly enumerating each Integer, for example, t is an integer selected from 1 to 10, indicating that t is any integer selected from the integer group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. Additionally, when multiple scopes are provided to describe a feature or characteristic, these scopes can be combined. In other words, unless otherwise indicated, the ranges disclosed herein should be understood to include any and all subranges subsumed therein.

The temperature parameter in the present invention, unless otherwise specified, is allowed to be treated at a constant temperature, and is also allowed to vary within a certain temperature range. It should be understood that the thermostatic treatment described allows the temperature to fluctuate within the accuracy of the instrument control. It is allowed to fluctuate within the range of ±5℃, ±4℃, ±3℃, ±2℃ and ±1℃.

In the present invention, % (w/w) and wt% both represent weight percentage, % (v/v) refers to volume percentage, and % (w/v) refers to mass volume percentage.

All documents mentioned in this application are incorporated by reference in this application to the same extent as if each individual document was individually incorporated by reference. Unless it conflicts with the invention purpose and/or technical solution of the present application, the cited documents involved in the present invention are cited in their entirety and for all purposes. When referring to cited documents in the present invention, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When citing documents in the present invention, the cited examples and preferred modes of relevant technical features may also be incorporated into this application as references, but only to the extent that the present invention can be implemented. It should be understood that when the quoted content conflicts with the description in this application, this application shall prevail or be adapted to be modified according to the description in this application.

Traditional Chinese medicine compound preparations have the characteristics of multiple components, multiple targets, multiple pathways, and mild effects, and can be used as a choice for clinicians in conjunction with conventional antiplatelet treatment options. Huatuo Zaizao Pills (Guangzhou Baiyunshan Qixing Pharmaceutical Co., Ltd., national drug approval number Z44020748) has the effects of activating blood circulation and removing blood stasis, resolving phlegm and dredging collaterals, promoting qi and relieving pain. It is used for the recovery period and sequelae of stroke, but it has not been used for aspirin resistance. See report.

The invention provides the application of Huatuo Zaizao Pills in preparing medicine for treating aspirin resistance.

In some embodiments of the present invention, the medicine includes the Huatuo Zaoxiao Pills and pharmaceutically acceptable excipients.

It can be understood that the present invention does not specifically limit the types of auxiliary materials contained in the medicine. Appropriate types of auxiliary materials can be selected according to the required dosage form and route of administration. The types of auxiliary materials include but are not limited to one or more of the following types: Categories: diluents, wetting agents, binders, disintegrants, lubricants, color and flavor regulators, solvents, solubilizers, co-solvents, emulsifiers, antioxidants, metal complexing agents, inert gases, preservatives, Topical analgesics, pH adjusters and isotonic or isotonic adjusters.

The diluent may be selected from at least one of starches, sugars, cellulose and inorganic salts. The wetting agent is selected from at least one of water and ethanol. The binder is selected from at least one selected from the group consisting of starch slurry, dextrin, sugar, cellulose derivatives, gelatin, povidone and polyethylene glycol. The disintegrant is selected from dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, surfactants and effervescent disintegrants. At least one. The lubricant is selected from at least one selected from the group consisting of talc, calcium stearate, magnesium stearate, magnesium lauryl sulfate, micronized silica gel and polyethylene glycol. The color and flavor modifier is selected from at least one selected from the group consisting of pigments, spices, sweeteners, glue agents and flavoring agents. The solvent is selected from at least one of water, oil, ethanol, glycerol, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil and ethyl acetate. The solubilizing agent is selected from at least one selected from Tweens, Zezes, polyoxyethylene fatty alcohol ethers, soaps, sulfates, and sulfonates. The co-solvent is selected from at least one of organic acids and their salts, amides and amine compounds, inorganic salts, polyethylene glycol, povidone and glycerol. The emulsifier is selected from the group consisting of spans, Tweens, benzene, glycerin fatty acid esters, higher fatty acid salts, sulfates, sulfonates, gum arabic, tragacanth, gelatin, fruit At least one of glue, phosphatide, agar, sodium alginate, hydroxide, silica and bentonite. The suspending agent is selected from at least one selected from the group consisting of glycerin, syrup, gum arabic, tragacanth, agar, sodium alginate, cellulose derivatives, povidone, carbopol, polyvinyl alcohol and thixotropic gum. . The antioxidant is selected from at least one of sulfite, metabisulfite, bisulfite, ascorbic acid, gallic acid and its esters. The metal complexing agent is selected from the group consisting of disodium ethylenediaminetetraacetate and polycarboxylic acid compounds. The inert gas is selected from nitrogen and carbon dioxide. The preservative is selected from at least one of parabens, organic acids and salts thereof, quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols and volatile oils. The local analgesic is selected from at least one selected from the group consisting of benzyl alcohol, chlorobutanol, lidocaine and procaine. The pH adjuster is selected from at least one of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphate, acetate and citrate. A sort of. The isotonic or isotonic regulator is selected from at least one selected from the group consisting of glucose, sodium chloride, sodium citrate, sorbitol and xylitol.

The dosage form of the drug is not particularly limited in the present invention, and the required dosage forms can be prepared according to clinical needs, such as tablets, granules, pills, powders, capsules, injections, enemas, oral liquids, and tube feeding preparations.

The method of drug administration is not particularly limited in the present invention and can be administered according to clinical needs, such as oral administration, enema administration, and injection administration.

Example 1

1. Test materials

1. Drug: Huatuo Zaizao Pill, the extract used in the experiment, dark brown thick paste, each gram of thick paste is equivalent to about 0.63g of crude drug, batch number: 060320, provided by Guangzhou Baiyunshan Qixing Pharmaceutical Co., Ltd., pharmacodynamics The dosage is calculated based on the amount of crude drug (g crude drug/kg); aspirin enteric-coated tablets (25 mg/tablet), produced by Beijing Shuguang Pharmaceutical Co., Ltd., batch number: 050924; adenosine diphosphate (ADP) disodium salt, Chinese Academy of Sciences Product of Shanghai Institute of Biochemistry, prepare a 1.0mM/L solution with physiological saline, store at 4°C for later use; arachidonic acid (AA), Fluka AG product, use 1.0mM/L NaOH to prepare sodium salt before use, concentration It is 5.0g/L; collagen (100ug/ml), a product of KOKEN.

2. Animals: Healthy male Japanese big-eared white rabbits, weighing 2.28±0.16kg, provided by Beijing Tongli Experimental Animal Breeding Farm, certificate number: SCXK (Beijing) 2005-003.

3. Instrument: Platelet aggregation meter, BS634 model, product of Beijing Biochemical Instrument Factory.

2. Test methods

Before administration, blood was taken from the central artery to measure the platelet aggregation rate. The rabbits were randomly divided into groups (8 rabbits in each group) according to the platelet aggregation rate level and body weight: (1) control group (equal volume of distilled water), (2) Hua Tuo's reconstituted Pill group (2g crude drug/kg, based on body weight, equivalent to 1.13 times the human clinical daily dosage of 24g), (3) Aspirin group (25mg/kg, based on body weight, equivalent to 5.35 times the human clinical daily dosage of 100mg). Each group was administered intragastric administration at the stated dose at a volume of 6 ml/kg, once a day for 7 consecutive days. One hour after the last administration, blood was taken from the central artery and the platelet aggregation rate was measured.

Platelet aggregation rate determination method: Use a siliconized syringe to puncture the middle artery of the ear to take blood, anticoagulate with 3.8% (m/v) sodium citrate solution (blood: anticoagulant = 9:1), centrifuge at 200×g for 8 minutes, and take The supernatant part is platelet-rich plasma (PRP), the remaining part is centrifuged at 1500×g for 10 minutes, and the supernatant part is platelet-poor plasma (PPP). The platelet count in PRP is about 4.0×10 ⁵ /mm ³ . According to Born's turbidimetric method, place a turbidimetric tube containing 200 μl PRP and 1 small magnetic rod in a platelet aggregator and incubate it at 37°C for 1 minute. After PPP calibration, add an inducer under stirring to induce aggregation. The final concentrations of inducers used were: ADP (47.6 μM/L), AA (782.0 μM/L), and collagen (4.8 mg/L). According to the aggregation curve and maximum aggregation rate automatically printed by the instrument, the effect of the drug on platelet aggregation was analyzed by t test. The formula for calculating the maximum aggregation rate is as follows:

3. Test results

It can be seen from Figure 1: ① When ADP induces aggregation, there is no significant difference in the platelet aggregation rate between the groups before administration; after administration, the platelet aggregation rate of the Huatuo Zaizao Pill group was significantly lower than that of the control group (P<0.01), and the aspirin The platelet aggregation rate of the group was also significantly lower than that of the control group (P<0.01). ② When AA induces aggregation, there is no significant difference in the platelet aggregation rate between the groups before administration; after administration, the platelet aggregation rate of the Huatuo Zaizao Pill group was significantly lower than that of the control group (P<0.01), and the platelet aggregation rate of the aspirin group was also lower. Significantly lower than the control group (P<0.01). ③When collagen induces aggregation, there is no significant difference in the platelet aggregation rate between the groups before administration; after administration, the platelet aggregation rate of the Huatuo Zaizao Pill group was significantly lower than that of the control group (P<0.01), and the platelet aggregation rate of the aspirin group was also lower. Significantly lower than the control group (P<0.01).

4. Conclusion

The above results show that Huatuo Zaizao Pills significantly reduced the rabbit platelet aggregation rate induced by adenosine diphosphate (ADP), arachidonic acid (AA) and collagen when administered intragastrically to rabbits for 7 consecutive days (P<0.01). , indicating that Huatuo Zaizao Pill has the effect of inhibiting platelet aggregation.

Example 2

1. Materials and methods

1. Animal: New Zealand rabbit, weight 2.5kg-3.0kg; placed in a suitable environment during the test, with free access to food and water, temperature 22.0±2.0℃, relative humidity 50±5%; adaptively raised for one week before the experiment.

2. Drugs and chemicals: Huatuo Zaizao Pills (Guangzhou Baiyunshan Qixing Pharmaceutical Co., Ltd.); Aspirin (Bayer Healthcare (Beijing) Co., Ltd.); Polyurethane (Sinopharm Chemical Reagent Co., Ltd. (Shanghai)).

3. Experimental design:

Intragastric administration: The control group was given 1 ml/kg of distilled water; the aspirin group was given aspirin 5 mg/kg (according to body weight, equivalent to 1.07 times the human clinical daily dosage of 100 mg); the Huatuo Zaozao Pill group was given aspirin 5 mg/kg. On the basis of the control group, Huatuo Zaizao Pills were given at 1g/kg (according to body weight, equivalent to 0.89 times the human clinical daily dosage of 24g).

Blood samples were collected before dosing and 2 hours and 4 hours after dosing. Collect blood and add 3.8% sodium citrate (sodium citrate: blood = 1:9, v/v) into a plastic tube for detecting whole blood viscosity (WBV). Centrifuge at 3000 × g for 10 min to separate the plasma for detection of plasma viscosity (PV) and coagulation function.

4. Viscosity measurement: Use a blood viscometer to measure viscosity; among them, WBV is measured at the shear rate of 10 sec ^-1 and 150 sec ^-1 ; PV is measured at the shear rate of 150 sec ^-1 .

5. Coagulation function measurement: Use a coagulometer to detect active partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT).

APTT: Incubate 50 μl plasma with 50 μl APTT activator at 37°C for 3 min, then add 50 μl CaCl ₂ .

PT: Incubate 50 μl of plasma solution at 37°C for 3 minutes, then add 100 μl of thrombolytic enzyme agent.

TT: Incubate 50 μl plasma solution at 37°C for 3 minutes, then add 100 μl thrombin preparation.

2. Data analysis: SPSS statistical software was used to analyze the data, expressed as mean ± SEM; comparisons between the two groups were made using Student's unpaired t test; P<0.05 was considered a statistically significant difference.

3. Results

1. Aspirin has no significant effect on hemorrheology and coagulation function of experimental animals

Compared with the control group, aspirin alone had no significant effect on blood rheology (WBV, PV) and blood coagulation parameters (APTT, PT, TT). See Figures 2 to 7 for details. This shows that the selected New Zealand rabbits have Aspirin insensitivity.

2. Huatuo Zaizao Pills have a significant impact on the hemorrheology and coagulation function of aspirin-resistant New Zealand rabbits

For New Zealand rabbits who are not sensitive to aspirin, compared with the control group, Huatuo Zazao Pills were used on the basis of aspirin. Huatuo Zaizao Pills significantly reduced WBV and PV, and significantly prolonged APTT, PT and TT. See Figure 8 for details. to Figure 13. In Figure 8 to Figure 13: *: Compared with the control group, P<0.05;

Compared with before treatment, P<0.05.

3. Conclusion

In New Zealand rabbits that are resistant to aspirin, the use of Huatuo Zaoxiao Pills reduced WBV and PV, and prolonged APTT, PT and TT. The results show that Huatuo Zaizao Pills can act on aspirin resistance and improve blood rheology and coagulation function.

The above examples show that Huatuo Zaizao Pills can act on aspirin resistance, effectively improve coagulation function and blood rheology indicators, and have a therapeutic effect on aspirin resistance. At the same time, Huatuo Zaizao Pills can reduce the platelet aggregation rate, suggesting that Huatuo Zaizao Pills treat aspirin resistance by acting on platelets and reducing the platelet aggregation rate.

The technical features of the above-described embodiments and examples can be combined in any suitable manner. To simplify the description, not all possible combinations of the technical features in the above-described embodiments and examples are described. However, as long as these There is no contradiction in the combination of technical features, and they should be considered to be within the scope of this specification.

The above-mentioned embodiments only express several implementation modes of the present invention to facilitate a specific and detailed understanding of the technical solutions of the present invention, but they should not be construed as limiting the scope of protection of the invention patent. It should be noted that, for those of ordinary skill in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and the equivalent forms obtained also fall within the protection scope of the present application. It should also be understood that technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited testing based on the technical solutions provided by the present invention are within the protection scope of the appended claims of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the contents of the appended claims, and the description and drawings may be used to interpret the contents of the claims.

Claims (10)

1. Application of Huatuo Zaizao Pills in the preparation of drugs for the treatment of aspirin resistance.
2. The application according to claim 1, characterized in that the medicine contains the Huatuo Zaoxiao Pills and pharmaceutically acceptable excipients.
3. The application according to claim 2, characterized in that the auxiliary materials include diluents, wetting agents, binders, disintegrants, lubricants, color and flavor regulators, solvents, solubilizers, co-solvents, and emulsifiers, One or more of antioxidants, metal complexing agents, inert gases, preservatives, local analgesics, pH adjusters and isotonic or isotonic adjusters.
4. The application according to claim 3, characterized in that the diluent is selected from at least one of starch, sugar, cellulose and inorganic salts; or/and the wetting agent is selected from water. and at least one of ethanol; or/and the binder is selected from at least one of starch slurry, dextrin, sugar, cellulose derivatives, gelatin, povidone and polyethylene glycol; or/and , the disintegrant is selected from dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, surfactants and effervescent disintegrants At least one of; or/and, the lubricant is selected from at least one of talc, calcium stearate, magnesium stearate, magnesium lauryl sulfate, micronized silica gel and polyethylene glycol; or/ And, the color and flavor modifier is selected from at least one of pigments, spices, sweeteners, glue agents and flavoring agents; or/and, the solvent is selected from water, oil, ethanol, glycerol, propylene glycol, At least one of polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil, and ethyl acetate; or/and, the solubilizing agent is selected from Tweens, Zezes, and polyoxyethylene fatty alcohol ethers. At least one of soaps, sulfates, and sulfonates; or/and, the co-solvent is selected from organic acids and their salts, amides and amine compounds, inorganic salts, polyethylene glycol, polyethylene glycol, At least one of vitriol and glycerin; or/and, the emulsifier is selected from the group consisting of spans, tween, emulsifiers, benzyl esters, glycerol fatty acid esters, higher fatty acid salts, sulfates, sulfonates At least one of acid compound, gum arabic, tragacanth, gelatin, pectin, phosphatide, agar, sodium alginate, hydroxide, silicon dioxide and bentonite; or/and, the suspending agent is selected From at least one of glycerin, syrup, gum arabic, tragacanth, agar, sodium alginate, cellulose derivatives, povidone, carbopol, polyvinyl alcohol and thixotrope; or/and, The antioxidant is selected from at least one of sulfite, metabisulfite, bisulfite, ascorbic acid, gallic acid and its esters; or/and, the metal complexing agent is selected from ethylenediaminetetrakis Disodium acetate and one of polycarboxylic acid compounds; or/and the inert gas is selected from nitrogen and carbon dioxide; or/and the preservative is selected from parabens, organic acids and their At least one of salts, quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols and volatile oils; or/and, the local analgesic is selected from benzyl alcohol, chlorobutanol, lidocaine and general At least one of lucaine; or/and, the pH adjuster is selected from hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, and phosphoric acid At least one of salt, acetate and citrate; or/and, the isotonic or isotonic regulator is selected from the group consisting of glucose, sodium chloride, sodium citrate, sorbitol and xylitol At least one.
5. The application according to any one of claims 1 to 4, characterized in that the dosage form of the drug is tablet, granule, pill or powder.
6. The application according to any one of claims 1 to 4, characterized in that the dosage form of the drug is a capsule.
7. The application according to any one of claims 1 to 4, characterized in that the dosage form of the drug is an injection.
8. The application according to any one of claims 1 to 4, characterized in that the dosage form of the drug is an enema.
9. The application according to any one of claims 1 to 4, characterized in that the dosage form of the drug is an oral liquid or a tube feeding preparation.
10. The application according to any one of claims 1 to 4, characterized in that the administration route of the drug is oral administration, enema administration or injection administration.

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