CN114668733A

CN114668733A - New application of Huatuo reforger pill

Info

Publication number: CN114668733A
Application number: CN202210269825.8A
Authority: CN
Inventors: 王楠楠; 郑秀梅; 黄秋凌; 宁娜
Original assignee: Guangzhou Baiyunshan Qixing Pharmaceutical Co ltd
Current assignee: Guangzhou Baiyunshan Qixing Pharmaceutical Co ltd
Priority date: 2022-03-18
Filing date: 2022-03-18
Publication date: 2022-06-28
Also published as: WO2023173581A1

Abstract

The invention relates to a new application of Huatuo Zaizao pills, and mainly relates to the application of Huatuo Zaizao pills in preparing medicines for treating aspirin resistance. Compared with the prior art, the invention has the beneficial effects that: the inventor finds that the Huatuo Zaizao pills have obvious effect on aspirin resistance, and the efficacy of the Huatuo Zaizao pills is verified on New Zealand rabbits insensitive to aspirin, and shows good effects of improving hemorheology and blood coagulation and reducing platelet aggregation. The invention solves the problem of aspirin resistance in antiplatelet therapy and provides a stable antiplatelet therapy means.

Description

Novel application of Huatuo Zaizao pills

Technical Field

The invention relates to the technical field of medicines, in particular to a new application of Huatuo Zaizao pills.

Background

According to international and domestic clinical guidelines or consensus, aspirin is the most commonly used drug for standard anti-platelet treatment regimens and is widely used in the treatment of pan-vascular disease. With the expansion of aspirin application, individual differences of aspirin sensitivity among people are found clinically, and 5% -65% of patients with cerebral apoplexy are insensitive to aspirin antiplatelet therapy, namely aspirin resistance. Aspirin resistance may occur immediately upon initiation of aspirin administration, or may occur after a period of time (effective), and is closely associated with an increased risk of recurrence of cardiovascular events.

Currently, effective intervention means for aspirin resistance is still lacking. Clinically, the aspirin resistance patients mainly adopt measures of adding or replacing other antiplatelet medicaments after the recurrence of cardiovascular and cerebrovascular events (namely, the adjustment of an antiplatelet medicament administration scheme). Relevant guidelines/consensus indicate that adjustment of an antiplatelet regimen may result in an increased risk of secondary death, bleeding, and other events, and adjustment of an antiplatelet regimen according to platelet function is not recommended and stability of an antiplatelet regimen needs to be maintained. Therefore, it is necessary to explore effective intervention means of aspirin resistance, relieve aspirin resistance, keep the antiplatelet medication stable, and relieve the disease burden of patients.

Disclosure of Invention

Based on the above, the invention aims to provide a new application of Huatuo Zaizao pills, mainly relates to the application of Huatuo Zaizao pills in preparing medicines for treating aspirin resistance, and provides an effective means for clinical aspirin resistance intervention.

The purpose of the invention can be realized by the following technical scheme:

application of HUATUOZAIZAO pill in preparing medicine for treating aspirin resistance is provided.

In some embodiments of the invention, the medicament comprises the Huatuo Zaizao pill and pharmaceutically acceptable auxiliary materials.

In some embodiments of the invention, the adjuvant comprises one or more of a diluent, a wetting agent, a binder, a disintegrant, a lubricant, a color, flavor, modifier, solvent, solubilizer, cosolvent, emulsifier, antioxidant, metal complexing agent, inert gas, preservative, topical analgesic, pH modifier, and isotonic or isotonic adjusting agent.

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

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

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

In some embodiments of the invention, the disintegrant is selected from at least one of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, surfactants, and effervescent disintegrants.

In some embodiments of the invention, the lubricant is selected from at least one of talc, calcium stearate, magnesium lauryl sulfate, aerosil and polyethylene glycol.

In some embodiments of the present invention, the color, flavor, and taste modifier is selected from at least one of a coloring agent, a flavoring agent, a sweetening agent, a mucilage, and a flavoring agent.

In some embodiments of the present invention, 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.

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

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

In some embodiments of the invention, the emulsifier is selected from at least one of span, tween, maize, benze, glycerol fatty acid ester, higher fatty acid salt, sulfate, sulfonate, gum arabic, tragacanth, gelatin, pectin, phospholipid, agar, sodium alginate, hydroxide, silica, and bentonite.

In some embodiments of the invention, 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.

In some embodiments of the invention, the antioxidant is selected from at least one of sulfites, pyrosulfites, bisulfites, ascorbic acid, gallic acid, and esters thereof.

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

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

In some embodiments of the invention, 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.

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

In some embodiments of the invention, the pH adjusting agent 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.

In some embodiments of the invention, the isotonic or isotonicity adjusting agent is selected from at least one of glucose, sodium chloride, sodium citrate, sorbitol, and xylitol.

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

In some embodiments of the invention, the pharmaceutical formulation is a granule.

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

In some embodiments of the invention, the medicament is in the form of a powder.

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

In some embodiments of the invention, the pharmaceutical formulation is an injection.

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

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

In some embodiments of the invention, the pharmaceutical dosage form is a tube feed formulation.

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

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

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

Compared with the prior art, the invention has the beneficial effects that:

the inventor finds that the Huatuo Zaizao pills have obvious effect on aspirin resistance, and the efficacy of the Huatuo Zaizao pills is verified on New Zealand rabbits insensitive to aspirin, and shows good effects of improving hemorheology and blood coagulation and reducing platelet aggregation. The invention solves the problem of aspirin resistance in antiplatelet therapy and provides a stable antiplatelet therapy means.

Drawings

In order to more clearly illustrate the technical solutions in the embodiments of the present application and to more fully understand the present application and the advantages thereof, the drawings used in the description of the embodiments will be briefly introduced below. It is obvious that the drawings in the following description are only some embodiments of the application, and that other drawings can be derived from these drawings by a person skilled in the art without inventive effort.

FIG. 1 shows the effect of HUATUOZAIZAO pill on rabbit platelet aggregation rate

A result graph;

FIG. 2 is a graph showing that aspirin has no significant effect on WBV at low shear rate

A result graph;

FIG. 3 is a graph showing that aspirin has no significant effect on WBV at high shear rate

A result graph;

FIG. 4 shows that aspirin has no significant effect on PV

A result graph;

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

A result graph;

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

A result graph;

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

A result graph;

FIG. 8 shows that HUATUOZAIZAO pill with low shear rate can significantly reduce WBV

A result graph;

FIG. 9 shows that HUATUOZAIZAO pill with high shear rate can significantly reduce WBV

A result graph;

FIG. 10 shows Huatuo Zaizao pill with remarkably prolonged PV

A result graph;

FIG. 11 shows that Huatuo Zaizao pill can prolong APTT significantly

A result graph;

FIG. 12 shows that Huatuo Zaizao Wan can prolong PT significantly

A result graph;

FIG. 13 shows that Huatuo Zaizao pills can prolong TT significantly

And (5) a result chart.

Detailed Description

The present invention will be described in further detail with reference to the drawings, embodiments and examples. It should be understood that these embodiments and examples are given solely for the purpose of illustrating the invention and are not to be construed as limiting the scope of the invention, which is provided for the purpose of providing a more thorough understanding of the present disclosure. It is also understood that the present invention may be embodied in many different forms and is not limited to the embodiments and examples described herein, and that various changes and modifications may be effected therein by one of ordinary skill in the art without departing from the spirit and scope of the invention and the resulting equivalents are within the scope and range of equivalents of the present application. Furthermore, in the following description, numerous specific details are set forth in order to provide a more thorough understanding of the present invention, and it is to be understood that the present invention may be practiced without one or more of these details.

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

Term(s) for

Unless otherwise stated or contradicted, terms or phrases used herein have the following meanings:

the term "and/or", "and/or" as used herein is intended to be inclusive of any one of the two or more items listed in association, and also to include any and all combinations of the items listed in association, including any two or more of the items listed in association, any more of the items listed in association, or all combinations of the items listed in association. It should be noted that when at least three items are connected by at least two conjunctive combinations selected from "and/or", "or/and", "and/or", it should be understood that, in the present application, the technical solutions definitely include the technical solutions all connected by "logic and", and also the technical solutions all connected by "logic or". For example, "A and/or B" includes A, B and A + B. For example, the embodiments of "a, and/or, B, and/or, C, and/or, D" include any of A, B, C, D (i.e., all embodiments using a "logical or" connection), any and all combinations of A, B, C, D, i.e., any two or any three of A, B, C, D, and four combinations of A, B, C, D (i.e., all embodiments using a "logical and" connection).

The term "plural", and the like in the present invention mean, unless otherwise specifically defined, 2 or more in number or 2 or less. For example, "one or more" means one or two or more.

As used herein, "a combination thereof," "any combination thereof," and the like, includes all suitable combinations of any two or more of the listed items.

In the present specification, the term "suitable" in "a suitable combination, a suitable manner," any suitable manner "and the like shall be construed to mean that the technical solution of the present invention can be implemented, the technical problem of the present invention can be solved, and the technical effect of the present invention can be achieved.

The terms "preferably", "better" and "preferably" are used herein only to describe preferred embodiments or examples, and should not be construed as limiting the scope of the present invention.

In the present invention, "further", "still further", "specifically" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of the present invention.

In the present invention, "optionally", "optional" and "optional" refer to the presence or absence, i.e., to any one of two juxtapositions selected from "present" and "absent". If multiple optional parts appear in one technical scheme, if no special description exists, and no contradiction or mutual constraint relation exists, each optional part is independent.

In the present invention, the terms "first", "second", "third", "fourth", etc. in the terms "first", "second", "third", "fourth", etc. are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or quantity, nor as implying an importance or quantity indicating the indicated technical feature. Moreover, "first," "second," "third," "fourth," etc. are used merely as non-exhaustive lists and should not be construed as limiting the number of instances.

In the present invention, the technical features described in the open type include a closed technical solution including the listed features, and also include an open technical solution including the listed features.

In the present invention, where a range of values (i.e., a numerical range) is recited, unless otherwise stated, alternative distributions of values within the range are considered to be continuous and include both the endpoints of the range (i.e., the minimum and maximum values) and each of the values between the endpoints. Unless otherwise specified, when a numerical range refers to integers only within the numerical range, both endpoints of the numerical range and each integer between the two endpoints are included, and in this document, it is equivalent to reciting each integer directly, for example, t is an integer selected from 1 to 10, meaning t is any integer selected from the group of integers consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. Further, when multiple range describing features or characteristics are provided, these ranges may be combined. In other words, unless otherwise indicated, the ranges disclosed herein are to be understood to include any and all subranges subsumed therein.

The temperature parameter in the present invention is not particularly limited, and may be a constant temperature treatment or a variation within a certain temperature range. It will be appreciated that the described thermostatic process allows the temperature to fluctuate within the accuracy of the instrument control. Allowing fluctuations in the range of, for example,. + -. 5 deg.C,. + -. 4 deg.C,. + -. 3 deg.C,. + -. 2 deg.C, + -. 1 deg.C.

In the present invention,% (w/w) and wt% are weight percentages,% (v/v) is volume percentage, and% (w/v) is mass volume percentage.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. The citation referred to herein is incorporated by reference in its entirety for all purposes unless otherwise in conflict with the present disclosure's objectives and/or technical solutions. Where a citation is referred to herein, the definition of a reference in the document, including features, terms, nouns, phrases, etc., that is relevant, is also incorporated by reference. In the present invention, when the citation is referred to, the cited examples and preferred embodiments of the related art features are also incorporated by reference into the present application, but the present invention is not limited to the embodiments. It should be understood that where the citation conflicts with the description herein, the application will control or be adapted in accordance with the description herein.

The Chinese medicinal compound preparation has the characteristics of multiple components, multiple targets, multiple ways, mild action and the like, and can be used as a selection for a clinician in combination with a conventional antiplatelet treatment scheme. Huatuo reproduced pills (Guangzhou Baiyunshan Qixing pharmaceutical Co., Ltd., Chinese medicine quai Z44020748) are composed of nux vomica powder, ligusticum wallichii, fructus evodiae, borneol and the like, have the effects of promoting blood circulation to remove blood stasis, reducing phlegm and dredging collaterals, and promoting qi circulation to relieve pain, are used for the recovery period and sequelae of stroke, but are not reported aiming at aspirin resistance.

The invention provides application of Huatuozaizao pills in preparation of a medicine for treating aspirin resistance.

It is understood that the invention is not limited to the types of adjuvants contained in the drugs, and suitable types of adjuvants can be selected according to the required dosage form and administration route, and the types of adjuvants include but are not limited to one or more of the following types: diluent, wetting agent, adhesive, disintegrating agent, lubricant, color, aroma and taste regulator, solvent, solubilizer, cosolvent, emulsifier, antioxidant, metal complexing agent, inert gas, preservative, local analgesic, pH regulator and isotonic or isotonic regulator. The diluent may be at least one selected from starches, sugars, celluloses, and inorganic salts. The wetting agent is selected from at least one of water and ethanol. The adhesive is selected from at least one of starch slurry, dextrin, sugar, cellulose derivative, gelatin, polyvidone and polyethylene glycol. The disintegrant is at least one selected from dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, surfactant and effervescent disintegrant. The lubricant is at least one selected from talcum powder, calcium stearate, magnesium lauryl sulfate, superfine silica gel powder and polyethylene glycol. The color, flavor and taste regulator is at least one selected from pigment, perfume, sweetener, mucilage and flavoring agent. The solvent is at least one selected from water, oil, ethanol, glycerol, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil and ethyl acetate. The solubilizer is selected from at least one of tween, maize, polyoxyethylene fatty alcohol ether, soap, sulfate and sulfonate. The cosolvent is at least one selected from organic acids and salts thereof, amides and amine compounds, inorganic salts, polyethylene glycol, povidone and glycerol. The emulsifier is selected from at least one of span, Tween, Brix, glycerol fatty acid ester, higher fatty acid salt, sulfate, sulfonate, gum arabic, tragacanth, gelatin, pectin, phospholipid, agar, sodium alginate, hydroxide, silicon dioxide and bentonite. The suspending agent is at least one selected from glycerol, syrup, gum arabic, tragacanth, agar, sodium alginate, cellulose derivatives, polyvidone, carbopol, polyvinyl alcohol, and thixotrope. The antioxidant is at least one selected from sulfite, pyrosulfite, bisulfite, ascorbic acid, gallic acid and esters thereof. The metal complexing agent is selected from one of disodium ethylene diamine tetraacetate and polycarboxylic acid compound. The inert gas is selected from one of nitrogen and carbon dioxide. The preservative is at least one selected from the group consisting of parabens, organic acids and salts thereof, quaternary ammonium compounds, chlorhexidine acetate, alcohols, phenols and volatile oils. The topical analgesic is selected from at least one of benzyl alcohol, chlorobutanol, lidocaine and procaine. The pH regulator is at least one selected from hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphate, acetate and citrate. The isotonic or isotonic regulator is at least one selected from glucose, sodium chloride, sodium citrate, sorbitol and xylitol.

The dosage form of the medicine is not particularly limited, and the required dosage form can be prepared according to clinical requirements, such as: tablet, granule, pill, powder, capsule, injection, enema, oral liquid, and tube feeding preparation.

The administration mode of the drug is not particularly limited, and the drug can be administered according to clinical requirements, for example: oral administration, enema administration, and injection administration.

Example 1

First, test materials

1. Medicine preparation: huatuo reproduced pill, its extract, black brown thick paste for experiment, one gram of thick paste is equivalent to about 0.63g crude drug, lot number: 060320, provided by Guangzhou Baiyunshan Qixing pharmaceutical Co., Ltd., the pharmacodynamic administration dose is calculated as crude drug amount (g crude drug/kg); aspirin enteric-coated tablets (25 mg/tablet), manufactured by Beijing eosin pharmaceutical industry, Limited liability company, lot number: 050924, respectively; adenosine Diphosphate (ADP) disodium salt, a product of Shanghai Biochemical research institute of Chinese academy of sciences, is prepared into a 1.0mM/L solution by using normal saline and stored at 4 ℃ for later use; arachidonic Acid (AA), Fluka AG product, was extemporaneously formulated with 1.0mM/L NaOH as sodium salt at 5.0 g/L; collagen (100ug/ml), a product of KOKEN.

2. Animals: healthy male white big-ear Japanese rabbits weighing 2.28 + -0.16 kg, provided by Beijing Tongli laboratory animal farms, certification No.: SCXK (Jing) 2005-003.

3. The instrument comprises: platelet aggregometer, model BS634, a product of beijing biochemical instrumentation factory.

Second, test method

Platelet aggregation rates were determined by puncturing the middle ear artery prior to dosing, and rabbits were randomized (8 per group) according to platelet aggregation rate level and body weight: (1) control group (equal volume of distilled water), (2) HUATUOZAIZAO pill group (2g crude drug/kg, calculated by body weight, is equivalent to 1.13 times of human clinical daily dose of 24 g), and (3) aspirin group (25mg/kg, calculated by body weight, is equivalent to 5.35 times of human clinical daily dose of 100 mg). The preparation is administered once daily by intragastric administration at a volume of 6ml/kg for 7 days, and blood is collected by puncturing middle artery of ear for 1 hr after the last administration to determine platelet aggregation rate.

The platelet aggregation rate measuring method comprises the following steps: the middle ear artery was punctured with a siliconized syringe to obtain blood, 3.8% (m/v) sodium citrate solution was anticoagulated (blood: anticoagulant: 9:1), centrifuged at 200 × g for 8 minutes, the supernatant fraction, i.e., Platelet Rich Plasma (PRP), was collected, and the remaining 1500 × g was centrifuged for 10 minutes, and the supernatant fraction, i.e., Platelet Poor Plasma (PPP), was collected. Platelet count in PRP was 4.0X 10⁵/mm³Left and right. According to the Born's turbidimetry, a turbidimetric tube containing 200. mu.l PRP and 1 small magnetic bar is placed in a platelet aggregation apparatus, and is subjected to heat preservation at 37 ℃ for 1 minute, and after being calibrated by PPP, an inducer is added under the stirring condition to induce aggregation. The final concentrations of the inducers used were: ADP (47.6. mu.M/L), AA (782.0. mu.M/L), collagen (4.8 mg/L). According to the aggregation curve and the maximum aggregation rate automatically printed by the instrument, the blood volume of the medicine is analyzed through t test The effect of plate clustering. The maximum aggregation rate is calculated as follows:

third, test results

As can be seen from fig. 1: when ADP induces aggregation, the platelet aggregation rates among groups before administration have no obvious difference; the platelet aggregation rate of Huatuo Zaizao pill group after administration is significantly lower than that of control group (P <0.01), and the platelet aggregation rate of aspirin group is also significantly lower than that of control group (P < 0.01). When AA induces aggregation, the platelet aggregation rate between groups before administration has no obvious difference; the platelet aggregation rate of Huatuo Zaizao pill group after administration is significantly lower than that of control group (P <0.01), and the platelet aggregation rate of aspirin group is also significantly lower than that of control group (P < 0.01). When collagen induces aggregation, the platelet aggregation rate between each group before administration has no obvious difference; the platelet aggregation rate of Huatuo Zaizao pill group after administration is significantly lower than that of control group (P <0.01), and the platelet aggregation rate of aspirin group is also significantly lower than that of control group (P < 0.01).

Fourth, conclusion

The above results show that: the Huatuo Zaizao pill can be administered by intragastric administration for 7 days, and can significantly reduce Adenosine Diphosphate (ADP), Arachidonic Acid (AA) and collagen-induced rabbit platelet aggregation rate (P <0.01), and has effect in inhibiting platelet aggregation.

Example 2

Materials and methods

1. Animals: new Zealand rabbit, body weight 2.5kg-3.0 kg; in the test, food and water can be freely obtained under a proper environment, the temperature is 22.0 +/-2.0 ℃, and the relative humidity is 50 +/-5%; one week of adaptive feeding before the experiment.

2. Drugs and chemicals: huatuo Zaizao pills (Guangzhou Baiyunshan Qixing pharmaceutical Co., Ltd.); aspirin (bayer health care (beijing) limited); polyurethane (national chemical group chemical agents limited (shanghai)).

3. Experiment design:

intragastric administration: the control group was given 1ml/kg of distilled water; aspirin 5mg/kg (calculated according to the body weight, which is 1.07 times of the clinical daily dosage of 100mg for a human); huatuo Zaizao pill group should give aspirin 1 mg/kg on the basis of aspirin 5mg/kg group give Huatuo Zaizao pill (calculated according to body weight, equivalent to human clinical daily dose 24g 0.89 times).

Blood samples were collected before and 2 hours, 4 hours after dosing. Blood was collected and added to a 3.8% sodium citrate (sodium citrate: blood 1:9, v/v) plastic tube for Whole Blood Viscosity (WBV) measurement. Plasma was separated by centrifugation at 3000 Xg for 10min and used to measure Plasma Viscosity (PV) and clotting function.

4. And (3) viscosity measurement: measuring viscosity using a blood viscometer; wherein, in 10 seconds ^-1And 150 seconds^-1WBV was measured; at 150 seconds^-1The shear rate of (2) measures PV.

5. And (3) blood coagulation function determination: the active fraction thromboplastin time (APTT), Prothrombin Time (PT) and Thrombin Time (TT) were measured using a coagulometer.

APTT: mu.l plasma was incubated with 50. mu.l APTT activator for 3min at 37 ℃ and 50. mu.l CaCl was added₂。

PT: 50 μ l of the plasma solution was incubated at 37 ℃ for 3min, and 100 μ l of the thromboplastin was added.

TT: mu.l of the plasma solution was incubated at 37 ℃ for 3min and 100. mu.l of thrombin preparation was added.

Secondly, data analysis: analyzing data by adopting SPSS statistical software, and expressing the data by using a mean +/-SEM; the comparison between the two groups adopts unpaired t test of students; p <0.05 is statistically significant for the differences.

Three, result in

1. The aspirin has no significant influence on the hemorheology and the blood coagulation function of the test animals

Compared to the control group, aspirin alone had no significant effect on hemorheology (WBV, PV) and blood coagulation parameters (APTT, PT, TT), as detailed in fig. 2 to 7, which illustrates that selected new zealand rabbits were not sensitive to aspirin.

2. Huatuo Zaizao pill has significant effect on aspirin resisting New Zealand rabbit hemorheology and blood coagulation

Compared with the control group, the new zealand rabbit insensitive to aspirin is provided with the Huatuo Zaizao pill based on the aspirin, which remarkably reduces WBV and PV and remarkably prolongs APTT, PT and TT, and is shown in figures 8 to 13 in detail. In fig. 8 to 13: it is: p in comparison with the control group <0.05；

Comparison with before treatment, P<0.05。

Third, conclusion

For aspirin-resistant New Zealand rabbit, HUATUOZAIZAO pill has reduced WBV and PV, and prolonged APTT, PT and TT. The results show that Huatuozheng pill can act on aspirin resistance, and improve hemorheology and blood coagulation function.

The above examples show that Huatuo Zaizao pills can act on aspirin resistance, effectively improve blood coagulation function and hemorheology index, and have therapeutic effect on aspirin resistance. Meanwhile, Huatuo Zaizao pills can reduce the platelet aggregation rate, and suggest that Huatuo Zaizao pills can treat aspirin resistance by acting on platelets to reduce the platelet aggregation rate.

The technical features of the embodiments and examples described above can be combined in any suitable manner, and for the sake of brevity, all possible combinations of the technical features of the embodiments and examples described above are not described, but should be considered within the scope of the present disclosure as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, which is convenient for specific and detailed understanding of the technical solutions of the present invention, but the present invention should not be construed as being limited to the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Furthermore, it should be understood that after reading the above teachings of the present invention, various changes or modifications may be made to the invention by those skilled in the art, and equivalents may be obtained and still fall within the scope of the present application. It should also be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the present invention as set forth in the appended claims. Therefore, the protection scope of the present invention should be subject to the content of the appended claims, and the description and the drawings can be used for explaining the content of the claims.

Claims

1. Application of HUATUOZAIZAO pill in preparing medicine for treating aspirin resistance is provided.

2. The use of claim 1, wherein the medicament comprises HUATUOZAIZAO pill and pharmaceutically acceptable adjuvants.

3. Use according to claim 2, wherein the adjuvants comprise one or more of diluents, wetting agents, binders, disintegrants, lubricants, colour and flavour modifiers, solvents, solubilisers, co-solvents, emulsifiers, antioxidants, metal complexing agents, inert gases, preservatives, topical analgesics, pH modifiers and isotonic or isotonic agents.

4. The use according to claim 3, wherein the diluent is selected from at least one of starches, sugars, celluloses and inorganic salts; or/and the wetting agent is selected from at least one of water and ethanol; or/and the adhesive is selected from at least one of starch slurry, dextrin, sugar, cellulose derivative, gelatin, povidone and polyethylene glycol; or/and the disintegrant is selected from at least one of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, surfactant and effervescent disintegrant; or/and the lubricant is selected from at least one of talcum powder, calcium stearate, magnesium lauryl sulfate, superfine silica powder and polyethylene glycol; or/and the color, aroma and taste regulator is selected from at least one of pigment, spice, sweetener, mucilage and flavoring agent; or/and the solvent is at least one selected from water, oil, ethanol, glycerol, propylene glycol, polyethylene glycol, dimethyl sulfoxide, liquid paraffin, fatty oil and ethyl acetate; or/and the solubilizer is selected from at least one of tween, maize, polyoxyethylene fatty alcohol ether, soap, sulfate and sulfonate; or/and the cosolvent is at least one selected from organic acids and salts thereof, amides and amine compounds, inorganic salts, polyethylene glycol, povidone and glycerol; or/and the emulsifier is selected from at least one of span, tween, maize, beneze, glycerin fatty acid ester, higher fatty acid salt, sulfate, sulfonate, acacia, tragacanth, gelatin, pectin, phospholipid, agar, sodium alginate, hydroxide, silicon dioxide and bentonite; or/and the suspending agent is at least one selected from glycerol, syrup, acacia gum, tragacanth gum, agar, sodium alginate, cellulose derivatives, povidone, carbopol, polyvinyl alcohol and thixotrope; and/or, the antioxidant is at least one selected from sulfite, pyrosulfite, bisulfite, ascorbic acid, gallic acid and esters thereof; or/and the metal complexing agent is selected from one of disodium ethylene diamine tetraacetate and polycarboxylic acid compound; or/and the inert gas is selected from one of nitrogen and carbon dioxide; or/and the preservative is at least one of nipagin, organic acid and salt thereof, quaternary ammonium compound, chlorhexidine acetate, alcohol, phenol and volatile oil; or/and the local analgesic is selected from at least one of benzyl alcohol, chlorobutanol, lidocaine and procaine; or/and the pH regulator is at least one selected from hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid, sodium hydroxide, sodium bicarbonate, ethylenediamine, meglumine, phosphate, acetate and citrate; and/or, the isotonic or isotonic regulator is at least one selected from glucose, sodium chloride, sodium citrate, sorbitol and xylitol.

5. The use according to any one of claims 1 to 4, wherein the medicament is in the form of a tablet, granule, pill or powder.

6. The use according to any one of claims 1 to 4, wherein the medicament is in the form of a capsule.

7. The use according to any one of claims 1 to 4, wherein the medicament is in the form of an injection.

8. The use according to any one of claims 1 to 4, wherein the medicament is in the form of an enema.

9. The use according to any one of claims 1 to 4, wherein the medicament is in the form of an oral liquid or a tube feed.

10. The use according to any one of claims 1 to 4, wherein the route of administration of the medicament is oral, enema or injection.