CN110638799A - A composition for preventing and treating ischemic stroke and application thereof - Google Patents

Abstract

The invention discloses a composition for preventing and treating ischemic stroke, comprising the following raw materials in parts by mass: 10-50 parts of eugenol, 10-50 parts of elemen, 0.5-3 parts of musk ketone and 10- 30 parts of crocin I; through the synergistic effect of compatibility, it can effectively prevent and treat brain damage caused by cerebral ischemia-reperfusion; and it is disclosed that the above composition can be used to prepare medicines, which can be used for clinical prevention and treatment of ischemic Stroke offers new drugs.

Description

A composition for preventing and treating ischemic stroke and application thereof

technical field

The present invention relates to the technical field of medicine, in particular to a pharmaceutical composition for preventing and treating ischemic stroke and a preparation method thereof.

Background technique

At present, ischemic stroke is one of the most common cerebrovascular diseases in clinical practice. The blood supply disorder in the local brain tissue area caused by various reasons leads to the necrosis of ischemic and hypoxic lesions in the brain tissue, which in turn produces a clinical response. of neurological deficits. At present, ischemic stroke has the characteristics of high morbidity, high mortality, high disability rate and many complications among the elderly. It has become a frequent disease that seriously affects the quality of life of middle-aged and elderly people in my country.

For the treatment of ischemic stroke, the current treatment methods mainly include surgical treatment and drug treatment. Among them, improving cerebral blood circulation and neuroprotection are the main means of pathological intervention for ischemic injury, but the curative effect is not significant, and both are accompanied by with a certain degree of side effects. Therefore, it is of great significance to develop new drugs that can prevent and treat ischemic stroke.

Therefore, how to provide a pharmaceutical composition for preventing and treating ischemic stroke and a preparation method thereof is an urgent problem to be solved by those skilled in the art.

SUMMARY OF THE INVENTION

In view of this, the present invention provides a composition for preventing and treating ischemic stroke and its application, which can effectively prevent and treat brain damage caused by cerebral ischemia-reperfusion through compatibility and synergy. New drugs are provided for prevention and treatment of ischemic stroke.

In order to achieve the above object, the present invention adopts the following technical solutions:

A composition comprising the following raw materials in parts by mass: 10-50 parts of eugenol, 10-50 parts of elemen, 0.5-3 parts of musk ketone and 10-30 parts of crocin I;

The structural formula of described eugenol is:

The structural formula of the elemenin is:

The structural formula of the musk ketone is:

The structural formula of the crocin I is:

Preferably, it includes the following raw materials in parts by mass: 35 parts of eugenol, 31 parts of elemenin, 1.3 parts of musk ketone and 20 parts of crocin I.

Another object of the present invention is to provide a method for preparing the composition, which specifically includes the following steps: mixing eugenol, elemenin, musk ketone and crocin I according to the above ratio.

The beneficial effects of the above preferred technical solution are: the present invention can effectively protect the brain damage caused by ischemia-reperfusion by mixing eugenol, elemenin, musk ketone and crocin I according to a specified ratio, and can effectively improve the neurological function score. and cerebral infarction area, and eugenol, elemenin, musk ketone and crocin I cooperate with each other to play a synergistic effect, which can significantly improve the effect.

The present invention also provides a pharmaceutical composition for preventing and treating ischemic stroke, comprising the above-mentioned composition and pharmaceutically acceptable excipients, wherein the mass ratio of the composition to the excipients is: 1:99 to 99:1; the adjuvant includes any one or more combinations of solvents, diluents, binders, disintegrants, lubricants, absorption enhancers, preservatives or flavoring agents.

Preferably, the solvent is selected from commonly used water, ethanol, propylene glycol or castor oil for injection.

Preferably, the diluent includes any one or more combinations of commonly used starch, powdered sugar, dextrin, lactose, pregelatinized starch, microcrystalline fibers or inorganic calcium salts.

Preferably, the inorganic calcium salt includes commonly used calcium sulfate, calcium hydrogen phosphate or mannitol.

Preferably, the binder includes any one of commonly used water, ethanol, starch pulp, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose or hypromellose one or more combinations.

Preferably, the disintegrant includes any one or more of commonly used dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone or cross-linked sodium carboxymethyl cellulose combination.

Preferably, the lubricant includes any one or a combination of common magnesium stearate, micropowder silica gel, talc, hydrogenated vegetable oil, polyethylene glycols or magnesium lauryl sulfate.

Preferably, the absorption enhancer includes any one or more combinations of commonly used aromatic acid compounds or aliphatic acids.

Preferably, the surfactant includes the most common sodium dodecyl sulfonate.

Preferably, the preservative includes any one or more combinations of commonly used benzoic acid, hydroxypropyl butyl ester, hydroxypropyl methyl ester, phenol or m-cresol; the carton flavor includes any one of sucrose or steviol one or more combinations.

As can be seen from the above technical solutions, compared with the prior art, the present invention provides a composition for preventing and treating ischemic stroke and its application, which have the following beneficial effects:

(1) In the present invention, eugenol, elemenin, musk ketone and crocin I cooperate with each other to exert a synergistic effect, which can significantly improve the effect of preventing and treating ischemic stroke;

(2) The present invention can effectively prevent and treat cerebral injury caused by cerebral ischemia-reperfusion through compatibility and synergy, and provides a new drug for clinical prevention and treatment of ischemic cerebral apoplexy.

Description of drawings

In order to explain the embodiments of the present invention or the technical solutions in the prior art more clearly, the following briefly introduces the accompanying drawings that need to be used in the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description are only It is an embodiment of the present invention. For those of ordinary skill in the art, other drawings can also be obtained according to the provided drawings without creative work.

Figure 1 is a columnar schematic diagram of the neurological function scores of rats in each administration group provided by the present invention.

"N" is the sham operation group, "M" is the model group, "P" is the positive drug group, "A" is the eugenol group, "B" is the elemenin group, "C" is the muskone group, " D" is the crocin I group, and "ABCD" is the active ingredient composition group;

^### p<0.001, compared with sham group "N"; ^* p<0.05, compared with model group "M"; ^** p<0.01, compared with model group "M"; ^*** p <0.001, compared to model group "M".

Figure 2 is a schematic diagram of TTC staining of rats in each administration group provided by the present invention.

Figure 3 is a schematic diagram of a column of cerebral infarction volume of rats in each administration group provided by the present invention.

"N" is the sham operation group, "M" is the model group, "P" is the positive drug group, "A" is the eugenol group, "B" is the elemenin group, "C" is the muskone group, " D" is the crocin I group, and "ABCD" is the active ingredient composition group;

^### p<0.001, compared with sham operation group "N"; ^** p<0.01, compared with model group "M"; ^*** p<0.001, compared with model group "M".

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, but not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

The embodiment of the present invention discloses a composition, comprising the following raw materials in parts by mass: 10-50 parts of eugenol, 10-50 parts of elemenin, 0.5-3 parts of musk ketone and 10-30 parts of crocin I ;

The structural formula of eugenol is:

The structural formula of elemenin is:

The structural formula of muskone is:

The structural formula of crocin I is:

In order to further optimize the technical scheme, the raw materials in the following parts by mass are included: 35 parts of eugenol, 31 parts of elemen, 1.3 parts of musk ketone and 20 parts of crocin I.

Another object of the present invention is to provide a preparation method of the composition, which specifically comprises the following steps: mixing eugenol, elemenin, musk ketone and crocin I according to the above ratio.

In the present invention, the mixture of eugenol, elemenin, musk ketone and crocin I according to the specified ratio can effectively protect the brain damage caused by ischemia-reperfusion, and can effectively improve the neurological function score and cerebral infarction area, and eugenol, Elemisin, musk ketone and crocin I play a synergistic effect with each other, which can significantly improve the effect.

The embodiment of the present invention also provides a pharmaceutical composition for preventing and treating ischemic stroke, including the above-mentioned composition, and also including a pharmaceutically acceptable auxiliary material, and the mass ratio of the composition to the auxiliary material is 1: 99-99:1; the excipients include any one or more combinations of solvents, diluents, binders, disintegrants, lubricants, absorption enhancers, preservatives or flavoring agents.

In order to further optimize the technical scheme, the solvent is selected from water, ethanol, propylene glycol or castor oil for injection.

In order to further optimize the technical solution, the diluent includes any one or more combinations of starch, powdered sugar, dextrin, lactose, pregelatinized starch, microcrystalline fibers or inorganic calcium salts.

In order to further optimize the technical solution, inorganic calcium salts include calcium sulfate, calcium hydrogen phosphate or mannitol.

In order to further optimize the technical solution, the binder includes any one of water, ethanol, starch pulp, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose or hypromellose one or more combinations.

In order to further optimize the technical scheme, the disintegrant includes any one or more of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone or cross-linked sodium carboxymethyl cellulose combination.

In order to further optimize the technical solution, the lubricant includes any one or a combination of magnesium stearate, micropowder silica gel, talc, hydrogenated vegetable oil, polyethylene glycols or magnesium lauryl sulfate.

In order to further optimize the technical solution, the absorption enhancer includes any one or more combinations of aromatic acid compounds or aliphatic acids.

In order to further optimize the technical solution, the surfactant includes sodium dodecyl sulfonate.

In order to further optimize the technical solution, the preservatives include any one or more combinations of benzoic acid, hydroxypropyl butyl ester, hydroxypropyl methyl ester, phenol or m-cresol; the flavoring agent includes any one of sucrose or steviol or multiple combinations.

Example 1

Embodiment 1 of the present invention discloses a pharmaceutical composition for preventing and treating ischemic stroke, which specifically includes the following components in parts by mass: 10 parts of eugenol, 10 parts of elemen, 0.5 part of musk ketone and 10 parts of crocin I; also including 2000 parts of starch, 900 parts of dextrin, 50 parts of low-substituted hydroxypropyl cellulose, 10 parts of magnesium stearate, 10 parts of sodium dodecyl sulfonate, 5 parts of hydroxypropyl ester and 5 parts of 50% ethanol in water.

The specific preparation method is:

Take 10 parts of eugenol, 10 parts of elemenin, 0.5 part of musk ketone and 10 parts of crocin I, after mixing, continue to add 2000 parts of starch and 900 parts of dextrin, 50 parts of low-substituted hydroxypropyl cellulose, 10 parts of Parts of magnesium stearate, 10 parts of sodium dodecyl sulfonate and 5 parts of hydroxypropyl butyl ester, after mixing, using 50% ethanol aqueous solution as a binder, wet granulation, drying at a low temperature of 40 ℃, 14 mesh sieves granules to obtain the pharmaceutical composition granules of the present invention.

Example 2

Embodiment 2 of the present invention discloses a pharmaceutical composition for preventing and treating ischemic stroke, which specifically includes the following components in parts by mass: 50 parts of eugenol, 50 parts of elemen, 3 parts of musk ketone and 30 parts crocin I; also includes 1800 and 900 parts lactose, 80 parts sodium carboxymethyl starch, 5 parts magnesium stearate and 5 parts salicylic acid and 5 parts water.

The specific preparation method is:

Take 50 parts of eugenol, 50 parts of elemenin, 3 parts of musk ketone and 30 parts of crocin I, after mixing, continue to add 1800 parts and 900 parts of lactose, 80 parts of sodium carboxymethyl starch, 5 parts of stearic acid Magnesium and 5 parts of Azone are mixed, and the aqueous solution is used as a binder to wet granulate, and after drying at low temperature, 14 mesh sieve to granulate and press into tablets to obtain the pharmaceutical composition tablet of the present invention.

Example 3

Embodiment 3 of the present invention discloses a pharmaceutical composition for preventing and treating ischemic stroke, which specifically includes the following components in parts by mass: 30 parts of eugenol, 30 parts of elemen, 1 part of musk ketone and 15 parts of crocin I; also including 1800 parts, 900 parts of lactose, 80 parts of sodium carboxymethyl starch, 5 parts of magnesium stearate and 5 parts of salicylic acid.

The specific preparation method is:

Take 30 parts of eugenol, 30 parts of elemenin, 1 part of musk ketone and 15 parts of crocin I, and after mixing, continue to add 2000 parts of castor oil for injection, 50 parts of polyethylene glycol, and 30 parts of lauroketone Mix with 10 parts of hydroxypropyl methyl ester to obtain the pharmaceutical composition injection of the present invention.

Example 4 Protective effect of the composition of the present invention on cerebral ischemia-reperfusion injury in rats

1. Experimental reagents and medicines

Eugenol (purity ≥ 98%; batch: AF8032802), elemen (purity ≥ 98%; batch: AF8032804), musk ketone (purity ≥ 98%; batch: AF8032803), crocin I (purity ≥ 98%; batch: AF8032803) ≥98%; batch: AF8061502) were purchased from Chengdu Aifa Biotechnology Co., Ltd.; 2,3,5-triphenyltetrazolium chloride (TTC) was purchased from Sigma Company in the United States; chloral hydrate was purchased from Tianjin University Mao Reagent Co., Ltd.; sodium carboxymethyl cellulose was purchased from Tianjin Damao Reagent Co., Ltd.; physiological saline was purchased from Chenxin Pharmaceutical Co., Ltd.

2. Establishment of animal model and group administration

Healthy SPF male SD rats, weighing about 220 g-250 g, were purchased from the Animal Experiment Center of Ningxia Medical University (experimental animal license number SCXK (Ning) 2015-0001), and were raised in an SPF standard laboratory. The feeding conditions of animals in each group were the same: ambient temperature (25°C) and relative humidity (50%-60%). Free food and water. The rat middle cerebral artery occlusion (MCAO) model was established by suture method.

SD rats were given continuous administration for 14 days before the MCAO operation (once a day), fasted for 12 hours after the last administration, anesthetized by intraperitoneal injection of 7% chloral hydrate, fixed in the supine position, and placed in the middle of the neck with iodophor Sterilize, make an incision of about 1.5-2 cm along the midline, separate the subcutaneous muscle tissue and fascia layer by layer, so that the common carotid artery is fully exposed, that is, the pulsating common carotid artery is clearly visible, and the surface membrane tissue of the common carotid artery is carefully separated. The proximal end of the artery was ligated with a thread for use, and the external carotid artery and the internal carotid artery were separated from the distal end, and a thread was prepared at the external carotid artery for ligation. Continue to separate along the internal carotid artery to the direction of the skull base. It can be seen that the blood vessel is slightly enlarged when it reaches the bulge and sends out a larger branch, the pterygopalatine artery. At this time, the silk thread located at the proximal end of the external carotid artery is ligated and temporarily clamped with a small artery clip. Internal and common carotid arteries. Use microsurgical scissors to cut an incision on the common carotid artery, the distance from the incision to the bifurcation of the internal carotid artery and the external carotid artery is about 3-4mm, and tie the prepared thread (the head is spherical and the distance from the There is a clear mark at 1.8-2.0cm) and slowly insert it, and the length of the incoming thread is about 18.5±0.5mm from the bifurcation of the common carotid artery. At this time, there is slight resistance to the incoming thread, that is, the thread plug is inserted into the starting end of the intracranial cerebral artery. , successfully blocked the opening of the middle cerebral artery. After blocking for 2 hours, gently pull out the suture for about 1 cm and cut it, tie the arterial stump tightly, suture the subcutaneous muscle tissue and skin layer by layer and disinfect. After modeling, penicillin was injected to avoid infection, and the rat middle cerebral artery occlusion (MCAO) model was established. Insulation pads and electric oven lamps were used to maintain the rats' body temperature during and after modeling. The operation of the sham operation group was the same as that of the MCAO model group, except that no suture was inserted. The rats after resumption of activity were scored according to Zea Longa grade 5, the rats with neurological function damage of 0 and 4 in each group (ie, the model was unsuccessful) were discarded, and the rats with successful model establishment were selected for follow-up experiments.

A total of 120 rats successfully established above were randomly divided into sham operation group, model group, positive drug group, eugenol group, elemenin group, musk ketone group, crocin I group and active ingredient composition group. 8 groups of 15 animals each. The mode of administration is by gavage. The sham operation group and the model group were given equal volume of 0.5% CMC-Na (100g/1ml); the positive drug nimodipine group was given a dose of 36mg/kg/d; the eugenol group was given a dose of 35mg/kg/d; The dosage of the fragrance group was 31 mg/kg/d; the dosage of the musk ketone group was 1.3 mg/kg/d, and the dosage of the crocin group I was 20 mg/kg/d; the active ingredient composition group was administered The dose is 35mg/kg/d clove+31mg/kg/d elemenin+1.3mg/kg/d musk ketone+20mg/kg/d crocin I. The above positive drug nimodipine and the test drugs eugenol, elemenin, musk ketone, crocin I, and the active ingredient composition were prepared with 0.5% carboxymethyl cellulose sodium (0.5% CMC-Na) as solvent respectively. to the required gavage concentration of the drug. The rats in each group were administered sequentially from 9:00 am to 12:00 am every day, and were administered consecutively for 14 days before MCAO modeling.

3. Observation indicators

3.1 Neurological function score

Neurological function scoring was performed 24 hours after the modeling operation (ie, ischemia-reperfusion), and the scoring standard was based on the Zea Longa 5 standard. No neurological deficit symptoms, 0 points; forelimb bending, unable to fully extend the forepaw on the opposite side of the lesion, 1 point; spontaneous rotation to the opposite side of the lesion, 2 points; unsteady standing, dumping to the opposite side of the lesion, 3 points; no spontaneous Sexual walking and loss of consciousness, 4 points. The lower the score, the more normal the neurological function, on the contrary, the higher the score, the more serious the neurological damage.

3.2 Cerebral infarct size (TTC) ratio

24 hours after the end of the modeling operation (ie, ischemia-reperfusion), the rats were rapidly decapitated and the brains were removed, and the intact brain tissue was placed in a -20 degree refrigerator for 20 minutes, and then routinely sliced. Cut into 5 slices and incubate them in 2% pre-warmed TTC staining solution at 37°C for 45 min in the dark, turning every 15 min to ensure that the brain slices are evenly stained. The ischemic area is white, and the non-ischemic area is rose red. The infarct area of the rat brain was determined according to the percentage of the total infarct area of each coronal section of the brain tissue in the total brain area. The average of 5 slices was taken from each rat as the ratio of cerebral infarction area of the rat.

4. Statistical analysis

The data were expressed as mean + standard deviation, and SPSS 18.0 was used for analysis. The comparison of sample means between groups was performed by t test, and P<0.05 was regarded as a significant difference.

5. Experimental results

5.1 Comparison of neurological function scores of rats in each group

As shown in Figure 1, the neurological function of the sham operation group was normal, and the behavioral score was 0. The rats in the model group developed neurological dysfunction that the contralateral front paw could not be fully extended, or turned to the contralateral side or dumped, and the neurological deficit score was significantly higher than that of the sham-operated group (p<0.001). Compared with the model group, the neurological function scores of each administration group were decreased (p<0.05), indicating that each index component had a certain degree of protective effect on neurological damage, and the protective effect of the composition of the four index components was better than that of each of the four index components. The active ingredients were more obvious (p<0.001), indicating that there was a synergistic effect after the four index ingredients were mixed.

5.2 Comparison of cerebral infarction volume in each group of rats

As shown in Figures 2 and 3, the brain tissue of the sham-operated group was stained uniformly red, and no pale infarct area was found. A large range of pale infarcts appeared in the model group, indicating that the cerebral infarction model was successfully established (p<0.001). Compared with the model group, the cerebral infarction volume of each index component administration group was reduced to varying degrees (p<0.01), and the four index component compositions of the present invention were the most obvious (p<0.001), indicating that the four index components There is a synergistic effect when used in combination.

6. Experimental conclusion

The present invention utilizes whole animal research, and finds that the index components of clove, nutmeg, musk and saffron have synergistic effects after being combined with eugenol, elemenin, musk ketone and saffron I, and can maximize the use of nerve Protective effect and effectively prevent ischemic stroke.

The various embodiments in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments, and the same and similar parts between the various embodiments can be referred to each other. As for the device disclosed in the embodiment, since it corresponds to the method disclosed in the embodiment, the description is relatively simple, and the relevant part can be referred to the description of the method.

The above description of the disclosed embodiments enables any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (10)

1. The composition is characterized by comprising the following raw materials in parts by mass: 10-50 parts of eugenol, 10-50 parts of elemene, 0.5-3 parts of muscone and 10-30 parts of crocin I;

the structural formula of the eugenol is as follows:

the structural formula of the elemene is as follows:

the structural formula of the muscone is as follows:

the structural formula of the crocin I is as follows:

2. use of the composition of claim 1 in the preparation of a medicament for the prevention and treatment of cerebral arterial thrombosis.

3. The pharmaceutical composition for preventing and treating ischemic stroke, which is characterized by comprising the composition as claimed in claim 1 and pharmaceutically acceptable auxiliary materials, wherein the mass ratio of the composition to the auxiliary materials is 1: 99-99: 1; the auxiliary materials comprise any one or a combination of more of a solvent, a diluent, a bonding agent, a disintegrating agent, a lubricant, an absorption enhancer, a preservative or a flavoring agent.

4. The pharmaceutical composition for preventing and treating ischemic stroke as set forth in claim 3, wherein the solvent is selected from the group consisting of water, ethanol, propylene glycol and castor oil for injection.

5. The pharmaceutical composition for preventing and treating ischemic stroke as claimed in claim 3, wherein the diluent comprises any one or more of starch, powdered sugar, dextrin, lactose, pregelatinized starch, microcrystalline cellulose or inorganic calcium salt.

6. The pharmaceutical composition for preventing and treating ischemic stroke as claimed in claim 3, wherein the binder comprises one or more of water, ethanol, starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and ethyl cellulose or hypromellose.

7. The pharmaceutical composition for preventing and treating ischemic stroke as claimed in claim 3, wherein the disintegrant comprises one or more of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone or croscarmellose sodium.

8. The pharmaceutical composition for preventing and treating ischemic stroke as claimed in claim 3, wherein the lubricant comprises one or more of magnesium stearate, silica gel, talc, hydrogenated vegetable oil, polyethylene glycol and magnesium lauryl sulfate.

9. The pharmaceutical composition for preventing and treating ischemic stroke as claimed in claim 3, wherein the absorption enhancer comprises any one or more of aromatic acid compound or aliphatic acid.

10. The pharmaceutical composition for preventing and treating ischemic stroke according to claim 3, wherein the preservative comprises any one or more of benzoic acid, hydroxypropyl butyl ester, hydroxypropyl methyl ester, phenol or m-cresol; the flavoring agent comprises one or more of sucrose and steviosin.

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