CN113398113A - Application of pinoresinol in preparing medicine for inhibiting thrombosis - Google Patents
Application of pinoresinol in preparing medicine for inhibiting thrombosis Download PDFInfo
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- CN113398113A CN113398113A CN202110700864.4A CN202110700864A CN113398113A CN 113398113 A CN113398113 A CN 113398113A CN 202110700864 A CN202110700864 A CN 202110700864A CN 113398113 A CN113398113 A CN 113398113A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
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Abstract
The invention provides application of pinoresinol in preparing a medicament for inhibiting thrombosis, and relates to the field of chemical medicaments. Specifically provides an application of the compound shown in the formula I, or a salt, a solvate, a hydrate or a prodrug thereof in preparing a medicament for inhibiting thrombosis. The compound represented by the formula I is preferably pinoresinol. The research of the invention finds that the compound pinoresinol extracted from the yellow clover can be used for inhibiting vasoconstriction and has obvious vasodilation effect. At the same time, the compound pinoresinol has inhibitory effect on thrombosis, and low dose of pinoresinol inhibitsThe effect of thrombosis is better than that of high dose, the thrombosis inhibition rate is as high as 76.92%, the dosage of the medicine is reduced while the excellent effect of inhibiting thrombosis is obtained, and the safety of the medicine use is improved. The compound pinoresinol can be used for preparing medicines for inhibiting thrombosis and preventing or treating thromboembolic diseases, and has good application prospect.
Description
Technical Field
The invention relates to the field of chemical medicines, in particular to application of pinoresinol in preparing medicines for inhibiting thrombosis.
Background
At present, the incidence rate of thromboembolic diseases is higher than that of various cardiovascular diseases, and the thromboembolic diseases have serious harm to the life health of human beings. Pathological research shows that the pathogenesis of the thrombus is related to the function in blood vessels, and the thrombus is mainly shown in that the blood vessel coagulation and fibrinolysis system disorder is caused when the function of the blood vessel endothelium is damaged, the formation of atherosclerotic plaques is promoted, and the atherosclerotic plaques fall off under the action of various inducers to form thrombus, block the blood vessels and cause the occurrence of thromboembolic diseases. Since thromboembolic diseases seriously threaten human life health and have high incidence rate at the head of various diseases, the diseases are increasing in recent years, and thus become one of the key points and hot spots of modern medical research.
The yellow day-lily oleaster is dry whole herb of a plant in the genus of Oenothera in the family of Liliaceae, has the effects of tonifying lung, relieving cough, promoting qi and blood circulation, dissipating stagnation, tonifying deficiency and the like, is widely used for treating various symptoms caused by diseases such as bone injury blood stasis and the like in folk, and has a remarkable curative effect; and has outstanding curative effect on symptoms such as dizziness, weakness of hands and feet, numbness of limbs, migraine and the like caused by thromboembolic diseases. However, the medicinal material belongs to a local conventional variety in Shaanxi province, the basic research of the material is weak, and the mechanism of the blood activating action is not clear at present.
A compound, Pinoresinol, is extracted from Dioscorea citrifolia L. The pinoresinol belongs to a lignan compound, and has the following structure:
colophonium has good antifungal activity, can destroy fungal plasmid membrane without causing erythrocyte hemolysis, and has antibacterial effect, and is a potential antibacterial agent for treating fungal infection of human body. Meanwhile, the pinoresinol can show good inflammatory activity after being absorbed and metabolized in the small intestine. In addition, pinoresinol can also prevent cardiovascular diseases such as atherosclerosis by inhibiting the oxidation of low density lipoprotein. Although pinoresinol has the above-mentioned biological activity, it has not been known that pinoresinol is useful for inhibiting thrombosis.
Disclosure of Invention
The invention aims to provide application of pinoresinol in preparing a medicament for inhibiting thrombosis.
The invention provides an application of a compound shown as a formula I, or a salt, a solvate, a hydrate or a prodrug thereof in preparing a medicament for inhibiting thrombosis:
wherein R is1、R2、R3、R4Are respectively and independently selected from hydrogen and C1~C8Alkyl radical, C1~C8Alkoxy, halogen, amino, nitro, carboxyl, hydroxyl.
Further, the compound is represented by formula II:
wherein R is1、R4Are respectively and independently selected from hydrogen and C1~C3A group, a halogen.
Further, the compound is the following compound pinoresinol:
further, the drug is FeCl inhibitor3A drug for inducing thrombosis.
Further, the drug is a vasodilating drug;
and/or, the drug is a vasoconstrictor-inhibiting drug.
Further, the drug is a drug that inhibits the contraction of vascular smooth muscle.
Further, the medicament is a medicament for preventing and/or treating thromboembolic diseases; the thromboembolic disorder is a disorder formed by thromboembolism.
Further, the thromboembolic disease is cerebral thrombosis, myocardial infarction, intermittent claudication, pulmonary embolism, splenic infarction, mesenteric arterial embolism and/or lower limb arterial sclerosis.
Furthermore, the medicine is a preparation prepared by taking the compound, the salt thereof, the solvate thereof, the hydrate thereof or the prodrug thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The invention also provides a medicament which is a preparation prepared by taking the compound, the salt thereof, the solvate thereof, the hydrate thereof or the prodrug thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
The research of the invention finds that the compound pinoresinol extracted from the yellow clover can be used for inhibiting vasoconstriction and has obvious vasodilation effect. Meanwhile, the compound pinoresinol has an inhibiting effect on the formation of thrombus, the effect of inhibiting the formation of thrombus by using low-dose pinoresinol is better than that of inhibiting the formation of thrombus by using high-dose pinoresinol, the inhibition rate of the formation of thrombus is as high as 76.92%, the excellent effect of inhibiting the formation of thrombus is obtained, the dosage of the medicament is reduced, and the safety of the medicament in use is improved. The compound pinoresinol can be used for preparing medicines for inhibiting thrombosis and preventing or treating thromboembolic diseases, and has good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a flow chart of the separation of pinoresinol from Dioscorea citrifolia.
FIG. 2 is a graph showing the effect of pinoresinol on vascular smooth muscle contraction following administration of the vasoconstrictor KCl.
FIG. 3 shows the results of the vasodilation rate after the addition of the positive drug or pinoresinol.
FIG. 4 shows the weights of carotid artery thrombus and the thrombus formation inhibition rates of rats; wherein, in comparison to the blank set,###p<0.001; in comparison with the set of models,***p<0.001,**p<0.01,*p<0.05。
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Example 1 preparation of Colophonium
(1) Preparation of ethyl acetate extract of daylily oil spot
The method comprises the steps of collecting the yellow day lily (10.0kg) picked in 2018 in Oak county in Shaanxi province, drying, crushing, extracting for 4 times by an 80% methanol immersion method at room temperature, wherein 4.5 times of 80% methanol (namely 4.5L of water is added to each 1kg of yellow day lily) is used for extraction, and the extraction time is 3, 5, 7 and 7 days in sequence. After extraction, the filtrates were combined, and methanol was recovered under reduced pressure and concentrated to obtain 495.0g of methanol extract. Dispersing the methanol extract in water, extracting with ethyl acetate for 5 times to obtain ethyl acetate phase, and concentrating under reduced pressure to obtain ethyl acetate extract.
(2) Separation of pinoresinol from ethyl acetate extract of daylily oil spot
160.0g of ethyl acetate extract is dissolved by 60mL of 100% methanol, after the solvent is completely volatilized, sample mixing is carried out by a dry method, and 50%, 75%, 85% and 100% methanol are eluted by macroporous resin (10 × 60cm, 5 × 6L) to obtain four fractions (Fr.1-4). Fr.2(24.0g) was eluted with methanol at three concentrations of 50%, 75% and 85% and three fractions (Fr.2A-2C) were separated on an MCI column (6X 20cm, 6X 180mL) using a medium pressure separation system. Fr.2C (1.8g) was eluted with a chloroform-methanol system (v/v, 40:1 → 2:1) using a silica gel column (5X 6L) of 400 mesh using silica gel powder of 300-. Wherein the subfraction 2C3(0.6g) is obtained by silica gel column chromatography, gradient elution (3 × 100mL) is carried out under the conditions of 300-400 mesh silica gel powder and petroleum ether-ethyl acetate (v/v, 4:1 → 1:1), and eleven subfraction branches of 2C3a-2C3k are obtained after crude separation. Pinoresinol (5.4mg, tR ═ 16min) was purified by semi-preparative HPLC using subfraction 2C3g (12.7mg) under mobile phase conditions methanol-water (60: 40). The separation scheme is shown in FIG. 1.
As a result: and (3) carrying out structural analysis on the pinoresinol: a light yellow powder; 1H-NMR(CD3OD,600MHz)δ:6.93,6.78,6.75,4.69,4.20,3.84,3.75,3.11;13C-NMR(CD3OD,150MHz)δ:149.1,147.3,133.9,120.0,15.1,111.1,87.5,72.6,56.5,55.4。
example 2 functional test of Colophonium for inhibiting thrombosis
(1) Preparation of the principal solution
Krebs-Henseleit K-H (mmol/L) buffer (hereinafter referred to as K-H buffer): 6.903g NaCl, 0.358g KCl, 2.1g NaHCO were weighed3、0.163g KH2PO4、0.278g CaCl2、0.144g MgSO41.938g D-glucose, was brought to 1L with deionized water at pH 7.4.
High K+K-H buffer (hereinafter referred to as high K)+K-H buffer): 3.674g NaCl, 4.470g KCl, 2.1g NaHCO were weighed3、0.163g KH2PO4、0.278g CaCl2、0.144g MgSO41.938g D-glucose, was brought to 1L with deionized water at PH 7.4.
(2) Preparation of vascular rings
a. Laboratory animal
SD rats, 20, with a weight of 200.00-250.00g, male, provided by the center of the Szechwan Kyoda Shuo laboratory animals with license number SCXK 2020 one 030. The experimental animals are raised in a pharmacology experimental animal laboratory of college of pharmacy of Shanxi traditional Chinese medicine university, sufficient water and feed are supplied, good ventilation and illumination are kept, adaptive feeding is carried out for 4 days, cages, padding and feed are all subjected to high pressure and ultraviolet disinfection treatment, and drinking water is bottled drinking water of Hangzhou child haha group limited company.
b. Preparation process
After the SD rat is sacrificed, the mesenteric aorta is quickly taken out, immersed into a K-H buffer solution, fat and redundant connective tissue wrapped outside the blood vessel are separated under a microscope, and the separated blood vessel is cut to a blood vessel ring with the length of about 2-3mm for standby.
1mL of K-H buffer was added to a 37 ℃ super-incubator and 95% O was continuously added thereto2With 5% CO2Mixed gas to simulate the environment in vivo. And the prepared vascular ring is hung on two L-shaped metal needles, wherein one of the two L-shaped metal needles is connected with a tension transducer, and the other one of the two L-shaped metal needles is connected with a fine adjustment device for adjusting load tension. The mounted vascular ring is placed in a prepared super thermostatic bath environment, the tension is adjusted, 5mg of pretension is given, the balance is carried out for 60min, and the K-H buffer solution is replaced every 10min in the period. After the balance is finished, the high K is used+K-H buffer solution is used for testing the contractility of the blood vessel rings, and the blood vessel rings with contraction amplitude less than 10% are selected twice for experiments. The loop was washed with normal K-H buffer until the tension stabilized at baseline and the dosing assay was started.
(3) Shrinkage test
The method comprises the following steps: endothelial function was examined by KCl-stimulated vasoconstriction: the contraction experiment uses methanol as solvent to prepare 1 μ M pinoresinol, 10 μ L of the prepared pinoresinol solution is added into the blood vessel for incubation for 30min, 10 μ L of 0.5mM KCl solution is added each time by concentration accumulation method to make the final concentration of KCl in a constant temperature tank be 1 × 10-3~3×10-3M, detecting the effect of the compound for inhibiting KCl stimulation to cause vascular smooth muscle contraction under different KCl concentrations, recording the change condition of vascular tension, calculating a concentration gradient dose-response curve, and calculating the contraction rate; in the vascular ring onlyKCl was added and no pinoresinol was added as a blank control. The maximum shrinkage is the shrinkage at the maximum KCl concentration.
As a result: the effect of pinoresinol on vascular smooth muscle contraction after addition of KCl is shown in FIG. 2. The maximum contraction rate of the vascular smooth muscle of the blank control group without the addition of the pinoresinol is 93.06% +/-12.5%; the maximum contraction rate of the vascular smooth muscle is reduced to 49.39 +/-9.46% after the pinoresinol is used, and is obviously lower than that of a blank control group. Therefore, the pinoresinol can obviously inhibit vasoconstriction caused by KCl.
(4) Relaxation test
The method comprises the following steps: relaxation experiments administration of 0.5mg pre-tension to the vessel was initiated by adjusting the tension loader and incubation until the instrument showed the tension curve to be balanced.
a. Adding 10 μ L of pre-contracting blood vessel medicine PE (phenylephrine, 1 × 10)-2M) causing maximal constriction of blood vessels;
b. weighing appropriate amount of positive control drug and Colophonium, and respectively preparing into 1 × 10-8M、2×10-8M、7×10-8M、2×10- 7M、7×10-7M、2×10-6M、7×10-6M、2×10-5M、7×10-5M、2×10-4M、7×10-4M eleven concentrations;
c. taking endothelium-independent vasodilator Ach (acetylcholine) as positive control drug, and adding 10 μ L of pinoresinol or positive control drug each time by cumulative concentration method to induce vasodilatation (at the time, the final concentration of drug PE in thermostatic bath is 1 × 10)-10~1×10-5M);
d. Recording the vascular tension value when the pinoresinol or the positive control drug is added each time, and calculating the diastole rate according to the following formula; the maximum contraction rate is the relaxation rate at which the concentration of pinoresinol or positive control drug is maximum.
As a result: the results of vasodilation after addition of the positive drug or pinoresinol are shown in FIG. 3. The result shows that the maximum relaxation rate of the positive control drug Ach is 69.1% + -4.14%, the maximum relaxation rate of the pinoresinol is 68.78% + -1.21%, the result proves that the pinoresinol has obvious vasodilation effect, the final result of the action of the pinoresinol and the non-endothelium-dependent vasodilator Ach is nearly equal, the antithrombotic action mechanism of the pinoresinol has no correlation with the vascular endothelium, the effect of the pinoresinol in inhibiting KCl from contracting the blood vessels is very obvious, and the mechanism of the pinoresinol in playing the blood circulation effect is related to relaxing the vascular smooth muscle.
(5) In vivo Activity and mechanism of action
The method comprises the following steps:
a. laboratory animal
SD rats, 30, 100-150g in body weight, male, provided by Sichuan achievements center of action, license number: SCXK 2020-. The experimental animals are raised in an SPF experimental animal laboratory of the collaborative innovation center of Shanxi university of traditional Chinese medicine, sufficient water and feed are supplied, good ventilation and illumination are kept, adaptive feeding is carried out for 3 days, cages, padding and feed are all subjected to high pressure and ultraviolet disinfection treatment, and drinking water is self-made sterilized purified water.
b. Experimental procedure
30 female adult SD rats were divided into 6 groups according to body weight, 0.5mL of physiological saline was administered to the blank group (blank), 0.5mL of sodium carboxymethylcellulose was administered to the model group (model), 9.0mg/kg of aspirin enteric-coated tablet was administered to the positive drug control group (positive drug), and different doses of pinoresinol were administered to the pinoresinol administration group, among which the high dose group (8.8mg/kg), the medium dose group (4.4mg/kg), and the low dose group (2.2 mg/kg). The administration modes of SD rats are intragastric administration, the administration dose is calculated according to an experimental animal dose conversion formula of pharmacological experimental methodology for each group, the administration volume is 1mL, and the administration is continuously intragastric for 7 days. The mice were fasted for 12h before the last administration, and were anesthetized by intraperitoneal injection of 10% chloral hydrate (prepared just before use) to each group 30min after administration. Separating left carotid artery of rat, wrapping carotid artery blood vessel with plastic preservative film to separate from other tissues, and infiltratingFeCl of 4%3The filter paper (1.0cm multiplied by 1.0cm) is wrapped on the separated carotid artery blood vessel, a blank group is wrapped with normal saline, thrombus formation can be seen after 5min, the upper end and the lower end of the blood vessel are ligated, the blood vessel with the thrombus of 1.0cm in length is accurately cut off by a vernier caliper and placed on the blank filter paper, blood infected around the blood vessel is quickly sucked dry, then the blood vessel is cut off, the weight of the blood vessel wall is weighed, the secondary weighing difference value is the weight of the thrombus, and the experimental result is expressed by the average value +/-standard deviation. The formula of the thrombosis inhibition rate is as follows: the administration groups were positive drug control group, high dose group, medium dose group and low dose group.
As a result: through the data analysis in Table 1 and FIG. 4, FeCl was found3After the SD rat carotid artery thrombosis is induced for 5min, compared with the model group, the thrombus weight of each administration group is obviously reduced; the inhibition rate of thrombus formation of the low-dose administration group of the pinoresinol is 76.92 percent, and the inhibition rate of the medium-dose group of the pinoresinol is 72.65 percent which are both greater than the inhibition rate of the high-dose group of the pinoresinol by 43.59 percent, which indicates that the inhibition rate of thrombus formation is not in direct proportion to the administration dose within a certain range and may have a certain relation with the maximum dose of the medicine absorbed and metabolized in the rat body; each group was statistically different (P < 0.05) compared to the blank group; compared with a model group, the administration groups have obvious difference in high, medium and low doses (P is less than 0.05), each administration group has a certain inhibition effect on the carotid artery thrombosis of rats, and the inhibition effect of the low dose group is stronger than that of other groups. Shows that the pinoresinol can indeed inhibit FeCl3The induced thrombus is formed, the effect of inhibiting the thrombus formation is better if the dosage of the pinoresinol is lower, the dosage of the medicine can be reduced, and the medicine is safer.
TABLE 1 thrombogenic weight and inhibition rate for each administration group
Note: in comparison with the blank set, the results,###p<0.001; in comparison with the set of models,***p<0.001,**p<0.01,*p<0.05。
in conclusion, the research of the invention finds that the compound pinoresinol extracted from the yellow clover can be used for inhibiting vasoconstriction and has obvious effect of relaxing blood vessels. Meanwhile, the compound pinoresinol has an inhibiting effect on the formation of thrombus, the effect of inhibiting the formation of thrombus by using low-dose pinoresinol is better than that of inhibiting the formation of thrombus by using high-dose pinoresinol, the inhibition rate of the formation of thrombus is as high as 76.92%, the excellent effect of inhibiting the formation of thrombus is obtained, the dosage of the medicament is reduced, and the safety of the medicament in use is improved. The compound pinoresinol can be used for preparing medicines for inhibiting thrombosis and preventing or treating thromboembolic diseases, and has good application prospect.
Claims (10)
1. Use of a compound represented by formula I, or a salt thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof, in the preparation of a medicament for inhibiting thrombosis:
wherein R is1、R2、R3、R4Are respectively and independently selected from hydrogen and C1~C8Alkyl radical, C1~C8Alkoxy, halogen, amino, nitro, carboxyl, hydroxyl.
4. use according to any one of claims 1 to 3, characterized in that: the drug is FeCl3A drug for inducing thrombosis.
5. Use according to any one of claims 1 to 3, characterized in that: the drug is a vasodilating drug;
and/or, the drug is a vasoconstrictor-inhibiting drug.
6. Use according to claim 5, characterized in that: the medicament is a medicament for inhibiting the contraction of vascular smooth muscle.
7. Use according to any one of claims 1 to 3, characterized in that: the medicament is a medicament for preventing and/or treating thromboembolic diseases; the thromboembolic disorder is a disorder formed by thromboembolism.
8. Use according to claim 7, characterized in that: the thromboembolic disease is cerebral thrombosis, myocardial infarction, intermittent claudication, pulmonary embolism, spleen infarction, mesenteric artery embolism and/or lower limb arterial sclerosis.
9. Use according to any one of claims 1 to 3, characterized in that: the drug is a preparation prepared by taking the compound or the salt thereof, or the solvate thereof, or the hydrate thereof, or the prodrug thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
10. A medicament, characterized by: the pharmaceutical preparation is prepared by taking the compound or the salt thereof, the solvate thereof, the hydrate thereof or the prodrug thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
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