阅读说明：本技术 一种减轻戒断症状的中药组方制剂及其制备方法 (Traditional Chinese medicine formula preparation for relieving withdrawal symptoms and preparation method thereof ) 是由 董慧芳 于 2020-04-26 设计创作，主要内容包括：本发明为一种减轻戒断症状的中药组方制剂及其制备方法,中药组方制剂的原料包括夏天无、洋金花、天麻、红参等十四味药材,通过提取其有效成分制成清膏,最后制成颗粒。本制剂对阿片类毒品成瘾者戒断症状疗效显著,特别是对戒断症状中的哈欠、骨骼肌疼痛和失眠等症状,适用于阿片类毒品的脱毒治疗。另外本发明的制备工艺简便,疗效确切,耐受性良好,安全性较高,不良反应轻。(The invention relates to a traditional Chinese medicine prescription preparation for relieving withdrawal symptoms and a preparation method thereof, wherein the raw materials of the traditional Chinese medicine prescription preparation comprise fourteen medicinal materials such as corydalis amabilis, datura flower, gastrodia elata, red ginseng and the like, and active ingredients of the medicinal materials are extracted to prepare a clear paste, and finally the clear paste is prepared into granules. The preparation has obvious curative effect on withdrawal symptoms of opioid drug addicts, particularly on yawning, skeletal muscle pain, insomnia and other symptoms in the withdrawal symptoms, and is suitable for the detoxification treatment of opioid drugs. In addition, the invention has simple preparation process, definite curative effect, good tolerance, higher safety and light adverse reaction.)

1. A traditional Chinese medicine formula preparation for relieving withdrawal symptoms is characterized in that: the raw materials of the traditional Chinese medicine composition comprise, by weight, 1-340 parts of corydalis amabilis, 1-6 parts of datura flower, 1-85 parts of turmeric, 1-130 parts of red sage root, 1-43 parts of asarum, 1-130 parts of radix stephaniae tetrandrae, 1-85 parts of cortex albiziae, 1-85 parts of wild jujube seed (fried), 1-130 parts of gastrodia elata, 1-85 parts of red ginseng, 1-60 parts of dried ginger, 1-60 parts of fructus amomi, 1-85 parts of fructus forsythiae and 1-85 parts of liquorice.

2. The formulation of claim 1, wherein the formulation comprises a combination of the following ingredients: the raw materials of the traditional Chinese medicine comprise, by weight, 333.3 parts of corydalis decumbens, 5 parts of datura flower, 83.3 parts of turmeric, 125 parts of red sage root, 41.7 parts of asarum, 125 parts of radix stephaniae tetrandrae, 83.3 parts of cortex albiziae, 83.3 parts of fried spina date seed, 125 parts of gastrodia elata, 83.3 parts of red ginseng, 50 parts of dried ginger, 50 parts of fructus amomi, 83.3 parts of fructus forsythiae and 83.3 parts of liquorice.

3. A method of preparing a formulation of a Chinese medicinal composition as claimed in claims 1-2, wherein: it comprises the following steps:

step 1: pulverizing rhizoma corydalis Decumbentis and flos Daturae Metelis powder, extracting with ethanol under reflux for several times, mixing extractive solutions, recovering ethanol, and concentrating to obtain fluid extract A;

step 2: distilling herba asari, Curcuma rhizome, Zingiberis rhizoma, fructus forsythiae, and fructus Amomi with steam to obtain volatile oil, and collecting the distilled water solution;

and step 3: mixing the residues in the step 2 with the salvia miltiorrhiza, the radix stephaniae tetrandrae, the cortex albiziae, the spina date seed (fried), the gastrodia elata, the red ginseng and the liquorice, adding water for decocting for multiple times, mixing decoction, filtering residues, and mixing the filtrate with the aqueous solution in the step 2 to form a mixed solution; concentrating the mixed solution, adding ethanol to precipitate the mixed solution, extracting supernatant, recovering ethanol, and further concentrating to obtain fluid extract B;

step 4, preparing mixed clear paste by the clear paste A and the clear paste B;

and 5: adding appropriate amount of sucrose powder into the mixed fluid extract of step 4, granulating, drying, spraying the volatile oil of step 2, mixing, and sealing for 30 min.

4. The preparation method of the traditional Chinese medicine prescription preparation according to claim 1 is characterized in that:

step 1: crushing corydalis amabilis and datura flower powder, extracting for 2-3 times and 2-3 hours each time by using ethanol reflux liquid with the weight being 7-10 times of the medicinal powder and the concentration being 45-55%, recovering ethanol by using a decompression mode after combining extracting solutions, and concentrating to obtain clear paste A with the relative density being 1.25-1.30 (80 ℃).

5. The preparation method of the traditional Chinese medicine prescription preparation according to claim 1 is characterized in that:

and step 3: mixing the residues in the step 2 with the salvia miltiorrhiza, the radix stephaniae tetrandrae, the cortex albiziae, the spina date seed (fried), the gastrodia elata, the red ginseng and the liquorice, adding water, decocting for 3 times, 2 hours each time, mixing decoction, filtering residues, and mixing the filtrate with the aqueous solution in the step 2 to form a mixed solution; concentrating the mixed solution to relative density of 1.08-1.10 (60 deg.C), adding 95% ethanol to precipitate the mixed solution, extracting supernatant, recovering ethanol, and further concentrating to obtain fluid extract B with relative density of 1.25-1.30 (80 deg.C).

Technical Field

The invention relates to the technical field of medicinal preparations, in particular to a traditional Chinese medicine formula preparation for relieving withdrawal symptoms and a preparation method thereof.

Background

Methadone replacement therapy is a drug rehabilitation method generally adopted internationally, but cannot completely get rid of the physiological dependence of drug addicts on drugs.

Therefore, the country encourages to develop Chinese medical treasury and develop Chinese herbal medicine preparation which can relieve withdrawal symptoms, has definite curative effect, safety and reliability, low toxic and side effects and does not generate new physical dependence and helps drug addicts to get rid of the harm of drugs.

Disclosure of Invention

The invention aims to: a Chinese medicine in the form of prescription for relieving the withdrawal symptom of drug-taking person is prepared from fourteen Chinese-medicinal materials including corydalis tuber, datura flower, gastrodia tuber, red ginseng, etc.

The invention is realized by the following technical scheme:

a traditional Chinese medicine formula preparation for relieving withdrawal symptoms comprises the following raw materials, by weight, 1-340 parts of Tianwu, 1-6 parts of datura flower, 1-85 parts of turmeric, 1-130 parts of red sage root, 1-43 parts of asarum, 1-130 parts of radix stephaniae tetrandrae, 1-85 parts of cortex albiziae, 1-85 parts of fried spina date seed, 1-130 parts of gastrodia elata, 1-85 parts of red ginseng, 1-60 parts of dried ginger, 1-60 parts of fructus amomi, 1-85 parts of fructus forsythiae and 1-85 parts of liquorice.

A preparation method of a traditional Chinese medicine prescription preparation for relieving withdrawal symptoms comprises the following steps:

step 1: pulverizing rhizoma corydalis Decumbentis and flos Daturae Metelis powder, extracting with ethanol under reflux for several times, mixing extractive solutions, recovering ethanol, and concentrating to obtain fluid extract A;

step 2: distilling herba asari, Curcuma rhizome, Zingiberis rhizoma, fructus forsythiae, and fructus Amomi with steam to obtain volatile oil, and collecting the distilled water solution;

and step 3: mixing the residues in the step 2 with the salvia miltiorrhiza, the radix stephaniae tetrandrae, the cortex albiziae, the spina date seed (fried), the gastrodia elata, the red ginseng and the liquorice, adding water for decocting for multiple times, mixing decoction, filtering residues, and mixing the filtrate with the aqueous solution in the step 2 to form a mixed solution; concentrating the mixed solution, adding ethanol to precipitate the mixed solution, extracting supernatant, recovering ethanol, and further concentrating to obtain fluid extract B;

step 4, preparing mixed clear paste by the clear paste A and the clear paste B;

and 5: adding appropriate amount of sucrose powder into the mixed fluid extract of step 4, granulating, drying, spraying the volatile oil of step 2, mixing, sealing for 30 min, and making into 1000 parts.

Further, step 1: crushing corydalis amabilis and datura flower powder, extracting for 2-3 times and 2-3 hours each time by using ethanol reflux liquid with the weight being 7-10 times of the medicinal powder and the concentration being 45-55%, recovering ethanol by using a decompression mode after combining extracting solutions, and concentrating to obtain clear paste A with the relative density being 1.25-1.30 (80 ℃);

further, step 3: mixing the residues in the step 2 with the salvia miltiorrhiza, the radix stephaniae tetrandrae, the cortex albiziae, the spina date seed (fried), the gastrodia elata, the red ginseng and the liquorice, adding water, decocting for 3 times, 2 hours each time, mixing decoction, filtering residues, and mixing the filtrate with the aqueous solution in the step 2 to form a mixed solution; concentrating the mixed solution to relative density of 1.08-1.10 (60 deg.C), adding 95% ethanol to precipitate the mixed solution, extracting supernatant, recovering ethanol, and further concentrating to obtain fluid extract B with relative density of 1.25-1.30 (80 deg.C).

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

1. the preparation has obvious curative effect on withdrawal symptoms of opioid drug addicts, particularly on yawning, skeletal muscle pain, insomnia and other symptoms in the withdrawal symptoms, and is suitable for the detoxification treatment of opioid drugs.

2. The invention has simple preparation process, definite curative effect, good tolerance, higher safety and light adverse reaction.

Detailed Description

The present invention will be described in detail with reference to the following examples:

example 1

A traditional Chinese medicine prescription preparation for relieving withdrawal symptoms is prepared by the following raw materials according to a preferred scheme: the traditional Chinese medicine composition comprises 333.3 parts of corydalis decumbens, 5 parts of datura flower, 83.3 parts of turmeric, 125 parts of salvia miltiorrhiza, 41.7 parts of asarum, 125 parts of radix stephaniae tetrandrae, 83.3 parts of cortex albiziae, 83.3 parts of fried spina date seed, 125 parts of gastrodia elata, 83.3 parts of red ginseng, 50 parts of dried ginger, 50 parts of fructus amomi, 83.3 parts of fructus forsythiae and 83.3 parts of liquorice in parts by weight.

Example 2

A preparation method of a traditional Chinese medicine prescription preparation for relieving withdrawal symptoms, wherein the medicine components and parts are referred to example 1, and the preparation method comprises the following steps:

step 1: pulverizing rhizoma corydalis Decumbentis and flos Daturae Metelis powder (particle size of 1-3 mm), extracting with 50% ethanol reflux solution 8 times the weight of the powder for 3 times (each time for 3 hr), mixing the two extractive solutions, filtering, recovering ethanol under reduced pressure, and concentrating to obtain fluid extract A with relative density of 1.25-1.30 (80 deg.C);

step 2: distilling herba asari, Curcuma rhizome, Zingiberis rhizoma, fructus forsythiae, and fructus Amomi with steam to obtain volatile oil, and collecting the distilled water solution;

and step 3: mixing the residues in the step 2 with the salvia miltiorrhiza, the radix stephaniae tetrandrae, the cortex albiziae, the spina date seed (fried), the gastrodia elata, the red ginseng and the liquorice, adding water, decocting for 3 times, 2 hours each time, mixing decoction, filtering residues, and mixing the filtrate with the aqueous solution in the step 2 to form a mixed solution; concentrating the mixed solution to relative density of 1.08-1.10 (60 deg.C), adding equal amount of 95% ethanol to precipitate the mixed solution, extracting supernatant, recovering ethanol, and further concentrating to obtain fluid extract B with relative density of 1.25-1.30 (80 deg.C);

step 4, preparing mixed clear paste by the clear paste A and the clear paste B;

and 5: adding appropriate amount of sucrose powder into the mixed fluid extract of step 4, granulating, drying, spraying the volatile oil of step 2, mixing, sealing for 30 min, and making into 1000 parts.

Example 3

Acute toxicity test: the maximum daily tolerance of 18g/kg of gavage Kunming mice (20 mice, half each female and half each male) are administrated three times a day, and the dosage is reduced to 180g/kg of crude drug, which is equivalent to 90 times of the daily dosage of a human body (70 kg); and the Wistar rats (20 rats with half of the male and female rats) with the maximum daily tolerance of 11.25g/kg are administrated three times a day, the total dose is 112.5g/kg, which is equivalent to 56 times of the daily dose of a human body (70 kg), the Wistar rats are continuously administrated for one week, the change of the appearance behaviors of the animals is observed, and the death number of the animals is counted. The results show that: after the first gavage administration of the rats, except for the action retardation of individual animals, no abnormal behavior change is seen, after the second gavage administration, the rats are sleepy and slow in response to different degrees, and the animals of the third administration part have loose fur. The symptoms disappeared on day four and the animals returned to normal. The animals had a normal diet within one week, and one animal was not shown to die. After three times of administration, the mice have no abnormal expression, the diet, the activity and the hair are all normal, and the weight of the mice averagely increases by about 3g after 7 days.

Example 4

Long-term toxicity test: 60 Wistar rats, half male and female, are randomly divided into 3 groups, each group comprises 20 animals, a high dose group (16 g/kg, which is equivalent to 80 times of daily dosage for clinical use), a low dose group (6 g/kg, which is equivalent to 30 times of daily dosage for clinical use) and a negative control group (only fed with feed), the animals are continuously dosed for 1 month by a feeding method, 1/2 animals are killed in each group on the 31 th day, venous blood is taken for checking biochemical indexes and blood routine, and gross observation and pathological microscopic examination are carried out on organs such as heart, liver, lung, spleen, kidney, intestine, testis, uterus, ovary, brain and the like. The other half of the animals were observed for recovery, sacrificed after one week and tested for various indices. The results show that: the appearance signs and the behavior activities of the animals in each group are observed without obvious difference from those in the control group by the administration and withdrawal of the medicine, and the animals have smooth hair, active behaviors and normal diet. During the test period, the weight of each group of animals continuously increases, and the administration group has no significant difference from the control group (P > 0.05); the biochemical indexes and the blood routine indexes of the administration group have no significant difference (P is more than 0.05) with those of the control group; the appearance of each organ of all animals has no abnormal change, the pathological microscopic examination has no organic lesion, and the organ coefficients of the administration group and the control group after administration for one month and withdrawal for one week have no obvious difference (P > 0.05); no delayed toxic reaction was observed after withdrawal, and no significant change in body weight was observed (P > 0.05).

For the main pharmacodynamic studies:

example 5

Morphine-dependent mouse withdrawal-promoting preventive treatment trial: 50 mice of Kunming species, half male and half female, were randomly divided into 5 groups: (1) a saline control group; (2) morphine control group; (3) the components (4) and (5) are three traditional Chinese medicine formula preparations with different dosages. Except for group (1), each group of mice was subcutaneously injected with morphine at 30mg/kg 2 times per day (6 hours apart) for 4 consecutive days, resulting in a physical dependence model of mice on morphine. (3) And (4) feeding morphine for each time, and respectively performing intragastric administration on 0.75g/kg and 1.5g/kg of the traditional Chinese medicine formula preparation; (5) the traditional Chinese medicine prescription preparation is administrated by intragastric administration for 40min before naloxone promotion, and the dosage is 1.5 g/kg. 2-3 hours after the last morphine administration, each group was subjected to an acceleration test by intraperitoneal injection of naloxone 8.0mg/kg, and the number of jumps within 10min after acceleration and the weight loss after 2 hours were recorded.

The results are shown in Table 1. Mice that are dependent on morphine may develop withdrawal symptoms such as jumping and weight loss after being promoted with naloxone. The traditional Chinese medicine formula preparation is given while morphine is given each time, so that the jumping times and weight loss of mice can be obviously reduced. The Chinese medicinal formula preparation can also reduce the jumping times of mice 40min before promotion, but the weight change of the mice is not obviously different from that of a morphine group.

TABLE 1 naloxone promotion test results of the Chinese medicinal formulation for morphine-dependent mice

P <0.001 compared to saline group;

p <0.01 compared to morphine group;

p <0.05 compared to morphine group.

Example 6

Heroin-dependent mouse urge withdrawal prevention and treatment test: 50 mice of Kunming species, half male and half female, were randomly divided into 5 groups: (1) a saline control group; (2) heroin control group; (3) the components (4) and (5) are three traditional Chinese medicine formula preparations with different dosages. Except for group (1), each group of mice was subcutaneously injected with heroin 16mg/kg 2 times per day for 4 consecutive days, resulting in a physical dependence model of mice on morphine. (3) And (4) feeding morphine for each time, and respectively performing intragastric administration on 0.75g/kg and 1.5g/kg of the traditional Chinese medicine formula preparation; (5) the traditional Chinese medicine prescription preparation is administrated by intragastric administration for 40min before naloxone promotion, and the dosage is 1.5 g/kg. 2-3 hours after the last morphine administration, each group was subjected to an acceleration test by intraperitoneal injection of naloxone 8.0mg/kg, and the number of jumps within 10min after acceleration and the weight loss after 2 hours were recorded.

The results are shown in Table 2. In mice with heroin dependence, naloxone can be used for promoting the mice to have withdrawal symptoms such as jumping and weight loss. The traditional Chinese medicine formula preparation is given while heroin is given each time, so that the jumping frequency and weight loss of mice can be obviously reduced. The traditional Chinese medicine prescription preparation is given 40min before promotion, and has no inhibition effect on the jumping times and weight loss of mice.

TABLE 2 naloxone acceleration test results of the Chinese medicinal formulation for heroin dependent mice

P <0.001 compared to saline group;

p <0.01 compared to heroin group;

p <0.05 compared to heroin group.

Example 7

Morphine-dependent rat urge withdrawal prevention and treatment test:

wistar rats 40, male and female halves, were randomly divided into 4 groups: (1) a saline control group; (2) morphine control group; (3) and (4) are Chinese medicinal formula preparations with different dosages. Except for group (1), rats in each of the other groups were injected subcutaneously with morphine at 30mg/kg for 3 times/day (4 hours apart) for 5 consecutive days, resulting in a physical dependence model of rats on morphine. (3) And (4) feeding morphine for each time, and respectively performing intragastric administration on 0.5 g/kg and 0.75g/kg of the traditional Chinese medicine formula preparation. And carrying out an acceleration test by injecting naloxone 8.0mg/kg into the abdominal cavity of each group 2-3 hours after morphine is given at the last time, recording withdrawal symptoms of rats of each group within 15min after acceleration and weight loss conditions after 1 hour, and scoring according to the scoring standard of the Histis Adhatodae.

The results are shown in Table 3. Rats with dependence on morphine can be stimulated to have withdrawal symptoms such as wet dog-like shiver, writhing, tooth biting, salivation, diarrhea, weight loss and the like after being promoted by naloxone. The Chinese medicinal formula preparations with two doses can effectively control the withdrawal symptoms and the weight loss of rats.

TABLE 3 naloxone promotion test results of the Chinese medicinal formulation for morphine-dependent rats

P <0.001 compared to saline group;

p <0.01 compared to morphine group;

p <0.05 compared to morphine group.

Example 8

Heroin-dependent rat urge withdrawal prevention and treatment test: wistar rats 40, male and female halves, were randomly divided into 4 groups: (1) a saline control group; (2) heroin control group; (3) and (4) are Chinese medicinal formula preparations with different dosages. Except for group (1), rats in each of the other groups were injected subcutaneously with heroin at 16mg/kg for 3 times/day (4 hours apart) for 5 consecutive days, resulting in a physical dependence model of the rats on heroin. (3) And (4) feeding morphine for each time, and respectively performing intragastric administration on 0.5 g/kg and 0.75g/kg of the traditional Chinese medicine formula preparation. And (3) carrying out an acceleration test by injecting naloxone 8.0mg/kg into the abdominal cavity 2-3 hours after the last heroin administration, recording withdrawal symptoms and weight loss conditions of rats in each group within 15min after acceleration and scoring according to the scoring standard of the Hibiscus mutabilis.

The results are shown in Table 4. For rat with heroin dependence, withdrawal symptoms such as wet dog-like shiver, writhing, biting, salivation, diarrhea and weight loss can be caused after naloxone is used for promoting. The Chinese medicinal formula preparations with two doses can effectively control the withdrawal symptoms and the weight loss of rats.

TABLE 4 naloxone promotion test results of the Chinese medicinal formulation on heroin dependent rats

P <0.001 compared to saline group;

p <0.01 compared to heroin group;

p <0.05 compared to heroin group.

Example 9

Morphine-dependent natural monkey withdrawal treatment trial: morphine-dependent monkeys were formed by dose-escalation, and administered with morphine subcutaneously 3 times daily at doses of 3, 6, 9, and 12mg/kg in weeks 1-4 and 15mg/kg in weeks five for 3 months. Behavioral characteristics were recorded for each monkey observed prior to morphine withdrawal, and body weight and performance were recorded for each monkey (8: 30, 14:30, 20: 30) 1 day prior to morphine withdrawal. The morphine monkeys were divided into 4 groups of 3-6 according to weight and sex. The following day after morphine withdrawal, therapeutic dosing was started, intragastric 3 times daily (8: 30, 14:30, 20: 30), Chinese medicinal formulation (0.4, 0.2, 0.13 g/kg), clonidine (0.02 mg/kg) and an equal volume of normal saline, respectively. The monkeys were weighed prior to each dose to calculate percent weight change, observed for various withdrawal symptoms and scored.

13-17 hours after morphine withdrawal, various groups of animals successively showed withdrawal symptoms of different degrees, such as irritability, restlessness, fighting, cage shaking, chain biting, appetite reduction, etc. After 24 hours, the symptoms become worse, and the moderate and severe symptoms in the normal saline group increase, such as tropism tremor, paroxysmal convulsion, abdominal cramp and weakness of lying. The results are shown in table 5, the high-dose traditional Chinese medicine formula preparation has the effect of obviously controlling the withdrawal symptoms after morphine withdrawal for 1 to 3 days with the most serious withdrawal symptoms, and the withdrawal score is obviously lower than that of the normal saline group. The total average component of the high-dose traditional Chinese medicine formula preparation after continuous administration for 7 days is obviously lower than that of a normal saline group (P < 0.05) and is equivalent to that of a clonidine group (P > 0.05); the total average fraction of the medium dose is also lower than that of the normal saline group, but has no statistical significance; the effect of a small dose is not obvious. And the traditional Chinese medicine formula preparation with three doses can inhibit anorexia and anorexia symptoms, and has obvious inhibition effect on weight loss of the morphine-dependent monkeys (Table 6).

TABLE 5 comparison of symptom scores (Mean + -SD) of each group of morphine during natural withdrawal

P <0.05 in saline.

TABLE 6 comparison of percent weight loss during natural withdrawal of morphine (Mean SD) for each group

P <0.05 in saline.

While the invention has been illustrated and described with respect to specific embodiments and alternatives thereof, it will be understood that various changes and modifications can be made without departing from the spirit and scope of the invention. It is understood, therefore, that the invention is not to be in any way limited except by the appended claims and their equivalents.