CN110882247A

CN110882247A - Use of isorhynchophylline in preparing drug-relief medicine

Info

Publication number: CN110882247A
Application number: CN201911122698.3A
Authority: CN
Inventors: 李璟; 莫志贤; 朱晨
Original assignee: Southern Medical University
Current assignee: Southern Medical University
Priority date: 2019-11-16
Filing date: 2019-11-16
Publication date: 2020-03-17

Abstract

The invention relates to a medicine containing a six-membered ring heterocyclic system with nitrogen as a ring heteroatom, in particular to application of isorhynchophylline as a unique effective component in preparing a medicine for preventing and treating opioid addiction or amphetamine dependence. The medicine provided by the invention is composed of isorhynchophylline and pharmaceutically acceptable auxiliary materials, wherein the content of the isorhynchophylline is 10-80%. The medicine of the invention is an oral preparation such as a tablet or a capsule.

Description

Use of isorhynchophylline in preparing drug-relief medicine

Technical Field

The invention relates to pharmaceutical preparations containing organic active ingredients, in particular to a medicament containing a six-membered ring heterocyclic system with nitrogen as a ring heteroatom.

Background

Currently, the global drug problem has posed a significant threat to human survival and development. Conventional narcotics represented by opioids and novel narcotics represented by Amphetamine-type Stimulants (ATS) are major abusive drugs. At present, the common drug rehabilitation method at home and abroad is mainly drug therapy. The treatment of opioid addiction is mainly the alternative subtraction of opioid preparations, such as methadone replacement therapy. The drug treatment for ATS addiction is mostly symptomatic treatment, such as the use of tricyclic antidepressants, antipsychotics, sedative hypnotics and the like. The clinical application of the above chemical synthetic drugs is limited because most of the drugs have obvious neurotoxic effects, and some drugs have the potential of psychotropic dependence or can enhance the dependence of some psychoactive substances. Compared with chemical synthetic drugs, the natural botanical drugs with wide resources and the effective components have the advantages of low toxicity, high efficiency and safe use, and a very wide approach is provided for seeking drug treatment of novel drug addiction resistance. However, no effective natural medicine or active ingredient of traditional Chinese medicine is used for treating the opioid or amphetamine drug dependence so far.

Isorhynchophylline (Isorhynchophylline), which is also called (16E, 20- α) -16, 17-dihydroxy-17-methoxy-2-oxo-corynox-16-carboxylic acid, belongs to tetracyclic oxindole alkaloid, has the chemical structure shown as the following formula 1 and the molecular formula C₂₂H₂₈N₂O₄Molecular weight is 384.47, CAS registry number 6859-01-4.

The isocoumarin is derived from Uncaria rhynchophylla of Rubiaceae. Modern pharmacological studies show (Shijing mountain, Liu Guo Xiong, Wu celery, Zhang Ying 29010in Huangnan, the antihypertensive effect of isorhynchophylline on conscious rats and anesthetized dogs, the four-river science journal, 1988, (04) 58-59; Huang nan, Wu celery, Shijing mountain, the influence of rhynchophylline and isorhynchophylline on the contraction reaction of mesenteric vessels and caudal arteries of rats, according to the academy of medicine, 1994: 7-10; Xie Longong, Wumin, Wuqi, Huang nan, Gonghai, Shijing mountain, the influence of isorhynchophylline on platelet aggregation and thrombosis, Chinese pharmacy journal, 2008, 43(4):280 283), isorhynchophylline has the effects and activities of reducing blood pressure, inhibiting platelet aggregation, resisting thrombosis, resisting arrhythmia and the like.

The uncaria rhynchophylla has the effects of clearing heat, calming the liver, calming endogenous wind and arresting convulsion, and is a common traditional Chinese medicine for clinically treating liver wind stirring, frightened epilepsy and convulsion in traditional Chinese medicine. The 2010 version of the pharmacopoeia of the people's republic of China stipulates that the traditional Chinese medicine uncaria is a dried stem branch with hooks of uncaria Uncaria rhyhophyla (Miq.) Miq.Ex Havil., Uncaria rhynchophylla U.sinensis (Oliv.) Havil., Uncaria macrophylla U.macrophylla Wall., Uncaria hirsuta U.hirsuta Havil., Uncaria without stalk U.S. sessilifrutus Roxb. Pharmacological research of traditional Chinese medicines shows that the uncaria and alkaloid thereof have obvious effects of reducing blood pressure, tranquilizing, improving sleep, relieving spasm and the like. In the aspect of preventing and treating drug dependence and withdrawal, certain Chinese herbal medicine compound for drug rehabilitation in China also applies uncaria as one of the components (Yang zheng, research progress of Chinese drug rehabilitation medicine Guiyuan Compound and rehabilitation Xin capsule, China drug dependence will, 2001, 10(1): 16-18; Wu jin, and the like, experimental research on drug rehabilitation effect of compound Dongyuan ointment, China J.Med.J.Med.Med.Med.1995, 15(9): 541) 543, Zhu Quan, and the like, influence of Shutong' an capsule on hemorheology and nail fold microcirculation of heroin dependence, China drug science and technology, Yu 2001, 8(3): 182) 183, Xia, and the like, research progress of Chinese drug rehabilitation medicine, Chinese herbal medicine 2016, 47(3):519 527). Isorhynchophylline (isorhynchophylline) and rhynchophylline (rhynchophylline) are two active alkaloids of uncaria rhynchophylla. The report reports (Zhongjiyin, Mongolian gambogic acid, influence of gambogic acid on the conditional site preference of the rat induced by the phenylpropylamine, study on the mechanism, Shandong medicine, 2006, 46(30):1-3, Zhongjiyin, Mongolian gambogic acid, influence of gambogic acid on the expression of NR2B mRNA in the nucleus pulposus of the rat dependent on the phenylpropylamine, Chinese pharmacological report, 2007, 23 (9): 1141-1145, Zhongjiyin, Mongolian gambogic acid, influence of gambogic acid on the content of amino acid neurotransmitter in the brain of the rat dependent on the phenylpropylamine, Chinese drug dependence journal, 2007, 16 (2): 95-98, Chengfei, etc., influence and mechanism of gambogic acid on the behavioral of methamphetamine dependent zebrafish, southern medical university, report, 2016, 36(11): 1541-1545; morning, etc., research and development on the relationship between NR2B and the alkaloid-inhibited methamphetamine dependent zebrafish, 2019, 31(03): 512-516; the relation research of inhibition of methamphetamine dependent mice by tyrosine hydroxylase and rhynchophylline on conditional position preference, Chinese pharmacology report, 2018, 34(09):1226-1230), and the main alkaloid rhynchophylline of rhynchophylla has obvious effect on preventing and treating amphetamine addiction. However, no reports related to other people exist for the application of the isorhynchophylline in the aspects of preventing and treating drug addiction and withdrawal, and no preparation for treating drug dependence and withdrawal symptoms such as opium, amphetamine and the like by using the isorhynchophylline as a main raw material is available on the market.

Disclosure of Invention

The invention aims to solve the technical problem of providing a new application of isorhynchophylline in pharmacy.

The new application is the drug rehabilitation application of isorhynchophylline, in particular to the application of isorhynchophylline as the only effective component in preparing the drug for preventing and treating opioid substance addiction or amphetamine substance dependence.

The Isorhynchophylline (Isorhynchophylline) is named as (16E, 20- α) -16, 17-dihydroxy-17-methoxy-2-oxo-coryxoan-16-carboxylic acid and has the molecular formula of C₂₂H₂₈N₂O₄The molecular weight was 384.47.

The isocoumarin can be extracted from uncaria, and can also be prepared by synthesis or other methods. The extraction method of the invention is an alkaloid extraction method commonly used in the field.

The Uncaria is Uncaria Uncaria rhyhophyla (Miq.) Miq. Ex Havil.) of Uncaria genus of Rubiaceae family, Uncaria rhynchophylla U.S.Sinense (Oliv.) Havil., Uncaria macrophylla U.macrophylla Wall., Uncaria hirsuta U.hirsuta Havil., Uncaria sessilifolia U.S.Sessilifructus Roxb., and stem branches with hooks of plants in the same genus.

The medicine of the invention adopts the preparation method commonly used in the field, and the following documents can be specifically referred: 1. "traditional Chinese medicine chemistry" by Chongzhu, the major (Shanghai science and technology Press, 1 st edition, Shanghai, 1997); 2. liangshengwang, ed "alkaloid component analysis" (Aster Press, Beijing, 1999); 3. song Xiaomei, Tang Shi Shu eds "extraction, separation and preparation of chemical components of Chinese herbs" (Min Wei publishing Co., Beijing, 2004.). The inventors consider that a recommended method is as follows:

1. pulverizing ramulus Uncariae cum uncis into coarse powder, extracting with 20% ethanol under reflux for 2 times, and mixing filtrates;

2. after the filtrate prepared in the step 1 is subjected to reduced pressure recovery of ethanol, dissolving and filtering the filtrate by using a 0.75mol/L hydrochloric acid solution, extracting the filtrate for 2 times by using chloroform, collecting a chloroform layer, and recovering a solvent under reduced pressure to obtain a chloroform extracting solution;

3. and (2) loading the chloroform extracting solution prepared in the step (1) on a silica gel (200-300 meshes) column, performing gradient elution by using chloroform-methanol (volume ratio of 99: 1) as an eluent, removing the eluent, and separating and refining the obtained flow by using a preparative HPLC (using acetonitrile-water as a mobile phase) to obtain white powder, namely the isorhynchophylline.

The isorhynchophylline has the effect of resisting drug dependence, particularly the effect of resisting dependence of opioid or amphetamine substances.

The medicine provided by the invention is composed of isorhynchophylline and pharmaceutically acceptable auxiliary materials, wherein the content of the isorhynchophylline is 10-80%.

The medicine can be oral dosage forms commonly used in the field, such as capsules (hard capsules and soft capsules), tablets (plain tablets, sugar-coated tablets and film-coated tablets), pills (micro-pills and dropping pills) and the like.

The anti-drug dependence effect of isocoumarine, especially the anti-opioid or amphetamine dependence effect and the beneficial effect in treating drug addiction diseases will be further illustrated by animal experiments.

1. Effect of isocoumarin on morphine-dependent mouse urge withdrawal symptoms

(1) Animal grouping: the Kunming mice are taken, the weight is 20-24g, the male and female halves are randomly divided into 5 groups, namely a blank control group, a morphine model group, a positive drug control group and an isocoumarin high and low dose group.

(2) Copying a model: except for the blank control group, the other groups adopt subcutaneous morphine injection and a dose increasing method to prepare a mouse morphine-dependent model. Mice were administered 2 times daily (8: 30, 16: 30) sc morphine in a volume of 0.2ml/10 g. The dose was increased from 25mg/kg day by day to 150mg/kg on day 6, and a morphine-dependent mouse model was prepared. Naloxone-induced withdrawal was performed on day 7.

(3) And (3) drug treatment: on day 7 of the experiment, morphine was discontinued and treatment was initiated for 3 consecutive days. The blank control group and the morphine model group are respectively administered with physiological saline (20ml/kg) with the same volume, the positive control group is administered with buprenorphine (0.4mg/kg), the low-dosage group and the high-dosage group of the isorhynchophylline are respectively administered according to the dosage of 40mg/kg and 80mg/kg, and the groups are respectively administered by intraperitoneal injection (ip). Naloxone (6mg/kg, ip) was given 30min after each mouse group, and the number of jumps occurred in the mice within 30min and the weight change of the mice after 1h were observed and recorded.

(4) As a result:

A. effect of drug on mouse skip response: a mouse morphine-dependent model is prepared by adopting a subcutaneous morphine injection method and a dose increasing method. After naloxone is used for addiction promotion, the morphine model group mice have obvious jump reaction accompanied with weight reduction, the normal saline control group mice only occasionally have one-time jump reaction of individual mice after the naloxone is ip, and compared with a blank control group, the model group has the P <0.01 and has very significant difference, which indicates that the animal model of the experiment is successfully made. The isorhynchophylline is respectively injected into the abdominal cavity of each drug group mouse 30min before naloxone is given, so that the withdrawal symptoms of the addicted mice are obviously relieved, and the jumping times of the addicted mice are obviously reduced compared with that of the model groups after naloxone is promoted, which shows that the drugs can relieve the withdrawal symptoms of morphine-dependent mice to a certain extent. See table 1.

TABLE 1 number of morphine-dependent mice that induced withdrawal skip responses ((II))

n＝10)

*P<0.05，**P<0.01, compared to a blank control group.^#P<0.05，^##P<0.01, compared to the morphine model group.

B. Effect of drug on mouse body weight: the weight of mice in a blank control group without morphine is increased along with time, the weight average of bodies at 7, 8 and 9 days (i.e. abstinence d1, d2 and d3) of the experiment is obviously increased compared with that before the morphine is administrated, and P is less than 0.01, so that the significant difference exists. After each morphine-dependent mouse is promoted by naloxone, the weight of the mouse is obviously reduced along with the appearance of withdrawal symptoms. The body weights of mice in the morphine model group and the buprenorphine-administered positive group are not obviously different from those before administration, and P is more than 0.05. The mice gained weight following isorhynchophylline treatment. In the abstinence d3, the body weight of the isocoumarin high-dose group mice is significantly different from that before longitudinal administration, and P is less than 0.05. See table 2.

TABLE 2 results of body weight (g) Change in mice of each group: (

n＝10)

*P<0.05，**P<0.01, compared to a blank control group.^▲P<0.05，^▲▲P<0.01 compared to pre-dose.

2. Therapeutic effect of isorhynchophylline on withdrawal symptom of morphine-dependent rats

(1) Animal grouping: SD rats with the weight of 200-.

(2) Copying a model: except for the blank control group, the morphine-dependent model of rats was replicated in each of the other groups by intraperitoneal injection of morphine and dose escalation. Morphine was injected 2 times a day (8:00, 20:00), and the dose was gradually increased from 5mg/kg to 90mg/kg for 10 days to obtain morphine-dependent rat model. Naloxone-induced withdrawal was performed on day 11.

(3) And (3) drug treatment: on day 11 of the experiment, morphine was discontinued and treatment was initiated. The blank control group and the morphine model group are respectively given equal volume of physiological saline, the positive control group is given buprenorphine (0.2mg/kg, ip), and the isorhynchophylline group is given according to the dosage of 20 mg/kg. Each group of the pickles is administrated by intraperitoneal injection (ip) for 5 days continuously. Rats had free access to water and food. Naloxone (4.0mg/kg, ip) is given for addiction after d1, d3 and d5 are given for 1h, and withdrawal reaction of rats within 30min and weight change of rats 1h after the withdrawal are promoted are observed.

(4) As a result:

A. effect of drug on morphine-dependent rat urge withdrawal symptoms: after naloxone administration in the placebo group, the rats had no apparent withdrawal symptoms. The morphine-dependent rats in each group have obvious withdrawal symptoms after being promoted by naloxone, and have significant difference compared with a blank control group, wherein P is less than 0.01. Morphine-dependent rats were treated with isorhynchophylline and had different reductions in withdrawal symptom scores. The withdrawal symptom scores of the administration groups are significantly different from those of the morphine model group, and P is less than 0.05 or P is less than 0.01. See table 3.

TABLE 3 morphine-dependent rat withdrawal symptom score: (

n＝10)

B. Effect of drug on the accelerated withdrawal of body weight change in morphine dependent rats: the results show that the body weight of rats in the blank control group without morphine is increased along with time, the body weight average of the rats at 11, 13 and 15 days (i.e. abstinence d1, d3 and d5) of the experiment is obviously increased compared with that before administration, and the P is less than 0.05, and has significant difference. After each morphine-dependent rat is promoted by naloxone, the weight of the rat is obviously reduced along with the appearance of withdrawal symptoms. On days 1 and 3 of withdrawal, the body weight of the rats in the morphine model group is obviously reduced compared with that before model building, and P is less than 0.05. The rats gained weight after isorhynchophylline treatment in the isorhynchophylline group. In the abstinence d1, d3 and d5, the weight of rats in each administration treatment group is significantly different from that in the morphine model group, and P is less than 0.05 or P is less than 0.01. Table 4.

TABLE 4 weight (g) change results of rats in various groups promoting withdrawal: (

n＝10)

*P<0.05，**P<0.01, compared to a blank control group.^#P<0.05，^##P<0.01 compared to the morphine model group.

^▲P<0.05，^▲▲P<0.01 compared to pre-dose.

3. Effect of isocoumarin on the Effect of phenylpropylamine-induced conditioned site preference in mice

(1) Animal grouping: selecting Kunming mice qualified by natural position preference determination, weighing 20-24g, and dividing into 4 groups at random, namely blank control group, amphetamine model group, and isorhynchophylline low and high dosage group.

(2) Copying a model: except for the blank control group, the other groups adopt a black and white position preference box preference training program to copy an amphetamine-induced mouse position preference model. Mice were placed in a white box for 60min immediately after intraperitoneal (ip) amphetamine (4mg/kg) injection (8:00) in the morning. Even days in the morning (8:00), mice were immediately placed in a black box for 60min by intraperitoneal injection of (ip) an equal volume of saline. The subsequent 6d were trained for 8 days by the above method. The site preference was checked at 8:00am on day 9, and the time spent by the mouse in the white box (companion box) within 15min was recorded and analyzed by the animal behavioural analysis system.

(3) And (3) drug treatment: each drug treatment group was administered beginning on day 7 of the experiment, at 16:00 pm each day in the corresponding dose. The blank control group and the morphine model group were given equal volume of physiological saline, and the low and high dose groups of isorhynchophylline were given at doses of 40mg/kg and 80mg/kg, respectively. Each group of the pickles is administrated by intraperitoneal injection (ip). Dosing was continued for 3 days, during which time the mice were free to drink and eat food.

(4) As a result: the time of the white box after the blank control group mouse drug stay is not obviously different from that before the drug (P > 0.05). Compared with a blank control group, the residence time of the mice in the white box is obviously prolonged (P <0.01), and compared with the time before administration, the residence time of the mice in the white box is also obviously prolonged (P <0.01), which shows that the mice generate obvious position preference effect. When the administration groups are continuously administrated for 3 days, the time of the mice staying in a white box is obviously shortened in the isorhynchophylline high-dose group (20mg/kg) compared with the amphetamine model group, (P <0.05 or P <0.01), and the time of the mice staying in the white box is not obviously prolonged in comparison with the group before the administration and a blank control group (P > 0.05). Table 5.

TABLE 5 Effect of isorhynchophylline on the Poncirus trifoliatus Induction of mouse Locus preference Effect

n＝10)

*P<0.05，**P<0.01, compared to a blank control group;^#P<0.05，^##P<0.01, with amphetamine model

Comparing the groups;^△P<0.05，^△△P<0.01, compared to pre-dose.

4. Effect of isocoumarin on Methamphetamine-induced conditioned place preference Effect in rats

(1) Animal grouping: SD rats qualified by natural position preference determination are selected, the weight of the SD rats is 200-240g, and males are randomly divided into 3 groups, namely a blank control group, a model group and an isorhynchophylline group.

(2) Copying a model: except for the blank control group, the other groups adopt a black and white position preference box preference training program to copy a methamphetamine-induced rat position preference model. Several odd days in the morning (8:00), i.p. (ip) methamphetamine (2mg/kg) was injected intraperitoneally, and the rats were immediately placed in a white box. Several days in the morning (8:00), rats were immediately placed in a black box by intraperitoneal injection (ip) of an equal volume of saline. The standing time is 1 h. The subsequent 6d were trained for 8 days by the above method. The site preference test was performed at 8:00am on day 9, and the time spent in the white box within 15min of the rats was recorded and analyzed by an animal behavioural analysis system.

(3) And (3) drug treatment: each drug treatment group was administered beginning on day 4 of the experiment, at 16:00 pm each day in the corresponding dose. The blank control group and the morphine model group were given an equal volume of physiological saline, and the isorhynchophylline group was given at a dose of 20 mg/kg. Each group of the pickles is administrated by intraperitoneal injection (ip). Dosing was continued for 5 days, during which the rats had free access to water and food.

(4) As a result: the time of the white box after the blank control group rat poison staying in the white box is not obviously different from that before the poison (P > 0.05). Compared with a blank control group, the residence time of the rats in the white box is obviously prolonged (P <0.01) in the methamphetamine model group, and compared with that before administration, the residence time of the rats in the white box is also obviously prolonged (P <0.01), which indicates that the rats have obvious position preference effect on the methamphetamine. When the administration groups are continuously administrated for 5 days, compared with the methamphetamine model group, the residence time of the rats in the white box is obviously shortened (P <0.05 or P <0.01) in the isocorydine group (10mg/kg), and compared with the administration group and the blank control group, the residence time of the rats in the white box is not obviously prolonged (P > 0.05). Table 6.

TABLE 6 Effect of isocoumarin on methamphetamine induced rat positional preference ((S))

n＝10)

*P<0.05，**P<0.01, compared to a blank control group;^#P<0.05，^##P<0.01, model with methamphetamine

Comparing the groups;^△P<0.05，^△△P<0.01, compared to pre-dose.

5. Isorhynchophylline body dependence evaluation test

30 SPF SD rats with half male and female are randomly divided into 3 groups, namely a negative control group, a morphine control group and an isorhynchophylline group, and each group comprises 10 animals. The morphine control group and the isorhynchophylline group are both administered by an incremental method, and the morphine control group is subcutaneously injected (sc) with morphine, and the isorhynchophylline group is intraperitoneally injected (ip) with isorhynchophylline, and the administration is carried out once every 12 hours (8:00am, 8:00 pm). According to the principle of increasing dosage, the dosages of morphine and isorhynchophylline are increased from 10mg/kg each time to 100mg/kg each time and are continued to the 9 th day. The negative control group had the same volume of saline per day, and the administration time and frequency were the same as those of the administration group. Day 9 rats in each group were at 8: naloxone (4mg/kg ip) was given 60min after administration of 00 to prompt. The withdrawal state of the rats within 1h after the promotion of withdrawal and the weight change before and after the promotion are observed. Withdrawal symptoms were scored on rats and the percent change in body weight was statistically processed for each group of rats. [ weight change percentage of rat ═ weight before withdrawal-weight after withdrawal x 100% ]

The experimental result shows that after the morphine control group rats are promoted by the naloxone, the withdrawal symptom score and the weight reduction percentage of the tested animals are obviously higher than those of a negative control group (P <0.01), which indicates that the morphine control group rats form obvious physical dependence. The isorhynchophylline group rats are continuously administrated for 9 days according to a dose increasing method, are promoted by naloxone, do not show obvious withdrawal symptoms, and have no obvious difference in the scoring value and the weight reduction percentage of the rats compared with a negative control group (P is more than 0.05); the difference is very significant compared with a morphine control group, and P is less than 0.01. The results show that no body-dependent reaction is formed after the isorhynchophylline group rats are administrated. See table 7.

TABLE 7 promotion of withdrawal response scores and percent weight change for each group of rats: (

n＝10)

**P<0.01, compared to a blank control group;^##P<0.01, compared to the morphine group.

6. Evaluation test of the potential of isocoumarin for mental dependence

30 SPF-level Kunming mice qualified by natural position preference determination are selected, and the mice are divided into a negative control group (normal saline with the same volume), a morphine control group (9mg/kg) and an isorhynchophylline group (80mg/kg) randomly. Each group contained 10 animals. Animals in each group were dosed twice daily with 8h intervals (8:00, 16: 00). The negative control group had normal saline ip twice, morphine group had morphine hydrochloride and normal saline once each, and isorhynchophylline group had corresponding medicinal liquid and normal saline once each according to the dosage ip. Each group was dosed with the drug in the morning and saline in the afternoon. Mice were dosed in a white box on the non-preferential side and in a black box on the preferential side with saline. The mice were placed in the box for 40 min. And 6d of co-training. The site preference test was performed 24h after the last dose. And (3) drawing out the partition plates of the preference box, putting the mice into the box body one by one, observing for 15min, and recording the residence time of the mice in the companion medicine box by taking the heads of the mice as reference.

The experimental result shows that after the morphine control group mice are administrated for 6d, the stay time of the test animals in the concomitant kit is obviously prolonged than that before the administration (P <0.01) and is also obviously longer than that of the negative control group (P < 0.05). Indicating that morphine induced mice to produce a significant site-preference effect. After the isocoumarin group is dosed for 6d, the residence time of the mice in the concomitant drug box is not obviously prolonged, and compared with the group before dosing, the mice have no significant difference (P >0.05), compared with a negative control group, the mice also have no significant difference (P >0.05), and compared with a morphine control group, the mice have very significant difference, and P is less than 0.05 or P is less than 0.01. It was shown that the mice did not produce a reward effect or aversion effect on isorhynchophylline. See table 8.

TABLE 8 conditioned place preference Effect of groups of mice: (

n＝10)

*P<0.05, compared to a blank control group;^##P<0.01, compared to the morphine group.^△△P<0.01, compared to pre-dose.

The experimental results show that the isorhynchophylline has a treatment effect on the symptoms of morphine dependence and promotion of withdrawal by body dependence of mice, can inhibit the withdrawal reaction of morphine dependence model animals, reduce weight loss caused by withdrawal symptoms and promote the recovery of organisms. The conditional place preference test was a newer method developed in the foreign country in the 80 s for evaluating the potential for drug psychic dependence. The experimental results show that the isorhynchophylline has obvious inhibition effect on conditioned place preference induced by the central stimulant in the phenylpropylamine. Through the action of the isorhynchophylline, the mental dependence of the big mouse and the mouse is relieved.

The experiments simultaneously prove that the isorhynchophylline does not have the characteristic of body dependence and can not induce animals to generate position preference, and the potential of the isorhynchophylline without body dependence and mental dependence is shown. Pharmacological experiments and drug dependence experiments prove that the isorhynchophylline has the effects of resisting opioid or amphetamine central stimulant dependence and preventing and treating withdrawal symptoms, and the isorhynchophylline does not have physical dependence and mental dependence and addiction.

Detailed Description

Example 1

The commercial isorhynchophylline is rare, so the inventor refers to Yuan Dan and the like in the research on the chemical components of uncaria rhynchophylla (Wang ice, Yuan Dan, horse bin, Yangying girl, Yinju, Diye Meihong, the research on the chemical components of uncaria rhynchophylla, Chinese journal of pharmaceutical chemistry 2006, 16(6):369 one 372.) to extract the isorhynchophylline, and the specific steps are as follows:

pulverizing ramulus Uncariae cum uncis into coarse powder, extracting with 20 vol% ethanol under reflux for 2 times, filtering, mixing filtrates, and recovering ethanol under reduced pressure to obtain extract. Dissolving the extract with 0.75mol/L hydrochloric acid, extracting with chloroform for 2 times, collecting acid water layer, and recovering solvent from chloroform layer under reduced pressure to obtain chloroform extract. Loading on silica gel column (300 mesh), gradient eluting with chloroform-methanol as eluent, eluting with chloroform-methanol (volume ratio 99: 1), separating and refining the obtained fraction with preparative HPLC apparatus (acetonitrile-water as mobile phase) to obtain white powder.

Mixing the obtained white powderAnd (5) carrying out identification. Wherein MS is 384[ M + H]⁺(ESI-MS(m/z))，¹H-NMR and¹³the C-NMR data are shown in the attached Table 1. MS of the obtained white powder,¹H-NMR and¹³C-NMR data are consistent with the reports in Wenkert E, Bindra JS, Chang CJ, et al, carbon-13nuclear magnetic resonance imaging of naturrally university, Acc Chem Res, 1974, 7:46-51, and were therefore determined to be isorhynchophylline.

Attached table 1

Of compounds (isorhynchophylline)¹³C-NMR (125MHz) and¹H-NMR (500MHz) nuclear magnetic data

Example 2

The formula is as follows:

the preparation method comprises the following steps: the preparation process in the embodiment 1 is adopted to prepare the isorhynchophylline, the starch, the dextrin and the superfine silica gel powder are added according to the dosage, the main medicine and the auxiliary medicine are fully and uniformly mixed, and then the mixture is sieved by a 100-mesh sieve, granulated, dried at low temperature, granulated, tabletted and coated with a film coating to prepare a film coated tablet. Each tablet contains isorhynchophylline 10 mg.

The taking method comprises the following steps: it is administered orally 3 tablets at a time, 3-4 times a day.

Example 3

The formula is as follows:

the preparation method comprises the following steps: the preparation process in example 1 is adopted to prepare the isorhynchophylline, the powdered sugar, the starch, the aerosil and the magnesium stearate are added according to the dosage, the main medicine and the auxiliary medicine are fully mixed, sieved, granulated, uniformly mixed and encapsulated to prepare the capsule. Each capsule contains isorhynchophylline 25 mg.

The taking method comprises the following steps: it is administered orally 2 granules at a time, 2-3 times a day.

Example 4

The formula is as follows:

isorhynchophylline 15g obtained in example 1

PEG 4000 50g

PEG 6000 45g

The preparation method comprises the following steps: placing PEG 4000 and PEG 6000 in a container, heating and melting in 85-90 deg.C oil bath, adding isorhynchophylline prepared by the preparation method of example 1, stirring, placing in dripping pill equipment, dripping into liquid paraffin, and making into pellet. Each pill contains isorhynchophylline 15 mg.

The taking method comprises the following steps: it is administered orally 3 granules at a time, 2-3 times daily.

Example 5

The formula is as follows:

the preparation method comprises the following steps: the isorhynchophylline prepared by the preparation process in the embodiment 1 is mixed with the edible plants which are heated, sterilized and clarified, and then is stirred uniformly and put into a liquid medicine storage tank. Placing mixed gelatin solution of gelatin, glycerol and water in gelatin solution storage tank, and making into dripping pill. Each pill contains isorhynchophylline 10 mg.

The taking method comprises the following steps: it is administered orally 3-4 times a day 3-4 times.

Example 6

The formula is as follows:

the preparation method comprises the following steps: the preparation process in the embodiment 1 is adopted to prepare the isorhynchophylline, dextrin, starch, aerosil and magnesium stearate are added according to the dosage, the main medicine and the auxiliary medicine are fully mixed, sieved, granulated, tabletted and coated with sugar, and the sugar-coated tablets are prepared. Each tablet contains isorhynchophylline 20 mg.

Claims

1. The isorhynchophylline is used as the only effective component in preparing the drugs for preventing and treating opioid substance addiction or amphetamine substance dependence.

2. The use of claim 1, wherein the content of isorhynchophylline in the medicament is 10-80%.

3. The use of claim 1, wherein the medicament is a tablet, capsule or pill.