Medicine with effects of drug rehabilitation and relapse prevention as well as preparation method and application of medicine

Abstract

The invention relates to a medicine with drug rehabilitation and relapse prevention effects as well as a preparation method and application thereof, and belongs to the field of medicines. The medicine comprises rotundine and salts and is prepared through a chemical synthesis method, and experiments prove that the medicine preparation has the effects of treating opioid substances including heroin, morphine, dolantin, methadone and the like as well as other psychoactive substances, such as opioid and the like. Independent or addiction formed by cocaine, amphetamine stimulants, wine, smoke, cannabis sativa, sedative and hypnotic drugs and the like has the effects of detoxifying, relieving symptoms, inhibiting psychological craving and reducing relapse rate.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a drug with the effects of treating drug addiction and preventing relapse, as well as a preparation method and application thereof. Background Art

[0002] Once people are exposed to and use drugs, they quickly become addicted. This not only harms their health and costs money, but over time often leads to the separation of families and even the destruction of their loved ones. Regardless of the medication used in the early stages of drug rehabilitation, the relapse rate remains high at over 95%. The psychological dependence or persistent addiction that long-term drug users develop, as well as the lingering effects of prolonged withdrawal symptoms, are major factors contributing to relapse. Currently, there is no single, specifically effective medication for maintenance treatment in the later stages of drug rehabilitation.

[0003] In recent years, traditional Chinese medicine compound preparations have become a new force in drug addiction treatment and relapse prevention, resulting in numerous patent applications and extensive preclinical and clinical trials. The inventors have identified a common characteristic of these compound preparations: they all contain the herb Corydalis yanhusuo (Yuanhusuo), whose primary component is tetrahydrobamatin. Academician Jin Guozhang of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, systematically studied the pharmacological effects of tetrahydrobamatin's L-isorotandine (L-THP), confirming that L-THP is the primary active ingredient in Corydalis yanhusuo. Rotandine exhibits analgesic and tranquilizer effects, making it the first naturally occurring DA receptor blocker and playing a key role in treating prolonged withdrawal symptoms associated with drug addiction and reducing relapse rates. The drug has been included in the Chinese Pharmacopoeia, and its safety is unquestionable. These compound preparations are effective in treating stimulant withdrawal symptoms and prolonged withdrawal symptoms associated with opioid addiction.

[0004] However, Corydalis yanhusuo does not contain cephaladine, and the tetrahydrobamazine extracted is racemic dl-THP, which needs to be further decomposed to obtain L-THP. On the other hand, the content of racemic dl-THP in Corydalis yanhusuo is low, and the large amount of Corydalis yanhusuo used in compound preparations mainly relies on artificial cultivation, and the high yield and low cost cannot meet the needs of large-scale industrial production.

[0005] Based on this, the present inventors conducted comprehensive research on the use of chemically synthesized high-purity Rotundine as a raw material for the treatment of drug abuse and relapse prevention, and achieved very good therapeutic results. Summary of the Invention

[0006] The purpose of the present invention is to provide a drug that can treat drug addiction and prevent relapse, so as to solve the above problems.

[0007] In order to achieve the above object, the present invention provides the following technical solutions A drug with drug addiction treatment and relapse prevention effects comprises rotundine and salts, and the drug is prepared by a chemical synthesis method.

[0008] Furthermore, the salts include hydrochloride, sulfate, citrate, tartrate and any acid group that can form a salt with rotundine.

[0009] Furthermore, the drug is in the form of a capsule, tablet, granule, sustained-release preparation, immediate-release preparation, controlled-release preparation, oral liquid preparation or injection.

[0010] Furthermore, the therapeutic and relapse prevention effects are based on the increase in Penk mRNA expression or POMC mRNA expression in the arcuate nucleus as a standard, and are used to abstain from drugs, alleviate drug abuse symptoms, suppress psychological cravings, or reduce relapse rates.

[0011] A method for preparing a drug for treating drug addiction and preventing relapse comprises the following steps: The raw material powder of rotundine is added with conventional excipients, mixed evenly, and prepared into tablets, capsules, granules, sustained-release preparations, rapid-release preparations, controlled-release preparations, oral liquid preparations or injection preparations according to conventional processes.

[0012] Furthermore, the dosage of the drug is not less than 30 mg per unit.

[0013] The beneficial effects of the present invention are: The synergistic effects of the drug of the present invention are primarily manifested in: blocking the acquisition and expression of morphine behavioral sensitization in mice, inhibiting the formation and expression of morphine behavioral sensitization, preventing the development of morphine-addictive behaviors, and suppressing morphine-induced sensitized behaviors; reducing mouse activity and suppressing the acute hyperactivity effect of methamphetamine; and blocking the acquisition and expression of methamphetamine behavioral sensitization in mice. The drug has been shown to inhibit the rewarding effects of methamphetamine and to intervene in environmentally induced relapse to intravenous self-administration in morphine-addicted rats. Animal pharmacodynamic experiments have demonstrated that the drug preparation of the present invention exhibits analgesic, sedative, sleep-prolonging, and anxiolytic effects.

[0014] Experiments have shown that the pharmaceutical preparation of the present invention has the effects of detoxification, relieving symptoms, suppressing psychological cravings, and reducing relapse rates for dependence or addiction caused by opioids, including heroin, morphine, pethidine, methadone, and other psychoactive substances, including cocaine, amphetamine stimulants, alcohol, tobacco, marijuana, sedatives, and hypnotics.

[0015] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the specification, the following is a description of the preferred embodiments of the present invention. DETAILED DESCRIPTION

[0016] The technical solution of the present invention will be described clearly and completely below. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0017] In addition, the technical features involved in the different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other. Example

[0018] Raw Material Rotundine and Its Identification Experiment Instrument: Shimadzu 210A UV spectrophotometer.

[0019] Solvent: anhydrous ethanol.

[0020] UV spectrum measurement data: UV input nm: MeOH (loge) nm: 210 (4.46), 219 (sh, 4.23), 281 (3.72).

[0021] Analysis: 210nm is the B band of the aromatic ring, 219nm is the K band of the aromatic ring, and 281nm is the characteristic absorption peak.

[0022] Infrared absorption spectroscopy (IR) identification: Instrument: Bio-Red FTS-135 infrared spectrometer.

[0023] Determination conditions: Potassium chloride tablets.

[0024] Analysis: 3612cm-1: -OH stretching vibration. 29502920cm-1: CH stretching vibration.

[0025] 1626, 1515, 1461 cm-1: Characteristic absorption peaks of aromatic rings. 863, 811 cm-1: Fingerprint peaks of strongly substituted aromatic rings.

[0026]

[0027] Mass spectrometry (EIMS) identification: Instrument: AUTOSPEC3000 mass spectrometer.

[0028] Conditions: Fast atom bombardment EI-MS (20 eV).

[0029] Determination data m / z (relative intensity %): m / z355(M+,100),340[(M-Me)+,10:,324[(M-OMe)+,18:,190(25),164(72),149(48),121(15).

[0030] Analysis: am / z 355 is the molecular ion peak of this molecule, corresponding to the molecular formula C21H25NQ4; bm / z 340 is the fragment ion peak of this molecule losing a methyl group, indicating the presence of a methyl group. cm / z 324iH nuclear magnetic resonance spectrum (1HNMR): Instrument: Bruker DR-500 superconducting nuclear magnetic resonance instrument.

[0031] Conditions: CDC13 as solvent, TMS as internal standard, and measurement at 500 MHz.

[0032] Solution: a. 86.82 (1H, d, J = 8.3 Hz) and 6.73 (1H, d, J = 8.3 Hz) indicate the presence of protons in the ortho-positions of the aromatic ring, corresponding to H-11 and H-12. b. 6.63 (1H, s) and 6.57 (1H, s) indicate the presence of two proton-free hydrogen atoms in the ortho-positions of the aromatic ring, corresponding to H-1 and H-4. c. 83.83 (3H, s), 3.80 (6H, s), and 3.78 (3H, s) indicate the presence of four methoxy groups in the molecule.

[0033]

[0034] 13C Nuclear Magnetic Resonance Spectrum (13CNMR): Instrument: Bruker DR:-500 superconducting nuclear magnetic resonance instrument Determination conditions: TMS was used as internal standard and the measurement was performed at a frequency of 125 MHz.

[0035]

[0036] Comprehensive analysis confirmed that the compound was positive for the modified potassium carbonate test solution, indicating that it was an alkaloid.

[0037] EI-MS mass spectrometry determined the molecular ion peak at m / z 355, consistent with C₂₁₇NO₄, indicating the correct molecular composition of the compound. UV spectra indicate the presence of aromatic rings in the compound. The IR spectrum of 3612 cm⁻¹ indicates the presence of hydroxyl radicals at 1626, 1515, and 1461 cm⁻¹, indicating the presence of aromatic rings in the molecule. 5. The 1H NMR spectrum of the compound exhibited characteristic resonance signals consistent with α-tetrahydrobamatin. The 13C NMR spectrum of the compound exhibited 21 carbon atom signals, which, combined with the 13C NMR DEPT spectrum, further confirmed that the carbon atom identities were consistent with those of rotundine. The compound's physical properties, melting point, and optical rotation values were all consistent with those of rotundine.

[0038] In summary, the structure of this compound is Rotundine, English name: Rotundine, molecular formula: C21-N04, molecular weight: 355.4275.

[0039] Example 2: Purity inspection of Rotundine: silica gel thin plate (TLCGF254) inspection a. Prepare 1 ml of a 1,000 μg rotundine methanol test solution with 10, 20, or 30 μg of the sample. Develop the sample on a silica gel G plate with acetone-benzene (2:8, v / v) at a depth of 8.0 cm. Use a modified potassium sulfonate test solution for color development. A single orange-red spot (Rf value = 0.60) is observed at 4.8 cm. No impurity spots are visible in the chromatogram.

[0040] b. Prepare 1 ml of a methanol test solution containing 1000 μg of the rotundine reference substance. Quantitatively spot 10 μl, 20 μl, and 30 μl of the sample on a silica gel G plate using methanol-benzene (1:12, v / v) at a depth of 8.0 cm. Use modified potassium carbide test solution for color development. A single orange-red spot (Rf value = 0.63) is observed at 5.0 cm. No impurity spots are visible in the chromatogram.

[0041] High-performance liquid chromatography Sample preparation: Accurately weigh 0.002 ml of crotonic acid and dilute to a concentration of 1.00 mg / mL in a 2.0 mL volumetric flask.

[0042] Chromatographic conditions: Instrument: Waters 2996 diode array detector; Column: Waters ODS2 (3.9:150 mm, 5 μm); Mobile phase: acetonitrile-water (40:60); Flow rate: 1 mL / min; Detection wavelength: 225 nm; Column temperature: 35°C; Injection volume: 30 μl.

[0043]

[0044] Result analysis: The results showed that the purity of the Rotundine sample was 99.98%, which met the purity requirements of the standard product.

[0045] Example 3: Study on the effects of Rotundine on prolonged withdrawal symptoms of opioid drug dependence 145 inpatient heroin-dependent drug addicts, all meeting DSM-IV criteria for opioid dependence, were randomly assigned to three groups seven days after discontinuing heroin use. They received either two identical 30 mg tablets of Rotundine twice daily or an identical placebo twice daily for one month and were followed up for three months. Protracted withdrawal symptoms and craving were assessed on days 7, 14, 21, 28, 35, 42, 56, and 70 after admission. There were no significant differences among the groups in age, education, occupation, age at drug use initiation, type of drug, or number of times per day. These factors were relatively evenly distributed across the groups.

[0046] Effects of Rotundine on Overall Protracted Withdrawal Symptoms The overall protracted withdrawal symptom score decreased faster in the rotundine group than in the control group. The two groups were homogeneous at the α = 0.05 level. A one-way ANOVA test showed that the rotundine group had lower scores than the placebo group on the 7th day of treatment, 5th day after discontinuation, and 14th day after treatment (P < 0.05).

[0047]

[0048] Effects on physical withdrawal symptoms The one-way ANOVA CF test showed that there were no significant differences among the groups at the time of enrollment, 7th, 21st, and 28th days after medication, and 5th and 14th days after discontinuation of medication. However, there were significant differences among the groups at 14th day after medication and 5th day after discontinuation of medication (P<0.05).

[0049]

[0050] *P<0.05, Effect of the Rotundine group and the placebo group on the symptom of mental dependence "craving" Rotundine had a significant effect on psychological craving. The one-way ANOVA CF test showed that there were significant differences (P<0.05) on the 7th, 14th, and 21st days after treatment compared with the control group. There were also significant differences (P<0.01) on the 28th day after treatment, the 5th, 14th, and 28th days after discontinuation of treatment.

[0051]

[0052] *P<0.05, comparison between the rotundine group and the placebo group **P<0.01, comparison between the rotundine group and the placebo group The above trial employed a double-blind, randomized, parallel, controlled design to minimize subjective interference and objectively evaluate the efficacy of rotundine. The results showed that protracted withdrawal symptoms persisted for a long time but gradually diminished over time, initially rapidly but then slowly. Symptoms diminished rapidly during the first three weeks of withdrawal, then significantly slowed. Rotundine demonstrated an effect on overall protracted withdrawal symptoms. This trial confirmed the significant efficacy of rotundine on individual symptoms of protracted heroin withdrawal, including pain, palpitations, anxiety, and sleep disturbances.

[0053] Example 4: Rotundine on the expression of PenkmRNA in some brain structures of morphine-dependent rats. In all the parts tested, the expression of PenkmRNA in the dependent group was significantly decreased compared with the normal control group (P <O.05)。

[0054] On the 12th day of treatment, in the rotundine group. The results were obtained from Example 2. Compared with the normal saline group, the expression of Penk mRNA in all detected parts except the expression of Penk mRNA in the CPu was not significantly increased, and the expression of Penk mRNA in the remaining detected parts was significantly increased (P<0.05). After 30 days of treatment, compared with the normal saline group, the expression of Penk mRNA in all detected parts of the rotundine group was significantly increased (P<0.05).

[0055]

[0056] **: P<0.01, compared with the normal control group ##: P<0.01, compared with the morphine+normal saline group. Experimental Example 5: Experiment on the expression of POMC mRNA in the arcuate nucleus of rotundine morphine-dependent rats. After morphine dependence, the expression of POMC mRNA in the arcuate nucleus of the normal saline group was significantly decreased compared with the normal control group (P<0.05), and there was still no significant natural recovery at 30 days after administration, which was significantly lower than the control group. On the 12th day of treatment, the expression of POMC mRNA was the same as that of the normal saline group and was significantly lower than that of the normal control group. After continuous administration of rotundine obtained from Example 2 for 30 days, the expression of POMC mRNA was significantly increased, and there was a significant difference compared with the normal saline group (P<0.05); there was no significant difference compared with the normal control group.

[0057] Through the above experiments, it was found that except for the inhibition of the expression of DR mRNA gene in the nucleus accumbens area on the 12th day after rotundine intervention treatment, the Penk mRNA in the ventral tegmental area and caudate putamen, and the POMC mRNA in the arcuate nucleus were lower than the control group on the 12th day and recovered to normal on the 30th day: other ventral tegmental area (VTA), amygdala (AM), caudate putamen (CPU) and prefrontal cortex (PFC) in the D1R mRNA gene expression, ventral tegmental area, caudate putamen DR mRNA gene expression, and whether it was 12 days or 30 days of medication, it was significantly higher than the normal saline group and there was no significant difference from the normal control group.

[0058] The above experiments showed that: Rotundine had a significant reversing effect on the increase of TH and the decrease of DR mRNA after drug addiction withdrawal. It avoided the over-strong TH immunoreactive response, reduced the inhibition of the expression of DR mRNA and D2R mRNA genes in related brain regions, and accelerated the natural recovery process of the EOP and DA nervous system functions in the brain after morphine addiction withdrawal. This provided an important basis for the use of the drug of the present invention to prevent and treat opioid addiction.

[0059] Example 5: Study on the effect of rotundine tablets on the self-administration behavior of rats Experimental medication: Rotundine tablets, obtained in Example 1 of the present invention. Model medication: Morphine hydrochloride, Northeast Pharmaceutical Group. Surgical anesthetic: Sodium pentobarbital. Conventional antibiotic: Penicillin G. Animals: SD rats, 280-350 g, male, secondary size.

[0060] Self-administration experimental apparatus: Developed by the Institute of Drug Dependence at Peking University, the rat self-administration experimental apparatus consists of two basic systems: a self-administration system and a control system. It comprises an industrial computer, a self-administration data acquisition and control system, a dedicated self-administration cage, a constant-rate infusion pump, an intravenous infusion line system including an air filter, a backflow prevention valve, a rotating shaft, a fluid protection tube, and a vest.

[0061] Route of Administration: Morphine hydrochloride was administered intravenously for the model: 1.0 mg·kg⁻¹ / INJ (MA:=50), 0.5 mg·kg⁻¹ / INJ (MA:=100), and 2.0 mg·kg⁻¹ / INJ (MA:=50). During the rehabilitation period, morphine was administered intravenously to simulate clinical administration. The control group (8 rats) received normal saline (1 ml / rabbit) intravenously. The GA group (8 rats) received 5.25 mg·kg⁻¹ of Rotundine extract intravenously. The GB group (8 rats) received 5.25 mg·kg⁻¹ of Rotundine extract intravenously.

[0062] Establishment and Comparison of Self-Administration Model Results: A successful self-administration model is characterized by the animals actively seeking the drug, triggering the nose switch, and expressing their desire for the drug. During the initial training phase, the number of responses and drug dosages were highly erratic. In this experiment, the animals were trained approximately ten times daily, and after an average of 5-7 days (average 5 days), the rats established a conditioned reflex to receive the drug. The reinforcing effects of morphine now drive the rats to actively seek and trigger the nose switch to obtain the drug. Once stable self-administration behavior was established, there was no significant difference in the number of self-administration responses among the 22 rats.

[0063] Effects of Rotundine Tablets on the Frequency of Self-Administration Reactions Before and After Treatment

[0064] Rats that had established stable self-administration behavior were removed from the shelf and treated with either the extract of the tablets of this drug or a saline control for one month. After being returned to the shelf and placed in their previous drug-related environment to induce the corresponding stress response, the control and GA groups gradually resumed self-administration of morphine. The control group recovered faster, with sensitive rats returning to pre-dose levels by the third day, an average of 5 days. The GA group's response rate was slower than the control group, averaging 8 days. After 8 days, there was no difference between the two groups. The GB group, after undergoing a different dosing regimen and being placed on the shelf, continued to receive daily injections of the extract of the tablets of this drug at 5.25 mg kg-1. This completely suppressed self-administration behavior.

[0065]

[0066]

[0067] Effects of Rotundine Tablets on TDD Before Administration After the self-administration model was established, TDD was relatively stable. Rats would actively seek to touch the nose-touch switch to seek morphine injection. Increasing the injection dose (2 mg•kg-1 / NJ) would reduce the number of nose-touch reactions accordingly. Reducing the injection dose (0.5 mg•kg-1 / INJ) would increase the number of nose-touch reactions accordingly. Keeping the morphine dosage unchanged, there was no difference in the self-administration TDD among the three groups before treatment.

[0068]

[0069] Effects of Rotundine on TDD in the Relapse Stage When the rats were returned to the dosing cage to induce TDD, self-administration and morphine-induced behaviors gradually recovered in both the saline and Guiyuan A groups. TDD in the saline group recovered faster, returning to pre-drug levels within an average of three days. TDD in the Guiyuan A group was lower than in the control group, returning to pre-drug levels after an average of eight days. TDD in the Guiyuan B group remained unchanged despite continued dosing after placement. Interestingly, the rats appeared to have completely forgotten their previously learned self-administration behavior, remaining indifferent to the dosing environment and cues, and making no effort to touch the nose switch. Compared with the control group, Rotundine tablets showed a significant effect on TDD during the relapse phase (p < 0.001).

[0070]

[0071]

[0072] Rats in the saline control group, which had completely eliminated physical withdrawal symptoms under environmentally induced conditions, resumed intravenous self-administration the same day after returning to the dosing cage and drug-using environment. In contrast, rats treated with rotundine tablets for one month during recovery showed reduced frequency and number of self-administration responses, relapsing after an average of eight days. However, rats in the rotundine-treated group, which continued to receive rotundine tablets once daily after returning to the dosing cage, completely suppressed intravenous self-administration. This suggests that rotundine tablets have an interventional effect on environmentally induced relapse to intravenous self-administration in morphine-addicted rats.

[0073] Example 6: Study on the clinical efficacy of Rotundine tablets on protracted withdrawal symptoms The research subjects were heroin addicts who were subjected to compulsory drug rehabilitation treatment due to injection or smoking of heroin and other drugs and voluntarily took Rotundine tablets obtained in Example 1 of the present invention. A total of 26 subjects were randomly divided into Rotundine tablets group (11 cases), compound Chinese medicine for drug rehabilitation control group (9 cases) and blank control group (6 cases). All subjects met the DSM-IV drug dependence diagnostic criteria and opioid withdrawal reaction diagnostic criteria and had ruled out various mental disorders and other serious physical diseases. All subjects in the group had undergone drug rehabilitation capsules, an opium-containing preparation developed by the researchers themselves, for 4-7 days of detoxification treatment. All of them stopped taking the drugs, but some acute residual withdrawal symptoms and chronic prolonged withdrawal symptoms still existed. The general situation and grouping of the subjects are shown in the following table. There was no statistical difference in age among the three groups of subjects in terms of cumulative drug use time (P>0.05), but there was a statistical difference in average daily drug use and weight at the time of entry due to sampling error factors (P <O.05)。

[0074]

[0075] Drugs. Evaluation criteria. Evaluation content. Evaluation methods and inclusion criteria Administration and dosage: The principle is to significantly control acute and chronic withdrawal symptoms and avoid obvious toxic and side effects. The two study groups used different medications. The Rotundine group was given tablets alone. The single dose of the Rotundine group was equal to the dose of the compound. The blank group was not given any medication. All three groups were given one tablet three times a day for 10 days.

[0076] Evaluation criteria: The Withdrawal Symptom Observation Scale, the Treatment Adverse Effect Scale (TESS), and the HAMA Anxiety Rating Scale, approved by the State Drug Administration, were used. The Heroin Protracted Withdrawal Symptom Rating Scale of the Chinese Institute of Drug Dependence was also used for assessment.

[0077] Evaluation content: Record truthfully according to the research plan requirements: Brief research medical record: 1 Withdrawal symptom observation scale: 1 Drug side effect scale (TESS): 1 HAMA anxiety rating scale: 1 Heroin protracted withdrawal symptom rating scale: Urine morphine detection (TLC); Blood. Routine urine and blood tests: Liver and kidney function tests.

[0078] Evaluation method: At 7-8 pm every day, conduct the scoring of the 1 Withdrawal symptom observation scale and the 1 Drug side effect scale (TESS), and measure and record blood pressure, pulse rate and body weight at the same time. Conduct the assessment of the 1 HAMA anxiety rating scale once every 5 days. Urine morphine, blood routine and urine routine tests are carried out before enrollment and after the end of treatment. All subjects are managed according to the management mode and regulations of the compulsory detoxification center. During the treatment and observation period, the subjects照常 participate in the daily morning exercises, study, queue training, entertainment activities and productive labor in the detoxification center and do not enjoy any special treatment compared with other drug addicts.

[0079] Enrollment criteria: Stop using other detoxification drugs: The acute withdrawal symptoms are basically eliminated but there are still a certain degree of withdrawal symptoms remaining. Drop-out criteria: Those with a positive reaction in the urine morphine test at the end of treatment: Those who cannot adhere to the treatment due to abnormal test results or physical diseases after the start of treatment: Those who drop out due to non-treatment reasons, such as criminal cases: Those who refuse to take medicine after persuasion is ineffective.

[0080] Comparison of the daily scores of withdrawal symptoms of the three groups of subjects during the drug administration period.

[0081]

[0082] Comparing the traditional Chinese medicine detoxification drug group and the rotundine drug group with the blank control group, it can be seen that the effects of controlling or relieving the overall withdrawal symptoms remaining in the detoxification period after medication have the following characteristics: The scores of withdrawal symptoms decreased significantly in the first 4 days of medication. There was a significant difference in the effect between the rotundine drug group and the blank control group on the 1st - 4th day of medication (P<0.05), while there was no significant difference between the traditional Chinese medicine detoxification drug group and the blank control group.

[0083] (P>0.05); The control of withdrawal symptoms was stable and showed a decreasing trend day by day, and there was no phenomenon of withdrawal symptom rebound.

[0084] Comparison of the scores of withdrawal symptoms of the two groups of subjects after stopping the drug

[0085] After stopping the drug, there was no phenomenon of withdrawal symptom rebound in the scores of withdrawal symptoms of the two groups of subjects, and both showed a decreasing trend day by day, and there was no significant difference between the two groups (P>0.05).

[0086] Comparison of the average daily sleep time of the three groups of subjects after medication Except for the 9th and 10th days of medication, the sleep duration of the Rotundine group compared with the traditional Chinese medicine detoxification and blank control groups (P<0.05), there was no significant difference in the other days (P>0.05). (Note: During the medication period, the subjects were called up for work and the sleep duration was affected.)

[0087] Comparison of mean adverse reaction scores The adverse reaction scores of the Rotundine group were significantly lower than those of the Chinese medicine detoxification group on the 2nd and 5th days of treatment, and the difference was significant (P<0.05).

[0088]

[0089] The above experiments have proved that both traditional Chinese medicine detoxification drugs and Rotundine have the effect of controlling acute residual withdrawal symptoms after detoxification treatment for heroin dependence, but Rotundine is better than traditional Chinese medicine detoxification drugs in controlling symptoms: the adverse reactions are also milder than traditional Chinese medicine detoxification drugs, and no obvious toxic and side effects are observed, and the effect is safer and more reliable: the subjects have a good acceptance of the drug and no dependence is produced.

[0090] Experimental Example 7: Effects of intravenous self-administration on relapse behavior in cocaine-dependent rats The inventors conducted a cocaine intravenous self-administration experiment at the National Institute on Drug Abuse of the National Institutes of Health (NIH / NIDA) in the United States, and simultaneously observed the intervention effect of rotundine on environmentally induced relapse behavior.

[0091] Route X used cocaine hydrochloride (0.5 mg / kg / iv) at a fixed ratio of 2 (i.e., one injection for every two lever presses). After establishing an intravenous self-administration model, subjects were randomly divided into five dose groups and observed once daily for three hours. Rotundine (1, 3, 10, 20, or 30 mg / kg) was administered intraperitoneally 30 minutes prior to each experiment. Results showed that doses ranging from 3 to 30 mg / kg inhibited intravenous cocaine self-administration in a dose-dependent manner, suggesting that rotundine has an interventional effect on the psychological dependence and relapse behavior of cocaine addicts.

[0092] Example 8: Preparation of Rotundine and Its Salt Tablets Take rotundine or its salt, add corn starch, sodium starch glycolate and microcrystalline cellulose, mix well, dry, crush, sieve, granulate, tablet, and coat to obtain the product.

[0093] Example 9: Preparation of Rotundine and Its Salt Capsules Rotundine or its salt is added with conventional excipients, mixed evenly, and prepared into capsules according to conventional processes.

[0094] Example 10: Preparation of Rotundine and Its Salt Sustained-Release Tablets Rotundine or its salt is added with conventional excipients, mixed evenly, and prepared into sustained-release tablets according to conventional processes.

[0095] Example 11: Preparation of Rotundine and Its Salt Oral Solution Rotundine or its salt is added with conventional excipients, mixed evenly, and prepared into an oral solution according to conventional process.

[0096] Example 11: Preparation of Rotundine and Its Salt Injection Take rotundine or its salt and prepare injection according to conventional methods.

[0097] Example 12: Preparation of Rotundine and Its Salt Granules Take rotundine or its salt, add appropriate dressing, prepare granules by conventional method, and package to obtain the product.

[0098] Example 13: Preparation of Rotundine and Its Salt Oral Solution Take rotundine or its salt, add appropriate dressing, prepare oral liquid by conventional method, and package to obtain the product.

[0099] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0100] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A drug for treating drug addiction and preventing relapse, characterized in that: The invention comprises rotundine and salts thereof, and the medicine is prepared by a chemical synthesis method.

2. The drug for treating drug addiction and preventing relapse according to claim 1, wherein The salts include hydrochloride, sulfate, citrate, tartrate and any acid group that can form a salt with rotundine.

3. The drug for treating drug addiction and preventing relapse according to claim 1, wherein The medicine is in the form of capsules, tablets, granules, sustained-release preparations, rapid-release preparations, controlled-release preparations, oral liquid preparations or injections.

4. A use of a drug for treating drug addiction and preventing relapse, wherein the drug is used as claimed in any one of claims 1 to 3, wherein: The therapeutic and anti-drug relapse effects are measured by increasing the expression of Penk mRNA or POMC mRNA in the arcuate nucleus.

5. The use of the drug for treating drug addiction and preventing relapse as claimed in claim 4, characterized in that: Used to quit drugs, relieve drug abuse symptoms, suppress psychological cravings or reduce relapse rates.

6. The method for preparing the drug for treating drug addiction and preventing relapse according to claim 1, wherein: The following steps are involved: The raw material powder of rotundine is added with conventional excipients, mixed evenly, and prepared into tablets, capsules, granules, sustained-release preparations, rapid-release preparations, controlled-release preparations, oral liquid preparations or injection preparations according to conventional processes.

7. The method for preparing the drug for treating drug addiction and preventing relapse according to claim 6, wherein: The dosage of the drug is not less than 30 mg per unit.

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