WO2019057221A1 - 蛞蝓或其提取物及其用途 - Google Patents

蛞蝓或其提取物及其用途 Download PDF

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WO2019057221A1
WO2019057221A1 PCT/CN2018/115650 CN2018115650W WO2019057221A1 WO 2019057221 A1 WO2019057221 A1 WO 2019057221A1 CN 2018115650 W CN2018115650 W CN 2018115650W WO 2019057221 A1 WO2019057221 A1 WO 2019057221A1
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extract
group
detoxification
organic solvent
dose
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French (fr)
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阮俊
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广西久福生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/618—Molluscs, e.g. fresh-water molluscs, oysters, clams, squids, octopus, cuttlefish, snails or slugs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/334—Foods, ingredients or supplements having a functional effect on health treating the effects of consuming alcohol, narcotics or other addictive behavior, e.g. treating hangover or reducing blood alcohol levels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/37—Extraction at elevated pressure or temperature, e.g. pressurized solvent extraction [PSE], supercritical carbon dioxide extraction or subcritical water extraction
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

Definitions

  • the invention belongs to the technical field of natural Chinese medicine development, and particularly relates to a new use of earthworms, and particularly relates to the use of earthworms in preparing medicines for detoxification or detoxification.
  • Drugs are anesthetic and psychotropic drugs that can cause addiction, which can cause serious harm to human body mechanism, human body and body health and social environment.
  • addiction can cause serious harm to human body mechanism, human body and body health and social environment.
  • the age is getting younger, and the types of drugs are becoming more and more diverse, from opium and cannabis to heroin, K powder, and ice.
  • ⁇ also known as ⁇ , is the dry whole of the footer Vaginulus alte (Ferussac). Vaginulalte (Ferussac); "Guangxi Zhuang Medicine Quality Standards Volume II", [sexual taste and returning] Chinese medicine salty, cold. Return to the lungs, liver, and large intestine. Zhuang doctor salty, cold. [Functions and Indications] Chinese medicine hurricane fixed shock, clearing away heat and detoxification, reducing swelling and pain. For stroke Secluded, tendons, convulsions, wheezing, wheezing, throat, bloated, erysipelas, sputum nucleus, hemorrhoids swelling, pain, prolapse.
  • the first technical problem solved by the present invention is to provide a new use of the crucible.
  • the new use of the hydrazine provided by the present invention is the use of hydrazine or its extract in the preparation of drugs for detoxification or detoxification, health foods, foods, especially in the preparation of drugs for physiological and mental dependence on detoxification or detoxification. , health food, food use.
  • the cockroach includes an ankle scorpion animal and/or a mollusc scorpion scorpion scorpion, wherein the scorpion scorpion animal includes a covering foot scorpion, and the mollusk gantry genus scorpion animal includes Limax maximus L., L. flavus L., Agriolimax agrestis L., Phiolomycus bilineatus.
  • the cockroach is a whole medicinal powder
  • the sputum extract is a sputum supercritical CO 2 extract or an organic solvent as a solvent.
  • the organic solvent is one or two of n-hexane, ethanol, methanol, acetone, chloroform, oil, gasoline, petroleum ether, diethyl ether, ethyl acetate, and the like.
  • the method for preparing the cockroach supercritical CO 2 extract comprises the following steps:
  • step S2 The hydrazine treated in step S1 is put into a supercritical CO 2 extractor for extraction, and the extract is obtained, dried, and obtained.
  • the preparation method of the extract obtained by using the organic solvent as a solvent comprises the following steps:
  • the treated sputum is put into a multi-functional extraction tank, refluxed by adding an organic solvent, filtered, and the extract liquid is recovered under reduced pressure to obtain a thick paste, which is dried and obtained.
  • a second technical problem to be solved by the present invention is a composition for detoxification or detoxification, which is originally prepared by using hydrazine or an extract thereof as a main active ingredient, and adding an acceptable carrier or auxiliary component. Preparation.
  • the invention adopts cockroach or its extract for preparing detoxification or detoxification medicines, health foods and foods, has the functions of calming and hypnosis, and has obvious effects on physiological and mental dependence on detoxification or detoxification, and provides for detoxification or detoxification. A new choice.
  • the preparation method of all the raw powders is:
  • the crucible is 100kg, the impurities are removed, crushed, and passed through a 80 mesh sieve.
  • the preparation method of the supercritical extract of cockroaches comprises the following steps:
  • the treated glutinous powder is put into a supercritical CO 2 extractor for extraction, the extraction pressure is 25 KPa, the temperature is 65 ° C, the flow rate is 500 PV, and the extract is obtained, dried, and obtained.
  • the preparation method of the supercritical extract of cockroaches comprises the following steps:
  • the treated glutinous powder is put into a supercritical CO 2 extractor for extraction, the extraction pressure is 25 KPa, the temperature is 65 ° C, the flow rate is 400 PV, and the extract is obtained, dried, and obtained.
  • the preparation method of the cockroach extract obtained by using an organic solvent as a solvent comprises the following steps:
  • T1 Will be ⁇ 100kg, remove impurities, smash, pass through 30 mesh sieve, spare;
  • the treated glutinous powder is put into a multi-functional extraction tank, and extracted by adding petroleum ether under reflux for 2 times, filtered, and the extract is combined, and petroleum ether is recovered under reduced pressure to obtain a thick paste, which is dried and obtained.
  • the preparation method of the cockroach extract obtained by using an organic solvent as a solvent comprises the following steps:
  • T1 Will be ⁇ 100kg, remove impurities, smash, pass through 30 mesh sieve, spare;
  • the treated glutinous powder is put into a multi-functional extraction tank, extracted by refluxing with ethanol twice, filtered, combined with the extract, and the ethanol is recovered under reduced pressure to obtain a thick paste, which is dried and obtained.
  • the preparation method of the cockroach extract obtained by using an organic solvent as a solvent comprises the following steps:
  • T1 Will be ⁇ 100kg, remove impurities, smash, pass through 30 mesh sieve, spare;
  • the treated glutinous powder is put into a multi-functional extraction tank, extracted with ethyl acetate under reflux for 2 times, filtered, and the combined extracts are taken, and the ethyl acetate is recovered under reduced pressure to obtain a thick paste, which is obtained by drying.
  • the preparation method of the cockroach extract obtained by using an organic solvent as a solvent comprises the following steps:
  • T1 Will be ⁇ 100kg, remove impurities, smash, pass through 30 mesh sieve, spare;
  • the preparation method of the cockroach extract obtained by using an organic solvent as a solvent comprises the following steps:
  • T1 Will be ⁇ 100kg, remove impurities, smash, pass through 30 mesh sieve, spare;
  • group (1) was set as a blank control group, rats were given subcutaneous injection of normal saline, and the remaining groups (2)-(11) were dose-incremented to replicate morphine-dependent rat model, subcutaneous injection of morphine hydrochloride, once every 12 hours, dose From 5 mg/kg each time, it was sequentially increased to 80 mg/kg each time, and was continuously used until the seventh day, and the injection amount was 0.2 ml/100 g, and the administration volume of each group was the same. On the 8th day of the experiment, morphine was stopped and the naloxone rushed withdrawal test was performed.
  • each group was given different treatments: (1) group, blank control group, given the same volume of normal saline; (2) group, morphine model group, given the same volume of normal saline; (3) group, positive drug control group, methadone 20 mg /kg; (4), (5) group are the low- and high-dose groups of the medicinal powder of the first embodiment of the present invention, and the doses administered by intragastric administration are 5g/kg and 10g/kg, respectively; (6) and (7) respectively
  • the doses of the cockroach extracts were 0.2g/kg and 0.4g/kg, respectively; (8) and (9) were respectively
  • the low- and high-dose groups of the hydrazine organic solvent solvent extract prepared in Example 6 were administered at doses of 0.2 g/kg and 0.4 g/kg, respectively; the groups (10) and (11) were respectively prepared according to Example 7 of the present invention.
  • the doses of the sputum extract were 0.2 g/kg and 0.4 g/kg, respectively. Each group was administered continuously for 3 days. Rats drink water and eat freely. After 45 minutes of administration on the first and third days of treatment, naloxone (5 mg/kg) was given an addiction, and the withdrawal response of the rats within 30 minutes and the changes of body weight before and after (1h) were observed. The results are shown in Table 1. ,Table 2.
  • Example 6 high dose group 52.4+14.60 22.2+8.86 10
  • Example 7 low dose group 73.8+39.12 27.4+8.96 (11)
  • Example 1 low dose group 2 1.8 ⁇ 3.25 2.9 ⁇ 2.59 (5)
  • the present invention provides a drug powder, a supercritical extract, and an organic solvent solvent extract. After treatment in the middle and high dose groups, the body weight of the mice increased. In the d1 of withdrawal, the difference between the low and high body weight of the sputum extract and the morphine model group were significantly different. The withdrawal was lower for 3 days. There was no significant difference in the body weight change of the rats.
  • the high and low doses of the antibiotic powder of the present invention, the supercritical extract thereof and the organic solvent solvent extract promoted the recovery of the body weight of the addicted rats.
  • group (1) was set as a blank control group, rats were given subcutaneous injection of normal saline, and the remaining groups (2)-(11) were morphogen-dependently replicated in a morphine-dependent rat model, subcutaneously injected with morphine, administered twice a day, each time. Once every 12 hours, the dose was increased from 25 mg/kg each time, increasing to 160 mg/kg every day on the 6th day, and the injection volume was 0.2 ml/100 g, and the doses of the groups were the same. On the 7th day of the experiment, morphine was discontinued and the naloxone-induced withdrawal test was performed.
  • each group was given different treatments: (1) group, blank control group, given the same volume of vegetable oil; (2) group, morphine model group, given the same volume of vegetable oil; (3) group, positive drug control group, methadone 20mg/kg (4), (5) are the low- and high-dose groups of the medicinal powder of the first embodiment of the present invention, and the doses administered by intragastric administration are 4g/kg and 8g/kg, respectively; (6) and (7) are respectively In the low- and high-dose groups of the cockroach extract prepared in the third embodiment, the doses of the cockroach extracts were 0.2 g/kg and 0.4 g/kg, respectively; the groups (8) and (9) were respectively the examples of the present invention.
  • the low- and high-dose groups of the organic solvent solvent extracts prepared were dosed at 0.2 g/kg and 0.4 g/kg, respectively; (10) and (11) were respectively obtained from the organic matter obtained in Example 7 of the present invention.
  • the doses of the sputum extract were 0.2 g/kg and 0.4 g/kg, respectively.
  • Each group of rats was administered continuously for 3 days. Rats drink water and eat freely. After 1 hour of treatment on the 1st and 3rd day of treatment, naloxone (8mg/kg) was given an addiction, and the jump response of each group of mice within 30 minutes and the weight change before and after withdrawal were observed. The results are shown in Table 3. 4.
  • mice After continuous administration of morphine to mice, morphine-dependent mice showed a significant jumping response after naloxone urging.
  • the symptoms of the mice were given different degrees of reduction in the number of jump responses in the mice treated with the high-dose and low-dose two-dose treatments, and the morphine powder was compared with the morphine model group.
  • the number of jumps of the super-critical extract, the organic solvent-soluble extract high- and low-dose two-dose group and the positive control group was significantly reduced, and it can be seen that the sputum of the present invention has a therapeutic effect on morphine-dependent mice, and has a therapeutic effect. Inhibition of morphine-dependent mice urged withdrawal withdrawal responses.
  • the body weight of the mice decreased significantly with the appearance of withdrawal symptoms.
  • Two doses of high and low doses of the herbicide powder, supercritical extract, and organic solvent solvent extract of the present invention were administered. After the treatment, the body weight of the mice increased, and in the d1 of withdrawal, the weight difference between the two groups of high and low doses of the probiotic powder, supercritical extract and organic solvent extract of the present invention was positive and the morphine model group and the positive group. There was a significant difference between the control group and the withdrawal for 3 days. There was no significant difference in body weight between the mice of the present invention, the supercritical extract, the supercritical extract, and the organic solvent solvent extract. It can be seen that the sputum of the present invention is antagonistic to morphine-dependent mice. Weight loss has a role in promoting recovery.
  • mice Take 100 Kunming mice, half male and half female, fasting for 12 hours, drinking water is not limited.
  • the mice were randomly divided into 10 groups, namely (1) blank control group; (2) positive drug control group (estazolam 2 mg/kg); (3) and (4) groups were respectively Example 1 of the present invention.
  • the low- and high-dose groups of crude drug powder were administered at a dose of 4g/kg and 8g/kg, respectively.
  • the groups (5) and (6) were the low- and high-dose groups of the cockroach extract prepared in Example 3 of the present invention.
  • the doses of the stomach-administered sputum extract were 0.4 g/kg and 0.8 g/kg, respectively; the groups (7) and (8) were the low- and high-dose groups of the hydrazine organic solvent solvent extract prepared in Example 6 of the present invention, respectively.
  • the doses were 0.4 g/kg and 0.8 g/kg, respectively; the groups (9) and (10) were respectively low and high dose groups of the organic solvent solvent extract prepared in Example 7 of the present invention, and the doses of the extracts were given respectively. It is 0.4 g/kg and 0.8 g/kg. After continuous administration for 3 days in each group, each group of mice was placed in the YLS-1A multifunctional small animal autonomous activity recorder.
  • mice After 5 minutes of adaptation, the number of spontaneous activities before administration of the mice was measured, and the recording time was 10 min. Each group of mice was administered at the above dosage, and the blank control group was administered with the same volume of physiological saline. Each mouse was intraperitoneally injected with morphine (10 mg/kg) 30 min after administration. After 15 minutes, the recorder was placed in the recorder to observe and record the number of activities in the mouse within 10 minutes. The results are shown in Table 5.
  • the number of activities of the mice increased significantly, and there was a significant difference compared with the administration.
  • P ⁇ 0.01 the positive drug estazolam was pre-administered, which significantly inhibited morphine.
  • the high- and low-dose two-dose groups of the probiotic powder, the supercritical extract and the organic solvent solvent extract of the present invention have different degrees of inhibitory effects on morphine excitatory effects, and are more obvious than the blank control group.
  • the difference is that the sputum of the present invention has a certain inhibitory effect on the excitability of mice induced by morphine.
  • mice Take 100 Kunming mice, half male and half female, fasting for 12 hours, drinking water is not limited.
  • the mice were randomly divided into 10 groups, namely (1) blank control group; (2) positive drug control group (estazolam 2 mg/kg); (3) and (4) groups were respectively Example 1 of the present invention.
  • the low- and high-dose groups of crude drug powder were administered at a dose of 4 g/kg and 8 g/kg, respectively; (5) and (6) were respectively low- and high-dose groups of cockroach extracts prepared in Example 3 of the present invention.
  • the doses of the stomach-administered sputum extract were 0.4 g/kg and 0.8 g/kg, respectively, and the rats in each group were continuously administered for 3 days; the groups (7) and (8) were respectively the hydrazine organic solvent prepared in Example 6 of the present invention.
  • the low and high dose groups of the solvent extract were administered at a dose of 0.4 g/kg and 0.8 g/kg, respectively; (9) and (10) were respectively low and high in the organic solvent solvent extract prepared in Example 7 of the present invention.
  • the doses of the sputum extract were 0.4 g/kg and 0.8 g/kg, respectively, and the rats in each group were continuously administered for 3 days.
  • mice Each group of mice was placed in the YLS-1A multifunctional small animal autonomous activity recorder. After 5 minutes of adaptation, the number of spontaneous activities before the administration of the mice was measured, and the recording time was 10 min. Each group of mice was intragastrically administered according to the above dosage, and the blank control group was administered with the same volume of normal saline. Each mouse was intraperitoneally injected with amphetamine (8 mg/kg) 30 min after administration. After 15 minutes, the recorder was placed in the recorder to observe and record the number of activities in the mouse within 10 minutes. The results are shown in Table 6.
  • mice Take 100 Kunming mice, half male and half female, fasting for 12 hours, drinking water is not limited.
  • the mice were randomly divided into 10 groups, namely (1) blank control group; (2) positive drug control group (estazolam 2 mg/kg); (3) and (4) groups were respectively Example 1 of the present invention.
  • the low- and high-dose groups of crude drug powder were administered at a dose of 4 g/kg and 8 g/kg, respectively; (5) and (6) were respectively low- and high-dose groups of cockroach extracts prepared in Example 3 of the present invention.
  • the doses of the stomach-administered sputum extract were 0.4 g/kg and 0.8 g/kg, respectively; the groups (7) and (8) were the low- and high-dose groups of the hydrazine organic solvent solvent extract prepared in Example 6 of the present invention, respectively.
  • the doses were 0.4 g/kg and 0.8 g/kg, respectively; the groups (9) and (10) were respectively low and high dose groups of the organic solvent solvent extract prepared in Example 7 of the present invention, and the doses of the extracts were given respectively. It is 0.4 g/kg and 0.8 g/kg.
  • Each group of rats was administered continuously for 3 days. The doses were administered in the above groups, and the blank control group was given the same volume of physiological saline.
  • mice After 45 minutes, each mouse was given 50 mg/kg of pentobarbital sodium, and then the sleep time of each group of mice was recorded (after the administration, the righting reflex of the mice disappeared into sleep time, and the righting reflex disappeared to return to sleep time) The results are shown in Table 7.
  • Example 1 high dose group 32.8 ⁇ 9.56 Example 3 low dose group 50.5 ⁇ 11.43 (6)
  • Example 3 high dose group 57.8 ⁇ 9.82 Example 6 low dose group 35.5 ⁇ 10.47 (8)
  • Example 6 high dose group 37.8 ⁇ 9.83 Example 7 low dose group 33.34 ⁇ 10.46 (10)
  • the 6, 7 ⁇ extract group was administered, with 10 animals per group.
  • the morphine control group and the sputum extract group were all administered by increasing dose, and the morphine control group was injected subcutaneously with morphine hydrochloride twice a day. According to the principle of increasing dose, the dosage of morphine was increased from 5 mg/kg each time to 60 mg/kg each time, and continued until the 7th day.
  • the medicinal powder, the cockroach extract obtained in the third embodiment, the quinone organic solvent solvent extract prepared in the invention examples 6 and 7, the medicinal powder group is administered by the principle of increasing dose, per day. 3 times, the dose increased from 0.7g/kg to 4.2g/kg day by day.
  • the sputum extract group was administered by intragastric administration twice a day. The dose was from 0.3g/kg and increased to 2.1g daily. /kg, the sputum extract group was administered by intragastric administration twice a day according to the principle of increasing dose. The dose was increased from 0.3 g/kg to 2.1 g/kg day by day, and continued until the seventh day.
  • the negative control group was given the same volume of vegetable oil every day, and the administration time and frequency were the same as those of the sputum extract group. On the 8th day, rats in each group were given naloxone (5 mg/kg), and the withdrawal state of the rats within 30 minutes after withdrawal and the weight change before and after withdrawal were observed. The results are shown in Table 8.
  • Weight loss is an important sign of opioid addiction and withdrawal. From the data in the table, the rats in the morphine control group were significantly higher than the negative control group after the naloxone-induced aging, indicating that the morphine group formed a significant physical dependence. The rats in the high- and low-dose groups of the drug powder, supercritical fluid extract and organic solvent solvent extract were continuously dosed according to the dose escalation method. After naloxone was urged, the withdrawal symptoms were not obvious, and the scores and weight loss of the rats were decreased. There was no significant difference compared with the negative control group. It can be seen that the cockroach extract of the present invention has no dependence on the withdrawal of the rat, indicating that the cockroach of the present invention does not have a body-dependent property.
  • the anti-drug powder, the extract and the organic solvent solvent extract thereof have the effect of detoxification treatment on the withdrawal symptoms of morphine-dependent rats or mice, and the mice excited by morphine and amphetamine are excited. It has an inhibitory effect and has a sedative and hypnotic effect.
  • the cockroach is acutely toxic and safe, and is suitable for developing detoxification or detoxification medicines, health foods, and foods.

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Abstract

蛞蝓生药粉、超临界萃取物或蛞蝓有机溶剂提取物在制备用于脱毒或戒毒药品、保健食品、食品的用途。一种用于脱毒或戒毒的组合物，其特征在于蛞蝓或其提取物为主要活性成分，加入可接受的载体或辅助性成分制备。

Description

[根据细则37.2由ISA制定的发明名称]　蛞蝓或其提取物及其用途 技术领域
本发明属于天然中药开发技术领域，具体涉及蛞蝓的新用途，特别涉及蛞蝓在制备用于脱毒或戒毒药物中的用途。
背景技术
毒品是一种能够使人形成瘾癖的麻醉药品和精神药品，它对人体机理、人体身心健康以及社会环境都会产生严重的危害。目前，吸毒人群越来越多，年龄也越趋低龄化，而且毒品的类型也越来越多样化，从鸦片、大麻发展到海洛因、K粉、冰毒等。
戒毒、禁毒一直是世界性难题，至今未能有很好的解决办法，全球戒毒方式均以强制性戒毒或以毒攻毒的替代疗法进行戒毒。强制性戒毒既痛苦而又艰辛漫长；以美沙酮、纳曲酮等替代疗法是以一种毒品代替另一种毒品，或者暂时性阻断阿片受体，但都不能彻底让戒毒者从生理和心理上摆脱毒品，容易反弹和复吸，正如以低度白酒代替高度酒治疗酗酒一样，只不过以致瘾性稍微小的毒品替代了高致瘾性的毒品。
蛞蝓，又名碾沐，为足襞蛞蝓科动物覆套足襞蛞蝓Vaginulus alte(Ferussac)的干燥全体。覆套足襞蛞(Vaginulalte(Ferussac))；《广西壮药质量标准第二卷》，【性味与归经】中医咸，寒。归肺、肝、大肠经。壮医咸，寒。【功能与主治】中医祛风定惊，清热解毒，消肿止痛。用于中风
Figure PCTCN2018115650-appb-000001
僻，筋脉拘挛，惊痫，喘息，咽肿，喉痹，痈肿，丹毒，痰核，痔疮肿痛，脱肛。壮医清热毒，调气道，通龙路。用于货烟妈(咽炎)、墨病(哮喘)，尊寸(脱肛)，兵嘿细勒(疝气)，呗农(痈疮)，京瑟(闭经)，蜈蚣咬伤。
目前，尚未见以蛞蝓用于脱毒或戒毒药物的相关报道。
发明内容
本发明所解决的第一个技术问题为提供一种蛞蝓的新用途。
本发明所提供的蛞蝓的新用途是蛞蝓或其提取物在制备用于脱毒或戒毒药品、保健食品、食品方面的用途，尤其是在制备用于生理性及精神性依赖脱毒或 戒毒药品、保健食品、食品方面的用途。
进一步的，所述蛞蝓包括足襞蛞蝓科蛞蝓动物和/或软体动物门腹足纲蛞蝓科动物，其中足襞蛞蝓科蛞蝓动物包括覆套足襞蛞蝓，软体动物门腹足纲蛞蝓科动物包括大蛞蝓(Limax maximus L.)、黄蛞蝓(L.flavus L.)、野蛞蝓(Agriolimax agrestis L.)，双线粘液蛞蝓(Phiolomycus bilineatus)。
进一步的，所述蛞蝓为其全体生药粉；所术蛞蝓提取物为蛞蝓超临界CO 2萃取物或以有机溶剂为溶媒所得提取物。
更进一步的，所述机溶剂为正已烷、乙醇、甲醇、丙酮、三氯甲烷、油、汽油、石油醚、乙醚、乙酸乙酯等中的一种或两种。
进一步的，所述蛞蝓超临界CO 2萃取物的制备方法，包括以下步骤：
S1.将蛞蝓粉碎，备用；
S2.将步骤S1中处理好的蛞蝓投入至超临界CO 2萃取器中萃取，得萃取物，干燥，即得。
进一步的，所述以有机溶剂为溶媒所得提取物的制备方法，包括以下步骤：
T1.将蛞蝓粉碎，备用；
T2.将处理好的蛞蝓投入至多功能提取罐中，加入有机溶剂回流提取，滤过，提取液减压回收溶剂，制得稠膏，干燥，即得。
本发明要解决的第二个技术问题为一种用于脱毒或戒毒的组合物，该组合物原来以蛞蝓或其提取物为主要活性成分，加入可接受的载体或辅助性成分制备而成的制剂。
本发明取得的有益效果：
本发明采用蛞蝓或其提取物用于制备脱毒或戒毒药品、保健食品、食品，具有镇静催眠的作用，对生理性、精神性依赖脱毒或戒毒的效果显著，为脱毒或戒毒提供了一种全新的选择。
具体实施方式：
为更好的解释本发明蛞蝓用于制备戒毒或脱毒药品、保健食品、食品的效果，本发明采用以下具体实施例进一步描述：
一、蛞蝓全体生药粉的制备
实施例1：
蛞蝓全体生药粉的制备方法为：
将蛞蝓100kg，去除杂质，粉碎，过80目筛，即得。
二、蛞蝓提取物的制备
(一)蛞蝓超临界CO 2萃取物的制备
实施例2
蛞蝓超临界萃取物的制备方法，包括以下步骤：
S1.将蛞蝓100kg，去除杂质，粉碎，过30目筛，备用；
S2.将处理好的蛞蝓粉投入至超临界CO 2萃取器中萃取，萃取压力为25KPa，温度为65℃，流量为500PV，得萃取物，干燥，即得。
实施例3
蛞蝓超临界萃取物的制备方法，包括以下步骤：
S1.将蛞蝓100kg，去除杂质，粉碎，过30目筛，备用；
S2.将处理好的蛞蝓粉投入至超临界CO 2萃取器中萃取，萃取压力为25KPa，温度为65℃，流量为400PV，制得萃取物，干燥，即得。
(二)以有机溶剂为溶媒所得蛞蝓提取物的制备
实施例4
以有机溶剂为溶媒所得蛞蝓提取物的制备方法，包括以下步骤：
T1.将蛞蝓100kg，去除杂质，粉碎，过30目筛，备用；
T2.将处理好的蛞蝓粉投入至多功能提取罐中，加入石油醚回流提取2次，滤过，合并提取液，减压回收石油醚，制得稠膏，干燥，即得。
实施例5
以有机溶剂为溶媒所得蛞蝓提取物的制备方法，包括以下步骤：：
T1.将蛞蝓100kg，去除杂质，粉碎，过30目筛，备用；
T2.将处理好的蛞蝓粉投入至多功能提取罐中，加入乙醇回流提取2次，滤过，合并提取液，减压回收乙醇，制得稠膏，干燥，即得。
实施例6
以有机溶剂为溶媒所得蛞蝓提取物的制备方法，包括以下步骤：：
T1.将蛞蝓100kg，去除杂质，粉碎，过30目筛，备用；
T2.将处理好的蛞蝓粉投入至多功能提取罐中，加入乙酸乙酯回流提取2次， 滤过，合并提取液，减压回收乙酸乙酯，制得稠膏，干燥，即得。
实施例7
以有机溶剂为溶媒所得蛞蝓提取物的制备方法，包括以下步骤：：
T1.将蛞蝓100kg，去除杂质，粉碎，过30目筛，备用；
T2.将处理好的蛞蝓粉投入至多功能提取罐中，加入混合溶剂(正己烷:丙酮＝1:1)回流提取2次，滤过，合并提取液，减压回收溶剂，制得稠膏，干燥，即得。
实施例8
以有机溶剂为溶媒所得蛞蝓提取物的制备方法，包括以下步骤：：
T1.将蛞蝓100kg，去除杂质，粉碎，过30目筛，备用；
T2.将处理好的蛞蝓粉投入至多功能提取罐中，加入混合溶剂(甲醇:乙醚＝1:1)回流提取2次，滤过，合并提取液，减压回收溶剂，制得稠膏，干燥，即得。
二、戒毒药效试验：
为了验证本发明的蛞蝓的戒毒药效，本发明进行了以下实验：
实验一：
取Sprague-Dawley大鼠110只，雌雄各一半，随机分为11组。其中(1)组设为空白对照组，给大鼠皮下注射生理盐水，剩余(2)-(11)组按剂量递增法复制吗啡依赖大鼠模型，皮下注射盐酸吗啡，每12小时一次，剂量从每次5mg/kg起，逐次增加到每次80mg/kg，连续用至第7天，注射量为0.2ml/100g，各组给药体积相同。到实验第8天，停用吗啡，进行纳洛酮催促戒断试验。各组分别给予不同处理：(1)组，空白对照组，给予同容量生理盐水；(2)组，吗啡模型组，给予同容量生理盐水；(3)组，阳性药对照组，给予美沙酮20mg/kg；(4)、(5)组分别为本发明实施例1蛞蝓生药粉低、高剂量组，灌胃给予剂量分别为5g/kg、10g/kg；(6)、(7)组分别为本发明实施例3制得的蛞蝓萃取物低、高剂量组，灌胃给予蛞蝓萃取物的剂量分别为0.2g/kg、0.4g/kg；(8)、(9)组分别为本发明实施例6制得的蛞蝓有机溶剂溶媒提取物低、高剂量组，给予剂量分别为0.2g/kg、0.4g/kg；(10)、(11)组分别为本发明实施例7制得的蛞蝓有机溶剂溶媒提取物 低、高剂量组，给予蛞蝓提取物的剂量分别为0.2g/kg、0.4g/kg。各组连续给药3天。大鼠饮水、进食自由。分别在治疗第1天和第3天给药45min后，给予纳洛酮(5mg/kg)催瘾，观察30min内大鼠的戒断反应及催促前后(1h)体重变化情况，结果见表1、表2。
表1 吗啡依赖大鼠催促戒断症状评分值
序号 组别 第1天 第3天
(1) 空白对照组 4.5+3.88 1.4+1.69
(2) 吗啡模型组 81.3+32.11 44.5+8.09
(3) 阳性药对照组 49.35+14.41 35.6+18.73
(4) 实施例1低剂量组 80.2+28.03 32.57+12.26
(5) 实施例1高剂量组 73.8+23.25 28.1+13.90
(6) 实施例3低剂量组 51.9+41.03 23.5+12.26
(7) 实施例3高剂量组 50.21+16.23 14.1+10.90
(8) 实施例6低剂量组 74.4+40.18 28.16+10.58
(9) 实施例6高剂量组 52.4+14.60 22.2+8.86
(10) 实施例7低剂量组 73.8+39.12 27.4+8.96
(11) 实施例7高剂量组 53.1+13.60 21.7+7.98
从表1中数据可知，空白对照组给予纳洛酮后，大鼠未见明显的戒断症状，吗啡依赖模型组大鼠阶段后1、3天，经纳洛酮催促后均出现明显的戒断症状，与空白对照组比较，有显著性差异，吗啡依赖大鼠经本发明且超临界萃取物、有机溶剂溶媒提取物、蛞蝓生药粉、阳性药对照组大鼠的戒断症状积分值均有不同程度的差异，蛞蝓生药粉、超临界萃取物、有机溶剂溶媒提取物高、低两个剂量组明显低于模型组吗啡模型组。
表2 各组大鼠体重差值(催促前体重-催促后体重)
序号 组别 第1天体重下降值(g) 第3天体重下降值(g)
(1) 空白对照组 0.5±3.20 1.0±1.05
(2) 吗啡模型组 10.5±5.48 8.6±2.41
(3) 阳性药对照组 15.6±6.39 2.6±2.75
(4) 实施例1低剂量组 21.8±3.25 2.9±2.59
(5) 实施例1高剂量组 19.8±3.25 2.1±2.13
(6) 实施例3低剂量组 12.3±2.95 0.1±2.78
(7) 实施例3高剂量组 13.3±1.05 0.7±1.30
(8) 实施例6低剂量组 11.2±2.90 0.9±2.80
(9) 实施例6高剂量组 12.2±1.90 0.5±1.95
(10) 实施例7低剂量组 13.6±3.50 0.8±2.25
(11) 实施例7高剂量组 14.16±2.50 1.1±2.15
从表2中数据可知，各吗啡依赖小鼠经纳洛酮催促后，随着戒断症状的出现，小鼠体重均明显下降，本发明蛞蝓生药粉、超临界萃取物、有机溶剂溶媒提取物中高、低两个剂量组治疗后，小鼠体重有所增加，在戒断的d1,蛞蝓提取物低、高组体重差异与吗啡模型组，有显著差异，戒断低3天，各组小鼠体重变化物无明显差异，本发明蛞蝓生药粉、及其超临界萃取物、有机溶剂溶媒提取物中高低2个剂量对成瘾大鼠的体重下降有促进恢复的作用。
实验二：
取昆明种小鼠110只，雌雄各一半，随机分为11组。其中(1)组设为空白对照组，给大鼠皮下注射生理盐水，剩余(2)—(11)组按剂量递增法复制吗啡依赖大鼠模型，皮下注射吗啡，每天给药2次，每12小时一次，剂量从每次25mg/kg起，逐日递增，于第6天增至每次160mg/kg，注射量为0.2ml/100g，各组给药体积相同。到实验第7天，停用吗啡，进行纳洛酮催促戒断试验。各组分别给予不同处理：(1)组，空白对照组，给予同容量植物油；(2)组，吗啡模型组，给予同容量植物油；(3)组，阳性药对照组，给予美沙酮20mg/kg；(4)、 (5)组分别为本发明实施例1蛞蝓生药粉低、高剂量组，灌胃给予剂量分别为4g/kg、8g/kg；(6)、(7)组分别为本发明实施例3制得的蛞蝓萃取物低、高剂量组，灌胃给予蛞蝓萃取物的剂量分别为0.2g/kg、0.4g/kg；(8)、(9)组分别为本发明实施例6制得的蛞蝓有机溶剂溶媒提取物低、高剂量组，给予剂量分别为0.2g/kg、0.4g/kg；(10)、(11)组分别为本发明实施例7制得的蛞蝓有机溶剂溶媒提取物低、高剂量组，给予蛞蝓提取物的剂量分别为0.2g/kg、0.4g/kg。各组大鼠连续给药3天。大鼠饮水、进食自由。分别在治疗第1天和第3天给药1h后，给予纳洛酮(8mg/kg)催瘾，观察30min内各组小鼠的跳跃反应和催促戒断前后体重变化，结果见表3、4。
表3 吗啡依赖小鼠催促戒断跳跃反应次数
序号 组别 第1天(次/30min) 第3天(次/30min)
(1) 空白对照组 0.4±0.699 0.5±0.84
(2) 吗啡模型组 63.2±14.65 12.5±6.09
(3) 阳性药对照组 25.1±6.9 22.9±6.81
(4) 实施例1低剂量组 40.12±9.31 25.5±10.09
(5) 实施例1高剂量组 45.12±8.51 23.5±0.19
(6) 实施例3低剂量组 35.5±10.29 8.2±2.86
(7) 实施例3高剂量组 32.0±2.28 6.12±0.68
(8) 实施例6低剂量组 25.5±15.29 12.2±0.06
(9) 实施例6高剂量组 22.1±10.78 11.5±1.28
(10) 实施例7低剂量组 26.0±10.28 14.5±0.68
(11) 实施例7高剂量组 23.5±13.19 10.2±2.86
从表3中数据可知，给小鼠连续给予吗啡后，经纳洛酮催促，吗啡依赖小鼠出现明显的跳跃反应，不给予吗啡的空白对照组在给予纳洛酮后，小鼠无明显戒断症状，给予本发明蛞蝓生药粉、超临界萃取物、有机溶剂溶媒提取物高、低两个剂量治疗后小鼠出现跳跃反应的次数均有不同程度的减少，与吗啡模型组比较 蛞蝓生药粉、超临界萃取物、有机溶剂溶媒提取物高、低两个剂量组及阳性对照组小鼠的跳跃次数均显著减少，可见本发明的蛞蝓对吗啡依赖小鼠催促戒断症状具有治疗作用，能够抑制吗啡依赖小鼠催促戒断跳跃反应。
表4 各组小鼠体重差值(催促前体重-催促后体重)
序号 组别 第1天(g) 第3天体重下降值(g)
(1) 空白对照组 0.19±0.17 0.34±0.31
(2) 吗啡模型组 0.53±0.19 3.55±0.29
(3) 阳性药对照组 0.22±0.19 1.46±0.23
(4) 实施例1低剂量组 2.98±0.13 0.49±0.18
(5) 实施例1高剂量组 1.86±0.21 0.37±0.31
(6) 实施例3低剂量组 0.51±0.53 0.11±0.14
(7) 实施例3高剂量组 0.9±0.01 0.09±0.31
(8) 实施例6低剂量组 0.65±0.53 0.56±0.28
(9) 实施例6高剂量组 0.87±0.12 0.41±0.21
(10) 实施例7低剂量组 0.73±0.53 0.46±0.28
(11) 实施例7高剂量组 0.65±0.22 0.25±0.21
各吗啡依赖小鼠经纳洛酮催促后，随着戒断症状的出现，小鼠体重均明显下降，给予本发明蛞蝓生药粉、超临界萃取物、有机溶剂溶媒提取物中高、低两个剂量组治疗后，小鼠体重有所增加，且在戒断的d1,本发明蛞蝓生药粉、超临界萃取物、有机溶剂溶媒提取物中高、低两个剂量各组体重差异与吗啡模型组及阳性对照组有显著差异，戒断3天，本发明的蛞蝓生药粉、超临界萃取物、有机溶剂溶媒提取物各组小鼠体重变化无明显差异，可见，本发明的蛞蝓对吗啡依赖小鼠的体重下降有促进恢复的作用。
实验三：
取昆明种小鼠100只，雌雄各一半，禁食12h，饮水不限。将小鼠随机分为10组，即(1)空白对照组；(2)阳性药对照组(艾司唑仑2mg/kg)；(3)、(4)组分别为本发明实施例1蛞蝓生药粉低、高剂量组，灌胃给予剂量分别为4g/kg、 8g/kg，(5)、(6)组分别为本发明实施例3制得的蛞蝓萃取物低、高剂量组，灌胃给予蛞蝓萃取物的剂量分别为0.4g/kg、0.8g/kg；(7)、(8)组分别为本发明实施例6制得的蛞蝓有机溶剂溶媒提取物低、高剂量组，给予剂量分别为0.4g/kg、0.8g/kg；(9)、(10)组分别为本发明实施例7制得的蛞蝓有机溶剂溶媒提取物低、高剂量组，给予蛞蝓提取物的剂量分别为0.4g/kg、0.8g/kg。各组连续给药3天后，将各组小鼠放入YLS-1A多功能小动物自主活动记录仪中，适应5min后，测定小鼠给药前的自主活动次数，记录时间为10min。按上述剂量给各组小鼠给药，空白对照组给予同体积生理盐水灌胃。给药后30min，给每只小鼠腹腔注射吗啡(10mg/kg)。15min后放入记录仪内观察并记录小鼠10min内的活动次数，结果见表5。
表5 蛞蝓提取物对吗啡诱导兴奋性的影响
Figure PCTCN2018115650-appb-000002
从表中数据可知，给空白对照组小鼠注射吗啡后，小鼠的活动次数明显增加，与给药相比有显著差异,P＜0.01，预先给予阳性药艾司唑仑，可明显抑制吗啡诱导小鼠兴奋作用，本发明蛞蝓生药粉、超临界萃取物、有机溶剂溶媒提取物中高、低两个剂量组对吗啡是兴奋性作用均有不同程度的抑制作用，与空白对照组比较 有明显差异，可见本发明份蛞蝓对吗啡引起的小鼠兴奋性提高具有一定的抑制作用。
实验四：
取昆明种小鼠100只，雌雄各一半，禁食12h，饮水不限。将小鼠随机分为10组，即(1)空白对照组；(2)阳性药对照组(艾司唑仑2mg/kg)；(3)、(4)组分别为本发明实施例1蛞蝓生药粉低、高剂量组，灌胃给予剂量分别为4g/kg、8g/kg；(5)、(6)组分别为本发明实施例3制得的蛞蝓萃取物低、高剂量组，灌胃给予蛞蝓萃取物的剂量分别为0.4g/kg、0.8g/kg，各组大鼠连续给药3天；(7)、(8)组分别为本发明实施例6制得的蛞蝓有机溶剂溶媒提取物低、高剂量组，给予剂量分别为0.4g/kg、0.8g/kg；(9)、(10)组分别为本发明实施例7制得的蛞蝓有机溶剂溶媒提取物低、高剂量组，给予蛞蝓提取物的剂量分别为0.4g/kg、0.8g/kg，各组大鼠连续给药3天。将各组小鼠放入YLS-1A多功能小动物自主活动记录仪中，适应5min后，测定小鼠给药前的自主活动次数，记录时间为10min。按上述剂量给各组小鼠灌胃给药，空白对照组给予同体积生理盐水灌胃。给药后30min，给每只小鼠腹腔注射苯丙胺(8mg/kg)。15min后放入记录仪内观察并记录小鼠10min内的活动次数，结果见表6。
表6 蛞蝓提取物对苯丙胺诱导兴奋性的影响
Figure PCTCN2018115650-appb-000003
Figure PCTCN2018115650-appb-000004
从表6中数据可知，从表中数据可知，给空白对照组小鼠注射苯丙胺后，小鼠的活动次数明显增加，与给药相比有显著差异,P＜0.01，预先给予阳性药艾司唑仑，可明显抑制吗啡诱导小鼠兴奋作用，本发明蛞蝓生药粉、超临界萃取物、有机溶剂溶媒提取物中高、低两个剂量组低、高剂量组对吗啡是兴奋性作用均有不同程度的抑制作用，与空白对照组比较有明显差异，可见本发明的蛞蝓对苯丙胺引起的小鼠兴奋性提高具有一定的抑制作用。
实验五：
取昆明种小鼠100只，雌雄各一半，禁食12h，饮水不限。将小鼠随机分为10组，即(1)空白对照组；(2)阳性药对照组(艾司唑仑2mg/kg)；(3)、(4)组分别为本发明实施例1蛞蝓生药粉低、高剂量组，灌胃给予剂量分别为4g/kg、8g/kg；(5)、(6)组分别为本发明实施例3制得的蛞蝓萃取物低、高剂量组，灌胃给予蛞蝓萃取物的剂量分别为0.4g/kg、0.8g/kg；(7)、(8)组分别为本发明实施例6制得的蛞蝓有机溶剂溶媒提取物低、高剂量组，给予剂量分别为0.4g/kg、0.8g/kg；(9)、(10)组分别为本发明实施例7制得的蛞蝓有机溶剂溶媒提取物低、高剂量组，给予蛞蝓提取物的剂量分别为0.4g/kg、0.8g/kg。各组大鼠连续给药3天。按上述各组剂量给药，空白对照组给予同体积生理盐水。45min后给每只小鼠戊巴比妥钠50mg/kg，然后记录各组小鼠的睡眠时间(以给药后小鼠翻正反射消失为入睡时间，翻正反射消失至恢复为睡眠时间)，结果见表7。
表7 蛞蝓对戊巴比妥钠诱导小鼠睡眠时间的影响
序号 组别 小鼠睡眠时间(min)
(1) 空白对照组 25.8±5.01
(2) 阳性药对照组 66.22±13.77
(3) 实施例1低剂量组 29.5±11.46
(4) 实施例1高剂量组 32.8±9.56
(5) 实施例3低剂量组 50.5±11.43
(6) 实施例3高剂量组 57.8±9.82
(7) 实施例6低剂量组 35.5±10.47
(8) 实施例6高剂量组 37.8±9.83
(9) 实施例7低剂量组 33.34±10.46
(10) 实施例7高剂量组 35.12±9.56
从表7中数据可知，蛞蝓生药粉、超临界萃取物、有机溶剂溶媒提取物中高、低两个剂量组给药后戊巴比妥钠阈下睡眠剂量所致小鼠睡眠时间明显延长，且本发明蛞蝓生药粉、超临界萃取物、有机溶剂溶媒提取物与空白对照组比较有显著性差异，可见本发明的蛞蝓能延长戊巴比妥钠阈剂量的小鼠睡眠时间。
试验六
取Sprague-Dawley大鼠60只，雌雄各一半，随机分为6组，即阴性对照组，吗啡对照组，本发明实施例1蛞蝓生药粉组，本发明实施例3蛞蝓萃取物组，本发明实施6、7蛞蝓提取物组，每组10只动物。吗啡对照组及蛞蝓提取物组均采用递增给药法，吗啡对照组皮下注射盐酸吗啡，每天给药2次。按剂量递增原则，吗啡的给药剂量均从每次5mg/kg起，依次增加，至每次60mg/kg，连续用至第7天。本发明实施例1蛞蝓生药粉、实施例3制得的蛞蝓萃取物、发明实施例6、7制得的蛞蝓有机溶剂溶媒提取物，蛞蝓生药粉组按剂量递增原则，灌胃给药，每天3次，剂量从0.7g/kg起，逐日递增至4.2g/kg，蛞蝓萃取物组按剂量递增原则，灌胃给药，每天2次，剂量从0.3g/kg起，逐日递增至2.1g/kg，蛞蝓提取物组按剂量递增原则，灌胃给药，每天2次，剂量从0.3g/kg起，逐日递增至2.1g/kg，连续用至第7天。阴性对照组每天给予同容量植物油，给药时间及次数与蛞蝓提取物组相同。第8天给各组大鼠给予纳洛酮(5mg/kg)催促，观察催促戒断后30min内大鼠的戒断状态及催促戒断1h前后体重变化情况，结果见表8。
表8蛞蝓提取物对吗啡依赖大鼠在催促戒断体重变化影响
序号 组别 戒断反应分值 体重下降值(g)
(1) 阴性对照组 2.9±2.24 0.2±3.39
(2) 吗啡对照组 76.9±14.53 9.5±3.62
(3) 实施例1组 15.21±21.53 5.21±0.53
(4) 实施例3组 7.2±3.37 0.1±0.46
(5) 实施例6组 10.05±0.13 1.21±0.32
(6) 实施例7组 8.22±2.5 1.58±0.22
体重下降是阿片类药物成瘾及戒断的一个重要体征。从表中数据可知，吗啡对照组大鼠经纳洛酮催促后，大鼠的戒断症状分值和体重下降均明显高于阴性对照组，表明吗啡组大鼠形成了明显的身体依赖性，蛞蝓生药粉、超临界萃取物、有机溶剂溶媒提取物中高、低剂量组大鼠按照剂量递增法连续给药后，经纳洛酮催促，戒断症状不明显，大鼠的评分值及体重下降与阴性对照组比较均无明显差异，可见本发明的蛞蝓提取物对大鼠催促戒断无依赖性作用，说明本发明的蛞蝓不具有身体依赖的特性。
经多项动物实验证明，本发明蛞蝓生药粉、萃取物、及其有机溶剂溶媒提取物对吗啡依赖大鼠或小鼠的戒断症状具有脱毒治疗效果，对吗啡和苯丙胺引起的小鼠兴奋性具有抑制作用，并且具有镇静催眠作用，所述蛞蝓急性毒性安全，适合开发脱毒或戒毒药品、保健食品、食品。
以上内容是结合具体的优选的实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，其还可以对这些已描述的实施例做出若干替代或变型，而这些替代或变型方式都应当视为属于本发明的保护范围

Claims (10)

  1. 蛞蝓或其提取物在制备用于脱毒或戒毒药品、保健食品、食品方面的用途。
  2. 蛞蝓或其提取物在制备用于生理性及精神性依赖脱毒或戒毒药品、保健食品、食品方面的用途。
  3. 根据权利要求1或2所述的用途，其特征在于，所述蛞蝓包括足襞蛞蝓科蛞蝓动物和/或软体动物门腹足纲蛞蝓科动物。
  4. 根据权利要求1或2所述的用途，其特征在于，所述足襞蛞蝓科蛞蝓动物包括覆套足襞蛞蝓，所述软体动物门腹足纲蛞蝓科动物包括大蛞蝓(Limax maximus L.)、黄蛞蝓(L.flavus L.)、野蛞蝓(Agriolimax agrestis L.)，双线粘液蛞蝓(Phiolomycus bilineatus)。
  5. 根据权利要求1或2所述的用途，其特征在于，所述蛞蝓为其全体生药粉。
  6. 根据权利要求1或2所述的用途，其特征在于，所述蛞蝓提取物为蛞蝓超临界CO 2萃取物或以有机溶剂为溶媒所得提取物。
  7. 根据权利要求6所述的用途，其特征在于，所述机溶剂为正已烷、乙醇、甲醇、丙酮、三氯甲烷、油、汽油、石油醚、乙醚、乙酸乙酯中的一种或两种。
  8. 根据权利要求6所述的用途，其特征在于，所述蛞蝓超临界CO 2萃取物的制备方法为，包括以下步骤：
    S1.将蛞蝓粉碎，备用；
    S2.将步骤S1中处理好的蛞蝓投入至超临界CO 2萃取器中萃取，得萃取物，干燥，即得。
  9. 根据权利要求6所述的用途，其特征在于，所述以有机溶剂为溶媒所得提取物的制备方法为，包括以下步骤：
    T1.将蛞蝓粉碎，备用；
    T2.将处理好的蛞蝓投入至多功能提取罐中，加入有机溶剂回流提取，滤过，提取液减压回收溶剂，制得稠膏，干燥，即得。
  10. 一种用于脱毒或戒毒的组合物，其特征在于，以蛞蝓或其提取物为主要活性成分，加入可接受的载体或辅助性成分制备而成的制剂。
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