WO2011153819A1 - 用于戒毒的药物组合物 - Google Patents

用于戒毒的药物组合物 Download PDF

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Publication number
WO2011153819A1
WO2011153819A1 PCT/CN2011/000900 CN2011000900W WO2011153819A1 WO 2011153819 A1 WO2011153819 A1 WO 2011153819A1 CN 2011000900 W CN2011000900 W CN 2011000900W WO 2011153819 A1 WO2011153819 A1 WO 2011153819A1
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Prior art keywords
medicinal material
golden flower
extract
extracts
filtrate
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PCT/CN2011/000900
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English (en)
French (fr)
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WO2011153819A8 (zh
WO2011153819A4 (zh
Inventor
常开义
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云南明镜亨利制药有限公司
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Application filed by 云南明镜亨利制药有限公司 filed Critical 云南明镜亨利制药有限公司
Priority to CN201180028036.5A priority Critical patent/CN102985099B/zh
Priority to RU2012157720/15A priority patent/RU2546522C2/ru
Priority to BR112012031318-5A priority patent/BR112012031318B1/pt
Priority to US13/702,239 priority patent/US9572851B2/en
Priority to EP11791811.0A priority patent/EP2578223B1/en
Priority to JP2013513522A priority patent/JP5764655B2/ja
Publication of WO2011153819A1 publication Critical patent/WO2011153819A1/zh
Publication of WO2011153819A4 publication Critical patent/WO2011153819A4/zh
Priority to ZA2012/09537A priority patent/ZA201209537B/en
Publication of WO2011153819A8 publication Critical patent/WO2011153819A8/zh
Priority to HK13104970.1A priority patent/HK1178044A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/56—Loganiaceae (Logania family), e.g. trumpetflower or pinkroot
    • 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
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition for detoxification, in particular to a pharmaceutical composition comprising a Chinese herbal medicine, Coprinus comatus and Flos Lonicera; the present invention also relates to the use of Chinese herbal medicines E. cerevisiae and Flos Lonicera in the preparation of a medicament, wherein The drug is used to eliminate or alleviate acute withdrawal symptoms and protracted symptoms caused by addictive substances, eliminate or reduce the subject's craving for addictive substances, and prevent the subject from being in need thereof. The tester then used the addictive substance.
  • Background technique is used to eliminate or alleviate acute withdrawal symptoms and protracted symptoms caused by addictive substances, eliminate or reduce the subject's craving for addictive substances, and prevent the subject from being in need thereof.
  • the tester then used the addictive substance.
  • Traditional detoxification methods include alternative declining therapy, natural withdrawal therapy, sub-hibernation detoxification therapy, antagonist therapy, and non-drug withdrawal methods using electrical stimulation, acupuncture, and physiotherapy.
  • the heroin-dependent detoxification treatments include methadone, opiates, buprenorphine, clonidine, dextromethorphan, and chlorpromazine. These drugs are mostly opioid receptor agonists and sedative and hypnotic drugs.
  • opioid receptor agonist drugs such as methadone, buprenorphine, etc.
  • Non-substitute therapy such as clonidine
  • Hibernating therapy is commonly used to suppress hypnotic drugs. Because of the large amount of use of this drug, the damage to the brain is too large. Improper use of drugs may also endanger life, and it is not good for relieving psychological dependence.
  • Naltrexone for antagonist therapy is an opioid receptor antagonist. Taking naltrexone after detoxification can greatly reduce the euphoria caused by drug use, block the strengthening effect, prevent relapse, but improve the protracted symptoms. It is not obvious, and it needs to be taken for a long time.
  • This acute withdrawal symptom makes the patient feel very painful, and the chemical often controls the acute withdrawal symptoms well, relieves or alleviates the pain.
  • the synthesis of endogenous opioid peptides and the increase in the number of opioid receptors are difficult to reach normal levels in the short term, in a relatively long period of time.
  • protracted withdrawal symptoms Mainly manifested as intractable insomnia, anxiety and irritability, pain in the body, fatigue, and poor mood.
  • Most of the chemicals are not effective in relieving protracted withdrawal symptoms.
  • mental dependence is associated with physical dependence.
  • Mental dependence refers to the psychological experience of the drug-dependent drug hunger and the euphoric experience achieved by repeated medication. It is also called “thinking addiction, or” addiction. "Because of emotional drive, the addicts continue to use drugs, thus changing their lifestyle, behavior and personality model.” Style. The euphoria and relaxation and tranquility produced by the medication are positively strengthened; and the uncomfortable withdrawal symptoms caused by withdrawal of medicine can only continue to be used in order to avoid such pain, which is a negative reinforcement. These two enhancements make it difficult for addicts to extricate themselves. After acute addiction treatment, physical dependence is eliminated, but mental dependence is difficult to eliminate. The so-called “heart addiction is difficult to remove", so the relapse rate is extremely high. It is reported that the relapse rate is as high as 90% or more. Reducing the relapse rate is a drug treatment. the biggest challenge! There are currently no drugs that can effectively treat mental dependence.
  • Drug abuse has become a major public hazard in the world today, both harming itself and causing harm to society. Once drug abuse is difficult to quit, relapse often occurs, causing great pain and mental and economic burden to drug abusers. Protracted withdrawal symptoms such as physical discomfort and insomnia are the main physiological factors for relapse. The irresistible psychological craving for drugs is the main psychological factor for relapse. Drug use environment and drug attraction are the main social factors for relapse. Psychological, physiological and social factors cause heroin dependent patients to relapse after detoxification. At present, nearly 10 kinds of Chinese medicines for drug rehabilitation approved by the State Food and Drug Administration are applicable to drug users who are dependent on mild and moderate opioids.
  • Commonly used drugs include Kangling tablets, Fukang tablets, Jitai tablets, and Yi'an Huisheng oral liquid. , Lingyi Gum, New Detoxification, vinegar, and so on.
  • the efficacy of traditional Chinese medicine for heavily drug addicts is not ideal enough and needs to be combined with other drugs. Summary of the invention
  • the inventors of the present invention have surprisingly discovered through experiments that a pharmaceutical composition comprising a certain proportion of E. cerevisiae and F. chinensis or their extracts can be used to eliminate or alleviate addiction in a subject in need thereof.
  • Substance-induced acute withdrawal symptoms and protracted symptoms eliminating or reducing the subject's craving for addictive substances and preventing the subject from reusing the addictive substance, for patients with varying degrees of drug dependence Effective, can be used alone or in combination with other drugs. Based on this finding, the inventors have completed the present invention.
  • the present invention provides the use of enteric grass and marigold in the preparation of a medicament,
  • the medicament is for eliminating or alleviating acute withdrawal symptoms and protracted symptoms caused by an addictive substance, eliminating or reducing the subject's craving for an addictive substance, and preventing the subject from being in need thereof
  • the subject uses the addictive substance, wherein the offspring and the golden flower are used as an extract of the original medicinal material or the original medicinal material.
  • the enteropath and the golden flower are used in their respective original medicinal materials, wherein the weight of the enteral steppe medicinal material accounts for the total weight of the two medicinal materials.
  • the original medicinal materials of the golden genus flower account for 30% ⁇ 15% of the total weight of the two medicinal materials; preferably the medicinal materials of the cut off the grassland account for 70% ⁇ 80% of the total weight of the two medicinal materials, the original medicinal materials of the genus 30% ⁇ 20% of the total weight of the two herbs.
  • the enteropath and the golden flower are used as an extract of the original medicinal material
  • the extract may be a separate solvent (for example, water and ethanol) of each of the sage and the golden flower, or may be A solvent (for example, water and ethyl intoxication) extract of a mixture of the offspring and the golden flower.
  • the extract of E E.
  • the cerevisiae is prepared by extracting the crude gut grass extract with ethanol one or more times, combining the extracts, filtering, and concentrating the filtrate into a thick paste; the filter residue is extracted once with water or Multiple times, the extracts are combined, filtered, and the filtrate is concentrated into a thick paste; then the thick paste is combined for use; the golden flower extract is prepared by the following method: extracting the coarse powder of the golden flower with water one or more times, The extracts are combined, filtered, and the filtrate is concentrated into a thick paste; or the golden flower is extracted one or more times with ethanol, the extracts are combined, filtered, and the filtrate is concentrated to a thick paste for use.
  • the present invention provides a method of eliminating or alleviating acute withdrawal symptoms and protracted symptoms caused by an addictive substance, eliminating or reducing the subject's desire for an addictive substance in a subject in need thereof.
  • Degree and method for preventing the subject from reusing the addictive substance comprising administering to the subject an effective amount of E.
  • the extract of the genus and the medicinal material The product is used, and the weight of the intestine grassland material accounts for 70% ⁇ 85% of the total weight of the two herbs, and the original medicine of the golden flower takes 30% ⁇ 15% of the total weight of the two herbs;
  • the medicinal materials account for 70% ⁇ 80% of the total weight of the two medicinal materials, and the original medicinal materials of the medicinal materials account for 30% to 20% of the total weight of the two medicinal materials.
  • the present invention provides the use of Herba Eclipta and Flos Lonicera in the preparation of a medicament for eliminating or alleviating acute withdrawal symptoms and protracted symptoms caused by addictive substances in a subject in need thereof And eliminating or reducing the subject's craving for an addictive substance and preventing the subject from reusing the addictive substance, wherein the enteric grass and the golden flower are used as an extract of the original medicinal material or the original medicinal material.
  • the enteropath and the marigold are used as the original medicinal material, and the weight/weight ratio of the ileal step grass medicinal material to the medicinal medicinal material is 2:1 to 6:1; preferably 3:1 ⁇ 5:1, most preferably 4:1.
  • the enteropath and the golden flower are used as extracts thereof, and the extract may be an extract of a separate solvent (for example, water and ethanol) of the enteropath and the golden flower, or an enteric grass and an ocean.
  • a solvent eg, water and ethanol
  • the extract of E is used as extracts thereof, and the extract may be an extract of a separate solvent (for example, water and ethanol) of the enteropath and the golden flower, or an enteric grass and an ocean.
  • a solvent eg, water and ethanol
  • the cerevisiae is prepared by extracting the crude gut grass extract with ethanol one or more times, combining the extracts, filtering, and concentrating the filtrate into a thick paste; the filter residue is extracted once with water or Multiple times, the extracts are combined, filtered, and the filtrate is concentrated into a thick paste; then the thick paste is combined for use; the golden flower extract is prepared by the following method: extracting the coarse powder of the golden flower with water one or more times, The extracts are combined, filtered, and the filtrate is concentrated into a thick paste; or the golden flower is extracted one or more times with ethanol, the extracts are combined, filtered, and the filtrate is concentrated to a thick paste for use.
  • the present invention provides a method of eliminating or alleviating acute withdrawal symptoms and protracted symptoms caused by an addictive substance, eliminating or reducing the subject's desire for an addictive substance in a subject in need thereof.
  • Degree and method for preventing the subject from reusing the addictive substance comprising administering to the subject an effective amount of E. cerevisiae and a golden flower, wherein the extract of the genus and the medicinal material Use, and the weight/weight ratio of the offspring steppe medicinal material to the medicinal medicinal material is 2:1 ⁇ 6:1; Choose from 3:1 to 5:1, most preferably 4:1.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising enteric grass and phoenix, and optionally comprising a pharmaceutically acceptable excipient, wherein the herbaceous and marigold are used as their original medicinal material or extract, and According to the weight, the enteric grassland medicinal materials accounted for 70% ⁇ 85% of the total weight of the two medicinal materials, and the medicinal materials of the genus Jinhuahua accounted for 30% ⁇ 15% of the total weight of the two medicinal materials; 70% ⁇ 80%, the original medicinal materials of the Golden Flower account for 30% to 20% of the total weight of the two herbs.
  • the enteropath and the golden flower are used as the original medicinal material
  • the gut medicinal materials account for 70% to 85% of the total weight of the two medicinal materials by weight, and the medicinal materials of the genus
  • the total weight of the medicinal materials is 30% ⁇ 15%
  • the medicinal materials of the cut grazing grasses account for 70% ⁇ 80% of the total weight of the two kinds of medicinal materials
  • the original medicinal materials of the medicinal materials account for 30% ⁇ 20% of the total weight of the two medicinal materials.
  • the enteropath and the golden flower are used as extracts thereof, and the intestinal grassland material accounts for 70% to 85% by weight of the total weight of the two herbs, and the golden medicinal herbs account for the two 30% ⁇ 15% of the total weight of the medicinal materials; preferably, the medicinal materials of the cut off the grassland account for 70% to 80% of the total weight of the two medicinal materials, and the original medicinal materials of the medicinal materials account for 30% to 20% of the total weight of the two medicinal materials.
  • the extract may be an extract of a separate solvent (for example, water and ethanol) of the sinensis and the golden flower, or a solvent (for example, water and ethanol) extract of the mixture of the comfrey and the golden flower.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising enteric grass and ocean Golden flower, and optionally comprising a pharmaceutically acceptable excipient, wherein the offspring and the golden flower are used as their original medicinal materials or extracts, and the weight/weight ratio of the enteral steppe medicinal material to the medicinal medicinal material is 2:1 ⁇ 6:1; preferably 3:1 ⁇ 5:1, most preferably 4:1.
  • the enteropath and the golden flower are used as extracts of the original medicinal material, and the weight/weight ratio of the enteral steppe medicinal material to the medicinal medicinal material is 2 1 to 6:1; preferably 3 : 1 ⁇ 5:1, most preferably 4:1, wherein the extract may be a separate solvent (such as water and ethanol) of the sinensis and the golden flower, or a solvent of a mixture of the comfrey and the golden flower. (eg water and ethanol) extracts.
  • the extract of E is a separate solvent of the sinensis and the golden flower, or a solvent of a mixture of the comfrey and the golden flower.
  • cerevisiae is prepared by the following method: extracting the crude gut grass extract with ethanol one or more times, combining the extracts, filtering, and concentrating the filtrate into a thick paste; the filter residue is extracted once with water or Multiple times, the extracts are combined, filtered, and the filtrate is concentrated into a thick paste; then the thick paste is combined for use; the golden flower extract is prepared by the following method: extracting the coarse powder of the golden flower with water one or more times, The extracts are combined, filtered, and the filtrate is concentrated into a thick paste; or the golden flower is extracted one or more times with ethanol, the extracts are combined, filtered, and the filtrate is concentrated to a thick paste for use.
  • the composition may further comprise an appropriate amount of other Chinese herbal medicines, which may be selected from the group consisting of licorice, woody and betel nut or their extracts.
  • the composition is for eliminating or alleviating acute withdrawal symptoms and protracted symptoms caused by an addictive substance, eliminating or reducing the subject in a subject in need thereof The degree of craving for the addictive substance and preventing the subject from using the addictive substance again.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Angelica, Flos Lonicerae, and optionally a pharmaceutically acceptable excipient, wherein the enteric grass and the ocean gold
  • the flower is used as its original medicinal material or extract, and the weight of the enteral grassland medicinal material accounts for 70% ⁇ 85% of the total weight of the two medicinal materials by weight, and the original medicinal material of the genus medicinal herbs accounts for 30% ⁇ 15% of the total weight of the two medicinal materials; It is preferred that the off-intestine grassland medicinal materials account for 70% to 80% of the total weight of the two medicinal materials, and the medicinal materials of the medicinal herbs account for 30% to 20% of the total weight of the two medicinal materials.
  • the enteropath and the golden flower are used as the original medicinal material
  • the gut medicinal materials account for 70% to 85% of the total weight of the two medicinal materials by weight, and the medicinal materials of the genus
  • the total weight of the medicinal materials is 30% ⁇ 15%
  • the medicinal materials of the cut grazing grasses account for 70% ⁇ 80% of the total weight of the two kinds of medicinal materials
  • the original medicinal materials of the genus Jinhuahua account for 30% ⁇ 20% of the total weight of the two kinds of medicinal materials.
  • the enteropath and the golden flower are used as extracts of the original medicinal material
  • the enteric grassland medicinal materials account for 70% to 85% of the total weight of the two medicinal materials by weight
  • the medicinal materials of the genus It accounts for 30% ⁇ 15% of the total weight of the two herbs; preferably, the herbicides of the cut off the grassland account for 70% ⁇ 80% of the total weight of the two herbs, and the original medicine of the golden flower takes 30% to 20% of the total weight of the two herbs.
  • the extract may be a separate solvent (for example, water and ethanol) extract of E. cerevisiae and F. chinensis, or a solvent (for example, water and ethanol) extract of a mixture of E.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Angelica, Flos Lonicerae, and optionally a pharmaceutically acceptable excipient, wherein the herbaceous grass and the golden flower are used as their original medicinal material or extract And the weight/weight ratio of the enteral steppe medicinal material to the medicinal medicinal material is 2:1 to 6:1; preferably 3:1 to 5:1, and most preferably 4:1.
  • the enteropath and the golden flower are used as the original medicinal material, and the weight/weight ratio of the enteral steppe medicinal material to the medicinal medicinal material is 2:1 to 6:1; preferably 3:1. ⁇ 5:1, most preferably 4:1.
  • the enteropath and the golden flower are used as an extract of the original medicinal material, and the weight/weight ratio of the enteral steppe medicinal material to the medicinal medicinal material is 2:1 to 6:1; preferably 3:1 ⁇ 5:1, most preferably 4:1, wherein the extract may be a separate solvent (such as water and ethanol) of the sinensis and the golden flower, or a mixture of the comfrey and the golden flower. Solvent (eg water and ethanol) extracts. In a specific embodiment, the extract of E.
  • cerevisiae is prepared by the following method: extracting the crude gut grass extract with ethanol one or more times, combining the extracts, filtering, and concentrating the filtrate into a thick paste; the filter residue is extracted once with water or Multiple times, the extracts are combined, filtered, and the filtrate is concentrated into a thick paste; then the thick paste is combined for use; the golden flower extract is prepared by the following method: extracting the coarse powder of the golden flower with water one or more times, The extracts are combined, filtered, and the filtrate is concentrated into a thick paste; or the golden flower is extracted one or more times with ethanol, the extracts are combined, filtered, and the filtrate is concentrated to a thick paste for use.
  • broken weed as used in the present invention, also known as hook-and-kick, means Ge/M/MW e/ ⁇ iiws Benth., a medicinal whole grass, ie, its roots, stems, leaves and All plants can be used as medicine.
  • foreign flower means a flower of the Solanaceae plant Datura metel L.
  • predictive substance includes any substance known in the art which enables the user to have physical dependence and mental dependence, but is not limited to, morphine, barbiturates, cocaine, India. Cannabis, amphetamines, Kurt (KHAT) and hallucinogens.
  • an effective amount as used in the present invention is meant that when the composition in question is administered to a subject in need thereof, it is effectively eliminated or alleviated by the addictive substance in the subject. Acute withdrawal symptoms and protracted symptoms, eliminating or reducing the subject's craving for addictive substances and preventing the subject from reusing the addictive substance.
  • the effective amount can be readily determined and adjusted by those skilled in the art in light of the disclosure herein.
  • a person skilled in the art can separately pulverize the components of the ratio into a powder and mix them by using conventional techniques and methods in the art, or mix and pulverize the components into a powder to prepare the drug of the present invention. combination.
  • the extract described in the pharmaceutical composition of the present invention may be an aqueous extract, an alcohol (e.g., methanol, ethanol, propanol, butanol, etc.) extract or other fat-soluble extract, and the extraction method may be known in the art.
  • a combination of any one or more of the extraction methods including but not limited to, cold dip extraction, heated reflux extraction, ultrasonic extraction, microwave extraction, and supercritical extraction methods.
  • the simplest and easiest application method of the pharmaceutical composition of the present invention is to make the original medicinal materials of the sinensis and the scented scented flowers into fine powder, and mix them in proportion, and fill the plastic sputum.
  • the two original medicinal materials or their extracts may be supplemented with appropriate pharmaceutical excipients to prepare pharmaceutically acceptable preparations, such as capsules, tablets, granules, pills, powders, lozenges, teas, etc. .
  • the pharmaceutical excipient may be selected from suitable diluents, absorbents, fillers, dispersing or suspending aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, depending on the particular dosage form desired. Wetting agents, binders, disintegrants, glidants and lubricants.
  • the pharmaceutical composition of the present invention can be used orally for a total course of about twenty days.
  • the first stage is the stage of withdrawal: after half an hour of taking the drug for the first time, the patient's withdrawal symptoms are terminated. Quiet and sleepy. Then you may enter the stage of distraction. At this stage, the patient consciously smokes a diet that is tasteless, upset, weak, weak, dry, dazzling, and insomnia. At this time, the patient is mostly excited, irritated, talked, incoherent, slang, and may lead to There are hallucinations and disturbances of consciousness, but there are no severe acute withdrawal symptoms, and patients will not feel painful. Later, it may enter a relatively quiet phase. The signs and symptoms of the disturbing phase are alleviated or disappeared to varying degrees.
  • the patient's conscious dreams are reduced, gradually calming down, and restoring spirit, appetite and sleep.
  • This process takes about three days.
  • the second stage is the rehabilitation period: This stage may have milder protracted withdrawal symptoms, such as dry mouth, vertigo, weakness, sweating, palpitation, etc., and will have a close feeling to the drug and the drug, and then the symptoms will disappear. This process takes about seven days.
  • the third stage is the consolidation period: At this stage, the symptoms of protracted withdrawal such as anxiety, insomnia, poor appetite, palpitation, irritability, etc. have been comprehensively improved.
  • the patient has good appetite, good sleep, and full of energy, which basically eliminates the drug hunger for drug users. , return to normal living habits. This process takes about ten days.
  • the enteric grass and the golden flower used in the present invention are all derived from natural plants, and do not contain an addictive drug component such as opioids, and are not addictive.
  • the pharmaceutical composition or the medicament of the present invention not only maintains the therapeutic effect of detoxification, but also reduces toxicity by mutual cooperation, and has small toxic and side effects and remarkable curative effect.
  • the pharmaceutical composition or the medicament of the invention can not only effectively alleviate the symptoms during the withdrawal period, but also effectively eliminate the addiction, the possibility of relapse is greatly reduced, the relapse rate of the drug addict is greatly reduced, the auxiliary medication is not needed, and the dosage is small. It has a short life cycle and is not addictive, so it can be used as an excellent drug for detoxification. Detailed ways
  • Example 1 Preparation of powder
  • the intestine grassland medicine 140g was removed, and the golden medicinal herbs were 60g, and the intestines and 30g of the golden flower were broken into fine powder for use.
  • the remaining 30 g of the golden flower was pulverized into a coarse powder, and ultrasonically extracted three times with water for 2 hours each time, the extract was combined, filtered, and the filtrate was concentrated into a thick paste, and the above fine powder was added to the thick paste, and the hook was mixed.
  • Another take glutinous rice flour 320g add water to make agglomerate, steamed, mix with the above powder, press into an ingot, dry at low temperature, that is.
  • Example 9 Preparation of tea
  • the crude powder of the enteric grass was extracted three times with ethanol for 2 hours each time.
  • the extracts were combined, filtered, and the filtrate was concentrated into a thick paste; the filter residue was extracted three times with water for 2 hours, the extracts were combined, filtered, and the filtrate was concentrated into a thick paste.
  • the crude powder of the golden flower is extracted by microwave for three times, each time for 2 hours, the extract is combined, filtered, and the filtrate is concentrated into a thick paste; the above three thick pastes are combined, and 200 g of sucrose powder and 100 g of dextrin are added per 100 g of crude drug. , mixed hook, made Granules, dry, mixed hooks, briquettes, that's it.
  • Example 10 Acute toxicity test
  • the crude drug powder obtained in Example 1 was finely ground and formulated into a paste having a maximum concentration of 0.3 g/ml with distilled water, and further diluted to a four-dose group with distilled water in the order of 0.75.
  • Sixty 18 to 20 g ICR mice (sourced from Kunming Pharmaceutical Group Co., Ltd. animal house) were selected, male and female, randomly divided into 6 groups according to gender and body weight, with 10 rats in each group. After fasting for 6 hours, the rats in each group were given a single intragastric administration according to the dose, and the administration volume was about 40 ml/k g . The mice were observed to react immediately after administration, and the dead animals were dissected for observation.
  • Treatment method Two tablets of uninvented capsule (prepared according to Example 2) were taken daily for 2 times a day for treatment. After 3 days of detoxification, 7 days of rehabilitation and 10 days of anti-relapse and consolidation treatment. Do not administer after the end of the treatment, and do not use any auxiliary detoxification during the treatment.
  • the muscles or joint pain According to the "Heroin Protracted Withdrawal Symptom Rating Scale" revised by the China Institute of Drug Dependence, Peking University, the muscles or joint pain, general malaise, limb discomfort, general weakness, poor appetite, palpitation, irritability, difficulty falling asleep, etc. Early sleep, early awakening and other symptom items, using 0 ⁇ 3 points and four grades, the severity scores are: 0 - asymptomatic; 1 a mild, asked out, mild symptoms; 2 - moderate, complaining symptoms, but can Endure; 3 - severe, can't stand it.
  • Example 1 Patient Zhang x, male, 28 years old, Han nationality. It has been 10 years since the friend was tempted to start taking heroin.
  • the intravenous method is used, and the average daily dose is lg. Also take stability.
  • the drug was prepared according to Example 2, and the first day began to be quiet and drowsiness, and then began to be irritable, dry mouth, vertigo, incoherent, insomnia, second day, temper, illusion, third day Dazzling, dry mouth, The incompetent withdrawal symptoms gradually disappeared, the hallucinations disappeared, the appetite increased, the mental state improved, and insomnia was alleviated. 3 ⁇ , 10 days occasionally there will be "thinking addiction", 10 days later is completely normal. After the end of the treatment, the weight increased by 8kg. After 6 years of follow-up, no relapse.
  • Example 2 Patient Song xx, female, 36 years old, Han nationality. Heroin has been used for more than 20 years due to the influence of brothers.
  • the average daily dose is 0.8 g .
  • the drug was prepared according to Example 2, and the first day began to be quiet and lethargic, and then began to be irritable, sweating, dry mouth, incoherent, insomnia, second day, temper, illusion, third
  • the symptoms of abstinence such as sunrise sweat, dry mouth, and incoherence, gradually disappeared, hallucinations disappeared, appetite increased, mental state improved, and insomnia was alleviated.
  • abstinence such as sunrise sweat, dry mouth, and incoherence, gradually disappeared, hallucinations disappeared, appetite increased, mental state improved, and insomnia was alleviated.
  • the weight increased by 6kg. After 1 year of follow-up, no relapse.
  • Example 3 Patient Ma X, male, 23 years old, Hui nationality. It has been more than 5 years since I started to take heroin because of my friend's influence. The average daily dose is 1.0g.
  • the medicine prepared according to Example 4 was used for treatment, and the first day began to be quiet and lethargic, and then began to be irritated, insomnia, hallucinations, second day, and incoherent, third day irritability, insomnia, incoherent withdrawal, etc. Symptoms gradually disappeared, hallucinations disappeared, appetite increased, mental state improved, and insomnia was alleviated. Occasionally there will be "thinking addiction” in 3 ⁇ 10 days, and it will be completely normal after 10 days. After the end of the treatment, the weight increased by 3k g . After 8 years of follow-up, no relapse.
  • Example 5 Patient Xiao XX, male, 26 years old, Han nationality. Due to lack of spirit, people were tempted to start taking cocaine. For six months, they used cocaine several times a day. According to the method of the present invention, the preparation of the drug according to Example 2 was used for treatment. The first 10 ⁇ felt upset and sweated, and the feeling of upset after 10 days gradually disappeared. The treatment is terminated after 20 days. 011/153819
  • PCT/CN2011/000900 The mental state is good after the end of the treatment. After half a year of follow-up, no relapse.
  • Example 6 Patient Li XX, male, I 9 years old, Han nationality. I have been taking ecstasy by friends in the dance hall for 4 years. I can take more tablets of ecstasy every day.
  • the treatment according to the method of the present invention was carried out according to the method of the present invention, and the first 10 days felt discomfort, and the feeling of upset after 10 lapse gradually disappeared. The treatment is terminated after 20 days. The mental state is good after the treatment. After 10 months of follow-up, no relapse.

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Description

用于戒毒的药物组合物 技术领域
本发明涉及一种用于戒毒的药物组合物， 尤其涉及一种包含 中药材断肠草和洋金花的药物组合物； 本发明还涉及中药材断肠 草和洋金花在制备药物中的用途， 其中所述药物用于在有需要的 受试者中消除或緩解由成瘾性物质引起的急性断瘾症状和稽延性 症状、 消除或降低该受试者对成瘾性物质的渴求程度以及防止该 受试者再使用该成瘾性物质。 背景技术
近些年来， 毒品在世界各地日益泛滥， 危害人类的健康和国 际社会的安宁。世界卫生组织的统计数据表明， 每年有 1000万人 因为吸毒而丧失正常的生活工作能力，并且每年有 10万人因此而 丧命。世界卫生组织（WHO )将当成毒品使用的物质分成 8大类： 吗啡类、 巴比妥类、 酒精类、 可卡因类、 印度大麻类、 苯丙胺类、 柯特 （KHAT ) 类和致幻剂类。 其他还有烟碱、 挥发性溶液等。 其中吗啡类即阿片类药物有海洛因、 吗啡等， 具有较强的成瘾性 和耐受性， 滥用后易产生依赖。 海洛因在全球范围内传播范围广， 危害大。 传统的戒毒方法有替代递减疗法、 自然戒断法、 亚冬眠 脱毒疗法、 拮抗剂疗法、 和采用电刺激、 针灸、 理疗仪等的非药 物戒断法。 就目前所知， 现在世界范围内的戒毒常用药主要有以 下种类： 海洛因依赖脱毒治疗用药有美沙酮、 阿片制剂、 丁丙诺 啡、 可乐定、 路脱菲、 氯丙嗪。 这些药物多属阿片受体激动剂类 以及镇静催眠类药物。 实践中， 阿片受体激动剂类药物如美沙酮、 丁丙诺啡等， 被作为替代递减疗法的常用药， 主要是通过替代毒 品抑制神经兴奋， 减轻戒断症状， 脱除毒瘾较慢， 容易转为另种 依赖， 容易中毒、 易成瘾。 非替代疗法多使用可乐定等， 用于轻 中度阿片类药物依赖的吸毒人员， 脱毒效果较好， 但是不良反应 较多， 不宜长期使用。 冬眠疗法中常用镇压催眠类药物， 这种药 物因需大量使用， 对脑神经损害过大， 用药不当还可能危及生命， 且对解除心理依赖作用欠佳。 用于拮抗剂疗法的纳曲酮是一种阿 片受体拮抗剂， 脱毒后服用纳曲酮可以大大降低吸毒引起的欣快 感， 阻断强化作用， 预防复吸， 但对改善稽延性症状作用不明显， 而且需长期坚持服用， 患者多不能坚持。
长期滥用毒品会造成吸毒者的身体依赖和精神依赖。 由于阿 片类毒品药物的长期使用， 导致身体机能状态的改变。 神经细胞 适应了药物的存在， 产生耐受性。 身体内的药物必需维持一定浓 度， 才能保持身体机能状态的稳定。 如果中断或骤然减少药物， 导致神经细胞发生脱抑制现象， 而出现流涕、 流泪、 打哈欠、 瞳 孔散大、 立毛肌收缩、 出汗、 腹泻、 全身酸痛、 自发射精、 血压 升高、 脉搏加快、 发热、 失眠及焦虑烦躁等一系列的戒断症状， 同时伴有对阿片类药物的强烈渴求感。 戒断症状的出现， 表明躯 体依赖性已形成。 这种急性戒断症状使患者感到十分痛苦， 而化 学药往往可以很好地控制急性戒断症状， 緩解或减轻痛苦。 但阿 片类药物依赖者经脱毒治疗后， 随着外源性阿片类药物的逐渐消 除， 内源性阿片肽的合成及阿片受体数量的增加难以在短期内达 到正常水平， 在相当长的时间内会出现躯体、 精神的不适， 称为 稽延性戒断症状。 主要表现为顽固性失眠、 焦虑烦躁、 周身疼痛、 疲乏无力、 心境恶劣等。 化学药多数对于緩解稽延性戒断症状效 果不佳。 通常会与躯体依赖伴随发生精神依赖， 精神依赖性指的 是已形成药物依赖者的心理觅药渴求与通过重复用药所达到的欣 快感的内心体验， 又称"想瘾，，或"心瘾"。 由于受情绪上的驱使， 导致成瘾者持续用药不停， 从而改变其生活方式、 行为和人格模 式。 用药产生的欣快感和松弛宁静感， 属于正性强化； 而停药产 生的难受的戒断症状， 为了避免这种痛苦又只能继续用药， 这属 于负性强化。 这两种强化使成瘾者难于自拔。 急性脱瘾治疗后， 躯体依赖消除了， 但精神依赖难以消除， 所谓"心瘾难除"， 所以 复吸率极高， 据报道其复吸率高达 90 %以上， 降低复吸率是戒毒 治疗最大的挑战！ 目前尚无药物能有效地治疗精神依赖。
吸毒已成为当今世界一大公害， 既伤害自身又给社会造成危 害， 一旦吸毒又很难戒掉， 常出现复吸现象， 给戒毒者造成很大 痛苦和精神和经济负担。 身体不适、 失眠等稽延性戒断症状是产 生复吸的主要生理因素， 难以抗拒的对药物的心理渴求是产生复 吸的主要心理因素， 吸毒环境和毒友引诱是产生复吸的主要社会 因素， 心理、 生理、 社会诸因素造成海洛因依赖者脱毒后容易复 吸。 目前经国家食品药品监督管理局批准的戒毒中药近 10种， 适 用于轻、 中度阿片类药物依赖的吸毒人员， 常用药有康灵片、 福 康片、 济泰片、 益安回生口服液、 灵益胶嚢、 新生戒毒灵冲剂、 香藤胶嚢等等。 对重度依赖的吸毒人员单纯使用中药疗效尚不够 理想， 需要与其他药物联合使用。 发明内容
本发明的发明人通过实验令人意外地发现， 包含一定比例的 断肠草和洋金花原药材或它们的提取物的药物组合物可用于在有 需要的受试者中消除或緩解由成瘾性物质引起的急性断瘾症状和 稽延性症状、 消除或降低该受试者对成瘾性物质的渴求程度并且 防止该受试者再使用该成瘾性物质， 对各种程度的药物依赖患者 均有效， 可单独使用也可搭配其他药物使用。 基于此发现， 本发 明人完成了本发明。
一方面， 本发明提供断肠草和洋金花在制备药物中的用途， 所述药物用于在有需要的受试者中消除或緩解由成瘾性物质引起 的急性断瘾症状和稽延性症状、 消除或降低该受试者对成瘾性物 质的渴求程度以及防止该受试者再使用该成瘾性物质， 其中断肠 草和洋金花以其原药材或原药材的提取物使用。
在该方面的一个实施方案中， 断肠草和洋金花以它们各自的 原药材使用， 其中按重量计断肠草原药材占这两种药材总重量的
70% ~ 85% , 洋金花原药材占这两种药材总重量的 30% ~ 15%； 优选断肠草原药材占这两种药材总重量的 70% ~ 80%， 洋金花原 药材占这两种药材总重量的 30% ~ 20%。
在该方面的另一个实施方案中， 断肠草和洋金花以其原药材 的提取物使用， 该提取物可以是断肠草和洋金花各自单独的溶剂 (例如水和乙醇）提取物， 也可以是断肠草和洋金花混合物的溶 剂 （例如水和乙醉）提取物。 在一个具体的实施方案中， 断肠草 提取物是通过如下方法制备的： 将断肠草粗粉用乙醇提取一次或 多次， 合并提取液， 滤过， 滤液浓缩成稠膏； 滤渣用水提取一次 或多次， 合并提取液， 滤过， 滤液浓缩成稠膏； 然后合并所述稠 膏备用； 洋金花提取物是通过如下方法制备的： 将洋金花的粗粉 用水提取一次或多次， 合并提取液， 滤过， 并将滤液浓缩成稠膏； 或将洋金花粗粉用乙醇提取一次或多次， 提取液合并， 滤过， 滤 液浓缩成稠膏备用。
可替代地， 本发明提供一种在有需要的受试者中消除或緩解 由成瘾性物质引起的急性断瘾症状和稽延性症状、 消除或降低该 受试者对成瘾性物质的渴求程度以及防止该受试者再使用该成瘾 性物质的方法， 该方法包括将有效量的断肠草和洋金花给予该受 试者 , 其中断肠草和洋金花以其原药材或原药材的提取物使用 , 并且按重量计断肠草原药材占这两种药材总重量的 70% ~ 85%， 洋金花原药材占这两种药材总重量的 30% ~ 15%； 优选断肠草原 药材占这两种药材总重量的 70% ~ 80%， 洋金花原药材占这两种 药材总重量的 30% ~ 20%。
另一方面，本发明提供断肠草和洋金花在制备药物中的用途， 所述药物用于在有需要的受试者中消除或緩解由成瘾性物质引起 的急性断瘾症状和稽延性症状、 消除或降低该受试者对成瘾性物 质的渴求程度以及防止该受试者再使用该成瘾性物质， 其中断肠 草和洋金花以其原药材或原药材的提取物使用。
在该方面的一个实施方案中， 断肠草和洋金花以其原药材使 用，并且断肠草原药材与洋金花原药材的重量 /重量比为 2:1 ~ 6:1; 优选为 3:1 ~ 5:1， 最优选为 4:1。
在该方面的另一个实施方案中， 断肠草和洋金花以其提取物 使用， 该提取物可以是断肠草和洋金花各自单独的溶剂 （例如水 和乙醇）提取物， 也可以是断肠草和洋金花混合物的溶剂 （例如 水和乙醇）提取物。 在一个具体的实施方案中， 断肠草提取物是 通过如下方法制备的： 将断肠草粗粉用乙醇提取一次或多次， 合 并提取液， 滤过， 滤液浓缩成稠膏； 滤渣用水提取一次或多次， 合并提取液， 滤过， 滤液浓缩成稠膏； 然后合并所述稠膏备用； 洋金花提取物是通过如下方法制备的： 将洋金花的粗粉用水提取 一次或多次， 合并提取液， 滤过， 并将滤液浓缩成稠膏； 或将洋 金花粗粉用乙醇提取一次或多次， 提取液合并， 滤过， 滤液浓缩 成稠膏备用。
可替代地， 本发明提供一种在有需要的受试者中消除或緩解 由成瘾性物质引起的急性断瘾症状和稽延性症状、 消除或降低该 受试者对成瘾性物质的渴求程度以及防止该受试者再使用该成瘾 性物质的方法， 该方法包括将有效量的断肠草和洋金花给予该受 试者， 其中断肠草和洋金花以其原药材或原药材的提取物使用， 并且断肠草原药材与洋金花原药材的重量 /重量比为 2:1 ~ 6:1; 优 选为 3:1 ~ 5:1， 最优选为 4:1。
再一方面， 本发明提供一种药物组合物， 其包含断肠草和洋 金花， 并且任选包含药学上可接受的赋形剂， 其中断肠草和洋金 花以其原药材或提取物使用， 并且按重量计断肠草原药材占这两 种药材总重量的 70%~85%， 洋金花原药材占这两种药材总重量 的 30%~15%；优选断肠草原药材占这两种药材总重量的 70% ~ 80%, 洋金花原药材占这两种药材总重量的 30%~20%。
在该方面的一个实施方案中， 其中断肠草和洋金花以其原药 材使用， 并且按重量计断肠草原药材占这两种药材总重量的 70% ~85%, 洋金花原药材占这两种药材总重量的 30%~15%； 优选断肠草原药材占这两种药材总重量的 70%~80%, 洋金花原 药材占这两种药材总重量的 30%~20%。
在该方面的另一个实施方案中， 断肠草和洋金花以其提取物 使用， 并且按重量计断肠草原药材占这两种药材总重量的 70% ~ 85%, 洋金花原药材占这两种药材总重量的 30% ~ 15%; 优选断 肠草原药材占这两种药材总重量的 70%~80%， 洋金花原药材占 这两种药材总重量的 30%~20%， 其中所述提取物可以是断肠草 和洋金花各自单独的溶剂 （例如水和乙醇）提取物， 也可以是断 肠草和洋金花混合物的溶剂 （例如水和乙醇）提取物。 在一个具 体的实施方案中， 断肠草提取物是通过如下方法制备的： 将断肠 草粗粉用乙醇提取一次或多次， 合并提取液， 滤过， 滤液浓缩成 稠膏； 滤渣用水提取一次或多次， 合并提取液， 滤过， 滤液浓缩 成稠膏； 然后合并所述稠膏备用； 洋金花提取物是通过如下方法 制备的： 将洋金花的粗粉用水提取一次或多次， 合并提取液， 滤 过， 并将滤液浓缩成稠膏； 或将洋金花粗粉用乙醇提取一次或多 次， 提取液合并， 滤过， 滤液浓缩成稠膏备用。
再一方面， 本发明提供一种药物组合物， 其包含断肠草和洋 金花， 并且任选包含药学上可接受的赋形剂， 其中断肠草和洋金 花以其原药材或提取物使用， 并且断肠草原药材与洋金花原药材 的重量 /重量比为 2:1 ~ 6:1; 优选为 3:1 ~ 5:1， 最优选为 4:1。
在该方面的一个实施方案中， 断肠草和洋金花以其原药材使 用，并且断肠草原药材与洋金花原药材的重量 /重量比为 2:1 ~ 6:1； 优选为 3:1 ~ 5:1， 最优选为 4:1。
在该方面的另一个实施方案中， 断肠草和洋金花以其原药材 的提取物使用， 并且断肠草原药材与洋金花原药材的重量 /重量比 为 2 1 ~ 6:1； 优选为 3:1 ~ 5:1， 最优选为 4:1 , 其中所述提取物可 以是断肠草和洋金花各自单独的溶剂 （例如水和乙醇）提取物， 也可以是断肠草和洋金花混合物的溶剂（例如水和乙醇）提取物。 在一个具体的实施方案中，断肠草提取物是通过如下方法制备的： 将断肠草粗粉用乙醇提取一次或多次， 合并提取液， 滤过， 滤液 浓缩成稠膏； 滤渣用水提取一次或多次， 合并提取液， 滤过， 滤 液浓缩成稠膏； 然后合并所述稠膏备用； 洋金花提取物是通过如 下方法制备的： 将洋金花的粗粉用水提取一次或多次， 合并提取 液， 滤过， 并将滤液浓缩成稠膏； 或将洋金花粗粉用乙醇提取一 次或多次， 提取液合并， 滤过， 滤液浓缩成稠膏备用。
在上述组合物方面的任一实施方案中， 所述组合物还可以进 一步包含适量的其它中药材， 该其它中药材可以选自甘草、 木香 和槟榔或它们的提取物。
在上述组合物方面的任一实施方案中， 所述组合物用于在有 需要的受试者中消除或緩解由成瘾性物质引起的急性断瘾症状和 稽延性症状、 消除或降低该受试者对成瘾性物质的渴求程度以及 防止该受试者再使用该成瘾性物质。
再一方面， 本发明提供一种药物组合物， 其由断肠草、 洋金 花和任选包含的药学上可接受的赋形剂组成， 其中断肠草和洋金 花以其原药材或提取物使用， 并且按重量计断肠草原药材占这两 种药材总重量的 70%~85%, 洋金花原药材占这两种药材总重量 的 30%~15%；优选断肠草原药材占这两种药材总重量的 70% ~ 80%, 洋金花原药材占这两种药材总重量的 30%~20%。
在该方面的一个实施方案中， 其中断肠草和洋金花以其原药 材使用， 并且按重量计断肠草原药材占这两种药材总重量的 70% ~85%, 洋金花原药材占这两种药材总重量的 30%~ 15%; 优选断肠草原药材占这两种药材总重量的 70%~80%， 洋金花原 药材占这两种药材总重量的 30%~20%。
在该方面的另一个实施方案中， 断肠草和洋金花以其原药材 的提取物使用， 并且按重量计断肠草原药材占这两种药材总重量 的 70%~85%， 洋金花原药材占这两种药材总重量的 30% ~ 15%； 优选断肠草原药材占这两种药材总重量的 70% ~80%, 洋 金花原药材占这两种药材总重量的 30%~20%， 其中所述提取物 可以是断肠草和洋金花各自单独的溶剂（例如水和乙醇）提取物， 也可以是断肠草和洋金花混合物的溶剂（例如水和乙醇 )提取物。 在一个具体的实施方案中 ,断肠草提取物是通过如下方法制备的： 将断肠草粗粉用乙醇提取一次或多次， 合并提取液， 滤过， 滤液 浓缩成稠膏； 滤渣用水提取一次或多次， 合并提取液， 滤过， 滤 液浓缩成稠膏； 然后合并所述稠膏备用； 洋金花提取物是通过如 下方法制备的： 将洋金花的粗粉用水提取一次或多次， 合并提取 液， 滤过， 并将滤液浓缩成稠膏； 或将洋金花粗粉用乙醇提取一 次或多次， 提取液合并， 滤过， 滤液浓缩成稠膏备用。
再一方面， 本发明提供一种药物组合物， 其由断肠草、 洋金 花和任选包含的药学上可接受的赋形剂组成， 其中断肠草和洋金 花以其原药材或提取物使用， 并且断肠草原药材与洋金花原药材 的重量 /重量比为 2:1 ~ 6:1; 优选为 3:1 ~ 5:1， 最优选为 4:1。 在该方面的另一个实施方案中， 断肠草和洋金花以其原药材 使用， 并且断肠草原药材与洋金花原药材的重量 /重量比为 2:1 ~ 6:1; 优选为 3:1 ~ 5:1， 最优选为 4:1。
在该方面的另一个实施方案中， 断肠草和洋金花以其原药材 的提取物使用， 并且断肠草原药材与洋金花原药材的重量 /重量比 为 2:1 ~ 6:1; 优选为 3:1 ~ 5:1， 最优选为 4:1， 其中所述提取物可 以是断肠草和洋金花各自单独的溶剂 （例如水和乙醇）提取物， 也可以是断肠草和洋金花混合物的溶剂（例如水和乙醇）提取物。 在一个具体的实施方案中，断肠草提取物是通过如下方法制备的： 将断肠草粗粉用乙醇提取一次或多次， 合并提取液， 滤过， 滤液 浓缩成稠膏； 滤渣用水提取一次或多次， 合并提取液， 滤过， 滤 液浓缩成稠膏； 然后合并所述稠膏备用； 洋金花提取物是通过如 下方法制备的： 将洋金花的粗粉用水提取一次或多次， 合并提取 液， 滤过， 并将滤液浓缩成稠膏； 或将洋金花粗粉用乙醇提取一 次或多次， 提取液合并， 滤过， 滤液浓缩成稠膏备用。 本发明中所述的术语 "断肠草"， 又名钩吻， 意指马钱科植物 断肠草 Ge/ M/MW e/^iiws Benth., 药用全草， 即其根、 茎、 叶及 全株均可入药。
本发明中所述的术语 "洋金花"意指茄科植物白花曼陀罗 Datura metel L.的花。
本发明中所述的术语"成瘾性物质"包括本领域中已知的能使 使用者产生躯体依赖和精神依赖的任何物质， 但不限于， 吗啡类、 巴比妥类、 可卡因类、 印度大麻类、 苯丙胺类、 柯特 （KHAT ) 类和致幻剂类。
本发明中所述的"有效量"意指所涉及的组合物被给予有需要 的受试者时， 有效地在该受试者中消除或緩解由成瘾性物质引起 的急性断瘾症状和稽延性症状、 消除或降低该受试者对成瘾性物 质的渴求程度以及防止该受试者再使用该成瘾性物质的量。 本领 域的技术人员根据本申请公开的内容可以轻易地确定和调整该有 效量。 本领域的技术人员可以使用本领域中的常规技术和方法， 将 所述比例的组分单独粉碎成粉末并均勾混合， 或者将各组分先混 合再粉碎成粉末， 从而制备得到本发明药物组合物。
可替代地， 本领域的技术人员也可以使用本领域中的常规技 术和方法， 将所述比例的组分单独或混合在一起， 用适合的溶剂 进行提取或煎煮， 合并提取物或煎煮液， 从而制备得到本发明药 物组合物0
本发明药物组合物中所述的提取物可以是水提取物、 醇 （例 如甲醇、 乙醇、 丙醇、 丁醇等）提取物或者其他脂溶性提取物， 提取方法可以是本领域中已知的提取方法中的任意一种或多种的 组合， 包括但不限于， 冷浸提取、 加热回流提取、 超声波提取、 微波提取和超临界提取方法。
本发明药物组合物的最简单、 最易用的应用方法是将断肠草 和洋金花两种原药材打成细粉， 按比例混合均勾， 填装胶嚢即可。 还可以将该两种原药材或其提取物， 辅以适当的药用辅料， 制成 医药上可接受的制剂， 如胶囊剂、 片剂、 颗粒剂、 丸剂、 散剂、 锭剂、 茶剂等。 根据所需的具体剂型， 所述药用辅料可以选自适 合的稀释剂、 吸收剂、 填充剂、 分散或悬浮助剂、 表面活性剂、 等渗剂、 增稠剂、 乳化剂、 防腐剂、 润湿剂、 粘合剂、 崩解剂、 助流剂和润滑剂等。
本发明所述药物组合物可以口服使用， 全疗程约二十天。 第 一阶段为脱瘾阶段： 首次服药半小时后， 患者戒断症状终止， 安 静而嗜睡。 然后可能进入烦乱阶段， 此阶段患者自觉吸烟饮食无 味， 心烦意乱， 全身软弱无力、 口干、 眼花、 失眠， 此时患者多 处于兴奋状态， 易怒、 话多、 语无伦次、 谵语， 并可能导致出现 幻觉和意识障碍， 但不会出现重度急性戒断症状， 患者不会感到 痛苦难忍。 随后可能又进入相对安静阶段， 烦乱阶段的体征和症 状不同程度地减轻或消失， 特别是患者自觉梦幻减少， 逐渐安静 下来， 恢复精神、 食欲和睡眠。 此一过程大约需要三天。 第二阶 段为康复期： 此阶段可能出现较轻微的稽延性戒断症状， 如口干、 眼花、 无力、 出汗、 心慌等， 并会对毒品和毒友有亲近感， 随后 症状会消失。 此一过程大约需要七天。 第三阶段为巩固期： 此阶 段其焦虑、 失眠、 食欲差、 心慌、 烦躁不安等稽延性戒断症状得 到全面改善， 患者食欲好、 睡眠好， 精神饱满， 基本消除了吸毒 者对毒品的渴求， 恢复正常的生活习惯。 该过程大约需要十天。
本发明所用断肠草和洋金花均源自天然植物， 不含阿片类等 成瘾性毒品成分， 无成瘾性。 本发明的药物组合物或药物不但保 持了戒毒的疗效， 还通过相互间的配合降低了毒性， 毒副作用小 而疗效显著。 本发明的药物组合物或药物不但可以有效减轻戒断 期症状， 还可以有效消除心瘾， 复吸可能性大为降低， 极大地降 低戒毒人员的复吸率， 无需辅助用药， 使用剂量小， 使用周期短， 并且无成癮性， 因此可以作为优异的戒毒药物。 具体实施方式
提供以下实施例仅为了对本发明作进一步的说明， 本发明的 范围不受这些实施例的限制。 实施例 1: 散剂的制备
取断肠草原药材 150g， 洋金花原药材 50g， 分别粉碎成细粉， 过筛， 混勾， 分装成 500袋， 即得 实施例 2: 胶嚢剂的制备（1 )
取断肠草原药材 160g， 洋金花原药材 40g， 分别粉碎成细粉， 过筛， 混勾， 装入胶嚢， 制成 1000粒， 即得。 实施例 3: 胶嚢剂的制备（2 )
取断肠草原药材 160g， 洋金花原药材 40g， 甘草药材 20g， 分 别粉碎成细粉， 过筛， 混勾， 装入胶嚢， 制成 1000粒， 即得。 实施例 4: 胶嚢剂的制备（3 )
取断肠草原药材 160g, 洋金花原药材 40g， 甘草原药材 60g, 木香原药材 70g, 槟榔原药材 70g, 其中 30g断肠草粉碎成细粉备 用， 其余药材及 130g断肠草分别粉碎成粗粉。 洋金花粗粉用乙醇 提取三次， 每次 2小时， 提取液合并， 滤过， 滤液浓缩成稠膏； 其余药材及 130g断肠草的粗粉合并， 用乙醇提取三次， 每次 2小 时， 提取液合并， 滤过， 滤液浓缩成稠膏； 合并上述两种稠膏， 加入上述细粉， 混匀。 加入糊精 40g 、 淀粉 60g， 混勾， 制粒， 干燥， 整粒， 加入硬脂酸镁 2g混勾， 装入胶嚢， 制成 1000粒， 即得。 实施例 5: 丸剂的制备
取断肠草原药材 165g， 洋金花原药材 35g， 分别粉碎成细粉， 过筛， 混匀。 每 100g粉末加炼蜜 130g 制成小蜜丸， 即得。 实施例 6: 片剂的制备
取断肠草原药材 155g,洋金花原药材 45g，分别粉碎成细粉， 过筛， 混勾。 加入蔗糖粉 400g、 糊精 100g 淀粉 100g， 混匀， 制粒， 干燥， 整粒， 加入硬脂酸镁 10g混匀， 压制成 2000片， 即 得。 实施例 7: 颗粒剂的制备
取断肠草原药材 170g，洋金花原药材 30g，其中洋金花和 30g 断肠草分别粉碎成细粉备用。 其余 140g 断肠草粉碎成粗粉， 用 乙醇冷浸过夜， 滤过， 滤渣再用乙醇加热回流提取两次， 每次 2 小时， 提取液合并， 滤过， 滤液浓缩成稠膏； 滤渣用水提取三次， 每次 2小时， 提取液合并， 滤过， 滤液浓缩成稠膏； 合并上述稠 膏， 加入上述细粉， 混勾。 加入蔗糖粉 400g、 糊精 100g ， 混匀， 制粒， 干燥， 分装成 500袋， 即得。 实施例 8: 锭剂的制备
取断肠草原药材 140g，洋金花原药材 60g，其中断肠草和 30g 洋金花分别粉碎成细粉备用。 其余 30g 洋金花粉碎成粗粉， 用水 进行超声波提取三次， 每次 2小时， 提取液合并， 滤过， 滤液浓 缩成稠膏， 稠膏中加入上述细粉， 混勾。 另取糯米粉 320g， 加水 做成团块， 蒸熟， 与上述粉末混匀， 压制成锭， 低温干燥， 即得。 实施例 9: 茶剂的制备
取断肠草原药材 160g， 洋金花原药材 40g， 分别粉碎成粗粉。 断肠草的粗粉用乙醇提取三次， 每次 2小时， 提取液合并， 滤过， 滤液浓缩成稠膏； 滤渣用水提取三次， 每次 2小时， 提取液合并， 滤过， 滤液浓缩成稠膏； 洋金花的粗粉用水进行微波提取三次， 每次 2小时， 提取液合并， 滤过， 滤液浓缩成稠膏； 合并上述三 份稠膏， 按每 100g生药加蔗糖粉 200g、 糊精 100g， 混勾， 制成 颗粒， 干燥， 混勾， 压块， 即得。 实施例 10: 急性毒性试验
实施例 1 中所得的生药粉研细并用蒸馏水配成最大浓度 0.3g/ml 的糊状物， 再往下按 0.75 的等比依次用蒸馏水稀释为 4 个剂量组。选 18 ~ 20g ICR小鼠 60只（来源为昆明制药集团股份 有限公司动物房） ， 雌雄各半， 按性别和体重随机分为 6组， 每 组 10只。 禁食不禁水 6小时后， 除空白对照组给予蒸馏水外， 各 组动物均按剂量设置分别一次灌胃给药，给药容积约为 40 ml/kg。 观察小鼠给药后即时反应， 死亡动物进行解剖观察， 存活动物继 续观察 1周， 并记录 1周内死亡情况。 1周后将存活动物进行解 剖， 观察实质性病变， 具有实质性病变的脏器需作病理检查。 根 据各组动物的死亡数， 以孙氏改进寇氏法计算 LD5。。 单次灌胃对 ICR 小鼠的急性毒性 LDS。为 7.57±1.08g/kg, 95%的可信限为 6.57 ~ 8.73 g/kgo 最大耐受量为 3.8 g/kg, 约相当于临床人一日用 量的 158倍。 实施例 11: 临床疗效观察
临床治疗海洛因依赖病例 20例， 其中男 18例， 女 2例； 入 围病例全部符合以下条件：
( 1 )符合中国医学会精神科学会制定的 CCMD-2-R依赖综 合征诊断标准；
( 2 )年龄 21 ~ 43岁， 平均 31.4岁；
( 3 ) 海洛因滥用史 2 ~ 20年， 平均 11.2年， 多数有 5 ~ 20 年吸毒史；
( 4 )血、 尿常规、 肝肾功能以及心电图检查正常。
治疗方法： 按每日服用未发明胶嚢（根据实施例 2制备） 2粒， 每日服 2 次进行治疗。 经过 3天脱毒期、 7天康复期和 10天抗复吸巩固治 疗。 疗程结束后不再给药， 疗程中不使用任何辅助戒毒药。
结果评价方法：
按北京大学中国药物依赖研究所修订的 《海洛因稽延性戒断 症状评定量表》 进行评分， 考察肌肉或关节疼痛、 全身难受、 四 肢不适、 全身无力、 食欲差、 心慌、 烦躁不安、 入睡困难、 早睡、 早醒等症状项目， 采用 0 ~ 3分四级评分， 严重程度评分标准为： 0—无症状； 1一轻度， 询问出来， 症状轻微； 2—中度， 主诉症状， 但能忍受； 3—重度， 不能忍受。
临床观察结果：
通过临床观察检测显示， 疗程结束后所有病例纳洛酮催瘾试 验阴性， 本发明药物治疗海洛因依赖者的有效率达 100%。 在脱 毒治疗的第二天戒断症状较为明显，评分达到峰值，为 8.23±2.15； 第三天戒断症状评分明显下降， 尤以乏力、 焦虑和失眠等类症状 下降最为明显， 10天以后分值低且较平稳。 治疗结束后稽延性戒 断症状最终总评分为 1.95±0.83， 接近正常人水平。 整个过程的戒 断症状从分值看均比多数戒毒药物轻微， 治疗过程中未见明显毒 副反应。 疗程结束后患者没有再索要本发明药物。 经过半年以上 随访， 除 1例在半年后复吸外， 其他均无复吸， 复吸率仅 5%。 实施例 12: 典型病例
例 1: 患者张 x， 男， 28岁， 汉族。 因朋友引诱开始吸食海洛 因， 已有 10年， 现采用静脉注射方式， 平均日用量 lg。 同时还 服用安定。 按本发明方法使用根据实施例 2制备药物进行治疗， 第一日开始安静嗜睡， 后来开始烦躁， 口干， 眼花， 语无伦次， 失眠， 第二日话多， 爱发脾气， 出现幻觉， 第三日眼花、 口干、 语无伦次等戒断症状逐渐消失， 幻觉消失， 食欲大增， 精神状态 好转， 失眠减轻。 3 ~, 10天偶尔会有"想瘾"， 10天以后完全正常。 疗程结束后体重增加 8kg。 经过 6年随访， 未复吸。
例 2: 患者宋 x x， 女， 36岁， 汉族。 因受兄弟影响开始吸食 海洛因， 已有 20余年， 现平均日用量 0.8g。 按本发明方法使用根 据实施例 2制备药物进行治疗， 第一日开始安静嗜睡， 后来开始 烦躁， 出汗， 口干， 语无伦次， 失眠， 第二日话多， 爱发脾气， 出现幻觉， 第三日出汗、 口干、 语无伦次等戒断症状逐渐消失， 幻觉消失， 食欲大增， 精神状态好转， 失眠减轻。 3 ~ 10天偶尔 会有"想瘾"， 10天以后完全正常。 疗程结束后体重增加 6kg。 经 过 1年随访， 未复吸。
例 3: 患者马 X , 男， 23岁， 回族。 因受朋友影响开始吸食海 洛因， 已有 5年余， 现平均日用量 1.0g。 按本发明方法使用根据 实施例 4制备药物进行治疗， 第一日开始安静嗜睡， 后来开始烦 躁， 失眠， 出现幻觉， 第二日话多， 常语无伦次， 第三日烦躁、 失眠、 语无伦次等戒断症状逐渐消失， 幻觉消失， 食欲大增， 精 神状态好转， 失眠减轻。 3 ~ 10天偶尔会有"想瘾"， 10天以后完 全正常。 疗程结束后体重增加 3kg。 经过 8年随访， 未复吸。
例 4: 患者黄 x， 男， 40岁， 汉族。 因追求刺激开始吸食冰毒， 已有 4年， 平均日用量 0.8g。 按本发明方法使用根据实施例 2制 备药物进行治疗， 前三日感觉心烦意乱， 3 ~ 10 日后心烦意乱的 感觉逐渐消失。 随即结束治疗。 疗程结束后体重增加 3kg。 经过 1 年随访， 未复吸。
例 5: 患者肖 X X , 男， 26岁， 汉族。 因精神空虚， 受人引诱 开始吸食可卡因， 已有半年， 每日吸食可卡因多次。 按本发明方 法使用根据实施例 2制备药物进行治疗， 前 10 曰感觉心烦意乱， 时有出汗， 10日后心烦意乱的感觉逐渐消失。 20 日后结束治疗。 011/153819
PCT/CN2011/000900 疗程结束后精神状态好。 经过半年随访， 未复吸。
例 6： 患者李 X X， 男， I9岁， 汉族。 在歌舞厅受朋友怂恿开 始服用摇头丸， 已有 4年， 每日服食可摇头丸多片。 按本发明方 法使用根据实施例 2制备药物进行治疗， 前 10日感觉心烦意乱， 10曰后心烦意乱的感觉逐渐消失。 20日后结束治疗。 疗程结束后 精神状态好。 经过 10个月随访， 未复吸。

Claims

1. 断肠草和洋金花在制备药物中的用途， 所述药物用于在有 需要的受试者中消除或緩解由成瘾性物质引起的急性断瘾症状和 稽延性症状、 消除或降低该受试者对成瘾性物质的渴求程度以及 防止该受试者再使用该物质， 其中断肠草和洋金花以其原药材或 原药材的提取物使用。
2. 权利要求 1所述的用途， 其中断肠草原药材与洋金花原药 材的重量 /重量比为 2:1 ~ 6:1。
3. 权利要求 1或 2所述的用途， 其中断肠草和洋金花以其原 药材的提取物使用， 并且断肠草提取物是通过如下方法制备的： 将断肠草粗粉用乙醇提取一次或多次， 合并提取液， 滤过， 滤液 浓缩成稠膏； 滤渣用水提取一次或多次， 合并提取液， 滤过， 滤 液浓缩成稠膏； 然后合并所述稠膏备用； 洋金花提取物是通过如 下方法制备的： 将洋金花的粗粉用水提取一次或多次， 合并提取 液， 滤过， 并将滤液浓缩成稠膏； 或将洋金花粗粉用乙醇提取一 次或多次， 提取液合并， 滤过， 滤液浓缩成稠膏备用。
4. 权利要求 1 ~ 3任一项所述的用途， 其中所述的成瘾性物质 选自吗啡类、 巴比妥类、 可卡因类、 印度大麻类、 苯丙胺类、 柯 特类和致幻剂类。
5. 一种药物组合物， 其包含断肠草和洋金花， 并且任选包含 药学上可接受的赋形剂， 其中断肠草和洋金花以其原药材或原药 材的提取物使用， 并且断肠草原药材与洋金花原药材的重量 /重量 比为 2:1 ~ 6:1。
6. 权利要求 5的药物组合物， 其中断肠草原药材与洋金花原药材 的重量 /重量比为 3:1 ~ 5:1。
7. 权利要求 6的药物组合物， 其中断肠草原药材与洋金花原 药材的重量 /重量比为 4:1。
8. 权利要求 5 ~ 7任一项所述的药物组合物， 其中断肠草和洋 金花以其原药材的提取物使用， 并且断肠草提取物是通过如下方 法制备的： 将断肠草粗粉用乙醇提取一次或多次， 合并提取液， 滤过， 滤液浓缩成稠膏； 滤渣用水提取一次或多次， 合并提取液， 滤过， 滤液浓缩成稠膏； 然后合并所述稠膏备用； 洋金花提取物 是通过如下方法制备的： 将洋金花的粗粉用水提取一次或多次， 合并提取液， 滤过， 并将滤液浓缩成稠膏； 或将洋金花粗粉用乙 醇提取一次或多次， 提取液合并， 滤过， 滤液浓缩成稠膏备用。
9. 权利要求 5 ~ 8任一项所述的药物组合物， 其中所述的成瘾 性物质选自吗啡类、 巴比妥类、 可卡因类、 印度大麻类、 苯丙胺 类、 柯特类和致幻剂类。
10. 权利要求 5 ~ 9任一项所述的药物组合物， 其中该药物组合 物还包含甘草、 木香和槟榔中的一种或几种。
11. 一种药物组合物， 其由断肠草和洋金花以及任选包含的药 学上可接受的赋形剂组成， 其中断肠草和洋金花以其原药材或原 药材的提取物使用， 并且断肠草原药材与洋金花原药材的重量 / 重量比为 2:1 ~ 0:1。
12. 权利要求 11所述的药物组合物， 其中断肠草原药材与洋金 花原药材的重量 /重量比为 3:1 ~ 5:1。
13. 权利要求 12的药物组合物， 其中断肠草原药材与洋金花原 药材的重量 /重量比为 4:1。
14. 权利要求 11 ~ 13任一项所述的药物组合物， 其中断肠草和 洋金花以其原药材的提取物使用， 并且断肠草提取物是通过如下 方法制备的： 将断肠草粗粉用乙醇提取一次或多次，合并提取液， 滤过， 滤液浓缩成稠膏； 滤渣用水提取一次或多次， 合并提取液， 滤过， 滤液浓缩成稠膏； 然后合并所述稠膏备用； 洋金花提取物 是通过如下方法制备的： 将洋金花的粗粉用水提取一次或多次， 合并提取液， 滤过， 并将滤液浓缩成稠膏； 或将洋金花粗粉用乙 醇提取一次或多次， 提取液合并， 滤过， 滤液浓缩成稠膏备用。
15. 权利要求 11 ~ 14任一项所述的药物组合物， 其中所述的成 瘾性物质选自吗啡类、 巴比妥类、 可卡因类、 印度大麻类、 苯丙 胺类、 柯特类和致幻剂类。
PCT/CN2011/000900 2010-06-07 2011-05-26 用于戒毒的药物组合物 WO2011153819A1 (zh)

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