KR20100064512A - Therapeutic agent for drug abuse and addiction comprising l-thp as active ingredient - Google Patents

Abstract

PURPOSE: A therapeutic agent for drug abuse containing L-tetrahydropalmatine(L-THP) is provided to suppress drug abuse cause by drug administration. CONSTITUTION: A therapeutic agent for drug abuse contains L-tetrahydropalmatine(L-THP) as an active ingredient and pharmaceutically acceptable carrier. The L-THP is isolated from Corydalis ochotensis TURCZ. The therapeutic agent effectively suppresses drug dependence by serotonins or morphines. The morphines include amorphine.

Description

Therapeutic Agent for Drug Abuse and Addiction Comprising L-THP as Active Ingredient}

The present invention relates to a drug abuse treatment comprising L-THP as an active ingredient. More specifically, the present invention relates to a drug abuse treatment agent comprising L-tetrahydropalmatine (L-THP) as an active ingredient and a pharmaceutically acceptable carrier.

To obtain mental pleasure, use a legal but non-therapeutic substance, such as alcohol, to the extent that damages or harms the user or others, or any illegal substance such as drugs. Drug abuse, which is a symptom of using substances, is known to the public as drug addiction, and is defined as "substance use disorder" in the formal diagnostic term.

Most drug abusers become increasingly resistant to continuous use of drugs, increasing the amount of drug to achieve an equivalent drug effect. Common pathological symptoms of these drug abusers include fatigue, emotional instability, anti-coma, and vomiting. When the electrical symptoms intensify, anti-social and anti-ethical behaviors occur, resulting in social problems. As a result, efforts to treat drug abusers continue. In particular, among drugs classified as narcotic drugs, some drugs such as serotonin and morphine are used medically as narcotic analgesics, but most drugs are illegal and have significantly more pathological symptoms than legal substances such as alcohol. Even if the narcotic analgesic is used as a symptom, it does not show any symptoms and does not show any pathological symptoms. On the contrary, long-term administration may cause more serious pathological symptoms, thereby preventing the use of narcotic drugs. Efforts to treat drug abusers of narcotic drugs or drugs are being made at national level. However, due to the complicated mechanism of drug dependence formation and various factors such as environment, genetics, race, medication behavior, and drug type, most drug abusers are not completely treated.

In order to treat such drug abuse, it is necessary to alleviate withdrawal symptoms and suppress re-administration. Withdrawal symptoms do not have any special medicines and can be used for symptomatic therapy. Understanding the function is important.

On the other hand, continuous administration of drugs results in the activation of the brain reward system (especially the dopamine nervous system), and withdrawal of the drug results in the suppression of the central nervous system dopamine nervous system due to the sudden absence of dopamine nervous system stimulants. Dopamine neurological agonists and antagonists have been used for drug treatment in the conventional drug abuse treatment, but dopamine receptor agonists alleviate narcolepsy and discomfort after medication, but do not provide a single condition irritant. When exposed to a similar time, place, and stress, addicts have an increased desire to consume drugs, and there is a risk of drug recurrence, and the drug itself is at risk of drug abuse. On the other hand, dopamine receptor antagonists reduce the response to conditional stimulation and the rewarding nature of drug abuse itself, but have side effects that are typical symptoms of dopamine nervous system suppression, such as mood swings, discomfort, Parkinson's disease, or dyskinesia. Because of this, efforts are being made to develop therapeutics that can overcome these shortcomings, but there are no results.

In general, dopamine neurological agonists or antagonists developed in the past cause serious side effects, according to the need for a therapeutic agent that can minimize the side effects even if the therapeutic effect is lowered, extracts extracted from natural products or compositions thereof Research is also in progress. For example, Korean Patent Publication No. 1988-1296 discloses Gyeji, Ginger, Jujube, Peony, Shiho, Banja, Bokryeong, Golden, Ginseng, Rhubarb, Licorice, Gyotae, Mochi and Keel, and then hot water extraction and concentration. A method of preparing a composition that can alleviate abuse of tobacco, coffee, etc., as well as manufactured addictive drugs, is disclosed, and Korean Patent Publication No. 1990-2793 discloses rich, cinnamon, peppermint, gilcho root, licorice, pepper, A drug abuse detoxification agent is disclosed, which is prepared by mixing peony, sandalwood, white paper, Hyunho Saeng, Bokryeong, motherwort, Hyuncho and Ginseng, and extracting and condensing it with hot water, and Korean Patent Publication No. 1992-3986 discloses sulfur. , The mixture of rich powder, gallium powder and alum powder was heated to high temperature for a long time and then immersed and filtered in water to obtain a filtrate, and dried to obtain a dry powder, and then licorice powder and ginseng powder. A drug abuse treatment agent and a preparation method thereof are disclosed, and Korean Patent No. 54246 discloses an ethanol extract of a powder mixture of Sanjago, Shando-geun, Daegeuk, Sugija, Pangolin, Donkey, Cheongung, Chihwang and Baek-Pak, Ginseng. A drug abuse antidote prepared by mixing powder and sanjoin powder is disclosed, and Korean Patent No. 313454 discloses Kang Hori, Ginseng, Hyunho Color, Rich, Hemp, Cucumber, Cheonma sprout, Astragalus, Honeysuckle, Gurugi, White Ginseng, Cinnamon And compositions for inhibiting withdrawal symptoms against drugs, alcohols and tobacco obtained from a mixture of peppermint and a method of preparing the same. The extract extracted from the natural products thus developed or a mixture thereof is excellent in safety and does not show fatal side effects on the human body, but the effects of treating drug abuse are extremely low, and thus are not used for the treatment of substantial drug abuse. It is true.

If it is possible to develop a drug that is safe for the human body and has the effect of treating drug abuse at a certain level, it is expected that a single electricity can be provided in the treatment of drug abuse, but there are no results yet. It is true.

Accordingly, the present inventors have made a thorough research and efforts to develop a drug that can safely and effectively treat the symptoms of drug abuse, and as a result, L-tetrahydropalmatin (L-) derived from Corydalis ochotensis TURCZ. Tetrahydropalmatine, L-THP) was confirmed that can suppress the occurrence of various pathological symptoms caused by drug abuse, and completed the present invention.

After all, the main object of the present invention is to provide a drug abuse treatment agent comprising L-tetrahydropalmatin as an active ingredient.

Drug abuse treatments using L-THP as an active ingredient of the present invention can significantly inhibit drug dependence formed by the administration of narcotic analgesics or drugs, and thus may be widely used for the treatment of drug abuse.

The present inventors have developed a drug that can increase the resistance and dependence on narcotic analgesics, thereby preventing drug abuse from occurring and treating patients who have already been diagnosed as drug abusers by forming resistance and dependence on the drug. To search for substances that can effectively cure drug abuse symptoms, natural products such as Bokryeong, Gardenia, Red Ginseng, Hyunho-red, Ganoderma lucidum, Cheonma, which are known to reduce drug addiction, are searched for.

As a result, two-year-old plants growing in wetlands in mountainous areas of Korea, Japan, Heilong River, etc., are able to lower heat, detoxify, treat boils, shelter, heat extinction, and obscure poisoning. The extract of Corydalis ochotensis TURCZ., Which is known to treat acute conjunctivitis, was able to inhibit the hair-shaking behavior formed by the administration of serotonin, a type of narcotic analgesic. However, since the corydalis extract used was obtained by extracting the corydalis from hot water, it was expected that the corydalis extract would contain many compounds, and to confirm what effective components are effective in treating drug abuse among these compounds. It was.

Thus, parlidine, kikemanine, L-tetrahydropalmatine (L-THP), protopin, capaurimine, which can be isolated from corydalis extract, From ingredients such as sinoacutine, isoboldine, corydaline, cryptopine and stylopine, it can effectively inhibit the hair-shaking behavior formed by drug abuse The components present were to be selected. As a result, it was confirmed that L-THP can significantly inhibit not only the head shaking behavior but also the climbing behavior, spontaneous movement, and location dependence formed by drug abuse. It can be seen that it can be used as.

L-tetrahydropalmatine, L-THP

L-tetrahydropalmatine, L-THP

Meanwhile, L-THP contained as an active ingredient of the drug abuse treatment agent of the present invention is a pharmaceutically acceptable binder (eg, polyvinylpyrrolidone, hydroxypropyl cellulose), a disintegrant (eg, carboxymethyl cellulose calcium, starch). Sodium glycolate), diluents (e.g. corn starch, lactose, soybean oil, crystalline cellulose, mannitol), lubricants (e.g. magnesium stearate, talc), sweeteners (e.g. white sugar, fructose, sorbitol, aspartame), stabilizers (carboxymethyl Sodium cellulose, alpha or beta cyclodextrin, citric acid, white lead), preservatives (e.g. methyl paraoxybenzoate, propyl paraoxybenzoate, sodium benzoate) and flavorings (e.g. ethyl vanillin, masking flavor, menthol flavono, herbal flavor) It may be mixed with and prepared into pharmaceutical preparations such as tablets, capsules, soft capsules, and liquids.

Acute Toxicity Test

Since L-THP, which is an active ingredient of the drug abuse treatment agent of the present invention, is derived from corydalis which has been used as a medicinal herb and proven to be safe, no separate acute toxicity test was performed.

Effective amount

The dose of L-THP, an active ingredient of the drug abuse treatment agent of the present invention, is preferably administered 10 mg to 15 mg per kg of body weight per day, depending on the patient's age, sex, symptoms, administration method or prevention purpose. Dosage levels for symptomatic patients may be varied by those skilled in the art depending on the patient's weight, age, sex, health condition, diet, time of administration, method of administration, excretion rate, severity of disease, and the like.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .

Example 1 Selection of Natural Products Having a Drug Abuse Treatment Effect

Injecting serotonin into the cerebral ventricles of mice, which is a type of narcotic analgesic, is known to activate the serotonin nervous system and show a pattern of shaking behavior (see Malick JB, et al. , Pharmacol.Biochem.Behav., 6: 325-329, 1977), sought to search for natural products that may have the effect of inhibiting serotonin-induced hair shaking.

First, extracts of natural products known as Bokyeong, Gardenia, Red Ginseng, Hyunho-red, Ganoderma lucidum and Cheonma, which are known to reduce the addictive properties of drugs, were obtained. Specifically, after drying each of the natural products, 10 times the weight of distilled water was added to each weight, and extracted by heating for 2 hours, and the filtrate was obtained, which was concentrated under reduced pressure and lyophilized to obtain each extract powder Next, it was dissolved in physiological saline at a concentration of 100 μg / μl to obtain an intraperitoneal injection solution.

On the other hand, injecting serotonin, a serotonin receptor agonist, into the cerebral chambers in an amount of 60 μg / 10 μl / mouse, and intraperitoneally injecting 30 mice at 500 mg / kg into the peritoneal injection solution containing the extract of each natural product, Serotonin nervous system activation was measured by measuring the average number of times the mice in each experimental group exhibited the shaking behavior three times over two minutes at five minute intervals. In this case, instead of serotonin, a mouse administered only saline was used as a negative control, and a mouse administered only serotonin was used as a positive control (see Table 1).

Inhibitory Effect of Shaking Head by Natural Extracts Natural product extract Average number of times Positive control
Negative control
Ghost
Gardenia
Red ginseng
Corydalis
wisdom
Cheonma 1.4
6.8
6.4
5.9
6.2
3.8
6.5
5.9

As shown in Table 1, it can be seen that the activity of shaking the hair formed by the administration of serotonin can be largely suppressed by the corydalis extract, which has a substance showing the therapeutic effect on the abuse of serotonin in the extract of the corydalis Could be predicted.

Example 2 Screening of Active Ingredients Having a Drug Abuse Treatment Effect Including Corydalis

The purpose of this study was to determine which of the various ingredients included in Hyunho color could effectively suppress the shaking behavior caused by such drug abuse.

Corydalis include palidine, kikemanine, L-tetrahydropalmatine (L-THP), protopin, capaurimine, sinoacutine, It is known to contain active ingredients such as isoboldine, corydaline, cryptopine and stylopine (see Kodama et al., Xenobiotica, 6: 377-89, 1976). Among these components, we searched for substances that could have an effect of inhibiting serotonin-induced hair shaking.

Palidine (Wako, Japan), Kikemanin (Wako, Japan), L-tetrahydropalmatin (Wako, Japan), Protopin (Wako, Japan) diluted with physiological saline and mixed 1: 1 (v / v) Japan, kappaurimin (Wako, Japan), cynoacutin (Wako, Japan), isoboldine (Wako, Japan), corridin (Wako, Japan), kryptopin (Wako, Japan) and stilopine (Wako) , Japan) was measured in the same manner as in Example 1, except that the dose of 1 ml / kg to the abdominal cavity of the mouse was measured (see Table 2).

Inhibitory Effect of Shaker Head Shaking Behavior on the Constituents compound Average number of times Positive control
Negative control
Palidine
Kikemanin
L-tetrahydropalmatin
Protopin
Kappurimin
Sinoacutin
Isoboldine
Corridin
Cryptopine
Styropine 1.5
6.7
5.4
5.5
3.5
5.2
5.1
6.0
5.9
5.6
5.4
6.4

As shown in Table 2, when L-THP was administered among various compounds present in corydalis extract, the number of times of shaking the head was remarkably reduced, but the number of times of shaking the head when other compounds were administered. It can be seen that is not significantly reduced. Therefore, it was predicted that L-THP present in corydalis extract would have a therapeutic effect on drug abuse.

Example 3 Effect of L-THP on Drug Abuse Symptoms

From the results of Example 2, it was confirmed that L-THP can improve the symptoms of drug abuse, it was confirmed how L-THP affects a variety of drug abuse symptoms.

Example 3-1 : Effect on Shaking Head Behavior

Inject the serotonin, a serotonin receptor agonist, into the cerebral chamber in an amount of 60 μg / 10 μl / mouse, and then dissolve L-THP, a compound present in corydalis, in a mixed solvent (3% methanol, 8% Tween 80). Serotonin nervous system activation was measured by intraperitoneal injection to 30 mice each at a dose of 10 or 15 mg / kg, and by measuring the average number of times the mice in each experimental group exhibited three times of shaking behavior for 2 minutes at 5 minute intervals. It was. At this time, as a control group, mice administered with saline instead of serotonin were used (see FIG. 1). 1 is a graph showing the effect of L-THP on serotonin-induced head shaking behavior, where 1 on the X axis represents the number of shaking hands in the control group, and 2 is the dose of 15 mg / kg L-THP alone without serotonin administration. Represents the number of times of shaking the head of the mouse administered, 3 represents the number of times of shaking the head of the mouse administered serotonin and L-THP at a dose of 0 mg / kg, 4 is 10 mg / L-THP administered serotonin The number of head shakes of the mice administered at the dose of kg, and 5 represents the number of head shakes of the mice administered with the serotonin and L-THP at a dose of 15 mg / kg. As shown in Figure 1, as the dosage of L-THP was found to inhibit serotonin-induced shaking, the L-THP was expected to be able to suppress the symptoms caused by drug abuse. .

Example 3-2 : Effect on Climbing Behavior

Subcutaneous injection of apomorphine, a type of narcotic analgesic, that can cause drug abuse, is known to activate the dopamine nervous system, resulting in climbing behavior patterns (Kim et al., Life Sci., 58: 1397-402, 1996).

First, L-THP, a compound present in corydalis, was dissolved in a mixed solvent (3% methanol, 8% Tween 80) and intraperitoneally injected into 10 mice at dosages of 0, 10, or 15 mg / kg, and 40 minutes At each point in time, the mice of each experimental group were injected subcutaneously with apomorphine, a dopamine receptor agonist, in an amount of 2 mg / kg / 10 μl / mouse, and then the mice in each experimental group exhibited climbing behavior for 10 minutes at 5 minute intervals. Dopamine nervous system activation was measured by measuring the average number of times. At this time, the control group was used as a mouse administered with saline instead of apomorphine (reference: Figure 2). Figure 2 is a graph showing the effect of L-THP on the climbing behavior induced by apomorphine, where 1 on the X axis represents the number of climbs of the control, 2 is administered L-THP at a dose of 15 mg / kg The number of climbs of mice that did not receive apomorphine was administered, 3 represents the number of climbs of mice that received L-THP at a dose of 0 mg / kg, and the dose of 4 was 10 mg / L-THP. The number of climbs of mice administered at a dose of kg and apomorphine was administered, and 5 represents the number of climbs of mice administered L-THP at a dose of 15 mg / kg and administered apomorphine. As shown in FIG. 2, even when L-THP was administered before apomorphine was administered, it was found that the shaking of the apomorphine-induced abrasion was increased as the dose of L-THP was increased. It was also expected that it would be possible to prevent symptoms caused by drug abuse.

Example 3-3 : Effect on spontaneous exercise

L-THP dissolved in mixed solvent (3% methanol, 8% Tween 80) under the same conditions as the control group in which rats were intraperitoneally injected into 10 rats at 1 day intervals for 4 days of 0, 10 or 15 mg / kg An experimental group was orally administered to 10 rats at a dose of 40 minutes and intraperitoneally injected with 1 mg / kg of methamphetamine.

Then, using conventional methods known in the art (Protais P. et al., Psychopharmacology, 50: 1-6, 1976), the distance the rats of each control group and each experimental group traveled for 60 minutes ( cm) was measured and considered as spontaneous momentum (see FIG. 3). Figure 3 is a graph showing the effect of L-THP on the spontaneous exercise induced by methamphetamine, where 1 on the X axis represents the spontaneous momentum of the control group, 2 is administered L-THP at a dose of 15 mg / kg, methamphetamine Indicated the spontaneous amount of rats not administered, 3 represents the amount of spontaneous exercise of rats administered L-THP at a dose of 0 mg / kg, and 4 represents the dose of 10 mg / kg of L-THP. 5 shows the spontaneous momentum of rats to which methamphetamine was administered and 5 mg / kg of L-THP was administered and methamphetamine to rats. As shown in Figure 3, it was confirmed that the spontaneous motility induced by the administration of methamphetamine can be reduced concentration-dependently by the pre-administration of L-THP, from which the L-THP-related behaviors (sensitization, It is thought to inhibit sensitization.

Example 3-4 : Effect on Place Dependence

First, three square rooms each having a length of 1m are continuously connected to each other, and an experimental table that can be opened and closed by an automatic guillotine door is installed between each rooms, and the inside of the center room is painted in gray ( Gray room), the interior of the left room of the gray room was painted white (white room), and the interior of the right room of the gray room was painted black (black room).

Next, each drug was administered to 5 rats and adjusted for 30 minutes in a white room, the other 5 rats were treated with physiological saline and then adjusted to a black room for 30 minutes, and each drug was elapsed after 24 hours. Rats administered with the rats and rats given the saline solution were alternately placed in each room, and adapted for another 30 minutes. The same method was repeated four times for 8 days, and then each rat was placed in a gray room without additional administration of each drug or saline solution, and then the automatic guillotine door was opened and the time spent in each room for 15 minutes was measured. . At this time, the time to stay in the white room is indicated by (+), and the time to stay in the black room is indicated by (-). In addition, as a drug, a group administered only saline was used as a control group, and as the drug, L-THP dissolved in a mixed solvent (3% methanol, 8% Tween 80) without administration of methamphetamine was administered at a dose of 100 mg / kg. One group was experimental group 1, 1 mg / kg of methamphetamine as intraperitoneal injection, and the group not administered the L-THP was experimental group 2, and 1 mg / kg methamphetamine as intraperitoneal injection, 40 After 3 minutes, the group administered with the L-THP at a dose of 10 mg / kg was experimental group 3.The drug was intraperitoneally injected with 1 mg / kg of methamphetamine, and 40 minutes later, the dose of L-THP was 50 mg / kg. Group 4 was administered as the experimental group 4, 1 mg / kg of methamphetamine as the drug was intraperitoneally injected, and 40 minutes later the L-THP group was administered as a dose of 100 mg / kg to Experiment group 5 (see: Figure 4). 4 is a graph showing the effect of L-THP on the place dependence induced by methamphetamine, where 1 on the X axis represents the time of place dependence of the control group, and 2 represents the time of place dependence of the experimental group 1. , 3 denotes the time to indicate the place dependency of the experimental group 2, 4 denotes the time to indicate the place dependency of the experimental group 3, 5 denotes the time to indicate the place dependency of the experimental group 4, 6 denotes the place dependency of the experimental group 5 In the graph, the black part represents the group administered only saline in each experimental group, and the white part represents the group administered with the drug in each experimental group. As shown in FIG. 4, in the case of the experimental group 1 administered only the control group or L-THP, the location dependence on the black room was shown. However, in the experimental groups 3, 4, 5, and 6 administered the methamphetamine, the place for the white room. Dependency was shown. In addition, it was found that the time to stay in the white room tended to decrease with increasing dose of L-THP among the experimental groups administered methamphetamine.

As such, it was confirmed that the site-dependence caused by the administration of methamphetamine could be reduced concentration-dependently by the administration of L-THP, from which L-THP could suppress even the psychopathological symptoms caused by methamphetamine. It was confirmed.

Figure 1 is a graph showing the effect of L-THP to inhibit the shaking behavior caused by serotonin (serotonin).

Figure 2 is a graph showing the effect of L-THP to inhibit the climbing behavior caused by apomorphine (apomorphine).

Figure 3 is a graph showing the effect of L-THP to inhibit spontaneous movement induced by methamphetamine (methamphetamine).

Figure 4 is a graph showing the effect of L-THP to suppress the place dependency induced by methamphetamine (methamphetamine).

Claims (2)

A drug abuse treatment agent comprising L-tetrahydropalmatine (L-THP) as an active ingredient and a pharmaceutically acceptable carrier. The method of claim 1, It is effective for drug abuse of serotonin or morphine Substance abuse treatment.

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