KR20240022248A - Composition comprising the syringin for the prevention, improvement or treatment of nicotine addiction and withdrawl symptoms - Google Patents

Abstract

The present invention relates to a composition for preventing, improving, or treating nicotine addiction and withdrawal symptoms containing syringine as an active ingredient. According to the present invention, a composition containing syringine as an active ingredient prevents, improves, or treats nicotine addiction and withdrawal symptoms. It can be improved or treated.

Description

Composition for preventing, improving or treating nicotine addiction and withdrawal symptoms comprising syringin {COMPOSITION COMPRISING THE SYRINGIN FOR THE PREVENTION, IMPROVEMENT OR TREATMENT OF NICOTINE ADDICTION AND WITHDRAWL SYMPTOMS}

The present invention relates to a composition for preventing, improving or treating nicotine addiction and withdrawal symptoms, and more specifically, to a pharmaceutical composition containing syringine for preventing or treating nicotine addiction and withdrawal symptoms, or a pharmaceutical composition for nicotine addiction and withdrawal symptoms. It relates to a health functional food composition for prevention or improvement.

The smoking rate among Korean adults is 20.6% in 2020, with 34.0% for men and 6.6% for women. The male smoking rate has been decreasing from 47.8% in 2008 to the present, but the smoking rate is still high, and for women, it has decreased slightly from 7.4% in 2008, but there has been no significant change.

Smoking is a type of drug addiction that is classified as ‘Tobacco dependence’ in the International Classification of Diseases (ICD-10) standards and as ‘Tobacco Use Disorder’ in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-V) standards. Nicotine contained in cigarettes is a psychoactive substance that causes symptoms of drug addiction and is contained in dried tobacco leaves at approximately 0.17-4.93%. This nicotine elevates mood and improves depression, causing people to continuously seek out and smoke cigarettes.

Nicotine addiction refers to dependence, which causes acute or chronic physical and mental symptoms. Dependence causes drug tolerance, craving, and withdrawal symptoms. Tolerance refers to a phenomenon in which the drug's effectiveness decreases if the drug is continuously administered and the amount of the drug must be increased later. Craving refers to the mental dependence on the drug that appears when a drug that has been used for a long time is stopped. Withdrawal symptoms are specific physical symptoms. This means that symptoms are visible. Withdrawal symptoms that appear after quitting smoking include insomnia, anxiety, fatigue, tension, nervousness, headache, cough, phlegm, and mental concentration difficulties, and various symptoms appear that vary from person to person.

Nicotine in cigarette smoke inhaled through direct and indirect smoking reaches within 10 seconds and binds to nicotine receptors in the central nervous system (brain), causing a positive feeling by increasing the release of dopamine in the short term, but repetitive and long-term exposure Repeated exposure to nicotine due to smoking desensitizes nicotinic acetylcholine receptors and generates a large amount of receptors, leading to increased smoking. That is why withdrawal symptoms occur when cravings are not met.

Treatment of nicotine addiction can be broadly divided into nicotine replacement therapy and drug treatment. Nicotine replacement therapy is a method of using nicotine substitutes such as nicotine patches, gum, and candy. Although it does not directly affect nicotine addiction treatment, it helps to make quitting smoking easier by suppressing withdrawal symptoms due to lack of nicotine. . Representative drug treatments include Varenicline and Bupropion. Varenicline is known to be the most effective, and binds to acetylcholine receptors to produce a similar effect to nicotine, thereby reducing withdrawal symptoms and suppressing the desire to smoke. However, it has the disadvantage of causing side effects such as nausea, sleep disorders, constipation, and headaches, as well as cardiovascular disease. Bupropion is a non-nicotine drug first approved by the FDA as a smoking cessation treatment in 1997. It is also known as an antidepressant treatment and relieves withdrawal symptoms by inhibiting dopamine reuptake in the mesolimbic pathway. However, there are side effects such as nausea, vomiting, dry mouth, convulsive seizures, nervousness, indigestion, and constipation. As such, because drugs used to treat nicotine addiction cause various side effects, attempts are being made to develop new drugs to replace nicotine addiction treatment drugs.

Previously, technology to replace nicotine addiction treatment drugs has been disclosed. Specifically, Korean Patent No. 0571853 includes angelica root extract as an active ingredient in a composition for preventing, improving, and treating nicotine addiction and withdrawal symptoms, and Korean Patent No. 0663181 uses Sanjoin extract as an active ingredient. and Korean Patent No. 0676403 includes Chrysanthemum root extract as an active ingredient. However, all of the above technologies include natural extracts as active ingredients, and when developing natural extracts into pharmaceuticals, there are difficulties in terms of quality control such as management of activity, purity, stability, and equivalence, and the toxicity of the natural product itself is high. There may be a problem that there is a possibility of toxicity due to drug interaction.

Meanwhile, syringin is also known as eleutheroside B (EB). Syringin is known to have the effect of stimulating the gonads, increasing the weight of the anterior capsule and prostate, and enhancing stamina. In addition, it is known to help prevent aging, improve vision and hearing, anti-fatigue effects, and excitability, and is also effective in preventing liver damage, dilating blood vessels, anti-convulsants, and anti-stress. However, the effectiveness of Syringine in preventing, improving, or treating nicotine addiction and withdrawal symptoms is not yet known.

Accordingly, the present inventors have made extensive research efforts to overcome the problems of the prior art and have confirmed that a composition containing syringine as an active ingredient can prevent, improve or treat nicotine addiction and withdrawal symptoms, and the present invention was completed.

KR 10-0571853 B1 KR 10-0663181 B1 KR 10-0676403 B1

Accordingly, the main object of the present invention is to provide a composition for preventing, improving or treating nicotine addiction and withdrawal symptoms, including syringine, which can prevent, improve or treat nicotine addiction and withdrawal symptoms.

According to one aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating nicotine addiction and withdrawal symptoms containing syringin as an active ingredient.

Substitutes and drugs that have been conventionally used to prevent, improve, or treat nicotine addiction and withdrawal symptoms have had the problem of being minimally effective or accompanied by various side effects even if the effects were excellent. Syringine, which is included as an active ingredient in the pharmaceutical composition for preventing or treating nicotine addiction and withdrawal symptoms of the present invention, has been known to have various effects in the past, but has the effect of reducing dependence, withdrawal symptoms, and sensitivity to nicotine. Nothing is known about. The present inventors completed the present invention after confirming that Syringine was not only significantly effective in reducing dependence, withdrawal symptoms, and sensitivity to nicotine, but also had minimal side effects.

The term “active ingredient” of the present invention refers to an ingredient that exhibits the desired activity alone or can exhibit activity together with an inactive carrier, and the activity reduces dependence, withdrawal symptoms, and sensitivity to nicotine. This ultimately means that nicotine addiction and withdrawal symptoms can be prevented or treated.

The term “nicotine dependence” in the present invention refers to the occurrence of acute or chronic physical and mental symptoms due to increased dependence on nicotine.

The term “withdrawal symptoms” in the present invention refers to physiological, cognitive, and functional maladaptive behavioral changes that occur when the use of a specific substance that has been used continuously and repeatedly is stopped, and the specific substance is included in cigarettes. Harmful ingredients such as nicotine, tar, 2-naphthylamine, and carbon monoxide may be present, especially nicotine. Typical withdrawal symptoms include insomnia, anxiety, fatigue, tension, nervousness, headache, cough, phlegm, and difficulty concentrating.

The term “prevention” in the present invention refers to any action that delays or suppresses nicotine addiction or withdrawal symptoms by administering the composition of the present invention to an individual.

The term “treatment” of the present invention refers to any action to relieve or improve nicotine addiction or withdrawal symptoms by administering the composition of the present invention to an individual.

In the pharmaceutical composition of the present invention, the content of syringine is not particularly limited, but may be included at 1 to 80% by weight, preferably 10 to 50% by weight, based on the total weight of the pharmaceutical composition. Dependence on nicotine, It may be included in an amount that can reduce withdrawal symptoms and sensitivity. If the content of syringine is less than the above range, it is undesirable because the effect of preventing or treating nicotine addiction and withdrawal symptoms is minimal, and if it exceeds the above range, it is undesirable from an economic standpoint because there is no synergistic effect relative to the content.

In the pharmaceutical composition of the present invention, the syringine can be administered in a therapeutically effective amount, and the term 'therapeutically effective amount' as used herein refers to an amount capable of preventing or treating nicotine addiction and withdrawal symptoms. do. The appropriate dosage may be applied differently depending on various factors and similar factors well known in the medical field, taking into account the patient's age, weight, general health, gender and diet, administration time, administration route, treatment period, etc. For a desirable effect, it may be administered at 1 mg/kg to 50 mg/kg, preferably at 1 mg/kg to 30 mg/kg, and more preferably at 10 mg/kg to 20 mg/kg, but is not limited thereto. . Administration may be administered once a day, or may be administered several times. The above dosage does not limit the scope of the present invention in any way.

The syringe or pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans through various routes. Administration may be oral or parenteral, such as oral, rectal, nasal, topical (including buccal and sublingual), subcutaneous, vaginal, intramuscular, It may be administered intraperitoneally or intravenously, but is not limited thereto.

In the pharmaceutical composition of the present invention, the pharmaceutical composition can be prepared in any dosage form commonly manufactured in the art, for example, granules, fine granules, powders, hard capsules, soft capsules, syrup, It can be formulated into pharmaceutical compositions for oral administration such as emulsions, suspensions, or solutions, and can be used as injections, drops, suppositories, transdermal absorbents, transmucosal absorbents, nasal drops, and nasal drops for intravenous, intramuscular, or subcutaneous administration. Now, it can be formulated into pharmaceutical compositions for parenteral administration such as eye drops, inhalants, creams, ointments, and patches. When formulated as a pharmaceutical composition in powder form, the prepared preparation can be dissolved at the time of use and used as an injection or mucus. Preferably, it may be formulated in one or more dosage forms selected from the group consisting of tablets, capsules, granules, and liquids.

The formulation of the pharmaceutical composition of the present invention can be prepared by mixing syringe with a binder, disintegrant, diluent, lubricant and pharmaceutically acceptable additives, such as polyvinyl pyrrolidone and gelatin. ), starch, sucrose, methyl cellulose, ethyl cellulose, hydroxypropylcellulose, hydroxypropylalkylcellulose, at least one binder selected from the group consisting of , Polyvinyl pyrrolidone, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, amylose, starch derivative, microcrystalline cellulose At least one disintegrant selected from the group consisting of microcrystalline cellulose, cellulose derivative, cyclodextrin and cyclodextrin derivative, lactose, dextrin, starch, At least one diluent selected from the group consisting of microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, saccharide, stearic acid, zinc stearate It may contain one or more lubricants selected from the group consisting of stearic acid zinc, stearic acid magnesium, stearic acid calcium, and talc, and the above-mentioned binder, disintegrant, In addition to diluents and lubricants, any ingredients conventionally used to formulate pharmaceutical compositions in various forms can be used.

According to another aspect of the present invention, the present invention provides a health functional food composition for preventing or improving nicotine addiction and withdrawal symptoms containing syringin as an active ingredient.

The term “improvement” in the present invention refers to any action that relieves or improves nicotine addiction or withdrawal symptoms by administering the composition of the present invention to an individual.

In the health functional food composition of the present invention, the content of syringine is not particularly limited, but may be included in an amount of 1 to 80% by weight, preferably 10 to 50% by weight, relative to the total weight of the health functional food composition. It can be included in amounts that can reduce dependence, withdrawal symptoms, and sensitivity. If the content of syringine is less than the above range, it is undesirable because the effect of preventing or improving nicotine addiction and withdrawal symptoms is minimal, and if it exceeds the above range, it is undesirable from an economic standpoint because there is no synergistic effect relative to the content.

In the composition for preventing or improving nicotine addiction and withdrawal symptoms of the present invention, the health functional food composition may have a formulation convenient for ingestion and use, and is preferably in the form of capsules, tablets, powders, granules, liquid, pills, or flakes. It is characterized in that it is one or more formulations selected from the group consisting of paste, syrup, gel, beverage, jelly, and bar. To prepare this formulation, conventional excipients, stabilizers, thickeners, etc. may be further included. In addition, food additives may be additionally included, and the suitability as a “food additive” is determined by the specifications and standards for the item in accordance with the general provisions and general test methods of the Food Additives Code approved by the Ministry of Food and Drug Safety, unless otherwise specified. It is decided by .

According to an experimental example of the present invention, as a result of confirming nicotine dependence according to syringine administration, the group administered only nicotine showed a preferential response to nicotine, whereas the group administered syringine and nicotine showed an aversive response to nicotine. This was confirmed (see Experimental Example 1 and FIG. 1). In addition, as a result of confirming the effect of syringine administration on withdrawal symptoms, it was confirmed that withdrawal symptoms significantly increased in the group administered only nicotine, while withdrawal symptoms significantly decreased in the group administered syringine and nicotine (Experimental Example 2 and Figure 2 reference). In addition, as a result of confirming the sensitization response according to syringine administration, the sensitization response tended to be normalized in the group administered syringine compared to the group administered nicotine (see Experimental Example 3 and FIG. 3). These results suggest that the composition containing syringine according to the present invention can prevent, improve, and treat nicotine addiction and withdrawal symptoms by reducing dependence, withdrawal symptoms, and sensitivity to nicotine.

As described above, the composition containing syringine according to the present invention is excellent in reducing dependence, withdrawal symptoms, and sensitivity to nicotine, and thus can prevent, improve, or treat nicotine addiction and withdrawal symptoms.

Figure 1 shows the results of the conditioned location preference test (SAL; normal control, SAL/NIC+; negative control, EB10/NIC+; syringe treatment group 1, EB20/NIC+; syringe treatment group 2).
Figure 2 shows the results of withdrawal symptom evaluation (SAL; normal control, SAL/NIC+; negative control, EB10/NIC+; syringine treatment group 1, EB20/NIC+; syringine treatment group 2).
Figure 3 shows the results of sensitization evaluation (SAL; normal control, SAL/NIC+; negative control, EB10/NIC+; syringine treatment group 1, EB20/NIC+; syringine treatment group 2).

Hereinafter, the present invention will be described in more detail through examples. Since these examples are merely for illustrating the present invention, the scope of the present invention is not to be construed as limited by these examples.

Example: Preparation of syringin

Purchased syringine (Career Henan Chemical) was dissolved in physiological saline and 10 mL of each concentration (0 to 20 mg/kg) was prepared.

Experimental Example 1: Conditional location preference experiment

In order to confirm the effectiveness of syringine prepared in the above example in preventing or treating nicotine addiction, a conditioned place preference test was conducted in a biased manner.

1) Preparation of experimental animals

ICR mice 7 weeks old were purchased, stabilized for a week, and then used in the experiment. Mice were classified into four groups as shown in Table 1 below, and five mice were used in each group.

classification Administration material and method normal control Intraperitoneal saline administration negative control Nicotine 0.5 mg/kg intraperitoneal administration Syringe treatment group 1 After administering 10 mg of syringine intraperitoneally, administer 0.5 mg/kg nicotine intraperitoneally. Syringin treatment group 2 After administering 20 mg of syringine intraperitoneally, administer 0.5 mg/kg nicotine intraperitoneally.

2) Experimental equipment

It consists of two boxes with different patterns and textures, and there is a door in the middle of the two boxes.

3) Administration conditions for each conditioning session (syringe treatment group)

(1) Pre-conditioning stage

The pre-conditioning stage was to adapt the mouse to the environment. The door in the middle of the two boxes was opened every 15 minutes for 2 days to allow the mouse to move freely. On the third day, the time spent in each box was recorded (reference value) to determine the preferred space of the experimental animals.

(2) Conditioning step

The conditioning step was conducted for 30 minutes at a time for 11 days. On days 1, 3, 5, 7, 9, and 11, nicotine 0.5 mg/kg was administered 30 minutes after syringe administration and placed in the non-preferred space, and on days 2, 4, 6, 8, and 10, the vehicle was administered and placed in the preferred space. placed in

(3) Post-conditioning stage

On day 12, open the door between the two boxes, place the animals in the boxes without administering nicotine or vehicle, and measure the time they remain in each box for 15 minutes (test value).

The test was conducted according to the same steps as above for the normal control group and the negative control group, but in the conditioning step, saline solution was administered instead of syringe and nicotine was not administered to the normal control group, and in the case of the negative control group, nicotine was administered only. proceeded.

4) Results

This measured value was compared with the reference value measured in the pre-conditioning stage. The degree of dependence formation is calculated by subtracting the value before conditioning from the value after conditioning, and the CPP score is shown in Figure 1.

As a result, as shown in Figure 1, it was confirmed that the negative control group (nicotine administered) showed a nicotine preference response (increased dependence) due to the increased time spent in the place compared to the normal control group (untreated), and the syringe treated group ( Syringine administration) showed a nicotine aversion response (inhibition of dependence) as the time spent in place decreased compared to the normal control group (untreated).

Experimental Example 2: Withdrawal symptom evaluation

1) Preparation of experimental animals

ICR mice 7 weeks old were purchased, stabilized for a week, and then five mice per group were used in the experiment. The administration materials and methods for each group are shown in Table 1.

2) Experimental method

Syringine was administered to mice twice daily, in the morning and afternoon, for a week. Nicotine was administered intraperitoneally 30 minutes after syringine was administered intraperitoneally. Thirty-six hours after the last nicotine treatment, the number of behaviors such as head shaking, paw tremor, body shaking, and rearing were recorded for 20 minutes, and the results are shown in Figure 2.

The normal control group and the negative control group were tested in the same manner as above. However, in the normal control group, saline solution was administered instead of syringine and nicotine was not administered. In the case of the negative control group, only nicotine was administered.

3) Results

As a result, as shown in Figure 2, in the negative control group (nicotine administration), the number of abnormal behaviors due to nicotine cessation increased compared to the normal control group (untreated), whereas in the syringine treatment group (syringine administration), nicotine cessation occurred. It was confirmed that the number of abnormal behaviors was significantly reduced.

Experimental Example 3: Nicotine sensitization evaluation

1) Preparation of experimental animals

ICR mice 7 weeks old were purchased, stabilized for a week, and then five mice per group were used in the experiment. The administration materials and methods for each group are shown in Table 1.

2) Experimental method

Before starting the experiment, the distance the mice moved and the time they moved were measured and randomly divided into groups (D0). Test substances were administered every other day for 13 days according to the conditions in Table 1, and nicotine was administered 30 minutes after test substance administration. After the above administration, the drug was taken off for one week, and then the test substance was administered again. The behavior of the first day of administering the test substance and the day of re-administration after taking a drug break was analyzed to analyze the difference in distance moved and time moved, and the results are shown in Figure 3.

3) Results

As a result, as shown in Figure 3, it was confirmed that the sensitivity phenomenon that was significantly high in the negative control group (nicotine administration) was normalized in the syringine treatment group (syringine administration).

Claims (7)

A pharmaceutical composition for preventing or treating nicotine addiction and withdrawal symptoms containing syringin as an active ingredient.
According to paragraph 1,
A pharmaceutical composition for preventing or treating nicotine addiction and withdrawal symptoms, wherein the syringine is contained in an amount of 10 to 50% by weight based on the total weight of the pharmaceutical composition.
According to paragraph 1,
A pharmaceutical composition for preventing or treating nicotine addiction and withdrawal symptoms, wherein the dosage of syringine is 1 mg/kg to 30 mg/kg.
According to paragraph 1,
The pharmaceutical composition is formulated in one or more dosage forms selected from the group consisting of tablets, capsules, granules, and liquids. A pharmaceutical composition for preventing or treating nicotine addiction and withdrawal symptoms.
A health functional food composition for preventing or improving nicotine addiction and withdrawal symptoms containing syringin as an active ingredient.
According to clause 5,
A health functional food composition for preventing or improving nicotine addiction and withdrawal symptoms, wherein the syringine is contained in an amount of 10 to 50% by weight based on the total weight of the health functional food composition.
According to clause 5,
The health functional food composition is one or more dosage forms selected from the group consisting of capsules, tablets, powders, granules, liquids, pills, flakes, pastes, syrups, gels, beverages, jellies, and bars, for nicotine addiction and withdrawal symptoms. Health functional food composition for prevention or improvement.