TWI599371B - Use of pharmaceutical composition for manufacturing drug of treating betel quid use disorder - Google Patents

Description

Pharmaceutical composition for the treatment of betel nut use disorders Drug use

The present invention relates to the use of a pharmaceutical composition, and more particularly to the use of a pharmaceutical composition for the manufacture of a medicament for the treatment of a betel nut use disorder.

According to the records of the Chinese Medical Pharmacopoeia, betel nut has the effect of boosting the spirit, killing insects, eliminating phlegm, qi, and water, and can treat insects, food stagnation, bloating, malaria, swelling, athlete's foot and sputum. Illness. Therefore, betel nut is the favorite of the aristocrats in the Qing Dynasty. In the summer, eating betel nuts can cool down the heat, and eating betel nuts in winter can warm the body and even refresh the mind and improve attention.

However, many studies have pointed out today that the euphoria, happiness, dependence, increased saliva and palpitations caused by repeated and continuous chewing of betel nut will cause the psychology of chewing betel nuts to produce material cravings. Produces physical dependence or tolerance and cannot be stopped. Therefore, betel nut is currently ranked fourth in the world in terms of caffeine, alcohol and nicotine. The psychotropic and psychoactive substances, the "betel nut" in the ingredients and the added "lime" are carcinogenic.

Most oral cancer patients in Taiwan have the habit of chewing betel nut, the ratio is about 90%, which shows that the betel nut is closely related to oral cancer, and according to the statistics of the top ten cancer deaths in the 103 years of the Ministry of Health, the incidence and mortality of oral cancer It is the fifth largest cancer among Taiwanese men, and more than 2,700 people die of oral cancer every year. In addition, because chewing people are used to chewing betel nut between the gums and buccal mucosa, making cheek mucosal cancer and gingival cancer in Taiwan account for more than half of oral cancer, but buccal mucosa and gingival cancer The incidence in the non-chewing betel nut area is quite low, highlighting the harmfulness of betel nut.

However, clinically relevant treatments for the use of betel nut are quite rare. In a large-scale long-term follow-up study in India, interventions were conducted through oral examinations and health education, and it was found that the withdrawal of the experimental group or the control group in the past ten years was found. The rate is only 15% at most, and the effect is limited. In other words, the use of betel nut has been unsuccessful in the past, and no effective withdrawal pathways have been identified. The side effects such as sleep disorders, emotional instability, and anxiety have made the betel nut's treatment path more difficult.

In view of the above, it is an aspect of the present invention to provide a pharmaceutical composition for the preparation of a medicament for treating a betel nut use disorder, the pharmaceutical composition comprising at least an effective dose of an antidepressant.

The anti-depressant is a monoamine oxidase inhibitor according to the use of the aforementioned pharmaceutical composition for the preparation of a medicament for treating a betel nut use disorder.

The use of the aforementioned pharmaceutical composition for the preparation of a medicament for the treatment of a betel nut use disorder, wherein the effective dose is from 300 mg to 600 mg per day.

The use of the aforementioned pharmaceutical composition for the preparation of a medicament for the treatment of a betel nut use disorder, wherein the antidepressant is a selective serotonin reuptake inhibitor.

The use according to the aforementioned pharmaceutical composition for the preparation of a medicament for treating a betel nut use disorder, wherein the effective dose is 5 mg to 20 mg per day.

The anti-depressant is a tricyclic antidepressant according to the use of the aforementioned pharmaceutical composition for the preparation of a medicament for treating a betel nut use disorder.

The use according to the aforementioned pharmaceutical composition for the preparation of a medicament for treating a betel nut use disorder, wherein the aforementioned pharmaceutical composition is administered at a frequency of 1 to 3 times per day for 3 to 12 weeks.

The use of the aforementioned pharmaceutical composition for the preparation of a medicament for treating a betel nut use disorder, wherein the aforementioned pharmaceutical composition is a dosage form for oral administration.

The use according to the aforementioned pharmaceutical composition for the preparation of a medicament for treating a betel nut use disorder, wherein the pharmaceutical composition is in the form of a solution, a suspension, an emulsion, a powder, a lozenge, a pill, a syrup, a buccal tablet, a tablet, and a mouth. Chew gum, thick paste or capsules.

The use of the aforementioned pharmaceutical composition for the preparation of a medicament for the treatment of a betel nut use disorder, wherein the aforementioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent or excipient.

Thereby, the pharmaceutical composition of the invention can effectively reduce the having a betel 榔 The use of betel nut in patients with dysregulation, which indirectly reduces the incidence of oral cancer.

The Summary of the Invention is intended to provide a simplified summary of the present disclosure in order to provide a basic understanding of the disclosure. This Summary is not an extensive overview of the disclosure, and is not intended to be an

S100, S102, S104, S106‧‧‧ steps

The above and other objects, features, advantages and experimental examples of the present invention will become more apparent and understood. The description of the drawings is as follows: Figure 1 shows the antidepressant for mice in Test Example 1 of the present invention. a flow chart of the method for affecting the use of betel nut; FIG. 2 is a diagram showing the amount of drinking water for adding the betel nut component to the mice before the use of the antidepressant in Test Example 1 of the present invention and after using the antidepressant for 4 weeks; 3 is a graph showing the amount of drinking water in which the mice were fed with the betel nut component before the use of the antidepressant in Test Example 1 of the present invention and after 4 weeks of use of the antidepressant.

As mentioned above, betel nut is an important risk factor for oral cancer. In Taiwan, oral cancer is the fifth largest cancer and its incidence is increasing year by year. In addition, the prevalence rate of male betel nut in Taiwan is about 10.7% to 16.4%. , so how to reduce the use of betel nut, and indirectly reduce the mouth The incidence of luminal cancer has become an extremely urgent issue in the new generation.

Accordingly, one aspect of the present invention is to provide a pharmaceutical composition for use in the manufacture of a medicament for treating a betel nut use disorder, the pharmaceutical composition comprising at least an effective amount of an antidepressant. The antidepressant may be a monoamine oxidase inhibitor, a selective serum reuptake inhibitor or a tricyclic antidepressant.

At this time, when the aforementioned anti-depressant is a monoamine oxidase inhibitor, the effective dose is 300 mg to 600 mg per day. When the aforementioned anti-depressant is a selective serotonin reuptake inhibitor, the effective dose is 5 mg to 20 mg per day. Further, the aforementioned pharmaceutical composition is administered at a frequency of 1 to 3 times per day for 3 to 12 weeks.

Specifically, the correlation between the antidepressant and the occurrence of oral cancer can be firstly performed by an epidemiological analysis method, and the present invention further determines the results and effects of the aforementioned epidemiological analysis by reducing the betel nut usage pattern of the animal. Finally, patients with betel nut use disorders are identified by oral examinations or health education in health clinics such as family medicine/oral surgery, and effective drugs are developed to assist in the use of betel nut disregard, thereby reducing the incidence of oral cancer.

Firstly, the use of epidemiological analysis methods to explore the relationship between antidepressants and oral cancer is based on the evaluation of two million people from the Health and Welfare Center for Health Value Added Application Collaboration Center from 1999 to 2008. The process description is as follows. The 89-year personal attribute file compiled from the Statistics Department of the Department of Health and Welfare will be used as the sampling parent after the repeated data, unclear gender, unclear birthday, age illogical, and unidentified areas are excluded. Next, each profile is stratified by gender, age, and region. The gender is divided into 2 layers for men and women, year The age is divided into 20 layers, and every 5 years old to 85 years old or older, but under 5 years old, subdivided into 28 days, 28 days to 1 year and 1 to 5 years old, and the area is divided into 6 by the health insurance branch. Floor. Therefore, the aforementioned number of layers is a total of 240 layers (i.e., 2 times 20 times 6). Next, calculate the proportion of each layer in the matrix, and then calculate how many people in each layer will be used as the number of samples for the layer. The number of samples of the layer is extracted in each layer, and the sampling method is random sampling.

Then, from the two million people, the people with the drug information older than 18 years old (about 857,541 people) were screened, and a nested case-control (NCC) study was established to exclude oral cancer. After using about 1492 people with antidepressants, follow the health insurance information to the diagnosis of oral cancer (about 5103 people) or until the end of 2008, and use the age, gender and place of residence to match about 20,412 people in a ratio of 1:4. In the control group, the conditional logistic regression model was used to estimate the odds ratio (OR) between antidepressants and oral cancer. The odds ratio can be used to predict the use of antidepressants. The relationship between the odds of having oral cancer and the odds of having oral cancer in those who do not use antidepressants. As for the estimation of the odds ratio, the following formula can be used to calculate with the following formula: odds ratio = [(A/A+C)/(C/A+C)]/[(B/B+D)/(D/B +D)], where A represents the number of people who have antidepressants and have oral cancer, B represents the number of people who have not used antidepressants but have oral cancer, and C represents the number of people who use antidepressants and do not have oral cancer. D represents the number of people who have not used antidepressants or oral cancer.

Table 1 Statistics of cases and control groups

In addition, a prospective cohort study was conducted for a case (about 95,452 people) who did not have oral cancer and started receiving at least one antidepressant within one year, followed for 10 years and utilized the Cox proportional hazard model (Cox The proportional hazard model) calculates the hazard ratio of oral cancer and estimates the treatment effect. When the hazard ratio is equal to 1, it means that the treatment effect between the case and the control group is not much different. When the hazard ratio is greater than 1, the rate of oral cancer in the anti-depressant is greater than that in the anti-depressant. A value of less than 1 indicates that the rate of oral cancer occurrence using an antidepressant is less than that of an antidepressant.

Please refer to Table 2, Table 2 for the use of overlapping case-control studies and prospective generation studies to assess the association between antidepressants and oral cancer, in which antidepressants are used in comparison to those who do not use antidepressants. The odds ratio for cancer is 0.53 (95% confidence interval is 0.48-0.70), which means that the use of antidepressants is less likely to develop oral cancer than those without antidepressants.

Next, it is subdivided into a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor and a tricyclic antidepressant according to the type of antidepressant. The odds ratio for the use of monoamine oxidase inhibitors relative to those who did not use monoamine oxidase inhibitors was 0.51 (95% confidence interval 0.22-1.19), and the use of selective serotonin reuptake inhibitors was relative to unused The odds ratio for selective serotonin reuptake inhibitors was 0.61 (95% confidence interval) 0.53-0.70), and the odds ratio for those who used tricyclic antidepressants compared to those who did not use tricyclic antidepressants was 0.57 (95% confidence interval 0.52-0.63). That is to say, the use of any of the three anti-depressants described above is less likely to cause oral cancer than without the user.

In addition, from the hazard ratio, the hazard ratio estimated by using a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor or a tricyclic antidepressant is less than 1, that is, using an antidepressant The rate of oral cancer is lower than those who do not use antidepressants. It can be seen that whether using overlapping case-control studies or prospective generation studies, antidepressants can reduce the risk of developing oral cancer.

Accordingly, the following specific test examples further demonstrate that the use of antidepressants to reduce the incidence of oral cancer is associated with a reduction in the use of betel nut by antidepressants, which is beneficial to those of ordinary skill in the art to which the present invention pertains. The present invention is to be fully utilized and practiced in the context of the present invention and should not be construed as limiting the scope of the invention. How to implement the materials, methods and uses of the present invention.

<Test example> Test Example 1: Effect of antidepressants on the use of mouse betel nut

Please refer to FIG. 1. FIG. 1 is a flow chart showing a method for performing the effect of antidepressant on the use of mouse betel nut in Test Example 1 of the present invention, which comprises steps S100, S102, S104 and S106.

As shown in the figure, the test example 1 of the present invention is carried out in four stages in accordance with steps S100 to S106. First, the first stage is to perform mouse training on betel nut dependence, as shown in step S100. Specifically, in the first stage, all the mice that grew up to 5 weeks were weighed and confirmed physiological indexes, and then divided into an experimental group (30 rats) and a control group (5 rats), wherein the control group was given normal drinking water, and the experiment was performed. The mice in the group were also given water, but unlike the control group, the mice in the experimental group were added with 1000 μg/ml of areca nut material and 100 to 500 μg/ml of lime. In the test example, the betel nut component is obtained by first grinding betel nut, extracting and extracting the extract, and the mouse is a C57BL/6 pure strain mouse, but the present invention does not intend to This is limited. In addition, the first phase of training lasted for 4 weeks, and the above mice were weighed weekly and observed for water intake.

Next, as shown in step S102, the second stage is a betel nut dependence test of the mouse. The so-called betel nut dependence tendency is defined as the fact that when the drinking water is freely selected, the amount of drinking water of the betel nut component in the mouse is greater than the amount of drinking water without the betel nut component. mouse. So after 4 weeks in the first phase, take untreated drinks The mice were selected with water and drinking water supplemented with betel nut ingredients, and a group of mice having a betel nut dependence tendency was selected.

The third stage is as shown in step S104, which is an experiment for reducing the tendency of the betel nut dependence of mice with an antidepressant. In detail, in the third stage, the mice selected in the second stage were weighed and confirmed physiological indexes, and then randomly divided into three groups. Specifically, the first group was a placebo group to which betel nut ingredients were added to drinking water. The betel nut component may be, for example, 1000 μg/ml of betel nut and 100 to 500 μg/ml of lime, but the concentration is only a test example, and the present invention is not intended to be limited thereto.

The second group of drinking water was supplemented with betel nut ingredients and an antidepressant at a concentration of about 0.25 mg/ml. Specifically, the betel nut component in the second group may be the same as the betel nut substance composition and concentration in the first group, and the concentration of the antidepressant may be 0.1875 mg/ml to 0.315 mg/ml, and the present invention is not intended to This is limited. In addition, the antidepressant in the second group may be a monoamine oxidase inhibitor such as Moclobemide. It must be noted that in the test example 1, the betel nut ingredient was still added to the drinking water, and the method was to reduce the withdrawal to avoid the withdrawal symptoms that may occur when the patient was immediately quit.

The third group of drinking water was added with betel nut ingredients and an antidepressant at a concentration of about 0.15 mg/ml to the drinking water of the mice. Specifically, the areca nut component in the third group may be the same as the betel nut substance composition and concentration in the first group, and the antidepressant concentration may be in the range of 0.1125 mg/ml to 0.875 mg/ml, and the present invention is not intended to This is limited. In addition, the antidepressant in the third group can be a selective serotonin reuptake inhibitor, such as Liepeng (Lexapro). In addition, the third phase lasted for 4 weeks, and it was observed that the amount of drinking water per day of the mice was about 3 ml to 5 ml.

Finally, as shown in step S106, the test of the betel nut dependence tendency of the mouse is again performed in the fourth stage. Specifically, after 4 weeks in the third stage, the mice were also given the choice of untreated drinking water and drinking water supplemented with betel nut ingredients, and whether the betel nut dependence tendency of the mice was changed due to the administration of the antidepressant. .

Please refer to Fig. 2 and Fig. 3, and Fig. 2 and Fig. 3 are diagrams showing the consumption of the betel nut in the mice before the use of the antidepressant in the test example 1 of the present invention and the use of the antidepressant for 4 weeks. The amount of water, in which the amount of drinking water refers to the average weekly drinking water. As shown in Figure 2, compared to the first group (placebo group), the second group (treated with a monoamine oxidase inhibitor) and the third group (treated with a selective serum reuptake inhibitor) There was a statistically significant decrease in the amount of drinking water that rats had when they added betel nut. Further, the changes after 4 weeks of treatment were observed from Fig. 3, and the mice of the second group (the second group-1 to the second group = 5) and the third group (the third group - 1 to the third group = 9) were both Significantly, the use of betel nut decreased, while the first group (group 1 - 1 to group 1 = 5) showed an increase and decrease in the use of betel nut. In the second and third groups, mice treated with monoamine oxidase inhibitors had a 48% reduction in the use of betel nut, and the use of betel nut in mice treated with selective serum reuptake inhibitors. The drop was 30%, but the mice in the first group differed by only 5% between the 4 weeks before and after. It can be seen that antidepressants such as monoamine oxidase inhibitors and selective serum reuptake inhibitors can indeed reduce the dependence of mice on betel nut.

Test Example 2: Effect of antidepressants on the use of betel nut

After confirming the correlation and the effect, the present invention further discovers that there are betel nut use disorders in the oral examination/teaching of the health check-up clinics such as family medicine/oral surgery, and develops effective drugs to assist the betel nut use disorder.

As in Test Example 1, the subject was also administered with at least one antidepressant such as a monoamine oxidase inhibitor, a selective serotonin reuptake inhibitor or a tricyclic antidepressant in Test Example 2. Among them, when the antidepressant is a monoamine oxidase inhibitor, it can be a pleasant solution, and its effective dose is 300 mg to 600 mg per day and is continuously administered for 8 to 12 weeks at a frequency of 2 to 3 times a day. Post evaluation of efficacy. Alternatively, when the antidepressant is a selective serum reuptake inhibitor, it may be Lexapro, and the effective dose is 5 mg to 20 mg per day and is administered continuously at a frequency of once a day. The efficacy was evaluated after 2 to 4 weeks. Alternatively, when the antidepressant is a tricyclic antidepressant, it may be Imipramine, and the effective dose is 25 mg to 50 mg per day and is administered continuously at a frequency of once a day. The efficacy was evaluated after 4 weeks.

At this time, please refer to Table 3, which shows the use of areca nuts before and after the use of antidepressants. As shown in Table 3, subjects with a betel nut use disorder ate about 23.3 ± 20.5 betel nuts per day before receiving antidepressant treatment, and the frequency of use was 5.9 ± 2.1 times per day, but in the anti-dosing After the treatment of depression, the amount of betel nut used and the frequency of use were significantly reduced.

According to the above Test Example 1 and Test Example 2, the present invention can provide a pharmaceutical composition for preparing a medicament for treating a betel nut use disorder, and for the various possibilities of administration of a subject and the convenience in the treatment process, the foregoing The pharmaceutical composition is a dosage form for oral administration such as a solution, suspension, emulsion, powder, lozenge, pill, syrup, buccal tablet, tablet, chewing gum, thick paste or capsule. Furthermore, the aforementioned pharmaceutical compositions may also comprise a pharmaceutically acceptable carrier, diluent or excipient.

In summary, based on the correlation between the antidepressant and the occurrence of oral cancer, the present invention provides a pharmaceutical composition for the preparation of a medicament for treating a betel nut use disorder, which can effectively reduce the betel nut of a patient having a betel nut use disorder. The amount of use indirectly reduces the incidence of oral cancer.

Although the present invention has been disclosed in the above embodiments, it is not intended to limit the present invention, and the present invention can be modified and modified without departing from the spirit and scope of the present invention. The scope is subject to the definition of the scope of the patent application attached.

S100, S102, S104, S106‧‧‧ steps

Claims (6)

A pharmaceutical composition for the manufacture of a medicament for the treatment of a betel nut use disorder, wherein the pharmaceutical composition comprises at least an effective amount of an antidepressant and the antidepressant is a selective serotonin reuptake inhibitor. The use of a pharmaceutical composition according to claim 1 for the preparation of a medicament for treating a betel nut use disorder, wherein the effective dose is 5 mg to 20 mg per day. The use of the pharmaceutical composition according to claim 1 for the preparation of a medicament for treating a betel nut use disorder, wherein the pharmaceutical composition is administered at a frequency of 1 to 3 times per day for 3 to 12 weeks. Use of the pharmaceutical composition according to claim 1 for the preparation of a medicament for treating a betel nut use disorder, wherein the pharmaceutical composition is a dosage form for oral administration. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is used for the preparation of a medicament for treating a betel nut use disorder, wherein the dosage form is a solution, a suspension, an emulsion, a powder, a tablet, a pill, a syrup, an ingot, and a tablet. Agent, chewing gum, thick paste or capsule. The use of the pharmaceutical composition according to claim 1 for the preparation of a medicament for treating a betel nut use disorder, wherein the pharmaceutical group The composition further comprises a pharmaceutically acceptable carrier, diluent or excipient.