TWI453027B - Pharmaceutical having jujuba cyclic adenosine monophosphate as main component for use to treat depression - Google Patents

Description

The main functional ingredient is jujube cyclic adenosine monophosphate as a medicine for treating depression

The invention relates to a medicine or health food for treating depression caused by jujube cyclic adenosine monophosphate (jujube cAMP). The invention also relates to a preparation method of a medicament for treating depression or a health food prepared by using jujube cAMP as a raw material.

Depression is a common disease. According to statistics, about 25% of women in the general population have experienced depression during their lifetime, and about 10% of men have experienced depression (Zhang Chunxing: Modern Psychology). According to the World Health Organization (WHO), the incidence of depression in the world is about 11%. At present, there are about 3.4 people with mental depression in the world, and this number is still on the rise. The survey found that in the next 20 years, depression It will rise to the second most common disease in the world.

In the prior art, antidepressants are mainly caused by Prozac, Celote, Zoloft, etc. (SSHT, SNRI, NDRI, etc. 5HT, NE, DA reuptake inhibitors), and the mechanism of action is by increasing human nerves. The content of serotonin and other components in the medium alleviate the symptoms of depression.

However, these drugs have varying degrees of side effects, such as: increased suicide rate, headache, dizziness, dizziness, insomnia, lethargy, tinnitus, dry mouth, anorexia, increased appetite, weight gain, increased blood pressure, gastrointestinal discomfort, nausea, nausea , vomiting, indigestion, diarrhea, constipation, lower limb pain, skin rash, trembling, cramps, excessive sweating, edema, decreased libido, sexual incompetence, etc. In recent years, anti-depressant drugs such as Prozac have become a serious concern in the society. The US Food and Drug Administration (FDA) in 2004 requested pharmaceutical companies to relabel the main 32 anti-depressants on the market. Part of its side effects and warnings, and stressing to medical staff that these drugs may increase the chances of suicide in children and adolescents. Among them, Selot was found to have potential safety hazards as early as 1996, and has been recalled from the market since 2001. In June 2004, the US Attorney General of New York accused the British GlaxoSmithKline of fraudulently concealing a study related to the use of Celote and “increasing the risk of suicidal tendencies and behavior among adolescents” in order to make a profit. In this context, how to develop and produce a new generation of drugs with low side effects and significant anti-depression effects has become a concern of the global pharmaceutical community.

As a result of the job, the Applicant, based on the lack of knowledge in the prior art, was carefully researched and explored, and a spirit of perseverance, and finally conceived the anti-depressant drug made from jujube cAMP. Its method of production, the following is a brief description of the case.

In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a medicine or health food for treating depression caused by a raw material containing jujube cAMP, in particular, a new technical solution which does not have many side effects of conventional antidepressant drugs. .

Another object of the present invention is to provide a method for preparing a medicament or a health food for treating depression, which is prepared from a raw material containing jujube cAMP.

The solution of the medicament of the present invention is the result of investigation and exploration by our people, combined with modern medical and pharmacological theories, especially in combination with adenylate cyclase (AC)-cyclic adenosine monophosphate (cAMP) signaling pathway. , cAMP-induced transcription process and other research directions, the traditional Chinese medicine for the treatment of depression has been deeply studied, after a large number of animal experiments prove that jujube cAMP as an exogenous non-hydrolyzable cAMP can participate in the metabolism of cAMP in the body, The analogous hormone action makes the intracellular cAMP content increase, which plays an anti-depressant effect. Jujube cAMP is extracted from the fruit jujube that is eaten daily. In the long-term clinical use of traditional Chinese medicine for long-term daily consumption and as a medicinal material, there is no adverse reaction to the side effects of anti-depressant drugs caused by taking jujube. The inventor extracted the jujube of the jujube cAMP with a very small content (about one ten thousandth), and further purified the jujube water extract into a jujube extract containing 1% jujube cAMP, and then tested it. The results of the depressive animal test showed that the jujube water extract with obvious anti-experimental depression function and no further purification of jujube cAMP concentration, although containing a trace amount of jujube cAMP, was tested at a conventional drug dose. In the experimental study of sexual depression, there is no obvious anti-experimental depression function. Therefore, the inventors proposed a new technical solution for treating depression drugs by using jujube cAMP as a raw material to improve the deficiency caused by the prior art.

Jujube cAMP: "Source": The dried ripe fruit of the Z. sylvestris zizyphus jujuba Mill.

"Synonym": 3', 5'-cyclic adenosine, 3', 5'-cyclic phosphate.

"English name": Cyclic adenosine-3', 5'-monophosphate

"Molecular formula and relative molecular weight": C ₁₀ H ₁₃ N ₅ O ₆ P. H ₂ O, 347.23.

"Biological activity": The activity of cAMP-like substances in jujube is very similar to that of cAMP. As an exogenous non-hydrolyzable cAMP, it can act like an analogous hormone to increase intracellular cAMP content.

The present invention discloses an oral drug for treating depression, which is made from a raw material including jujube cAMP.

Preferably, the oral medicament of the present invention can be processed into any pharmacy such as a tablet, a capsule, a powder, a tablet, a powder, a solution, a microcapsule, a suspension, an emulsion, a granule, a pill, a pill, and the like. Oral pharmaceutical dosage forms are well known.

Preferably, the dosage form of the oral medicine of the present invention taken once a day is prepared from a raw material comprising 0.003 to 0.3 mg of jujube cAMP; preferably, it is a raw material containing 0.01 to 0.25 mg of jujube cAMP. production.

Preferably, the dosage form of the oral medicine of the present invention taken twice a day is made of a raw material comprising 0.002 to 0.2 mg of jujube cAMP; preferably, it is a raw material containing 0.005 to 0.12 mg of jujube cAMP. Made.

Preferably, the dosage form of the oral drug of the present invention taken three times a day is made of a raw material comprising 0.001 to 0.1 mg of jujube cAMP; preferably, it is a raw material containing 0.003 to 0.08 mg of jujube cAMP. production.

Preferably, the dosage form of the oral medicine of the present invention taken four times a day is made from a raw material comprising 0.0008 to 0.06 mg of jujube cAMP; preferably, it is a raw material containing 0.002 to 0.04 mg of jujube cAMP. Made.

According to another concept of the present invention, the present invention discloses a method for preparing an oral medicament for treating depression, which comprises pulverizing jujube and adding water at room temperature, and then extracting by water extraction and alcohol precipitation to obtain jujube extract. Then, the macroporous resin OU-2 and ME-2 are successively adsorbed and separated by two columns, and dried to obtain the jujube extract containing the jujube cAMP of the present invention.

Preferably, the oral medicament of the present invention comprises a pharmaceutically acceptable carrier or additive.

Preferably, the oral medicament of the present invention further comprises a health food and a nutrient.

The oral drug and the preparation method for treating depression as described in the specification and the scope of the present invention are the core contents for achieving the object of the present invention. After the disclosure of the present invention, those skilled in the art can according to the theory of traditional Chinese medicine or According to the modern pharmacology theory, the above drugs are routinely flavored or replaced with other traditional Chinese medicine active ingredients with the same efficacy. Such conventional flavoring and replacement of other traditional Chinese medicines having the same or the same mechanism of action or corresponding active ingredients are common technical activities of those skilled in the art and are therefore within the scope of protection of the present invention. Inside.

The invention will be better understood by reference to the drawings and detailed description.

The invention will be further illustrated by the following figures and examples. The present invention is primarily directed to the preparation of the medicaments of the present invention using methods well known to those skilled in the art in conjunction with the features of the present invention. The following examples are for illustrative purposes only and are not intended to limit the invention.

In order to accomplish the object of the present invention, the present invention particularly proposes the following technical solutions.

Scheme 1: The raw material containing jujube cAMP is processed to prepare an oral medicament for treating depression in the present invention.

Scheme 2: processing the raw material containing jujube cAMP into a tablet, a capsule, a powder, a tablet, a powder, a solution, a microcapsule, a suspension, an emulsion, a granule, and the like for treating depression Any of the pharmaceutically acceptable oral pharmaceutical dosage forms such as pills, pills, and the like.

Scheme 3: a medicine containing 0.003 to 0.3 mg of jujube cAMP is prepared into a dosage form of the present invention once a day; more preferably, it is prepared from a raw material containing 0.01 to 0.25 mg of jujube cAMP. A single dosage form of the medicament of the invention.

Scheme 4: a medicine containing 0.002 to 0.2 mg of jujube cAMP, which is prepared into a dosage form of the present invention twice daily; more preferably, it is made from a raw material containing 0.005 to 0.12 mg of jujube cAMP. A second dosage form of the medicament of the invention is administered.

Scheme 5: a medicine containing 0.001 to 0.1 mg of jujube cAMP is prepared into a dosage form of the present invention which is administered three times a day; more preferably, it is prepared from a raw material containing 0.003 to 0.08 mg of jujube cAMP. Three doses of the medicament of the invention.

Scheme 6: The preparation of the invention is prepared by using a raw material containing 0.0008 to 0.06 mg of jujube cAMP in a dosage form of four times a day; more preferably, it is made from a raw material containing 0.002 to 0.04 mg of jujube cAMP. The drug of the present invention is administered in a dosage form four times.

Scheme 7: The jujube is crushed, then added with water to soak at room temperature, and then extracted by water extraction and alcohol precipitation method to obtain jujube extract. The extract is then continuously adsorbed on the column with macroporous resin OU-2 and ME-2. Separation and drying were carried out to obtain a jujube extract containing a high concentration of jujube cAMP as a raw material for preparing the medicament of the present invention.

Scheme 8: The oral medicament of the present invention may contain a pharmaceutically acceptable carrier or additive.

Scheme 9: The oral medication of the present invention can also be used to make health foods and nutrients.

In order to accomplish the object of the present invention, the following methods for producing the following drugs are proposed.

Method 1: According to the Good Manufacturing Practice (GMP) pharmaceutical standard method, the raw material containing jujube cAMP is processed and prepared into an oral medicine for treating depression.

Method 2: According to the GMP pharmaceutical standard method, the raw material containing jujube cAMP is processed into a tablet, a capsule, a powder, a tablet, a powder, a solution, a microcapsule, and a suspension for treating depression in the present invention. Oral pharmaceutical dosage forms well known in the art, such as agents, emulsions, granules, pills, pills, and the like.

Method 3: According to the GMP pharmaceutical standard method, the raw material containing 0.003~0.3 mg jujube cAMP is prepared into the dosage form of the present invention once daily; more preferably, it is composed of 0.01 to 0.25 mg jujube cAMP. The raw material is prepared into a medicament of the present invention in a dosage form which is administered once a day.

Method 4: According to the GMP pharmaceutical standard method, the raw material containing 0.002~0.2 mg jujube cAMP is prepared into the dosage form of the invention for taking the dosage twice a day; more preferably, it is composed of 0.005~0.12 mg jujube cAMP. The raw material of the present invention is prepared into a dosage form of the present invention which is administered twice daily.

Method 5: According to the GMP pharmaceutical standard method, a raw material containing 0.001 to 0.1 mg of jujube cAMP is prepared into a dosage form of the present invention which is administered three times a day; more preferably, it is composed of 0.003 to 0.08 mg of jujube cAMP. The starting material is prepared into a medicament of the present invention in a dosage form which is administered three times a day.

Method 6: According to the GMP pharmaceutical standard method, a raw material containing 0.0008 to 0.06 mg of jujube cAMP is prepared into a dosage form of the present invention which is administered four times a day; more preferably, it contains 0.002 to 0.04 mg of jujube cAMP. The raw material of the present invention is prepared into a dosage form of the present invention which is administered four times a day.

Method 7: According to the GMP pharmaceutical standard method, the jujube is crushed, soaked with water at room temperature, and then extracted by water extraction and alcohol precipitation method to obtain jujube extract, and then the macroporous resin OU-2 and ME-2 are successively successively. The upper column is adsorbed and separated, and dried to obtain a jujube extract containing a high concentration of jujube cAMP as a raw material for preparing the medicament of the present invention.

Method 8: According to the GMP pharmaceutical standard method, the jujube extract containing jujube cAMP and a pharmaceutically acceptable carrier or additive are used as the oral medicament for treating depression in the present invention.

Method 9: The raw material according to the present invention is processed into a health food for treating depression according to the method for producing and manufacturing a health food.

Specific embodiment

The invention will be further described below in conjunction with the drawings and specific embodiments.

Embodiment 1 Please refer to the first figure, which is a schematic flow chart of a method for preparing the drug of Example 1 of the present invention. In the first figure, according to the GMP pharmaceutical standard method, 30 g of jujube extract containing 1% jujube cAMP is prepared as raw material, and 270 g of starch, lactose, cerium oxide, magnesium stearate is added. The excipients and excipients are processed into a 10,000 tablet dosage form (30 mg/granule containing 0.03 mg of jujube cAMP) for the oral or health food for treating depression.

Embodiment 2 Please refer to the second figure, which is a schematic flow chart of a method for preparing the drug of Example 2 of the present invention. In the second figure, according to the GMP pharmaceutical standard method, 30 g of jujube extract containing 1% jujube cAMP has been prepared as raw material, plus 420 g of starch, lactose, cerium oxide, magnesium stearate. The excipients and excipients are processed into a 15,000 tablet dosage form (30 mg/granule containing 0.02 mg of jujube cAMP) for the oral or health food for treating depression.

Embodiment 3 Please refer to the third figure, which is a schematic flow chart of a method for preparing the drug of Example 3 of the present invention. In the third figure, according to the GMP pharmaceutical standard method, 50 g of jujube extract containing 1% jujube cAMP is prepared as raw material, plus 250 g of starch, lactose, cerium oxide, magnesium stearate. The excipients and excipients are processed into a 10,000 tablet dosage form (30 mg/granule containing 0.05 mg of jujube cAMP) for the oral or health food for treating depression.

Embodiment 4 Please refer to the fourth figure, which is a schematic flow chart of a method for preparing the drug of Example 4 of the present invention. In the fourth figure, according to the GMP pharmaceutical standard method, 30 g of jujube extract containing 1% jujube cAMP has been prepared as raw material, plus 210 g of starch, lactose, cerium oxide, magnesium stearate. The excipients and excipients were processed into a 12,000 tablet dosage form (20 mg/granule containing 0.25 mg of jujube cAMP) for the oral or health food for treating depression.

Embodiment 5 Please refer to the fifth figure, which is a schematic flow chart of a method for preparing the drug of Example 5 of the present invention. In the fifth figure, according to the GMP pharmaceutical standard method, 17 g of jujube extract containing 1% jujube cAMP has been prepared as raw material, plus 183 g of starch, lactose, cerium oxide, magnesium stearate. The excipients and excipients are processed into a 10,000 tablet dosage form (20 mg/granule containing 0.17 mg of jujube cAMP) for the oral or health food for treating depression.

Embodiment 6 Please refer to the sixth figure, which is a schematic flow chart of a method for preparing the drug of Example 6 of the present invention. In the sixth figure, according to the GMP pharmaceutical standard method, 13 g of jujube extract containing 1% jujube cAMP is prepared as raw material, and 187 g of starch, lactose, cerium oxide, magnesium stearate is added. The excipients and excipients are processed into a 10,000 tablet dosage form (20 mg/granule containing 0.013 mg of jujube cAMP) for the oral or health food for treating depression.

Embodiment 7 Please refer to the seventh figure, which is a schematic flow chart of a method for preparing the drug of Example 7 of the present invention. According to the GMP pharmaceutical standard method, 10 kg of jujube is crushed, soaked in water at room temperature, and then extracted by water extraction and alcohol precipitation to obtain jujube extract, and then the extract is made of macroporous resin OU-2 and ME-2. The column is successively adsorbed and separated on the upper column and dried to obtain 30 g of jujube extract containing jujube cAMP, and the extract contains 1% (300 mg) of jujube cAMP by high performance liquid chromatography to prepare the present invention. Oral or health food for the treatment of depression.

Experimental example 1

Effect of Example 3 on Mouse Suspension Experiment 1.1 Experimental Animal ICR mice, male, weighing 22.0±2 g, secondary, provided by the Laboratory Animal Science Department of Beijing Capital Medical University.

1.2 Experimental Drugs Example 3: Provided by Beijing O'Neill Bioengineering Technology Co., Ltd.

Paroxetine (Selite): Sino-US Tianjin Shike Pharmaceutical Co., Ltd. products.

1.3 experimental instrument: stopwatch

1.4 Dose design Example 3 large dose: 5 mg / kg / d, medium dose: 2.5 mg / kg / d and small dose: 1.25 mg / kg / d.

1.5 Experimental methods and results 1.5.1 group administration The mice were randomly divided into groups of 10: Example 3 high dose group (5 mg / kg, PO, 7d administration); Example 3 medium dose group (2.5 mg / kg, PO, 7d administration); Example 3 low dose group (1.25 mg/kg, PO, 7d administration); Paroxetine group (3 mg/kg, PO, 7 days); Saline group (PO). A tail suspension experiment was performed 1 hour after the last administration.

1.5.2 Experimental method The mouse tail (1 c m from the tip of the tail) was suspended with a tape on a 5 c m wooden strip on a mountain table for 6 minutes, and the immobility time of the mouse within 5 minutes after recording was recorded.

1.5.3 statistical processing experimental data ± SD indicates that the experimental results were analyzed by SPSS 11.5 statistical software for analysis of variance.

1.5.4 Experimental Results Refer to Table 1 for the experimental results.

Conclusion: According to the above experiments, it can be seen that the large, medium-dose group and the paroxetine group of the present invention can reduce the immobility time after the tail suspension of the mouse, and there is a significant difference compared with the saline group (model group). Thus, it can be inferred that Example 3 of the present invention has an anti-experimental depression function.

Experimental example 2

Effect of Example 3 on forced swimming test in mice 2.1 Experimental animal ICR mice, male, weighing 22.0±2 g, secondary, provided by the Department of Laboratory Animal Science, Capital Medical University, Beijing.

2.2 Experimental Drugs Example 3: Provided by Beijing O'Neill Bioengineering Technology Co., Ltd.

Paroxetine (Selite): Sino-US Tianjin Shike Pharmaceutical Co., Ltd. products.

2.3 Experimental instrument stopwatch.

2.4 Dose design Example 3 large dose: 5 mg / kg / d, medium dose: 2.5 mg / kg / d, small dose: 1.25 mg / kg / d.

2.5 Experimental methods and results 2.5.1 Group administration The mice were randomly divided into groups of 10: Example 3 high dose group (5 mg / kg, PO, 7d administration); Example 3 medium dose group (2.5 mg / kg, PO, 7d administration); Example 3 low dose group (1.25 mg/kg, PO, 7d administration); Paroxetine group (3 mg/kg, PO, 7 days); Saline group (PO).

2.5.2 Experimental method One hour after the last administration of the mice, the mice were placed in a glass jar having a water depth of 10 cm and a diameter of 20 cm, and the water temperature was 25 ° C, and the cumulative time of the mice in the water was recorded for 5 minutes.

2.5.3 statistical processing experimental data ± SD indicates that the experimental results were analyzed by SPSS 11.5 statistical software for analysis of variance.

2.5.4 Experimental results Refer to Table 2 for the experimental results.

Conclusion: According to the above experiment, it can be seen that the high dose group and the paroxetine group of the present invention can significantly reduce the immobility time of forced swimming in mice, and thus it can be inferred that the third embodiment of the present invention has anti-experimental depression function.

The application range of the oral medicine for treating depression in the present invention: 1. The oral medicine for treating depression according to the present invention may contain a pharmaceutically acceptable additive; 2. The invention described in the present invention Oral drugs for treating depression can be processed into various conventional dosage forms such as powders, capsules, tablets, and the like; and 3. Oral drugs for treating depression according to the present invention can be used for treating depression. Health food.

This case has been modified by people who are familiar with this skill, but it is not to be protected as intended.

The first figure is a schematic flow chart of a method for preparing the drug of Example 1 of the present invention.

The second figure is a schematic flow chart of a method for preparing the drug of Example 2 of the present invention.

The third figure is a schematic flow chart of a method for preparing the drug of Example 3 of the present invention.

The fourth figure is a schematic flow chart of a method for preparing the drug of the fourth embodiment of the present invention.

The fifth figure is a schematic flow chart of a method for preparing the drug of Example 5 of the present invention.

Figure 6 is a schematic flow chart showing the process of preparing the drug of Example 6 of the present invention.

Figure 7 is a schematic flow chart showing the process of preparing the drug of Example 7 of the present invention.

Claims (14)

The utility model relates to a medicament for treating depression with a main functional component: jujube cyclic adenosine monophosphate, wherein the medicament is prepared by using 0.003~0.3 mg of the jujube cyclic adenosine monophosphate as raw material. One dose at a time. The use according to claim 1, wherein the dosage form is further prepared from the raw material containing 0.01 to 0.25 mg of the jujube cyclic adenosine monophosphate. The invention relates to a medicament for treating depression with a main functional ingredient: jujube cyclic adenosine monophosphate, wherein the medicament is prepared by using 0.002~0.2 mg of the jujube cyclic adenosine monophosphate as raw material. A second dosage form. The use according to claim 3, wherein the dosage form is further prepared from the raw material containing 0.005 to 0.12 mg of the jujube cyclic adenosine monophosphate. The invention relates to a medicament for treating depression with a main functional ingredient: jujube cyclic adenosine monophosphate, wherein the medicament is prepared by using 0.001 to 0.1 mg of the jujube cyclic adenosine monophosphate as a raw material. One dose of three doses. The use according to claim 5, wherein the dosage form is further prepared from the raw material containing 0.003 to 0.08 mg of the jujube cyclic adenosine monophosphate. The invention relates to a medicament for treating depression with a main functional ingredient: jujube cyclic adenosine monophosphate, wherein the medicament is prepared by using the jujube cyclic adenosine monophosphate containing 0.0008-0.06 mg as a raw material. One dose of four times. The use according to claim 7, wherein the dosage form is further prepared from the raw material containing 0.002 to 0.04 mg of the jujube cyclic adenosine monophosphate. The use according to any one of claims 1 to 8, wherein the raw material containing the jujube cyclic adenosine monophosphate is obtained by extracting jujube to obtain a first extract, and then purifying the first extract. Obtaining a second extract, wherein the concentration of the jujube ring adenosine monophosphate of the second extract is higher than the concentration of the jujube ring adenosine monophosphate of the first extract degree. The use according to any one of claims 1 to 8, wherein the dosage form comprises a tablet, a capsule, a powder, a tablet, a powder, a solution, a microcapsule, One of a suspension, an emulsion, a granule, a pill, a pill, and a pharmaceutically acceptable oral pharmaceutical dosage form. The use according to any one of claims 1 to 8, wherein the medicament comprises one selected from the group consisting of a pharmaceutically acceptable carrier, an additive, and a combination thereof. The use according to any one of claims 1 to 8, wherein the medicament is made into a health food or a nutrient. A method for preparing a medicament for treating depression comprises the steps of: (a) extracting jujube to obtain a first extract; and (b) adsorbing and separating the first colloidal resin OU-2 and ME-2, respectively. The extract obtains a second extract, wherein the concentration of the jujube cyclic adenosine monophosphate of the second extract is higher than the concentration of the jujube cyclic adenosine monophosphate of the first extract. A method for preparing jujube cycloadenosine monophosphate comprises the steps of: (a) extracting jujube to obtain a first extract; and (b) purifying the first extract to obtain a second extract, and the second The extract has a higher concentration of cyclic adenosine monophosphate than the first extract of jujube cyclic adenosine monophosphate, wherein step (b) selects one-hole resin OU-2 and one-hole resin ME-, respectively. 2 The upper column adsorbs and separates the jujube cyclic adenosine monophosphate in the first extract.