WO2006005219A1

WO2006005219A1 - A pharmaceutical composition for treating depression and the process for preparing the same

Info

Publication number: WO2006005219A1
Application number: PCT/CN2004/000551
Authority: WO
Inventors: Lixin Guo
Original assignee: Chengdu Kanghong Technology Enterprises (Group) Co., Ltd.
Priority date: 2004-05-27
Filing date: 2004-05-27
Publication date: 2006-01-19
Also published as: WO2006005219A8

Abstract

The present invention relates to a pharmaceutical composition for treating depression, which is prepared from forsythia fruit and acanthopanax bark. Meanwhile, a process for preparing the same is provided, mainly including steps of extracting forsythia fruit with alcohol and extracting acanthopanax bark with water, and producing the extracts into capsule or other solid dosage form.

Description

Antidepressant medicine and preparation method thereof

The present invention relates to a medicament for treating depression and a preparation method thereof. Specifically, the present invention provides an antidepressant medicine derived from a Chinese herbal medicine, having a low effective dose and a clear curative effect, and a preparation method of the medicament. technical background

Depression is a brain disease, a common disease in modern society. It is an emotional psychosis. It is characterized by low mood, distressed sadness, loss of appetite, insomnia, and fatigue. WHO survey analyzes the depression of the world's population. The rate is about 3%. In modern society, the disease has seriously affected people's work and quality of life. As social competition intensifies, the number of such patients will increase year by year. Although the etiology and pathophysiology of depression are not well understood, it does not prevent modern medicine from effectively treating this condition.

At present, most of the drugs for clinical treatment of depression at home and abroad are chemicals, such as selective serotonin (5-HT) reuptake inhibitors, tricyclic antidepressants, and tetracyclic antidepressants. The antidepressant is represented by imipramine, which replaces the first antidepressant monoamine oxidase inhibitor that was introduced in the 1950s. It has become the drug of choice for depression. It has been monopolized for 30 years, but the side effects of the drug are obvious. Patients are intolerable and difficult to achieve satisfactory results; currently selective serotonin (5-HT) reuptake inhibitors such as sulpiride, alprazolam, buspirone and methylphenidate, but these drugs The antidepressant effect is still controversial, and it is sometimes found in clinical treatment that it is limited by the patient's own condition (so-called contraindications). Therefore, people turn their attention to the anti-depression of traditional Chinese medicine. For example, Chinese patent CN1381242A discloses a traditional Chinese medicine for treating depression, which is composed of St. John's wort and Acanthopanax senticosus. Pharmacodynamic studies show that the drug has therapeutic effects on depression. However, the onset dose is higher and the efficacy may be uncertain at certain doses. Therefore, it is expected that a Chinese medicine antidepressant with less side effects and more remarkable effects can be developed. Summary of the invention

The invention provides a traditional Chinese medicine for treating depression, and a large number of experiments prove that the traditional Chinese medicine of the invention has the curative effect of treating depression, and has small toxic and side effects.

SUMMARY OF THE INVENTION The object of the present invention is to provide a pharmaceutical composition which is composed of a traditional Chinese medicine raw material, Hypericum perforatum L. and Wujijia, which can be used for the treatment of depression.

Another object of the present invention is to provide a medicament for treating depression, the active ingredient of which is mainly derived from the extract of the above traditional Chinese medicine, and the experiment proves that the therapeutic effect is obvious and the side effects are small.

It is also an object of the present invention to provide a method for preparing a medicament for treating depression as described above, which method comprises the steps of: extracting a hypericin and a water extracting thorn, and the method is practical and easy to handle.

The present invention provides a pharmaceutical composition comprising the following components by weight of a drug substance: Hypericum perforatum 51 - 65 %, thorn Wu Likou 35 - 49%; preferably: Hypericum perforatum 51-61%, Acanthopanax 39 - 49%.

The pharmaceutical composition can be processed into a pharmaceutical preparation of a suitable dosage form to obtain a natural medicine for treating depression.

The present invention also provides a medicament for treating depression, wherein the active ingredient in the medicine is an extract obtained by extracting the above-mentioned weight percentage of the raw material medicine, that is, the raw material medicine group used, including 51 - 65 % The Hypericum perforatum and 35-49% of Acanthopanax senticosus, and the active ingredient of the drug is mainly a mixture of the alcohol extract of the Hypericum perforatum raw material and the aqueous extract of the Acanthopanax raw material.

Meanwhile, the present invention also provides a method for preparing the above medicament, which comprises:

The Hypericum perforatum L. is extracted with at least 70% ethanol reflux at least once, and the reflux extraction time is at least 1 hour to prepare an extract having a relative density of about 1.10;

Acne medicinal herbs are boiled at least once with water to prepare an extract having a relative density of about 1.18; the two extracts are dried and mixed separately.

The above-mentioned antidepressant medicine provided by the invention is composed of pure Chinese medicine extract, has exact curative effect, small toxic and side effect, and is simple and easy to prepare, and is convenient for industrial production operation.

An antidepressant according to the present invention, wherein the alcohol extract of Hypericum perforatum can be The dried extract of Hypericum perforatum L. obtained by drying the ethanol extract of the raw material drug at a relative density of about 1.10; the water extract of the Acanthopanax senticosus can be dried when the aqueous extract of the raw material drug is at a relative density of about 1.18. The obtained Acanthopanax dry extract powder.

In a preferred embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable adjuvant comprising at least one of pregelatinized starch, talc, magnesium stearate, and the like, or a mixture thereof.

The drug is preferably a solid dosage form, and the capsule is more preferably a capsule because the capsule can improve the stability of the medicine, the production process is simple, and it is easy to mechanize the production.

Among the above drugs, the composition of the drug substance is preferably 51-61% by weight of Hypericum perforatum, 39-49% by weight of Acanthopanax senticosus; most preferably 54.55 % by weight of Hypericum perforatum L., and 45.45 % by weight of Acanthopanax senticosus.

The preparation method of the antidepressant according to the present invention further comprises drying the extract obtained by extracting the above two raw materials into dry extracts, and then uniformly mixing them into a capsule to prepare a capsule; After the two extracts are respectively dried to form a dry extract powder, one or more of an appropriate amount of pregelatinized starch, talc powder or magnesium stearate is uniformly mixed and filled into a plastic capsule. Other oral dosage forms such as tablets, granules and the like can also be prepared according to well-known pharmacy techniques.

The specific preparation method of the medicament of the present invention may be:

The extract of Hypericum perforatum L. and 70% ethanol is refluxed twice, the first time adding about 8-12 times the amount of ethanol, the second adding about 6-10 times the amount of ethanol, and extracting each time for 0.5 - 1.5 hours, combining the extracts, After filtration, the ethanol is recovered under reduced pressure, concentrated to an extract having a relative density of about 1.10, and spray-dried to obtain a dry extract powder; the acanthopanax medicinal material is pulverized into pieces, and about 6-10 times the amount of water is added, and decocted 3 times, each After 1.5-3 hours, the decoctions were combined, filtered, and the filtrate was concentrated to an extract having a relative density of about 1.18, and spray dried to obtain a dry extract powder.

If necessary, an appropriate amount of pregelatinized starch, talc, and magnesium stearate may be added and uniformly mixed, and the capsule may be added to form a capsule.

The invention has no special requirements for the raw material medicine used, but the Hypericum perforatum should comply with the relevant provisions of the current national drug standard under the Hypericum perforatum; Acanthopanax senticosus should comply with the current Chinese Pharmacopoeia under the acanthopanax senticosus Various regulations. The components of the above formulations can be prepared into a variety of pharmaceutical dosage forms suitable for use in patients using conventional techniques in the pharmaceutical industry.

The clinically recommended dose of the drug of the present invention is 1.0 to 2 g/day, preferably 1.2 g/day, based on the active ingredient, and can be divided into two daily use.

The medicament of the present invention has the following advantages:

1. Compared with similar antidepressant chemical drugs, it has the characteristics of low side effects and few contraindications.

2. After testing, the drug of the present invention has the following advantages compared with the anti-depressant of the same traditional Chinese medicine (for example, CN1381242A): a. The effective dose is significantly reduced; b. The dose-dependent effect is obvious, and the antidepressant effect is more accurate; c. The number of daily meals can be reduced while improving the therapeutic effect, and only takes twice a day.

3. The medicament of the invention can be prepared into a capsule or other solid oral preparation, and is convenient to take. Specific implementation

The invention is further described in detail below with reference to specific embodiments, which are not intended to limit the invention.

Pharmacodynamic study

The following test examples include pharmacodynamic comparison experiments of the drug obtained in Example 1 (hereinafter referred to as the drug of the present invention, the current trade name is Kai Yu Anzheng) and the CN1381242A drug (hereinafter referred to as A drug).

1. Rat forced swimming test

(1) Using the compulsive swimming test of the classical depression animal model rats to observe the effect of continuous oral administration of different doses of the medicament of the present invention on reducing the time (seconds) of forced swimming in rats, and evaluating the drug of the present invention and the drug A. The effect dose, antidepressant effect and the number of daily doses.

Test results: Rats were orally administered with a dose of 15.6 - 250 mg / kg of the present invention, administered twice at 24 hours before the test, compared with the solvent control group, 31.3 mg / kg, 62.5 mg / kg, 125 mg / kg group Significantly reduced immobility time was dosewise and statistically significant (P < 0.001, P < 0.01 and P < 0.05), and the positive control imipramine showed the same effect (Table 1). Table 1. Effect of oral administration of the drug of the present invention on the duration of forced swimming for 2 times/day

Immobility time (seconds) Drug dose (mg/kg) Route of administration Number of animals (n)

M + SD solvent control group Oral 15 108.8 ±30.5 Promethazine 10.0 Peritoneal injection 15 37.4 ±32.1 * * * Drug of the invention 15.6 Oral 15 90.5 ± 42.3

31.3 Oral 15 73.2 ±45.8*

62.5 Oral 15 65.7 ±35.4* *

125.0 Oral 15 58.9 ±36.2* * *

250.0 Oral 15 79.5 + 53.1 Comparison with the solvent control group: * P < 0.05; * *P<0.01; * * * P<0.001

(2) The same method A drug was forced to swim with the animal model of the stagnation animal. ^^ Results J3⁄4L 2.

Table 2. Effect of oral administration of A drug 3 times/day on forced swimming time

M±SD solvent control group orally 27 101.8 ±35.7 Promethazine ^p Qin 10.0 Peritoneal injection 13 36.4 ± 32.7 * *

A drug 15.6 oral 10 124.0 ± 59.3

31.3 Oral 16 89.2 + 56.3

62.5 Oral 16 70.3 ±41.2* *

125.0 Oral 16 73.3 Soil 48.4 *

250.0 Oral 16 89.5 ±53.1

500.0 Oral 13 93.95 ±47.4 Compared with the solvent control group: *P<0.05; * *P<0.01

The test results from Tables 1 and 2 can indicate:

(1) The drug of the present invention is orally administered twice a day, and the dose of compulsive swimming is significantly reduced at a dose of 31.3 mg/kg, and the drug A is orally administered three times a day, and can be significantly reduced at a dose of 62.5 mg/kg. The forced swimming in rats does not move for a long time, so the effective dose of the drug of the present invention is obviously lower than that of the A drug, and the number of sputum service is also less than that of the A drug;

(2) The drug of the present invention was orally administered twice a day, and the effects at doses of 31.3 mg/kg, 62.5 mg/kg, and 125 mg/leg were dose-dependent; while the effect of drug A at 62.5 mg/kg was better than that of A drug at 62.5 mg/kg. 125mg/kg, which is ineffective at doses of 250 mg/kg and 500 mg/kg, so The curative effect of the medicament of the invention for treating depression is more precise.

2. Mouse tail suspension test

(1) Using a mouse model of a typical animal model of dangling tail, observe the effect of continuous oral administration of different doses of the drug of the present invention on reducing the time of inactivity of the mouse (seconds), and evaluating the effect of the drug of the present invention and the drug A. The dose, antidepressant effect and number of daily doses are different.

Test results: The mice were orally administered with the drug of the invention at a dose of 31.3-250 mg/kg, once a day, 5 times in a row, 62.5 mg/kg, 125 mg/kg, 250 mg/kg. The time was significantly decreased in a dose-dependent manner, with statistical significance (P < 0.01 and P < 0.05) (see Table 3), and the positive control imipramine group also showed the same effect.

Table 3. Effect of oral administration of the drug of the present invention (1 time/day) on the time of suspension of the tail

Suspension time, drug dose (mg/kg), route of administration, number of animals (n)

(seconds) M + SD solvent control group Oral 15 107.7 soil 33.3 Propylene paint 10.0 Peritoneal injection 15 38.5 ±37.2* * * Drug of the invention 31.3 Oral 15 97.2 ± 35.2

62.5 Oral 15 85.6 ±24.2*

125.0 Oral 15 80.4 Earth 32.6 *

250.0 Oral 15 73.5 + 36.0 * * Compared with the control group: *P<0.05; * * P<0.01; * * *P< 0.001

(2) The same method A test results of the drug in the mouse tail suspension classic depression animal model are shown in Table 4.

Table 4. Effect of oral administration of A drug (2 times/day) in mice for 7 times on the time of suspension

(seconds) M±SD solvent control group Oral 28 111.7 ±34.3 imipramine 10.0 peritoneal injection 17 52.5 ±33.2* * deamimazine 10.0 peritoneal injection 16 69.8 + 33.8 * *

A drug 62.5 oral 16 101.3 ± 32.2

125.0 Oral 16 86.6 soil 24.2 * *

250.0 Oral 16 101.4 ±46.2

500.0 Oral 16 116.7 ± 38.0 Compared with the control group: * *p<o.01 The experimental results from Tables 3 and 4 can indicate:

(1) The drug of the present invention is orally administered once a day for 5 times, and the time of 62.5 mg/kg is significantly reduced, and the A drug needs to be taken orally twice a day for 7 times. In order to reduce the time of suspension of mice in the dose of 125 mg / kg, the effective dose of the drug of the invention is obviously lower than that of the drug A. The number of daily clothes is also less than that of the A drug.

(2) The drug of the present invention is administered once a day for 5 times. The effect at 62.5 mg/kg, 125 mg/kg, 250 mg/kg is dose-dependent; while drug A is only 125 mg / kg. It has an effect at the dose and is ineffective at the dose of 250 mg/kg and 500 mg/kg, so the curative effect of the medicament of the present invention for treating depression is more precise.

3, anti-living blood level eyelid face droop depression model test

In order to further prove the curative effect of the medicament of the present invention for treating depression, a model test for anti-Reserpine sag depression was also carried out, and the mice of the mice were observed to be at least closed by continuous oral administration of different doses of the medicament of the present invention. More than half of the animals. The antidepressant effect of the medicament of the present invention was evaluated. The test results are shown in Table 5.

Table 5. Effect of the drug of the present invention once/day on the drooping of the eye caused by reserpine in the group Group Dose X times The number of mice The eyelids are at least half closed

(mg/kg X c ) (only) number of animals (only) normal control group equal volume distilled water 10 0

Depression model group Equal volume distilled water 10 10

Chlorpromazine hydrochloride, Qin tablets group 10x5 10 5 * * * Venlafaxine hydrochloride capsule 30x5 10 ^ * * *

The drug group of the present invention 62.5 X 5 10 5 * * * The drug group of the present invention 125 x 5 10 ^ * * * The drug group of the present invention 250x 5 10 7 * * Note: Each administration group is compared with the depression model group: * *P< 0.01; * * * P < 0.001

Table 5 shows that 62.5 mg/kg, 125 mg/kg, 250 mg/kg of the drug of the present invention was taken once a day, and after 5 consecutive administrations, reserpine caused a significant antagonistic effect on the drooping of the eyelids in mice, and in three The dose was dose-dependent, demonstrating that the drug of the invention has an antidepressant effect. Toxicology research

The following test drug is the drug of the present invention obtained by the method of Example 1, and its trade name is Kaiyu Anjing, which is equivalent to the original drug l lg per gram.

1. Animal acute toxicity test:

The 30% thick liquid of Kaiyu Anshen Ginger Powder was given to the mice twice a day for 6 hours, 0.4ml/10g body weight. The mice were observed to have no death on the 7th day, and the maximum tolerance of the mice to the drug was known. It is 24g/kg - d.

Conclusion: The LD _5Q >24g/kg . d of Kai Yu Anzhen capsule is about 1200 times the amount of human, which indicates that the drug is low in toxicity to mice.

2. Animal long-term toxicity test:

Kaiyu Anshen capsules powder 3.3, 1.9, 0.95g / kg (equivalent to 164, 95, 47 times the clinical dose, respectively), continuous intragastric rats for 90 days, animal behavior, appearance signs, feed consumption and There was no significant effect on weight gain and peripheral blood levels. There were no significant differences in blood biochemical tests between the 10 indicators and the control group (P>0.05). There were no visible lesions in all major organs. The main organ coefficients were not significantly different from those in the control group (P > 0.05). Histopathological examination showed no abnormalities in the main organs of each animal.

Conclusion: The dosage of Kaiyu Anshen capsule powder of 3.3, 1.9, 0.95g/kg for 90 consecutive days did not cause toxic reaction in animals; 3.3g/kg dose was administered continuously for 90 days, the main organs of rats There is no obvious pathological effect on the tissue.

Example 1

API: St. Hypericum 1800g Acanthopanax 1500g

Prepare into a capsule according to the following method: Weigh the two formulas of the above formula, wherein the Hypericum perforatum and 70% ethanol are refluxed twice, the first time adding 10 times of ethanol, the second adding 8 times of ethanol, each The mixture was extracted under reflux for 1 hour, and the extracts were combined, filtered, and the ethanol was recovered under reduced pressure. The mixture was concentrated to a relative density of 1.10, and spray dried to obtain a dry extract powder; the acanthopanax medicinal material was pulverized into pieces, and 8 times the amount of water was added. Dilute 3 times, each time for 2 hours, combine the decoction, filter, and concentrate the filtrate to a relative density of 1.18. Spray dry to dry the extract powder to fill the capsule.

It is also possible to take the above two kinds of extracts, and add an appropriate amount of pre-gelatinized starch, talc powder, magnesium stearate and the like to be uniformly mixed and put into a plastic capsule.

The above capsule contains 0.36 g/grain of the above-mentioned Hypericum perforatum and Acanthopanax senticosus extract, and is recommended to be taken twice a day, 2 capsules each time.

Example 2

API: Hypericum perforatum 52% Acanthopanax 48%

The preparation method was the same as in Example 1 to prepare a capsule.

Example 3

API: Hypericum perforatum 62% Acanthopanax 38%

The preparation method was the same as in Example 1.

Example 4

API: Hypericum perforatum 65 % Acanthopanax 35 %

The preparation method was the same as in Example 1 to prepare a capsule.

Example 5

API: Hypericum perforatum 51% Acanthopanax 49%

The preparation method was the same as in Example 1 to prepare a capsule.

Claims

Rights request

A pharmaceutical composition characterized in that the composition of the drug substance is: Hypericum perforatum 51 - 65 % by weight, and 5% by weight of glutinous rice.

The pharmaceutical composition according to claim 1, wherein the drug substance composition is 51-61% by weight of Hypericum perforatum L., and 39-49% by weight of Acanthopanax senticosus.

A medicament for treating depression, wherein the active ingredient is a mixture of the Hypericum perforatum extract obtained from the pharmaceutical composition according to claim 1 and the aqueous extract of Acanthopanax senticosus.

The drug according to claim 3, wherein the alcohol extract of Hypericum perforatum L. is a dry extract of Hypericum perforatum obtained by drying the ethanol extract of the drug substance at a relative density of about 1.10; The water extract is an extract of Acanthopanax senticosus extract obtained by drying the aqueous extract of the drug substance at a relative density of about 1.18.

The medicament according to claim 3 or 4, which further comprises a pharmaceutically acceptable adjuvant.

6. The medicament of claim 3 which is a solid dosage form.

7. The medicament of claim 6 which is a capsule.

8. The medicament according to claim 7, wherein the pharmaceutic adjuvant is at least one of pregelatinized starch, talc and magnesium stearate or a mixture thereof.

9. The medicament according to claim 3, wherein the pharmaceutical composition of the pharmaceutical composition is 51-61% by weight of Hypericum perforatum, 39-49% by weight of Acanthopanax.

10. The medicament according to claim 9, wherein the pharmaceutical composition of the pharmaceutical composition is 54.55 % by weight of Hypericum perforatum L., and 45.45 % by weight of Acanthopanax senticosus.

11. A method of preparing a medicament according to claim 3, comprising:

The extract of Hypericum perforatum L. is refluxed with 70% ethanol at least once, and the reflux extraction time is at least 1 hour to prepare an extract having a relative density of about 1.10;

12. The preparation method according to claim 11, wherein the two extracts are separately dried to dry dipping After the powder is mixed, it is evenly mixed into the capsule.

13. The preparation method according to claim 11, wherein the two extracts are respectively dried to form a dry extract powder, and then one or more of a proper amount of pregelatinized starch, talc powder or magnesium stearate is uniformly mixed and filled into the gel. Hey.

The preparation method according to claim 11, wherein the Hypericum perforatum is refluxed with 70% ethanol for 2 times, the first time is added with 8-12 times of ethanol, and the second time is added with 6-10 times of ethanol, each time refluxing. After extracting for 0.5-1.5 hours, the extracts are combined, concentrated to a relative density of about 1.10, dried to obtain a dry extract powder; Acanthopanax senticols are crushed into pieces, 6-10 times the amount of water, and decocted 3 times, each 1.5-3 hours, combine the decoction, concentrate to the extract with a relative density of about 1.18, dry to dry