CN1261111C - A preparation method of oral medicine for treating depression - Google Patents

Abstract

The invention relates to a Jinyukang oral medicine for treating depression, which is extracted from the effective part of hypericum perforatum and is characterized in that: wherein the content of Hypericin and pseudohypericin is 0.15-48%, the content of rutin is 2.3-4%, the content of total flavone is 50-90%, and the content of Hyperforin is 2-46%. The oral preparation comprises tablets, capsules, powder and oral liquid. Can be directly extracted from herba Hyperici perforati, or further refined from the crude extract of herba Hyperici perforati.

Description

A preparation method of oral medicine for treating depression

Technical field

The invention relates to an oral medicine for treating depression—Jinyukang, which belongs to the technical field of international patent classification drug preparation A61K35/78.

Background technique

Depression is one of the major diseases in today's society. With the intensification of various stress factors, such as the accelerated pace of people's life, the aging population, and the intensified social competition, depression has become a common disease in modern society, with a high incidence and its incidence is increasing rapidly. According to statistics, the world's depressed patients account for 3% to 5% of the world's population.

With the popularization of depression and the improvement of people's living standards and the improvement of the quality of life requirements, depression has attracted more and more people's attention. The medical expenses for the treatment of depression have also increased sharply. At the same time, this type of drug has a huge market. Therefore, the development of new, efficient, broad-spectrum, and low-toxic antidepressants has become one of the hot spots of research and development by companies in various countries. According to statistics, the total sales of the global CNS drug market in 1997 was 26 billion US dollars, with an annual growth rate of 12%. There are as many as 16 CNS drugs with sales exceeding US$200 million. The sales of the antidepressant market were 3 billion US dollars in 1995 and 6 billion US dollars in 1998. The top three are fluoxetine (US$2.356 billion), sertraline (US$1.337 billion), and parkinoxetine (US$1.101 billion), all of which are antidepressants. The development of new broad-spectrum, high-efficiency, and low-toxic antidepressants is one of the hot spots that pharmaceutical companies all over the world pay attention to.

There are five main categories of antidepressant drugs in the world: selective serotonin reuptake inhibitors (SSRTS), norepinephrine and specific serotonin reuptake inhibitors (NASSAS), tricyclic antidepressants (TCAS), monoamine oxidase inhibitors (MAOT) and serotonin and norepinephrine reuptake inhibitors (SNARI). The classic antidepressant is tricyclic antidepressant (TCA), which has definite curative effect and low price, and has been in a dominant position clinically for decades. However, due to its anticholinergic effect and toxicity to the heart, it is difficult for some patients and the elderly to accept it. Tetracyclic antidepressants have been partially improved on the basis of TCA, but the effect is not very satisfactory. Serotonin reuptake inhibitors (SSRI) overcome the shortcomings of TCA, and have been widely used abroad because of its high efficiency, safety and good tolerance. It is characterized by few and mild side effects, and some drugs basically have no anticholinergic effect and cardiotoxicity. And the method of administration is simple, you only need to take it sequentially every day, and the vast majority of patients basically do not need to adjust the dosage, so it is easy to be accepted by patients. However, SSRI preparations are mostly monopolized by foreign or joint venture pharmaceutical companies, and the price is relatively expensive. There are some disadvantages in the above medicines, such as single mechanism of action, high price, large side effects, and high incidence, such as affecting heart function, sexual function, dry mouth, constipation, etc., which have seriously affected the popularization and use of these medicines.

Modern pathological studies have shown that the pathogenesis of depression is very complicated, and there are many causes. Drugs targeting a single link are often difficult to achieve satisfactory curative effect. Most synthetic antidepressants have defects such as narrow antidepressant spectrum, large side effects, high drug price and easy relapse. Therefore, more and more attention has been paid to the utilization of botanical resources in the research and development of antidepressants at home and abroad. Among them, the treatment of Hypericum perforatum for depression has attracted great attention all over the world.

The research status of commonly used antidepressants is as follows: 1. Classical antidepressants, the representative drugs include imipramine, desipramine and amitriptyline. Its pharmacological action is characterized by blocking the reabsorption of monoamine neurotransmitters in the brain, and at the same time, it has different degrees of anticholinergic side effects and cardiotoxicity on the M-cholinergic and adrenergic nervous systems in the brain. To reduce side effects and reduce toxicity. Several non-tricyclic antidepressants appeared in the 1970s, such as maprotiline and miraminoserin, but the toxic and side effects have not been completely overcome; 2. Selective serotonin reuptake inhibitors, typical drugs include fluoxetine Sertraline, Paroxetine, Sertraline, and Siptidelan. Its pharmacological feature is to specifically block the reabsorption of serotonin, and has a very low affinity to other neurotransmitter receptors in the brain, which is less toxic and side effects than tricyclics, but still has certain side effects. 3. Monoamine oxidase inhibitors are effective drugs for the treatment of depression discovered in the 1950s. These drugs are non-selective inhibitors with many side effects and high toxicity. Cyclopropylamine, etc., are used with extreme caution in clinical practice.

In view of the toxic side effects and shortcomings of the above-mentioned western medicine preparations, there are currently many studies on extracting antidepressant substances from herbal medicines. Chinese herbal medicines are rich in resources in our country and are a promising field.

Hypericum perforatum is widely used as herbal medicine and food additive in Europe and the United States respectively. Hypericum perforatum is a perennial herb that grows in Europe and Asia. It has been used clinically for thousands of years in Europe, mainly for trauma, diuresis, and peripheral neuralgia. It has been used for centuries to treat depression.

Hypericum perforatum has been studied in depth abroad, and its resources, pharmacy, pharmacology, toxicology, and clinical application have been basically clarified. The research progress is as follows:

1. Research on active ingredients The main antidepressant active ingredients of this plant are benzodanthrones (including hypericin, pseudohypericin, etc.), flavonoids (hyperin, rutin, quercetin, isoquercetin, etc.), phloroglucinol (hyperforin, pseudohyperforin) three categories. It is generally believed that hypericin, pseudohypericin, hypericin and certain flavonoids are the active ingredients for the treatment of depression, which is the result of the joint action of these ingredients.

2. Research on the mechanism of action is generally believed to be through the inhibition of MAO enzymes, the inhibition of 5-HT, DA, and NA reuptake, and the comprehensive effects of increasing 5-HT, DA, and NA in the brain.

3. Clinical efficacy and safety Hypericum perforatum crude extract 900mg has the same curative effect on mild and moderate depression as tricyclics and fluoxetine, and the incidence of side effects is significantly lower and milder than the latter, and the most common reaction is gastrointestinal symptoms (0.8), photosensitivity reaction (0.5), the occurrence rate of side effects was 19.8%, and the occurrence rate of side effects of common antidepressants was 35.9%, mainly manifested as abnormal cardiac function, abnormal sexual function and dry mouth.

4. Dosage form, quality control, and stability research Some pharmaceutical companies are speeding up the development of this plant as a prescription drug, and widely use the crude extract of Hypericum perforatum L. to treat mental depression. As a psychotropic drug, it is the result of modern Western research. The preparations used to treat depression in the European and American markets have been made into "standard extracts" - crude extracts of Hypericum perforatum, only specifying that the total hypericin content is 0.3% (HPLC method). Made into capsules and tablets with stable quality. The dosage is 300mg, tid. However, in some patents or preparations, in the preparation process, only the content of total hypericin (not including hyperforin) or only the content of hypericin is considered, and the requirements for the content of flavonoids are not clear enough.

The development of Hypericum perforatum has also attracted the attention of some domestic units. Hypericum perforatum is widely distributed in our country. It has been a kind of Chinese herbal medicine since ancient times. According to statistics, dozens of research papers on Hypericum perforatum have been published in China, which mainly focus on basic research on the distribution of resources, processing, processing and content of Hypericum perforatum in China, as well as extraction methods and analysis methods. In recent years, due to the large demand abroad, many domestic manufacturers mostly export crude extracts and produce them cheaply in the form of extracts.

Patent PCT/DE96/02444 proposes "a mixture consisting of one or several polycyclic diketones, selected from Hypericin, Pesudohypericin and their salts, with a concentration between 0.05% and 50%, and composed of another or Several other ingredients, with concentrations ranging from 50% to 99.95%, are derived from bioflavonoids (such as quercetin), flavonoid glycosides, phytic acids, hyperforin, tannins, lutein, fats and Wax, etc. The quality standard is similar to ours, but the requirements for the content of hypericin are vague, and the claim of the patent is to "treat a disease caused by a virus, especially a degenerative virus ", not for the treatment of depression.

Contents of the invention

The object of the present invention is to provide a new preparation for the treatment of mental depression, Jinyukang, which is more refined than the crude extract of Hypericum perforatum proposed by this patent.

Technical scheme of the present invention is as follows:

The Jinyukang oral medicine for treating depression extracted from the effective parts of Hypericum perforatum is characterized in that: the total content of hypericin (Hypericin) and pseudohypericin (Pesudohypericin) contained therein is 0.15-48%, The content of rutin is 2.3-4%, the content of total flavonoids is 50-90%, and the content of hyperforin is 2-46%.

Oral preparations include tablets, capsules, powders and oral liquids.

The effective parts of the Hypericum perforatum can be directly extracted from the Hypericum perforatum, or further refined from the crude extract of the Hypericum perforatum.

The crude extract of Hypericum perforatum refers to the mixture that is directly extracted from the original medicinal material of Hypericum perforatum by extraction with about 70% ethanol, spray drying method, or supercritical CO2 extraction. In addition to the active ingredients, it contains pigments and High sugar content.

Studies on the effects on the central nervous system, through animal experiments, prove that Jin Yukang is effective. It has a certain effect on the mental activity of animals, can enhance the exploration behavior of mice, prolongs the sleep time of hypnotics in a dose-dependent manner, and has an anti-reserpine effect within a certain dose range. Similar to most antidepressants, it can enhance the wheel activity of mice, and continuous administration can reduce the aggressive behavior of male mice, suggesting that it may be effective for mild and moderate depression. We have completed the mouse tail suspension and rat swimming tests for the efficacy of Jinyukang. The result is as follows:

Pharmacodynamic experiments were carried out according to the pharmacological guidelines of new drugs (western medicine part) and the instructions for pharmacological experiments on antidepressants. Tail suspension in mice and forced swimming experiments in rats have been completed.

Mouse tail suspension test: choose 16~20g male Kunming mice. One hour after the last administration, the mice were hung upside down in the experimental box, with the head 5 cm high from the bottom, and the time of hanging upside down was 6 minutes, and the immobility time of the mice within 4 minutes was observed.

The positive control drug is desipramine

The results show that: drug Dose (mg/kg) Immobility time (S) no CMC-Na 85.6±29.8 15 DMI 20 60.7±29.4* 14 Test drug 1 70.5±35.0 15 2 74.1±38.7 14 3 72.6±34.9 15 4 61.2±27.2* 13

Note: The dose of the test drug is gradually increased from 1 to 4, *P<0.05 compared with the control group

Rat forced swimming test: select 130-150g Wistar rats, put the rats into a glass cylinder with a diameter of 20cm and a height of 40cm, one for each cylinder. Control the water temperature and depth. On the day before the experiment, each rat swam for 15 minutes, and tested 24 hours later: the rats were put into the tank, observed for 5 minutes, and the immobility time in the water was accumulated. (stop struggling, be in floating state, only have occasional limb movement to keep the duration of phenomena such as head floating on the water surface) positive control drug is amitriptyline.

The results show: drug Dose (mg/kg) Immobility time (S) no CMC-Na 68.0±35.3 9 Amitriptyline 20 8.60±18.3** 10 Test drug 1 28.1±33.9* 10 2 36.2±31.6 10 3 21.0±13.2** 9 4 9.10±9.8** 9

Note: The dose of the test drug is gradually increased from 1 to 4, *P<0.05 compared with the control group **P<0.01

Conclusion: The test drug showed obvious antidepressant activity in these two experiments, which has the significance of further development.

At present, the study of rat olfactory bulb extraction and chronic depression model, and the determination of single 5-MT, DA, NA and MAO in the brain are being carried out at the same time.

Detailed ways

Hypericum perforatum was extracted three times. For the first time, add 10 times the amount of 55% ethanol, soak at room temperature for 12 hours, reflux for 2 hours, filter, add 6 times the amount of 55% ethanol for the second time, reflux for 1 hour, filter, and add 6 times the amount for the third time. Double the amount of 55% ethanol to reflux for 1 hour, filter, combine the filtrates three times, recover the ethanol, concentrate to a relative density of 1.35 (50-60°C), dry under reduced pressure (50-60°C), and pulverize through a 80-100 mesh sieve. Hypericum perforatum crude extract.

The crude extract of Hypericum perforatum was extracted twice, firstly add 20 times of 15% ethanol at 60°C and stir for 30 minutes, then centrifuge the extract (3000 rpm) for 25 minutes, add 10 times of 15% ethanol for the second time, 60 Stir and extract at ℃ for 20 minutes, centrifuge for 25 minutes, combine the secondary supernatant, mix well, pass through the D-101 macroporous adsorption resin column, stop loading the sample after the resin is saturated, and pass through the column with distilled water until the effluent is clear (water 4-5 times the volume of the resin), elute with 70% ethanol, collect the eluate, recover the ethanol and concentrate to a relative density of 1.35 (50-60°C) and dry under reduced pressure (50-55°C, vacuum degree: 0.09- 0.1Mpa), pulverize, and pass through a 80-100 mesh sieve to obtain the effective part of Hypericum perforatum.

Take 300g of effective parts of Hypericum perforatum, add 4.5g of antioxidant (medicinal vitamin C powder), 6.0g of glidant (micronized silica gel), mix well, pack into capsules, and obtain 1000 tablets of Jinyukang.

Claims (1)

1, a kind of preparation method for the treatment of the depression medicine is characterized in that the step of this method is as follows:

Get the Herba Hyperici perforati medicinal material extract three times, add 10 times of amount 55% ethanol for the first time, soaking at room temperature refluxed 2 hours after 12 hours, filtered; Add for the second time 6 times of amount 55% alcohol refluxs 1 hour, filter; Add 6 times of amount 55% alcohol refluxs 1 hour for the third time, filter; Merge three times filtrate, reclaim ethanol, be concentrated into 50-60 ℃ of relative density 1.35,50-60 ℃ of drying under reduced pressure pulverized, and crosses the 80-100 mesh sieve, promptly gets the Herba Hyperici perforati crude extract;

The Herba Hyperici perforati crude extract extracts secondary, adds 20 times of amount 15% ethanol for the first time and stirs extraction 30 minutes for 60 ℃, and 3000 rev/mins of extracting solution are centrifugal 25 minutes; Add for the second time 10 times of amount 15% ethanol, 60 ℃ are stirred extraction 20 minutes, centrifugal 25 minutes; Merge the secondary supernatant, mixing is crossed the D-101 macroporous adsorptive resins, stop after resin absorption is saturated going up sample, cross post, till the effluent clarification with distilled water, water consumption is 4-5 a times of resin volume, uses 70% ethanol elution, collects eluent, reclaim ethanol and be concentrated into 50-60 ℃ of relative density 1.35, at 50-55 ℃, drying under reduced pressure under the vacuum 0.09-0.1Mpa condition is pulverized, cross the 80-100 mesh sieve, promptly get Herba Hyperici perforati effective site;

Get Herba Hyperici perforati effective site 300g, add the medicinal vitamin c powder 4.5g of antioxidant, fluidizer micropowder silica gel 6.0g, mixing, encapsulated, get 1000 of capsules.