AU2018101247A4 - Application of persimmon leaf extract in the preparation of medicines for the treatment of primary insomnia - Google Patents
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Abstract
The present invention relates to the application of persimmon leaf extract in the preparation of medicines for the treatment of primary insomnia, especially the difficulty falling asleep. Each dose of persimmon leaf extract can increase the number of mice that fall asleep under the threshold dose of pentobarbital sodium in a dose-dependent manner, shorten the sleep latency induced by the upper threshold dose of pentobarbital sodium in a dose-dependent manner and extend the duration of sleep induced by the upper threshold dose of pentobarbital sodium. The persimmon leaf extract has good compliance and safety in the treatment of primary insomnia with low effective dose.
Description
Application of persimmon leaf extract in the preparation of medicines for the treatment of primary insomnia
Technical field
The present invention belongs to the field of medicine and pharmacy, and specifically relates to a new medical use of persimmon leaf extract.
Background Art
Insomnia is one of the manifestations of sleep disorders. It generally refers to the occurrence and/or maintaining of sleep occurs with obstacles, which is characterized by difficulty falling asleep, easy to wake up, early awakening and difficulty in falling asleep again.
According to the course of the disease, modem medicine classifies insomnia into transient insomnia (less than 1 week), acute insomnia (1 week to 1 month) and chronic insomnia (longer than 1 month). According to the cause of disease, it can be classified as primary and secondary insomnia and insomnia: ® primary insomnia: According to the diagnostic criteria of primary insomnia in the American diagnostic and statistical manual of mental disorders (DSM-4), primary insomnia refers to difficulty in falling asleep and maintaining sleep, and the onset of illness is at least one month. Sleep disorders cause distress or social or occupational disorders. The dysfunctions caused by paroxysmal diseases, respiratory related sleep disorders, circadian sleep disorders, major depression, generalized anxiety disorder and various physical diseases, alcohol or drugs are excluded.; ©Secondary insomnia: refers to insomnia caused by pain, anxiety or depression. There is also a view to replace secondary insomnia with chronic insomnia.
At present, the treatment of insomnia patients requiring medical treatment is still based on drugs. These drugs mainly include γ-aminobutyric acid A (GABAA) complex agonists, melatonin receptor agonists, antidepressants, non-classic antipsychotics, and antihistamines. However, only a few have been approved by the U.S. Food and Drug Administration (FDA) for insomnia indications. Only GABAA complex agonists (5 benzodiazepinesand 4 non-benzodiazepines),
2018101247 28 Aug 2018 ramelteon (melatonin receptor agonist) and low-dose doxepin (antidepressant) are included. GABAA agonists is mainly used in China for treating insomnia.
To treat different types of insomnia, different drugs should be selected. For example, to treat difficulty falling asleep, drugs that induce rapid sleep should be chosen, most of the which are sedative hypnotics of short half-life, such as triazolam, midazolam, oxazepam, zaleplon, eszopiclone, zolpidem and so on. For nocturnal wakeful insomnia, choose hypnotic drugs that can prolong the third and fourth stages of NREM sleep and shorten REM sleep time, such as estazolam, temazepam, nixepam, fluxepam, etc. Early wakening insomnia is usually seen in depressed patients. While treating the primary disease, moderate or long-acting sedative-hypnotics such as diazepam, nitrazepam, clonazepam and so on canbe used. It has been reported that antidepressants like mirtazapine, are effective for patients with light sleep and early wakefulness, but not for people with difficulty falling asleep.
The ideal sedative and hypnotic drugs should be able to induce to sleep quickly and have effect on sleep structure, no residual effects on the next day, do not affect the memory function, no respiratory inhibition and long-term use without dependence or withdrawal symptoms. However, the drugs commonly used in clinical practice to treat sleep difficulty insomnia, such as triazolam, midazolam, oxazepam, zallepron, dextropicolone and zolpidem, have more or less side effects. Among them, triazolam, midazolam, and oxazepam belong to benzodiazepines. Due to their poor selectivity of action target, long-term use may cause drug tolerance, dependence and withdrawal symptoms, they are no longer the first choice for treating insomnia in foreign countries at present, especially for the elderly and patients with respiratory diseases. Therefore, the choice of medication for patients with sleep difficulties is relatively limited.
With the rapid pace of society and intensified competition, the incidence of insomnia has been increasing year by year. According to the data from WHO, nearly 1/4 of people in the world suffer from insomnia, and about 30 to 35 percent of the people in developing countries suffer from insomnia. Insomnia has a great influence on individuals and society, as the yearly increase in the cost and treating expenditure of traffic accidents caused by insomnia showed. It can be seen that insomnia is not only a medical problem, but also a social problem, which has attracted great
2018101247 28 Aug 2018 attention in the world. Therefore, the research and development of new safer and more effective medicine for treating insomnia will be an ongoing research and development hotspot.
The clinical data show that the traditional Chinese medicine for treating insomnia has good effects and less adverse reactions, providing a rich resource for new medicine to treat insomnia.
Persimmon leaf is a fresh or dried leaf of Diospyros kaki Thunb. belongs to Ebenaceae, a Persimmon plant of the family Persimmon. Its application was first reported in the Ming dynasty's ’southern yunnan bencao1. ’Ben Cao Zai Xin‘, which was recorded to ‘cure the cough, spit blood, and quench thirst.’ The persimmon leaf extract recorded in the Chinese pharmacopoeia is mainly used for promoting blood circulation and removing blood stasis, mainly for treating qi stagnation and blood stasis, and can be used for coronary heart disease, cerebral atherosclerosis and other cardiovascular and cerebrovascular diseases. The prescription naoxinqing tablet, made from persimmon leaf ethyl acetate extract, has been widely used in clinical applications. The therapeutic effect of naoxinqing tablet in the treatment of type H hypertension in the elderly has been found to improve the symptoms of dizziness, headache and insomnia (Observation on the therapeutic effect of naoxinqing tablet in the treatment of type H hypertension in the elderly [J], zhou jing, etc. New Chinese medicine, 2014,46 (5): 38-39). However, as mentioned above, while treating hypertension, naoxinqing tablet has been observed that the improvement of insomnia symptoms should be secondary insomnia caused by pain, anxiety or depression. This study did not disclose the specific criteria for the assessment of insomnia symptoms, the indicators for the improvement of insomnia or the specific types of insomnia, and lacked guidance for accurate clinical medication.
Disclosure of the Invention
In order to make up for the deficiencies of the current technology, the present invention aims to provide a persimmon leaf extract and its preparation (such as naoxinqing tablet, naoxinqing capsule, etc.) for a new medical use in the treatment of sleep difficulty insomnia. In order to achieve the above mentioned purposes, the present invention adopts the following technical schemes:
2018101247 28 Aug 2018
Application of persimmon leaf extract in the preparation of drugs is used for primary insomnia.
Preferably, the persimmon leaf extract is the only active component of the drug.
Preferably, the primary insomnia is a type of primary insomnia with difficulty falling asleep.
Preferably, the drugs used to treat primary insomnia are clinically acceptable preparations, including or excluding pharmaceutically acceptable excipients.
Preferably, the clinically acceptable preparation is an oral preparation or a non-oral preparation, oral preparation is preferred.
The oral preparations are selected one or more from powders, tablets, capsules, soft capsules, pills, dropping pills, micro-pills, granules, orally disintegrating tablets and oral fast-dissolving film agents.
The non-oral preparation is selected one or more from injections, freeze-dried powders needles and large-capacity infusion agents.
The application of the present invention is applied to a mammal in need, preferably a human in need.
Preferably, the medicament for treating primary insomnia is an oral preparation.
Preferably, the present invention provides a method for preparing the persimmon leaf extract as follows:
The dry persimmon leaf was treated with the boiling water for twice, each time 1 ~ 2 hours. Combining water decoction, filtering, concentrating till relative density (60 °C) 1.12 ~ 1.15, adding ethanol to alcohol content is 80 ~ 90%. Standing overnight and filtering to get the supernatant for further use. The precipitate is washed with 60-70% ethanol, combined with washing liquid, and set overnight. The supernatant is filtered and combined with the spare supernatant liquid. The ethanol is recycled. Adding some water, mixing, filtering, then extracting the filtrate with ethyl acetate for at least 4 times, combining the ethyl acetate solution, recycling
2018101247 28 Aug 2018 the ethyl acetate and concentrating into thick paste, and drying it at low temperature to obtain the persimmon leaf extract.
As an optimal implementation plan, the drug used to treat primary insomnia is naoxinqing tablet or naoxinqing capsule. The medicine for treating primary insomnia, when given orally to a person in need, the administration dosage which is calculated by the persimmon leaf extract, can be 1.0 to 10 mg/kg of body weight per day, preferably 1.0 to 5.0mg/kg of body weight.
The persimmon leaf extract can be prepared by adding or not adding pharmaceutically acceptable excipients according to the conventional methods in this field.
In the specification of the present invention, the pharmaceutically acceptable excipients including but not limited to:
Diluents: such as selected one or more from starch, dextrin, pregelatinized starch, lactose, microcrystalline cellulose, calcium sulphate, calcium hydrophosphate, calcium carbonate, magnesium oxide, magnesium carbonate, aluminium hydroxide gel, β-cyclodextrin, mannitol, sorbitol, methyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose sodium.
Adhesives: such as selected one or more from distilled water, ethanol, starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose and ethyl cellulose, and hydroxypropyl methylcellulose.
Lubricants: such as selected one or more from Magnesium dodecyl sulfate, polyethylene glycol, aerosol, magnesium stearate and talcum powder.
Disintegrants: such as selected one or more from starch (com, potato), microcrystalline cellulose, alginic acid, sodium alginate, ion exchange resins, effervescent disintegrants, hydroxypropyl starch, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, carboxymethyl cellulose, calciumcarboxymethyl cellulose, low-substituted hydroxypropyl cellulose, partially pregelatinized starch and microcrystalline cellulose.
2018101247 28 Aug 2018
Film-forming materials: selected one or more from glutin, shell-lac, Arabic gum, agar, starch, dextrin, PVA05-88, PVA17-88 and ethylene-vinyl acetate copolymer (EVA).
Flavoringagents: such as selected one or more from saccharin sodium, sodium cyclamate, aspartame, stevioside and essences.
Solvents for injection: such as selected one or more from water for injection, sesame oil, tea oil, peanut oil, com oil, olive oil, cottonseed oil, soybean oil, castor oil and peach kernel oil, ethyl oleate, benzyl benzoate, propylene glycol, polyethylene glycol 400, dimethylacetamide (DMA), ethanol and glycerol.
The present invention has been proved by the experiment that persimmon leaf extract can dose dependently increase the number of mice that falling asleep induced by subthreshold dose of pentobarbital sodium, and the effect of high dose is equivalent to that of the positive control drug alprazolam. Persimmon leaf extract can also dose dependently reduce sleep latency caused by the threshold dose of pentobarbital sodium and prolong the sleep duration caused by the upper threshold dose of pentobarbital sodium. Moreover, the high dose group has shorter sleep latency than the positive control drug group, while the sleep duration of it is slightly shorter than the positive control drug alprazolam. The above experiment results showed that the persimmon leaf extract can shorten the sleep latency, but not too much prolong the sleep duration, so it can be used for treating insomnia of difficulty falling asleep and reduce after effects to some extent. In addition, according to the results of the animal experiment, the effective dosage of persimmon leaf extract for treating insomnia of difficulty falling asleep is lower than the therapeutic dose of cardiovascular and cerebrovascular diseases. In conclusion, the effective dosage of persimmon leaf extract used in the present invention is applied to the treatment of primary insomnia (sleep difficulty insomnia), which would ensure the good compliance of patients and curative effects.
Specific executing examples
The present invention is described below with references to specific embodiments. The technical personnel in this field can understand that these embodiments are used only to describe the invention and that they do not limit the scope of the invention in any way.
2018101247 28 Aug 2018
The experimental methods in the following embodiments, without special instructions, are conventional. The medicinal materials, reagents and other materials used in the following embodiments could be purchased from the market. Among them, some reagents and instruments are purchased as follows: Persimmon leaf extract (PLA): Guangzhou Baiyun mountain hutchison whampo Chinese medicine Co., Ltd., lot number: H16P006, the preparation method is as follows:
The dry persimmon leaf was treated with the boiling water for twice, each time 1 ~ 2 hours. Combining water decoction, filtering, concentrating till relative density (60 °C) 1.12 ~ 1.15, adding ethanol to alcohol content is 85%. Standing overnight and filtering to get the supernatant for further use. The precipitate is washed with 65% ethanol, combined with washing liquid, and set overnight. The supernatant is filtered and combined with the spare supernatant liquid. The ethanol is recycled. Adding some water, mixing, filtering, then extracting the filtrate with ethyl acetate for at least 4 times, combining the ethyl acetate solution, recycling the ethyl acetate and concentrating into thick paste, and drying it at low temperature to obtain the persimmon leaf extract.
Pentobarbital sodium (Merck Co., Shanghai chemical technology).
Alprazolam sheet: Beijing Yi-min Pharmaceutical Co., Ltd.;
Example
Effect of persimmon leaf extract on sleep of mice induced by pentobarbital sodium
1. Experimental animals healthy Kunming mice, cleaning grade, male and female in half, weight 18~22 g. Experimental animal license number: SCXK (Beijing) 2014-0004.Mice were fed for one week before the test to adapt the breeding environment. All mice are raised in experimental animal room at 21 plus or minus 2°C, and follow a circadian rhythm. The mice can freely eat and drink.
2. Experimental drugs
2018101247 28 Aug 2018
Persimmon leaf extract (PLA) and alprazolam are prepared with 0.5% sodium carboxymethyl cellulose as solvent,and the drug should be thoroughly mix prior to administration.
Preparation of persimmon leaf extract (PLA): 40mg persimmon leaf extract was dissolved in 0.5% sodium carboxymethyl cellulose of 10ml and prepared into 4mg/ml storage solution. Before use, the corresponding working solution was diluted according to the requirements of drug administration. For example, if the high dose of PLA is 40mg/kg, the dosage should be O.lml/lOg, and the dosage should be 4mg/ml.
The preparation of alprazolam: dissolves 0.25mg alprazolam to 0.5%sodium carboxymethyl cellulose of 10ml, and makes storage solution of 0.025mg/ml. Before use, it is diluted into the corresponding working liquid according to the requirements of drug administration.3. Experimental grouping and administration kunming mice were randomly divided into 5 groups according to their weight and gender. Each group has 12 mice: 1) Blank control group, 2) low-dose PLA group (10 mg/kg weight), 3) medium dose PLA group (20 mg/kg weight), 4) high-dose PLA group (40 mg/kg weight), 5) apzolam (0.25 mg/kg weight).All groups were gastric administrated, according to the actual body weight of the mice. The dosage volume was O.lml/lOg, and the blank group was given 0.5% sodium carboxymethyl cellulose aqueous solution of the same volume.
Experimental Method
4.1 The influence of PLA on sleep in Pentobarbital sodium-induced (subthreshold dose) mice
Each group mice were intraperitoneally injected with 28 mg/kg pentobarbital sodium after 30 min of PLA orally administration, The number of mice sleeping in each group was recorded by taking the disappearance of more than lmin of mice's righting reflex..
After the experiment, the mice were given a one-week drug eluting treatment. Mice were allowed to drink and feed freely, without any other treatment. 4.2 The influence of PLA on sleep in Pentobarbital sodium-induced (superthreshold dose) mice
2018101247 28 Aug 2018
4.2 The influence of PLA on sleep in Pentobarbital sodium-induced (superthreshold dose) mice
Each group mice were intraperitoneally injected with 40 mg/kg pentobarbital sodium after 30 min of PLA orally administration and the duration of sleep was observed to calculate the time between the disappearance of the mice's righting reflex and the recurrence of the righting reflex
5. Statistical analysis
All measuring data wereexpressed as mean+SD and analyzed by One way ANOVA followed by LSD or Dunnett’s comparison test. Differences between groups were considered significant when
P<0.05.
6. Experimental Results
6.1 Effects of PLA on the number of mouse sleep induced by subthreshold dose of pentobarbital sodium
As shown in Table 1, compared with the control group, PLA can increase the number of mice that fall asleep with Pentobarbital sodium-induced (subthreshold dose) in a dose-dependently manner. In addition, high dose of PLA (40 mg/kg) increased the number of sleeping mice to 7, the rate of sleep was 58.3% and the effect was close to the alprazolam (number= 8, 66.7%).
Table 1
Effects of PLA on the number of mouse sleep induced by-subthreshold dose of pentobarbital sodium
| Group | Number | Dose (40 mg/kg) | Sleep number | Sleep rate (%) |
| Control | 12 | - | 0 | 0 |
| Low-Dose PLA | 12 | 10 | 2 | 16.7 |
| Medium-Dose PLA | 12 | 20 | 4 | 33.3 |
| High-Dose PLA | 12 | 40 | 7 | 58.3 |
2018101247 28 Aug 2018
Alprazolam 12 0.25 8 66.7
6.2 Effect of PLA on sleep latency and sleep duration in Pentobarbital sodium-induced (superthreshold dose) mice
As shown in Table 2, compared with the Control group, each dose of PLA can reduce sleep latency and prolong the sleep duration with Pentobarbital sodium-induced (superthreshold dose) in some extent, the effect was dose dependent relationship, there were statistical significance in Medium and High dose of PLA (P < 0.05). In addition, the sleep latency of High-Dose PLA (40 mg/kg) was shorter than alprazolam, but the sleep time slightly less than alprazolam, the results indicated that PLA can shorten sleep latency and not caused by too long sleep.
Table 2 The influence of PLA on sleep latency and sleep duration in Pentobarbital sodium-induced (superthreshold dose) mice
| Group | Number | Dose (40 mg/kg) | sleep latency | sleep duration |
| Control | 12 | - | 242.7+19.8 | 13.8+4.3 |
| Low-Dose PLA | 12 | 10 | 235.0+31.1 | 16.2+6.6 |
| Medium-Dose PLA | 12 | 20 | 215.9+23.2* | 21.8+5.7* |
| High-Dose PLA | 12 | 40 | 204.3+24.4** | ** 26.3+8.3 |
| Alprazolam | 12 | 0.25 | 208.3+31.3** | ** 28.2+5.4 |
*P<0.05, ** P<0.01vs. Control group
Conclusions
Each dose of PLA can increase the number of mice that fall asleep with Pentobarbital sodium-induced (subthreshold dose) in dose dependent relationship, the effect of High-Dose PLA was close to the alprazolam.
Each dose of PLA can reduce sleep latency and prolong the sleep duration with Pentobarbital sodium-induced (superthreshold dose) in dose dependent relationship, the sleep latency of High-Dose PLA (40 mg/kg) was shorter than alprazolam, but the sleep time slightly less than
2018101247 28 Aug 2018 alprazolam, the results indicated that PLA can shorten sleep latency and not caused by too long sleep. The effect of inducing sleep is better than alprazolam.
The results indicate that, PLA can be used for treating insomnia which belong to difficulty sleeping type shorten sleep time, but not prolonged sleep duration too much, so as to reduce sequela on and improve the safety of medicine.
The test dose range of PLA was 10 ~40 mg/kg that converted into human clinical dose range was about 1.1 ~ 4.4mg/kg according to body surface area coefficient. When PLA treat coronary heart disease, cerebral arteriosclerosis, it requires 300~600mg/d according to the Chinese pharmacopoeia that converting to the Kg dose is 4.3 ~8.6mg/kg. Obviously, the dose of PLA that treat sleep difficult-insomnia is lower than the dose of treating the coronary heart disease and cerebral arteriosclerosis. As the same specification, the dose of treating sleep difficult-insomnia is significantly less than the current conventional clinical dose, it can greatly improve compliance, safety and reduce the drug tolerance.
In a word, the invention provides a new medical use of PLA for treating primary insomnia, especially sleep difficult-insomnia, and more important, compared with the existing technology, which has been reported for the treatment of coronary heart disease, cerebral atherosclerosis and so on, PLA can shorten the sleep time and improve sleep in low-dose.
Claims (10)
- There are two pages of claims only2018101247 28 Aug 20181. Application of persimmon leaf extract in the preparation of drugs for primary insomnia.
- 2. According to the application described in claim 1, the persimmon leaf extract is characterized as the only active component of the drug.
- 3. According to the application described in claim 1 or 2, it is characterized by the fact that the primary insomnia described is the primary insomnia of difficulty falling asleep.
- 4. The application described in claim 1 or 2 is characterized by the fact that the drugs used to treat primary insomnia are clinically acceptable preparations, including or excluding medically acceptable excipients.
- 5. The application described in claim 4 is characterized by the fact that the clinically acceptable preparation is oral or non-oral, Oral preparation is preferred.
- 6. According to the application described in claim 5, the characteristics of the oral preparation are as follows: the oral preparation is selected from one or more of the dispersants, common tablets, capsules, soft capsules, pills, drops, micropellets, granules, oral disintegrating tablets and oral fast-dissolving film agents.
- 7. The application described in claim 5 is characterized by the fact that the non-oral preparations are selected from one or more of the injections, freeze-dried powder needles and large-capacity infusion agents.
- 8. The application described in claim 5 is characterized by the fact that the drugs used to treat primary insomnia are oral preparations.
- 9. In accordance with any of the applications described in claims 1 to 8, the persimmon leaf extract is characterized by the following preparation: The dry persimmon leaf was treated with the boiling water for twice, each time 1 ~ 2 hours. Combining water decoction, filtering, concentrating till relative density (60°C) 1.12 ~ 1.15, adding ethanol to alcohol content is 80 ~ 90%. Standing overnight and filtering it to get the supernatant for further use. The precipitate is washed with 60-70% ethanol, combined with washing liquid, and set overnight. The supernatant is filtered and combined with the spare supernatant liquid. The ethanol is recycled. Adding some water, mixing, filtering, then extracting the filtrate with ethyl acetate for at least 4 times, combining the ethyl acetate solution, recycling the ethyl acetate and concentrating into thick paste, and drying it at low temperature to obtain the persimmon leaf extract.
- 10. In accordance with any of the applications described in claims 1 to 9, the characteristics of the application are that the drug used to treat primary insomnia is naoxinqing tablet or naoxinqing capsule.
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| CN201711334516.XA CN108014162A (en) | 2017-12-12 | 2017-12-12 | A kind of application of extractive from leaves of persimmon in treatment is had a sleepless night |
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