CN113893280B

CN113893280B - Combined medicine for treating insomnia and preparation method thereof

Info

Publication number: CN113893280B
Application number: CN202111258543.XA
Authority: CN
Inventors: 杨莉; 陈建伟; 龙涛; 张传辉; 陈小红; 杨旋; 涂慧涓; 李小辉
Original assignee: Chongqing Hilan Pharmaceutical Co ltd
Current assignee: Chongqing Hilan Pharmaceutical Co ltd
Priority date: 2021-10-27
Filing date: 2021-10-27
Publication date: 2022-11-22
Anticipated expiration: 2041-10-27
Also published as: CN113893280A

Abstract

The invention provides a combined medicament for treating insomnia, which comprises spina date seed total saponin and rotundine for simultaneous or separate administration and a pharmaceutically acceptable carrier. Experiments prove that the traditional Chinese medicine composition has obvious effects on promoting blood circulation in a body, utilizing melatonin and promoting sleep, is superior to the existing mature product compound jujube kernel capsules sold in the market, and has synergistic effect with rotundine and total saponins of spina date seeds.

Description

Combined medicine for treating insomnia and preparation method thereof

Technical Field

The invention particularly relates to a combined medicine for treating insomnia.

Background

Approximately l/3 of a person's life is spent asleep. Sleep has important effects on physical strength and energy recovery, growth and development of organisms and the like. Insomnia, a common sleep disorder, causes troubles to physical and mental health of many patients, and causes disorder of human circadian rhythm and reduced mobility. With the progress of modern society, the pressure of work and life of people increases, and people who face insomnia are more and more, and it is reported that about 20% of so-called normal people who have not been treated by medical doctors have insomnia in different degrees.

At present, the most common treatment method for insomnia is still a pharmacotherapy, the used medicines are mainly western medicines, but the western medicines such as barbiturates are easy to generate pharmacokinetic tolerance and pharmacodynamic tolerance after being used for a long time, and the rotundine can cause lethargy, dizziness, hypodynamia, nausea and other adverse reactions after being used for a long time; application research of traditional Chinese medicines and extracts in treating insomnia is continuous and deep, and a large number of researches show that a plurality of traditional Chinese medicine extracts have the effect of promoting sleep, such as spina date seed extract, platycladi seed extract, lucid ganoderma extract and the like. The Chinese medicine standard Z50020601 compound jujube kernel capsule treats insomnia by combining the traditional Chinese medicine extract of the wild jujube seed with western medicine rotundine, and has satisfactory treatment effect, but certain side effects can be generated after long-term large-scale taking, such as digestive tract symptoms including hypodynamia, nausea, vomiting and the like, and extrapyramidal system reaction, and severe patients can also have liver function damage symptoms including elevation of Valley's C or Valley's grass and the like, such as jaundice, somnolence and the like.

Disclosure of Invention

In order to solve the technical problems, the invention provides an application of the spina date seed total saponin and rotundine in preparing a medicine for treating insomnia.

Further, the drug is a drug for treating difficulty in falling asleep.

Further, the medicament is a medicament for treating dreaminess and wakefulness.

Furthermore, the mass ratio of the spina date seed total saponin to the rotundine is 5-30: 30 to 60, preferably 10 to 30:60, more preferably 20:60.

the invention also provides a combined medicament for treating insomnia, which contains the spina date seed total saponin and the rotundine for simultaneous or separate administration.

Further, the mass ratio of the total saponins of the spina date seeds to the rotundine is 5-30: 30 to 60 percent.

Furthermore, the mass ratio of the spina date seed total saponin to the rotundine is 10-30: 30 to 60, preferably 20:60.

the invention also provides a composition with the effect of soothing the nerves, which is an oral preparation prepared by taking the total saponins of the spina date seeds and the rotundine as active ingredients and adding pharmaceutically acceptable auxiliary materials.

Further, the mass ratio of the spina date seed total saponin to the rotundine is 10-30: 30 to 60 percent.

further, the oral preparation is granule, powder, pill, capsule or solution, preferably capsule.

The invention finally provides a process for the preparation of the aforementioned composition, which comprises the steps of:

weighing semen Ziziphi Spinosae total saponin and rotundine at a certain ratio, mixing, and adding pharmaceutically-acceptable adjuvants or auxiliary components.

The combined medicine for treating insomnia improves the rheological property of blood and melatonin dyscretion by combining the spina date seed total saponin and the rotundine in a specific proportion, thereby achieving the effect of promoting sleep and solving the fundamental problems of long-term insomnia, pale complexion, lassitude, haggard and other aging caused by the insomnia and the like. Meanwhile, adverse reactions of rapid rise of blood concentration caused by rapid release of rotundine are also solved, such as: dizziness, weakness, nausea, side effects of extrapyramidal reactions and damage to the liver.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Detailed Description

The raw materials and equipment used in the specific implementation mode of the invention are known products and are obtained by purchasing products sold in the market, wherein the spina date seed total saponin is obtained from Chongqing national comfort pharmaceutical Co., ltd, the content is more than 70%, and the rotundine is obtained from Chongqing Hieran pharmaceutical Co., ltd, and the content is 99.8%.

EXAMPLE 1 pharmaceutical compositions of the invention

The preparation method comprises the following steps: taking the spina date seed total saponin, the rotundine, the pregelatinized starch, the microcrystalline cellulose and the micro-powder silica gel according to the formula amount, sieving with a 80-mesh sieve, mixing for 5 times to fully and uniformly mix the raw materials and the auxiliary materials, and filling into a No. 0 capsule (0.4 g/capsule) to obtain the capsule.

Example 2 pharmaceutical compositions of the invention

Example 3 pharmaceutical compositions of the invention

Example 4 pharmaceutical compositions of the invention

The preparation method comprises the following steps: taking the spina date seed total saponin, the rotundine, the pregelatinized starch, the microcrystalline cellulose and the micro-powder silica gel according to the formula amount, sieving with a 80-mesh sieve, mixing for 5 times to fully and uniformly mix the raw materials and the auxiliary materials, and filling into a No. 0 capsule (0.4 g/capsule) to obtain the compound preparation.

EXAMPLE 5 pharmaceutical compositions of the invention

Example 6 pharmaceutical compositions of the invention

Example 7 pharmaceutical compositions of the invention

The advantageous effects of the present invention are further illustrated by the following test examples

Test example the effect of the invention is compared with the effect of the compound jujube kernel capsule, the total saponins of the spina date seed and the rotundine

Comparative example 1

Referring to Chinese patent CN200610078947.X (the existing preparation process of compound jujube kernel capsules), capsules are prepared, the specification is 0.4 g/capsule.

Comparative example 2

The preparation method comprises the following steps: taking the spina date seed total saponin, the pregelatinized starch, the microcrystalline cellulose and the micro-powder silica gel according to the formula amount, sieving with a 80-mesh sieve, mixing for 5 times to fully and uniformly mix the raw materials and the auxiliary materials, and filling into a No. 0 capsule (0.4 g/capsule) to obtain the capsule.

Comparative example 3

The preparation method comprises the following steps: taking rotundine, pregelatinized starch, microcrystalline cellulose and micro-powder silica gel according to the formula amount, sieving with a 80-mesh sieve, mixing for 5 times to fully mix the raw materials and the auxiliary materials, and filling into 0-size capsules (0.4 g/capsule).

Comparative experiment 1: effect of the compositions (examples 1, 3, 6) and comparative examples 1, 2, 3 samples on rat hemorheology

80 male SD rats (200 g + -10 g) were selected and randomly divided into 8 groups of 10 rats each. Dividing into (1) normal control group; (2) a model control group; (3) example 1 low dose group; (4) dose groups in example 3; (5) example 6 high dose group; (6) group of comparative example 1; (7) comparative example 2 group; (8) comparative example 3 group, fed normally during the test period. Each group of rats was administered with 2 g/kg/day) for 7 days, and the other groups were injected subcutaneously with 8 μ g/kg of epinephrine hydrochloride twice on day 6 with 4h intervals, and the rats were immersed in ice water for 5min between the two injections of epinephrine, and fasted after treatment to construct a blood stasis model. On day 7, blood was taken from the carotid artery and related indices of hemorheology were determined for each group. The results are shown in table 1, the blood stasis model was successfully constructed in the experiment, compared with the control group of the model group, the composition groups of examples 1, 3 and 6 have the effect of obviously improving the blood rheological property, and the comparative examples of 1, 2 and 3 have the effect of obviously improving the blood rheological property. The results show that the combined application of the spina date seed total saponin and the rotundine has a synergistic effect and can play a good role in improving the rheological property of blood.

TABLE 1 influence of Total saponins of Zizyphi Spinosae semen on hemorheology of rats in blood stasis model

Note: p <0.05, P <0.01, P <0.001, compared to model controls.

Comparative experiment 2: effect of the compositions (examples 1, 3, 6) and comparative examples 1, 2, 3 on hemorheology, melatonin and sleep in Insomnia rats

80 male SD rats (200 g + -10 g) were selected and randomly divided into 8 groups of 10 rats each. Dividing into (1) normal control group; (2) a model control group; (3) example 1 low dose group; (4) dose groups in example 3; (5) example 6 high dose group; (6) group of comparative example 1; (7) comparative example 2 group; (8) comparative example 3 group, fed normally during the test period. Except for the normal control group, the other groups are injected with parachlorophenylalanine (PCPA, 350 mg/kg) in the abdominal cavity for 1 time every day and continuously injected for 3 days, when the rat shows that the circadian rhythm disappears, the model is not only irritated in the daytime but also does not stop moving, and the model building success is indicated. After successful molding, the corresponding drug was administered to each group for 7 consecutive days (2 g/kg/day).

Blood was collected after the last administration to examine the rheological index of blood, and the results are shown in table 2, in which the blood viscosity of the model control group was increased as compared with that of the normal control group. Meanwhile, compared with the model control group, the composition groups of examples 1, 3 and 6 have the effect of remarkably improving the blood rheological property, and the comparative examples 1, 2 and 3 have the effect of remarkably improving the blood rheological property.

TABLE 2 influence of Zizyphi Spinosae semen Total Saponin on hemorheology of Insomnia rats

Note: p <0.05, P <0.01, P <0.001, compared to model controls.

Meanwhile, the content of the melatonin in the serum is detected, and the result is shown in table 3, wherein the model control group is obviously lower than a normal control group (P < 0.05); the groups of examples 1, 3 and 6 are significantly higher than the model control group (P <0.05, P < 0.01), and the groups of comparative examples 1, 2 and 3 have no statistical difference relative to the model control group. The research results show that the combined application of the spina date seed total saponin and the rotundine has a synergistic effect and can play a role in improving the melatonin dyssecrecy.

TABLE 3 influence of Total saponins of Zizyphi Spinosae semen on serum melatonin content in insomnia rat

Note: p <0.05, P <0.01, P <0.001, compared to model controls.

Pentobarbital sodium with suprathreshold dose is injected into the abdominal cavity after 30min of the last administration, the time from the beginning of the injection of the pentobarbital sodium to the disappearance of the righting reflex is the sleep latency, the time from the disappearance of the righting reflex to the restoration of the righting reflex is the sleep time, and the sleep latency and the sleep time of each group of rats are recorded. The results are shown in table 4, compared with the model group, the sleep latency of the high dose group in example 6 is significantly shortened, the sleep time of the low dose group in example 1 and the sleep time of the dose group in example 3 are significantly prolonged, the sleep time of the high dose group in example 6 is significantly prolonged, the sleep latency of comparative examples 1, 2 and 3 has no statistical difference, and the sleep time has only statistical difference.

TABLE 4 influence of Total saponins of Zizyphi Spinosae semen on sleep in rats

Group of	Dosage (g/kg)	Sleep latency (min)	Sleep time (min)
				Normal control group	——	6.31±1.92*	65.6±10.28
Model control group	——	12.07±2.30	79.4±5.95
				Example 1 Low dose	2g/kg	8.58±1.22	122.6±7.10**
Dosage in example 3	2g/kg	5.93±0.32*	153.8±11.43**
				Example 6 high dose	2g/kg	4.74±0.39**	209.6±6.89***
Comparative example 1 group	2g/kg	11.00±1.43	104.4±9.96*
				Comparative example 2 group	2g/kg	18.03±1.80	88.4±6.17*
Comparative example 3 group	2g/kg	11.09±1.64	102.5±8.42*

Note: p <0.05, P <0.01, P <0.001, compared to model control groups.

Comparative experiment 3: study of hepatoprotective Effect of the compositions (examples 1, 3, 6) and the samples of comparative examples 1, 2, 3

80 male SD rats (200 g + -10 g) were selected and randomly divided into 8 groups of 10 rats each. Dividing into (1) normal control group; (2) a model control group; (3) example 1 low dose group; (4) dose groups in example 3; (5) example 6 high dose group; (6) group of comparative example 1; (7) comparative example 2 group; (8) comparative example 3 group, fed normally during the test period. Each group of rats was continuously given the corresponding drug for 5 days (2 g/kg/day). On day 3, except for the normal control group, each group was gavaged with α -naphthalene isothiocyanate (ANIT, 60 mg/kg) for molding, and the normal control group was administered with the same amount of the corresponding vehicle. And after 48h of modeling, collecting serum samples 30min after each group of rats are subjected to the last administration, and carrying out related index detection.

The results are shown in table 5, compared with the normal control group, the liver function enzymology indexes (ALT, AST and ALP) in the serum of the rat of the model control group are obviously increased, which indicates that the ANIT-induced liver injury model is successfully constructed. The liver function enzymology indexes of the groups of examples 1, 3 and 6 were decreased compared with the model control group, indicating that the groups of examples 1, 3 and 6 can improve ANIT-induced liver damage. Compared with the model control group, the liver function enzymology index of the comparative example group has no significant change (P > 0.05). The comparative examples 1, 2 and 3 have no improvement effect on the liver injury of alpha-naphthalene isothiocyanate (ANIT, 60 mg/kg), which shows that the compound jujube kernel capsules, the independent adoption of the spina date seed total saponins and the independent adoption of the rotundine have no positive influence on biochemical indexes of a liver injury model, the combined application of the spina date seed total saponins and the rotundine can well improve the biochemical indexes of the liver injury model, and the combined application has a synergistic effect and can play a good liver protection role.

TABLE 5 Effect of Total saponins of Zizyphi Spinosae semen on Biochemical indicators of rat serum

Group of	Dosage (g/kg)	Glutamic-pyruvic transaminase (ALT, U/L)	Glutamic-oxaloacetic transaminase (AST, U/L)	Alkaline phosphatase (ALP, U/L)
					Normal control group	——	40.9±3.17**	64.5±7.52***	178.5±41.9***
Model control group	——	452.5±89.2	320.9±14.6	493.6±45.4
					Example 1 Low dose	2g/kg	375.4±96.8	214.0±23.3**	368.7±44.0*
Dosage in example 3	2g/kg	268.8±65.9*	192.3±15.2***	304.8±49.9**
					Example 6 high dose	2g/kg	195.6±47.4*	149.6±18.9***	285.9±23.8**
Comparative example 1 group	2g/kg	409.5±74.2	307.8±20.1	441.0±60.5
					Comparative example 2 group	2g/kg	410±57.9*	310±34.6	443.2±41.2
Comparative example 3 group	2g/kg	440.6±71.8	339±15.1	473.2±45.2

Note: p <0.05, P <0.01, P <0.001, compared to model controls.

In summary, the combined medicine for treating insomnia of the invention promotes the blood circulation in the body, accelerates the metabolism of the human body, improves the melatonin dyscretion and thus promotes the sleep by combining the spina date seed total saponin and the rotundine in a specific proportion, and tests prove that the combined medicine has obvious effects on improving the blood rheological property, the melatonin dyscretion and promoting the sleep, is superior to the current mature product compound jujube kernel capsules sold in the market, and has the synergistic effect by respectively administering the rotundine and the spina date seed total saponin, thereby solving the fundamental problems of long-term insomnia and aging such as pale complexion, lassitude, melancholy and the like caused by the insomnia, simultaneously avoiding the generation of side effects, protecting the liver and having wide market application prospect.

Claims

1. The application of only taking spina date seed total saponin and rotundine as active ingredients in preparing the medicament for treating insomnia;

the mass ratio of the spina date seed total saponin to the rotundine is 20:60.

2. use according to claim 1, characterized in that: the medicament is a medicament for treating difficulty in falling asleep.

3. Use according to claim 1, characterized in that: the medicine is used for treating dreaminess and easy wakening.

4. A combined medicine composition for treating insomnia is characterized in that: it only contains spina date seed total saponin and rotundine, and is administrated simultaneously or separately; the mass ratio of the spina date seed total saponin to the rotundine is 20:60.

5. a composition with a nerve soothing effect is characterized in that: the preparation is an oral preparation prepared by only taking spina date seed total saponin and rotundine as active ingredients and adding pharmaceutically acceptable auxiliary materials; the mass ratio of the spina date seed total saponin to the rotundine is 20:60.

6. the composition of claim 5, wherein: the oral preparation is granule, powder, pill, capsule or solution.

7. A method for producing the composition according to any one of claims 4 to 6, characterized in that: it comprises the following steps:

weighing semen Ziziphi Spinosae total saponin and rotundine according to proportion, adding pharmaceutically common adjuvants or adjuvant components, and mixing.