AU2021260664A1 - Sleep-improving pharmaceutical composition containing rare ginsenosides Rg6 and F4 - Google Patents
Sleep-improving pharmaceutical composition containing rare ginsenosides Rg6 and F4 Download PDFInfo
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- AU2021260664A1 AU2021260664A1 AU2021260664A AU2021260664A AU2021260664A1 AU 2021260664 A1 AU2021260664 A1 AU 2021260664A1 AU 2021260664 A AU2021260664 A AU 2021260664A AU 2021260664 A AU2021260664 A AU 2021260664A AU 2021260664 A1 AU2021260664 A1 AU 2021260664A1
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- ginsenoside
- pharmaceutical composition
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Anesthesiology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
The present invention relates to a sleep-improving pharmaceutical composition containing the rare ginsenosides Rg6 and F4. The pharmaceutical composition of the present invention contains an effective dose of ginsenoside Rg6 and ginsenoside F4 for improving sleep as active ingredients, and a pharmaceutically acceptable carrier. In the present pharmaceutical composition, the mass ratio between the ginsenoside Rg6 and the ginsenoside F4 is 1:1-3:1. On the basis of the present invention, a synergistically interacting rare ginsenoside pharmaceutical composition containing the rare ginsenosides Rg6 and F4 and having a sleep-aiding effect can be provided.
Description
GINSENOSIDES RG6 AND F4
The present application relates to the field of biomedicine, in particular to a synergistically
interacting rare ginsenoside Rg6/F4 composition with sleep-aiding activity.
According to the World Health Organization (WHO), 27% of the world's people have sleep problems,
that is, at least 1 in 4 people "do not sleep well". According to the latest China sleep data report, from
2013 to 2018, the per capita sleep duration in China has dropped from 8.8 hours to 6.5 hours, with
1.8 times of waking up during the night. On average, 38.2% of Chinese have sleep problems, which
is 11.2% higher than the global average. Decreased sleep quality not only affects the quality of work
during the day, but also affects blood pressure, blood sugar, endocrine and immune function and
leads to memory loss, dizziness, and dozing off while driving. Long-term sleep problems can also
cause negative emotions such asrestlessness, irritability, depression, etc. Severe cases can cause
psychological disorders and mental diseases, causing serious damage to the body and mind.
At present, the main drugs for the treatment of sleep disorders on the market are chemical drugs such
as barbiturates, benzodiazepines, Zolpidem, etc. Most of these drugs can shorten the time to fall
asleep, prolong the time of sleep and improve the quality of sleep, but after taking them, it will
produce a series of toxic and side effects on the body, such as drowsiness, fatigue, loss of appetite,
memory loss, intestinal discomfort and serious drug dependence. Although it was discovered in the
1990s that oral melatonin 20mg/d was effectively improve chronic insomnia caused by non-circadian
rhythm disorders and corresponding drugs and health care products were developed as a result, the
effect was not very satisfactory. As of October 2018, a total of 16,690 domestic health food products
have been approved, of which only 2.8% are for improving sleep. Therefore, the development of
sleep-improving products that have significant curative effects and are beneficial to human body is
an important task for the market and social development.
Ginseng, American ginseng and Panax notoginseng are traditional Chinese herbal medicines in
China, and their active ingredients, ginsenosides Rbl, Rd, Rgl, etc., have been reported to have the effects of enhancing immunity, diminish inflammation and improving sleep without dependence and withdrawal reactions. Ginsenosides Rg6 and F4 are obtained by deglycosylation and dehydration of triol group saponins Rgl and Re. Currently, they are mainly used in the treatment of non-small cell lung cancer, thrombotic, cerebral infarction and central retinal vein occlusion etc. There is no report on improving sleep and improving sleep quality.
The purpose of the present application is to provide a pharmaceutical composition for improving
sleep with ginsenoside Rg6 and/or F4 as active ingredients.
A series of experiments completed by the inventors showed that ginsenoside F4 inhibits neuronal
excitation by regulating the levels of y-aminobutyric acid (GABA) and Glu, and shows a calming
and tranquilizing effect, and that ginsenoside Rg6 can increase the content of 5-HTP in brain tissue
and improve slow-wave sleep in animals. Moreover, when ginsenosides Rg6 and F4 are used in
combination in a specific ratio, the effect of improving sleep is better than that of ginsenosides Rgl
and Rb, which have been reported to have sleep improving effects, and also better than the effect of
Rg6 and F4 when they act alone. This may be because the composition can simultaneously increase
the levels of GABA and 5-HTP in animal brain tissue and synergistically play a role in improving
sleep.
That is, the present application includes:
1. A pharmaceutical composition for improving sleep, comprising an effective amount of
ginsenoside Rg6 and ginsenoside F4 as active ingredients for improving sleep and a
pharmaceutically acceptable carrier,
wherein in the pharmaceutical composition, the weight ratio of the ginsenoside Rg6 to the
ginsenoside F4 is 1:1-3:1.
2. The pharmaceutical composition according to item 1, wherein in the pharmaceutical composition,
the weight ratio of the ginsenoside Rg6 to the ginsenoside F4 is 2:1.
3. The pharmaceutical composition according to item 1, wherein based on 100 parts by weight of the
total ginsenosides comprised in the pharmaceutical composition, the total amount of the ginsenoside
Rg6 and the ginsenoside F4 comprised in the pharmaceutical composition is 10 parts by weight or
more, preferably 50 parts by weight or more.
4. The pharmaceutical composition according to item 1, wherein based on 100 parts by weight of the
total ginsenosides comprised in the pharmaceutical composition, the total amount of the ginsenoside
Rg6 and the ginsenoside F4 comprised in the pharmaceutical composition is 100 parts by weight.
5. The pharmaceutical composition according to item 1, wherein the pharmaceutical composition
does not comprise other sleep-improving active ingredients other than the ginsenoside Rg6 and the
ginsenoside F4.
6. Use of ginsenoside Rg6 and ginsenoside F4 in the preparation of a pharmaceutical composition for
improving sleep, wherein, in the pharmaceutical composition, the weight ratio of the ginsenoside
Rg6 to the ginsenoside F4 is 1:1-3:1.
7. The use according to item 6, wherein in the pharmaceutical composition, the weight ratio of the
ginsenoside Rg6 to the ginsenoside F4 is 2:1.
8. The use according to item 6, wherein based on 100 parts by weight of the total ginsenosides
comprised in the pharmaceutical composition, the total amount of the ginsenoside Rg6 and the
ginsenoside F4 comprised in the pharmaceutical composition is 10 parts by weight or more,
preferably 50 parts by weight or more.
9. The use according to item 6, wherein based on 100 parts by weight of the total ginsenosides
comprised in the pharmaceutical composition, the total amount of the ginsenoside Rg6 and the
ginsenoside F4 comprised in the pharmaceutical composition is 100 parts by weight.
10. The use according to item 6, wherein the pharmaceutical composition does not comprise other
sleep-improving active ingredients other than the ginsenoside Rg6 and the ginsenoside F4.
In addition, as mentioned above, the inventors also found that ginsenoside F4 can inhibit neuronal
excitation by regulating the levels of y-aminobutyric acid (GABA) and Glu and show a calming and
tranquilizing effect, thereby improve sleep; while ginsenoside Rg6 can increase the 5-HTP content in
brain tissue, thereby improve slow-wave sleep in animals.
Therefore, the present application also includes:
11.Use of ginsenoside Rg6 in the preparation of a pharmaceutical composition for improving sleep.
12.The use according to item 11, wherein based on 100 parts by weight of the total ginsenosides
comprised in the pharmaceutical composition, the amount of the ginsenoside Rg6 comprised in the
pharmaceutical composition is 5 parts by weight or more, preferably 10 parts by weight or more,
more preferably 20 parts by weight or more, more preferably 50 parts by weight or more, more
preferably 70 parts by weight or more, more preferably 80 parts by weight or more, more preferably
parts by weight or more, more preferably 95 parts by weight or more, more preferably 99 parts by
weight or more, more preferably 100 parts by weight.
13.The use according to item 11, wherein the pharmaceutical composition does not comprise other
sleep-improving active ingredients other than the ginsenoside Rg6.
14.Use of ginsenoside F4 in the preparation of a pharmaceutical composition for improving sleep.
15.The use according to item 14, wherein based on 100 parts by weight of the total ginsenosides
comprised in the pharmaceutical composition, the amount of the ginsenoside F4 comprised in the
pharmaceutical composition is 5 parts by weight or more, preferably 10 parts by weight or more,
more preferably 20 parts by weight or more, more preferably 50 parts by weight or more, more
preferably 70 parts by weight or more, more preferably 80 parts by weight or more, more preferably
parts by weight or more, more preferably 95 parts by weight or more, more preferably 99 parts by
weight or more, more preferably 100 parts by weight.
16.The use according to item 14, wherein the pharmaceutical composition does not comprise other
sleep-improving active ingredients other than the ginsenoside F4.
The above-mentioned pharmaceutical composition may also comprise vitamins and/or trace elements
(e.g., iron) for calming the nerves and tonifying Qi. For example, the above pharmaceutical
composition may comprise 0.1-0.8 parts by weight of vitamins and/or 0.01-0.1 parts by weight of
trace elements iron relative to the total amount of 2-8 parts by weight of the ginsenoside Rg6 and the
ginsenoside F4.
The above-mentioned pharmaceutical composition may be, for example, an oral preparation or an
injection. The oral preparation can be, for example, hard capsules, soft capsules, slow-release
capsules, sugar-coated tablets, powders, granules, tablets, medicinal granules, dropping pills,
honeydew pills, syrups or oral liquids; the injections are solution type, mixed suspension type,
emulsion type or lyophilized powder. The above-mentioned pharmaceutical compositions may also be in external dosage forms, such as ointments, gels, sprays or patches. The above-mentioned pharmaceutical compositions may comprise adjuvants or other pharmaceutically acceptable carriers.
The ratio of the adjuvant to the active ingredient of the drug can be, for example, the active
ingredient accounts for 30% to 50% by weight, and the adjuvant accounts for 70% to 50% by weight.
The adjuvant can be, for example, one or more of sodium hyaluronate, magnesium stearate, sodium
alginate, starch, microcrystalline cellulose, chitosan, stachyose, adhesive or collagen.
First, in one aspect, the present application provides a pharmaceutical composition for improving
sleep, comprising an effective amount of ginsenoside Rg6 and ginsenoside F4 as active ingredients
for improving sleep and a pharmaceutically acceptable carrier,
wherein in the pharmaceutical composition, the weight ratio of the ginsenoside Rg6 to the
ginsenoside F4 is 1:1-3:1.
In the present specification, the ginsenoside Rg6 refers to the compound represented by the following
chemical formula 1.
[Chemical formula 1]
i 5OH
0OO
The above-mentioned ginsenoside Rg6 is a known compound and can be prepared by methods known in the art. For example, using ginsenoside Rbl or Rd as raw material, the ginsenoside Rg6 with a purity of 98% or more can be obtained through directional catalytic conversion. In the present specification, the ginsenoside F4 refers to the compound represented by the following chemical formula 2.
[Chemical formula 2] OH
_0
The above-mentioned ginsenoside F4 is a known compound and can be prepared by methods known in the art. Using the ginsenoside Rb Ior Rd as raw material, the ginsenoside F4 with a purity of 98% or more can be obtained by directional catalytic transformation. The inventors found that the combination of the ginsenoside Rg6 and the ginsenoside F4 according to the ratio range defined in the present application showed synergistic effects in improving sleep (CI value is less than 1, preferably CI value is less than 0.8, more preferably less than 0.7). The inventors also found that within the above ratio range, the ginsenoside Rg6 and the ginsenoside F4 are also low in toxicity. Moreover, the inventors found that if the contents of the ginsenoside Rg6 and the ginsenoside F4 in the pharmaceutical composition are not within the ratio range defined in the present application, there is no synergistic effect. Considering the significant synergistic effect, in the composition, the weight ratio of the ginsenoside Rg6 and the ginsenoside F4 is preferably 1.9-2.1:1, more preferably 2:1.
In the pharmaceutical composition of the present application, other ginsenosides may or may not be
comprised. When the pharmaceutical composition of the present application comprises other
ginsenosides, considering from the perspective of better synergistic effect, the content of the
ginsenoside Rg6 and the ginsenoside F4 is preferably 50 parts by weight or more, more preferably 60
parts by weight or more, more preferably 70 parts by weight or more, more preferably 80 parts by
weight or more, more preferably 90 parts by weight or more, more preferably 95 parts by weight or
more, more preferably 99 parts by weight or more, more preferably 100 parts by weight (that is, the
pharmaceutical composition comprises only the above two ginsenosides), based on 100 parts by
weight of the total ginsenosides comprised in the pharmaceutical composition. The purity of
ginsenoside Rg6 used in the pharmaceutical composition of the present application can be 98% or
more, and the purity of ginsenoside F4 can be 98% or more.
The content of the total ginsenosides can be measured by vanillin assay, and the contents of the
ginsenosides Rg6 and F4 can be measured by HPLC.
The pharmaceutical composition of the present application may comprise other sleep-improving
active ingredients or may not comprise sleep-improving active ingredients (i.e., the ginsenoside Rg6
and the ginsenoside F4 are used as the only sleep-improving active ingredients).
On the other hand, the inventors found that the pharmaceutical composition of the present application
has a significant sleep-improving effect. Therefore, the present application also provides the use of
the pharmaceutical composition of the present application in the preparation of a sleep-improving
drugs.
Pharmaceutically acceptable carriers, such as adjuvants, may be comprised in the pharmaceutical
compositions of the present application. There are no particular limitations to the adjuvants in the
pharmaceutical composition of the present application, for example, the adjuvants commonly used in
medicines or health products in the technical field can be used. Specifically, the adjuvants are starch,
dextrin, lactose, mannitol, sodium hypromellose, xanthan gum, aspartame and the like.
The dosage form of the pharmaceutical composition of the present application is not particularly
limited, for example, it may be an oral dosage form or an injection dosage form. The oral dosage
form can be a liquid dosage form or a solid dosage form. The oral dosage form can be, for example, hard capsule, soft capsule, slow-release capsule, compressed tablet, sugar-coated tablet, powder, granule, dropping pill, honeydew pill, syrup or oral liquid; the injection dosage form can be, for example, solution, suspension, emulsion or lyophilized powder. The administration mode of the pharmaceutical composition for improving sleep can be, for example, oral administration, drip or injection. When preparing a solid preparation for oral use, after adding excipients and, as needed, binders, disintegrants, lubricants, coloring agents, flavoring agents, etc. to the main drug, the tablets, coated tablets, granules, fine granules, powders, capsules, etc can be prepared according to conventional methods. As the excipients, for example, lactose, corn starch, white sugar, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc. can be used; as the binders, for example, polyvinyl alcohol, ethyl cellulose, methyl cellulose, gum arabic, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. can be used; as the lubricants, for example, magnesium stearate, talc, silicon dioxide, etc. can be used; as the coloring agents, those allowed to be added to pharmaceuticals can be used; as the flavoring agents, cocoa powder, menthol, aromatic acid, peppermint oil, borneol, and cinnamon powder can be used. Of course, the above-mentioned tablets and granules can also be coated with sugar coating, gelatin coating, and other necessary outer coatings. When preparing injections, pH adjusters, buffers,suspension auxiliary agents, solubilizers, stabilizers, isotonic agents, preservatives, etc. can be added to the main drug as needed, and then intravenous, subcutaneous, and intramuscular injections can be prepared according to conventional methods. At this time, if necessary, freeze-dried product can be prepared by conventional methods. Examples of the suspension auxiliary agents include methyl cellulose, Tween 80, hydroxyethyl cellulose, gum acacia, tragacanth gum, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate, and the like. Examples of the solubilizers include polyoxyethylene hydrogenated castor oil, Tween 80, niacinamide, polyoxyethylene sorbitan monolaurate, polyethylene glycol, castor oil fatty acid ethyl ester, and the like. Moreover, Examples of the stabilizers include sodium sulfite, sodium metasulfite, etc.; Examples of the preservatives include methylparaben, ethylparaben, sorbic acid, phenol, cresol, chlorocresol, etc.
Sleep can be improved by administering the pharmaceutical composition of the present application to
a subject. The subject may be a mammal, such as a human, a rat, a rabbit, a sheep, a pig, a cow, a cat,
a dog, a monkey, etc., preferably a human.
The pharmaceutical composition of the present application can be administered orally or parenterally.
The dosage varies depending on the degree of symptoms, patient age, sex, body weight, difference in
sensitivity, administration method, administration period, administration interval, the nature of the
pharmaceutical preparation, the type of active ingredient, etc. There is no particular limitation, but it
is usually 1 g~30000mg, preferably 10tg~3000mg, more preferably 100g~2000mg, more
preferably 1mg~1000mg, more preferably 5~900mg, more preferably 10mg~500mg, more
preferably 100mg~300mg (total of ginsenoside Rg6 and ginsenoside F4) per day for an adult (body
weight 60Kg), the above-mentioned dosage can usually be administered 1 to 3 times a day.
The present application will be further described below through specific examples. The following
examples describe the present application by way of example only, but the protection scope of the
present application is not limited thereto.
Example 1
This example provides a capsule for improving sleep, which is prepared from the following raw
materials in terms of mass: 500g of stachyose and 1OOg of starch are mixed evenly, passed through a
-80 mesh sieve, and used for later use. According to the corresponding proportion, 25g
ginsenoside Rg6, 25g ginsenoside F4, Ig vitamin, and 0.5g trace element iron were added and mixed
evenly, wet granulated with 80% ethanol, passed through a 20-80 mesh sieve, dried, granulated with
a 20 mesh sieve, and filled into capsules, each capsule comprises 300 mg.
Example 2
This example provides a tablet for improving sleep, which is prepared from the following raw
materials in terms of mass: 600g of stachyose and 100g of starch were mixed evenly, passed through
a 60-80 mesh sieve, and used for later use. According to the corresponding proportion, 28g
ginsenoside Rg6, 14g ginsenoside F4, 0.8g vitamin, and 0.5g trace element iron were added and mixed evenly, wet granulated with 80% ethanol, passed through a 20-80 mesh sieve, dried, granulated with a 20 mesh sieve, and compressed into tablets, each weighing 800 mg.
Example 3
This example provides a tablet for improving sleep, which is prepared from the following raw
materials in terms of mass: 400g of stachyose and 100g of starch were mixed evenly, passed through
a 60-80 mesh sieve, and used for later use. According to the corresponding proportion, 20g
ginsenoside Rg6, 30g ginsenoside F4, 2g vitamin, 0.3g trace element iron were added and mixed
evenly, wet granulated with 80% ethanol, passed through a 20-80 mesh sieve, dried, granulated with
a 20 mesh sieve, and compressed into tablets, each weighing 800 mg.
Example 4 Toxicity test report of sleep-improving composition
Oral toxicity test, two mutagenicity tests, mouse bone marrow polychromatic erythrocyte count
micronucleus test, sperm deformity test, safety evaluation test of 30-day feeding, and pathological
tissue examination and rat autopsy test were carried out on the products of Examples 1-3. The data of
all tests did not find that the test sample has obvious toxic effects. According to the evaluation of the
acute toxicity classification standard, the test sample is a non-toxic grade.
Example 5 Efficacy test report of sleep-improving composition
1. Materials and Methods
1.1 Raw material of the sample:
The sleep-improving composition of Example 2 was used as composition 1, and the daily intake of
an adult (60 kg) was 900 mg/60 kg BW.
In addition, Composition 2 was prepared as in Example 2, with the difference that Rg6:F4=1:2;
Composition 3 was prepared as in Example 2, with the difference that Rg6:F4=4:1.
1.2 Animal source: 90 Kunming mice, male, weighing 18-22 g, provided by the Animal Center of
Xi'an Jiaotong University, observed for 3 days before the test.
1.3 Dose selection: Mice in the experimental group were set at 150 mg/kg BW according to 10 times
the daily intake of adults and gavaged once daily, and the mice in the blank control group were given
0.5% sodium carboxymethyl cellulose by gavage once a day. The mice in the positive control group
were intraperitoneally injected with diazepam 2.5 mg/kg daily.
It was divided into 9 groups in total: taking the ratio of Example 2 as an example, set composition 1
group (150mg/kg), composition 2 group (150mg/kg), composition 3 group (150mg/kg), ginsenoside
Rg6 group (150mg/kg) kg), ginsenoside F4 group (150mg/kg), ginsenoside Rgl group (150mg/kg),
ginsenoside Rbl group (150mg/kg), blank control group, positive drug group, 10 mice in each group,
the gavage volume of each mouse was 0.2ml/lOg, once a day for 30 consecutive days.
1.4 Experimental reagents: sodium barbital and sodium pentobarbital reagents were purchased from
sigma company in the United States.
2. Experimental evaluation index
2.1 Effects of ginsenoside composition on direct sleep in mice
The mice were given the last gavage to observe whether there was sleep phenomenon. Sleep was
indicated by the disappearance of righting reflex. When the mice were placed in the dorsal
recumbent position, they could immediately turnto the right position. If the mice could not turn to
the right position for more than 30-60 s, it was considered that the righting reflex had disappeared
and the mice went to sleep. The recovery of the righting reflex indicateds that the animal is awake
and the time from the disappearance of the righting reflex to the recovery of the righting reflex was
the sleep time of the animal. The experimental results were described in the following table:
Table 1: Direct effect of ginsenoside composition on sleep in mice (n=10, x s)
group dose(mg/kg BW) Number of Number of time to fall
experimental sleeping animals asleep(min)
animals
Blank coutrol - 10 0 0
positive drug 2.5 10 0 0
Composition 1 150 10 0 0
Composition 2 150 10 0 0
Composition 3 150 10 0 0
Ginsenoside Rg6 150 10 0 0
Ginsenoside F4 150 10 0 0
Ginsenoside Rg1 150 10 0 0
Ginsenoside Rb1 150 10 0 0
After 30 days of oral administration, the mice in each experimental group moved freely without any
abnormality, no salivationand muscle tremor and none of the mice fell aspleep directly. Compared
with the blank control group, there was no significant difference in sleep time (P> 0.05).
2.2 Experiment on the effect of ginsenoside composition on the Sleep-prolonging Test of
pentobarbital sodium and sleep latency
First, determine the dose of sodium pentobarbital (50mg/kg BW) that makes the animals 100% enter
sleep without making the sleep time too long. This dose was used as the injection dose for the
Sleep-prolonging Test of pentobarbital sodium and sleep latency test. After the last administration of
mice, the animals in each group were intraperitoneally injected with sodium pentobarbital (50 mg/kg
BW), and the time from the injection of pentobarbital sodium to the disappearance of the righting
reflex, that was, the sleep latency, was recorded; the time from the disappearance of the righting
reflex to the recovery of the righting reflex was recorded, that was, sleep prolongingtime for
pentobarbital sodium. The results were shown in Table 2:
Table 2: Effects of ginsenoside composition on the Sleep-prolonging Test of pentobarbital sodium
and sleep latency (n=10, x s)
group Sleep-prolonging Test sleep latency test
dose(mg/kg) sleeping Elongation sleeping shortening
time(min) rate(%) time(min) rate(%)
Blank control - 42.72+1.69 39.09+1.14
positive drug 2.5 67.25+1.19* 57.42+2.79 28.02+1.06* 28.28+2.51
Composition 1 150 70.57+2.33*A 65.2+5.46 21.03+0.95*A 34.29+3.31
Composition 2 150 64.98+1.45* 51.16+7.31 32.12+1.9 17.86+2.21
Composition 3 150 62.63+1.07 51.34+5.3 30.02+1.7 23.21+2.21
Ginsenoside Rg6 150 57.83+1.64 52.11+3.39 31.73+1.68 18.74+4.93
Ginsenoside F4 150 59.29+2.68 42.61+2.49 30.13+2.06 22.77+6.05
Ginsenoside Rbl1 150 52.72±1.69 35.36±3.83 34.52±1.42 11.65±1.94
Ginsenoside Rgl 150 67.25±1.19* 38.79±6.28 34.24±2.24 12.25±6.65
Note: Compared with blank control group, *P<0.05; compared with ginsenosides Rg6 and F4,
AP<0.05
As can be seen from Table 2, in the Sleep-prolonging Test of pentobarbital sodium by oral
administration of different compositions to mice for 30 days, the groups of positive drug,
composition 1 and 2 and ginsenoside Rgl compared with the blank control group, had significant
differences (P<0.05), indicating that these groups of drugs have significant effects on prolonging
sleep time. And ginsenosides Rg6 and F4 were significantly different from composition 1 (P<0.05),
while not significantly different compared with composition 2 and 3 groups, indicating that the
combination of ginsenosides Rg6 and F4 in a certain ratio range (1:1-3:1) can achieve synergistic
effect. In the sleep latency experiment, there were significant differences between the positive drug
group and the composition 1 group compared with the blank control group (P<0.05), and the effect
of the composition 1 group was better than that of the positive drug group. Compared with
composition 1, ginsenosides Rg6 and F4 had significant differences (P<0.05), while compared with
compositions 2 and 3, there was no significant difference. It can be seen that the ginsenoside
composition has a significant effect on shortening the sleep latency time when Rg6 and F4 reach a
certain ratio range (1:1-3:1). Beyond this range, the sleep latency time can be shortened, but there
was no difference in the effect compared with the drug alone.
2.3 Effect of ginsenoside composition on hypnotic effect of pentobarbital sodium subthreshold dose
In the pre-experiment, the subthreshold dose of pentobarbital sodium was determined to be 28mg/kg
BW, that was, the maximum subthreshold dose of pentobarbital sodium in which 80% to 90% of
mice do not lose the righting reflex. After the last administration of mice, the animals in each group
were intraperitoneally injected with the maximum subthreshold dose of sodium pentobarbital, and
the number of animals that fell asleep within 30 min (those whose righting reflex disappeared for
more than 1 min) was recorded. Calculate the drug combination index CI=AB/(AxB) of ginsenosides
Rg6 and F4, T was the number of animals that did not fall asleep in the blank control group, C was
the number of animals that did not fall asleep in each experimental group, A and B were C/T values
of ginsenoside Rg6 and ginsenoside F4 single-administration group, AB was the C/T value of ginsenoside Rg6 and F4 in combination. When CI < 1, the two ginsenoside compositions have a synergistic effect. When CI < 0.7, the synergistic effect was very significant. The statistical results were as follows:
Table 3: Effect of ginsenoside composition on hypnotic effect of pentobarbital sodium subthreshold
dose (n=10, x s)
group dose(mg/kg BW) number of sleep incidence(%) CI value
sleeping animals
Blank control - 2 20
positive drug 0.25 5 50*
Composition 1 150 6 60* 0.89
Composition 2 150 4 40 1.33
Composition 3 150 5 50* 1.11
Ginsenoside Rg6 150 4 40
Ginsenoside F4 150 4 40
Ginsenoside Rgl 150 4 40
Ginsenoside Rbl 150 3 30
Note: Compared with blank control group, *P<0.05
As can be seen from Table 3, after oral administration of different groups of drugs to mice for 30
days, the groups of positive drug, composition 1 and composition 3 were significantly different from
the blank control group (P<0.05). The number of sleeping animals increased in other administration
groups compared with the blank control group. Compared with ginsenosides Rg6 and F4 alone, the
CI value of composition 1 was 0.89 (CI<1), indicating that ginsenosides Rg6 and F4 in certain
rations can synergistically improve sleep and increase the rate of falling asleep and are better than the
reported ginsenosides Rgl and Rbl experimental groups. However, outside the range of 1:1 to 3:1,
for example, the CI values of composition 2 and composition 3 were >1, indicating that there was no
synergistic effect.
3. Analysis on the mechanism of ginsenoside Rg6 and ginsenoside F4 synergistically improving
sleep
3.1 Sample reagents: ginsenoside Rg6 group, ginsenoside F4 group, and composition group were
prepared according to Example 2; barbital sodium and pentobarbital sodium reagents were purchased
from sigma company in the United States; 5-HT, GABA, Glu kits were purchased from Nanjing
jiancheng Bioengineering Institute.
3.2 Animal source: SD rats, male, weighing 200-250 g, provided by the Animal Center of Xi'an
Jiaotong University, and were fed adaptively at room temperature for 1 week before the experiment.
The rats were divided into 5 groups with 6 animals in each group. The rats wre moulded by
intraperitoneal injection of PCPA (400 mg/kg, for two consecutive days). The disappearance of
circadian rhythm within 28-30 hours after the first injection indicated that the model was successful.
3.3 Dose selection: Rats in the experimental groups were gavaged once daily at 150 mg/kg BW
according to 10 times the daily intake of adult. Rats in the negative control group and the model
group were gavaged with normal saline every day.
3.4 Experimental method: divided into 5 groups in total, 6 rats in each group, The gavage volume of
each rat was 0.2ml/10g and the rats were gavaged once a day for 7 consecutive days. After the last
administration, the hypothalamus was separated, weighed, and added with 9 times normal saline to
homogenize, centrifuged to take the supernatant, and the operation was performed according to the
kit instructions to measure the concentrations of 5-HT, GABA and Glu.
Table 6: Effects of ginsenosides on 5-HT, Glu and GABA levels in rats (n=10, x±s) group Number of 5-HT(ng/g) GABA(ng/g) Glu(pg/g) Glu/GABA samples Blank group 6 316+8.34 7.04+0.44 81.39+2.46 0.011+0.001 model group 6 246±7.26A 4.49±0.37A 119.59±2.03A 0.027±0.002A group Rg6 group 6 286+7.59* 4.20±0.22A 115.36±1.61A 0.027±0.001A group F4 group 6 259±10.27A 5.92+0.41* 97.99+2.26* 0.017+0.001* composition group 6 315+6.48** 6.96+0.07* 89.30+2.03* 0.013+0.0003**
Note: Compared with the blank group, AP<0.05; compared with the model group, *P<0.05
Compared with the blank group, the levels of GABA and 5-HT in the hypothalamus of the rats in
model group were significantly decreased, and the level of Glu was significantly increased. There was a significant difference between the data of each group and the model (p<0.05), indicating that the modeling was successful. Both the ginsenoside composition group and the ginsenoside Rg6 group could increase the level of 5-HT (*P<0.05), and the 5-HT level of the composition group had returned to the same level as the blank group. However, the 5-HT level of the ginsenoside F4 group was significantly different from that of the blank group ("p<0.05), indicating that the level of 5-HT in the ginsenoside F4 group did not return. For the level of Glu/GABA, there was a statistical difference between the ginsenoside Rg6 group and the blank group (^P <0.05), indicating that the
Glu/GABA level did not return.There was a statistical difference among the ginsenoside F4 group,
the composition group and the model group (*P<0.05), indicating that taking ginsenoside F4 and the
composition could significantly reduce Glu/GABA levels and the composition group could return
Glu/GABA to normal levels (comparable to the blank group).
-HT is one of the important neurotransmitters in sleep regulation and maintains the sleep-wake
rhythm. 5-HT is mostly distributed in the middle raphe of the brain stem, which can regulate and
maintain the quality of slow-wave sleep and play an important role in the recovery of fatigue.
Ginsenoside Rg6 can increase the level of 5-HT in the brain. The ratio of Glu/GABA has a decisive
effect on the sleep-wake system. When the level of Glu increases, neurons are excited, which
promotes the awakening of the body. When the level of GABA increases, the excitation of neurons is
inhibited, which promotes sleep in the body. Ginsenoside F4 can improve the GABA level in the
brain tissue while reducing the Glu level, thereby reduces the Glu/GABA ratio and helps maintain
the sleep state of the rats. When ginsenosides Rg6 and F4 are used in combination, the content of
-HT increases and Glu/GABA decreases at the same time. Through the combined action of the two
pathways, the effect of sleep improvement can be achieved. Ginsenosides Rg6 and F4 used in
combination showed superior effects in improving sleep phenology (prolonging sleep time,
shortening sleep latency time and increasing sleep incidence) than when used alone, indicating that
the two monomers are synergistic effect when used in combination.
It should be noted that, on the premise that it can be implemented and does not obviously violate the
gist of the present application, any technical feature or combination of technical features described in
this specification as a constituent part of a technical solution can also be applied to other technical
solutions; and, on the premise that it can be implemented and does not obviously violate the gist of the present application, the technical features described as constituent parts of different technical solutions can also be combined in any way to form other technical solutions. The present application also includes technical means obtained by combining in the above-mentioned cases, and these technical solutions are equivalent to being described in this specification. The present application has been described above through specific embodiments and examples, but those skilled in the art should understand that these are not intended to limit the scope of the present application, which should be determined by the claims.
INDUSTRIAL APPLICABILITY The present application provides a rare ginsenoside pharmaceutical composition comprising rare ginsenosides Rg6 and F4, which is synergistic and has the effect of promoting sleep.
Claims (10)
1. A pharmaceutical composition for improving sleep, comprising an effective amount of
ginsenoside Rg6 and ginsenoside F4 as active ingredients for improving sleepand a pharmaceutically
acceptable carrier,
wherein in the pharmaceutical composition, the weight ratio of the ginsenoside Rg6 to the
ginsenoside F4 is 1:1-3:1.
2. The pharmaceutical composition according to claim 1, wherein in the pharmaceutical composition,
the weight ratio of the ginsenoside Rg6 to the ginsenoside F4 is 2:1.
3. The pharmaceutical composition according to claim 1, wherein based on 100 parts by weight of
the total ginsenosides comprised in the pharmaceutical composition, the total amount of the
ginsenoside Rg6 and the ginsenoside F4 comprised in the pharmaceutical composition is 10 parts by
weight or more, preferably 50 parts by weight or more.
4. The pharmaceutical composition according to claim 1, wherein based on 100 parts by weight of
the total ginsenosides comprised in the pharmaceutical composition, the total amount of the
ginsenoside Rg6 and the ginsenoside F4 comprised in the pharmaceutical composition is 100 parts
by weight.
5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition
does not comprise other sleep-improving active ingredients other than the ginsenoside Rg6 and the
ginsenoside F4.
6. Use of ginsenoside Rg6 and ginsenoside F4 in the preparation of a pharmaceutical composition for
improving sleep, wherein in the pharmaceutical composition, the weight ratio of the ginsenoside Rg6
to the ginsenoside F4 is 1:1-3:1.
7. The use according to claim 6, wherein in the pharmaceutical composition, the weight ratio of the
ginsenoside Rg6 to the ginsenoside F4 is 2:1.
8. The use according to claim 6, wherein based on 100 parts by weight of the total ginsenosides
comprised in the pharmaceutical composition, the total amount of the ginsenoside Rg6 and the
ginsenoside F4 comprised in the pharmaceutical composition is 10 parts by weight or more,
preferably 50 parts by weight or more.
9. The use according to claim 6, wherein based on 100 parts by weight of the total ginsenosides
comprised in the pharmaceutical composition, the total amount of the ginsenoside Rg6 and the
ginsenoside F4 comprised in the pharmaceutical composition is 100 parts by weight.
10. The use according to claim 6, wherein the pharmaceutical composition does not comprise other
sleep-improving active ingredients other than the ginsenoside Rg6 and the ginsenoside F4.
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PCT/CN2021/089324 WO2021213502A1 (en) | 2020-04-24 | 2021-04-23 | Sleep-improving pharmaceutical composition containing rare ginsenosides rg6 and f4 |
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