CN113559128B - New use of five-cereal insects for improving sleep - Google Patents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/63—Arthropods
- A61K35/64—Insects, e.g. bees, wasps or fleas
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The present application relates to the use of five cereal worms or extracts thereof for improving, preventing and/or treating sleep disorders. The application also provides a pharmaceutical composition for improving, preventing and/or treating sleep disorders, comprising five cereal worms or extracts thereof and calcium levofolinate.
Description
Technical Field
The application relates to a new application of an anticancer drug, namely, five-cereal worms, in particular to an application of the five-cereal worms or extracts thereof in preparing a medicament for improving sleep.
Background
Insomnia is a condition of difficulty falling asleep and/or sustained feeling of sleep deficiency without obvious cause, possibly due to various emotional and physical disorders. Insomnia is the most common sleep disorder affecting millions of people as a primary or co-existence condition. Sleep disorders include six major categories: (1) insomnia, (2) hypersomnia, (3) sleep abnormality (paramnia), (4) circadian rhythm sleep-wake disorder (circadianrhythm sleep-wake disorder), (5) sleep-related respiratory disorder (sleep-related breathing disorder), and (6) sleep dyskinesia (sleep movement disorder). Sleep disorders create significant pain and/or dysfunction in people suffering from the disorder, requiring proper treatment.
The international sleep fund has been shown to be positively correlated with various diseases accompanying aging of the human body, and can increase the risk of onset of age-related chronic diseases such as congestive heart failure, renal failure, chronic obstructive pulmonary disease, cerebral apoplexy, parkinson's disease, diabetes, etc. The subtype of insomnia has sleep-onset difficulty type insomnia, sleep-maintenance difficulty type insomnia, early-wake type insomnia and heart-cause insomnia, and the sleep-maintenance difficulty type insomnia and the early-wake type insomnia of the old are common. Depending on the course of sleep disturbance, insomnia can be classified into acute or short-term insomnia (course < 1 month), persistent insomnia (course > 4 weeks), and chronic insomnia (course > 6 months).
There are a number of drugs in the prior art that alleviate sleep through a number of mechanisms. For example benzodiazepinesMedicaments such as lorazepam, temazepam, and the like, barbiturates such as phenobarbital, pentobarbital, and the like, and z-medicaments such as zaleplon, zolpidem, zopiclone, and the like. Benzodiazepine->The drug enhances GABA by increasing the frequency of chloride channel opening. Barbiturates potentiate GABA by increasing the duration of the chloride channel opening. z-drugs are agonists of the GABAa γ1 subunit. HoweverThese drugs generally have a long half-life and various side effects such as confusion, depression, etc., and long-term administration can result in high addictive potential.
The five-cereal insect is larva or pupa shell of Chrysomya megacephala or other closely related insects of the family of the Liriomyza, and the insect body is flat and cylindrical, has the length of 1-1.5cm, the width of 2-3mm, and is yellow-white and somewhat transparent. Five cereal worms are cold in nature, sweet in taste, salty and bitter in taste, five toxins enter spleen and stomach meridians, and have the functions of strengthening spleen to remove food, removing heat to remove infantile malnutrition and the like. The existing researches show that the five-cereal worm extract can kill escherichia coli, staphylococcus aureus and the like, has broad-spectrum antibacterial activity, can promote wound healing, resist atherosclerosis and reduce blood fat, and has inhibitory activity on leukemia cells, lung cancer cells, HIV-1 integrase and the like. However, there are no reports on the use of the wugu worm extract for treating insomnia.
The calcium levofolinate is also known as levofolinate, is commonly used as an antitumor auxiliary drug, is used together with fluorouracil to enhance the curative effect of the levofolinate, is used for treating tumors such as gastric cancer, colon cancer, rectal cancer and the like, can be used for preventing or treating high-dose folic acid antagonist poisoning, and is used for preventing or treating megaloblastic anemia caused by folic acid deficiency. Folic acid antagonists such as methotrexate bind to dihydrofolate reductase and block the conversion of folic acid to tetrahydrofolate. The calcium levofolinate can directly provide active folic acid, has the function of rescuing the toxic reaction of excessive folic acid antagonist in vivo and is beneficial to dTMP, DNA, RNA and protein synthesis.
Through years of research, the inventor discovers that the five-cereal worm extract has good effects of improving sleep disorder and treating insomnia. Furthermore, the inventor unexpectedly found that the composition of the five-cereal worm extract and the calcium levofolinate has a synergistic effect through one accidental mishandling, and can greatly improve the treatment effect on sleep disorders, particularly insomnia. The calcium levofolinate does not have pharmacological action for improving sleep, but can obviously enhance the activity of the five-cereal worm extract for improving sleep disorder and treating insomnia when being combined with the five-cereal worm extract, and the specific pharmacological action mechanism is unknown.
Disclosure of Invention
In one aspect of the present application, there is provided a pharmaceutical composition for improving, preventing and/or treating sleep disorders, comprising wu chong or an extract thereof and calcium levofolinate.
In another aspect of the application, the pharmaceutical composition, wherein the five cereal worm extract is prepared according to the following method:
(1) Freeze-drying artificially cultured five-cereal worms, crushing, sieving, and performing supercritical extraction with carbon dioxide fluid to obtain a crude product;
(2) Adding 3% distilled water into the crude product obtained in the step 1, and stirring and mixing; centrifuging to remove precipitate and obtain degummed oil;
(3) Adding sodium hydroxide into the degummed oil obtained in the step 2, stirring, condensing and centrifugally separating; adding distilled water into the supernatant, stirring, standing, separating, repeating for 1-3 times until the lower water and phenolphthalein are not discolored; taking supernatant for later use;
(4) Decolorizing the supernatant with activated carbon adsorbent: the addition amount of the active carbon is 4%, the decoloring temperature is 90 ℃, the decoloring time is 90 minutes, and the process is repeated three times to obtain the five-cereal worm extract.
In another aspect of the application, the pharmaceutical composition wherein the mass ratio of the wuliangye or extract thereof and the calcium levofolinate is 0.1-50:1, preferably 20:1, 10:1 or 5:1.
In another aspect of the application, the pharmaceutical composition comprises a pharmaceutically acceptable carrier.
In another aspect of the application, the pharmaceutical composition is a tablet, capsule, granule, injection, nasal drop, inhalant, sustained release formulation, aerosol or film.
In another aspect of the application, there is provided the use of said pharmaceutical composition for the manufacture of a medicament for the prevention and/or treatment of sleep disorders. The sleep disorder includes insomnia.
In another aspect of the present application, there is provided a medicament for improving, preventing and/or treating sleep disorders, comprising a five-cereal worm or an extract thereof.
In another aspect of the application, there is provided the use of a five-cereal worm or an extract thereof in the manufacture of a medicament for the prevention and/or treatment of sleep disorders.
In another aspect of the application, the sleep disorder is insomnia.
In another aspect of the present application, a method for preparing a five cereal worm extract is provided:
(1) Freeze-drying artificially cultured five-cereal worms, crushing, sieving, and performing supercritical extraction with carbon dioxide fluid to obtain a crude product;
(2) Adding 3% distilled water into the crude product obtained in the step 1, and stirring and mixing; centrifuging to remove precipitate and obtain degummed oil;
(3) Adding sodium hydroxide into the degummed oil obtained in the step 2, stirring, condensing and centrifugally separating; adding distilled water into the supernatant, stirring, standing, separating, repeating for 1-3 times until the lower water and phenolphthalein are not discolored; taking supernatant for later use;
(4) Decolorizing the supernatant with activated carbon adsorbent: the addition amount of the active carbon is 4%, the decoloring temperature is 90 ℃, the decoloring time is 90 minutes, and the process is repeated three times to obtain the five-cereal worm extract.
Detailed Description
Through many years of research, the inventor of the present application has found that the five-cereal worms or the extracts thereof have effective pharmacological activity for preventing and/or treating sleep disorders (preferably insomnia). Further, the combination of the five-cereal insects or the extracts thereof and the calcium levofolinate in a specific proportion can further enhance the activity of improving sleep disorder and has a synergistic effect.
The units of measure according to the application are, unless otherwise specified, mass.
In one aspect of the application, there is provided the use of a five cereal worm or an extract thereof in the manufacture of a medicament for the prevention and/or treatment of sleep disorders.
In one aspect of the application, a pharmaceutical composition is provided comprising wuliangye or an extract thereof and calcium levofolinate.
In another aspect of the application, there is provided the use of said pharmaceutical composition for the manufacture of a medicament for the prevention and/or treatment of sleep disorders.
The five cereal worm extract is prepared according to the following method:
1. freeze-drying artificial breeding of five-cereal worms, crushing, sieving, and performing supercritical extraction with carbon dioxide fluid to obtain a crude product.
2. Adding 3% distilled water into the crude product obtained in the step 1, and stirring and mixing; and (5) centrifugally separating, and removing sediment to obtain the degummed oil.
3. And (3) adding sodium hydroxide into the degummed oil obtained in the step (2), stirring, condensing and centrifugally separating. Adding distilled water into the supernatant, stirring, standing, separating, and repeating for 1-3 times until the lower water and phenolphthalein are not discolored. Taking the supernatant for later use.
4. Decolorizing the supernatant with activated carbon adsorbent: the addition amount of the active carbon is 4%, the decoloring temperature is 90 ℃, the decoloring time is 90 minutes, and the process is repeated three times to obtain the five-cereal worm extract.
In another aspect of the application, the content of the five-cereal worm extract in the medicament is 0.1-99.9%.
In another aspect of the application, the medicament comprises five cereal worms or extracts thereof and a pharmaceutically acceptable carrier.
In another aspect of the application, the medicament is in the form of a pharmaceutically acceptable formulation.
In another aspect of the application, the pharmaceutical composition is in the form of a pharmaceutically acceptable formulation.
In another aspect of the application, the mass ratio of the five cereal worms or the extracts thereof to the calcium levofolinate in the pharmaceutical composition is 0.1-50:1.
In another aspect of the application, the mass ratio of the five cereal worms or the extracts thereof to the calcium levofolinate in the pharmaceutical composition is 1-30:1.
In another aspect of the application, the mass ratio of the five cereal worms or the extracts thereof to the calcium levofolinate in the pharmaceutical composition is 2-25:1.
In another aspect of the application, the mass ratio of the five cereal worms or extracts thereof to the calcium levofolinate in the pharmaceutical composition is 20:1.
In another aspect of the application, the mass ratio of the five cereal worms or the extracts thereof to the calcium levofolinate in the pharmaceutical composition is 10:1.
In another aspect of the application, the mass ratio of the five cereal worms or the extracts thereof and the calcium levofolinate in the pharmaceutical composition is 5:1.
In another aspect of the application, the formulation forms include tablets, capsules, granules, injections, nasal drops, inhalants, sustained release agents, aerosols, films and the like.
In another aspect of the application, the combination of the five-cereal worm or an extract thereof and calcium levofolinate is a "combination or pharmaceutical composition for simultaneous, separate or sequential use", particularly a "kit of parts" meaning that the five-cereal worm or an extract thereof and calcium levofolinate may each be administered independently or by different fixed combinations with different component contents, i.e. at different points in time or simultaneously. The components of a component package may be administered, for example, simultaneously or at time-sequential intervals, i.e., any component of the component package is administered at different points in time and at the same or different time intervals. Preferably, the time intervals are selected such that the effect of the combination of the components on the treated disease or condition is higher than the effect obtained with any of the components alone.
The term "preventing" refers to the prophylactic administration of the combination to healthy patients to prevent the occurrence of the diseases and disorders described herein. Furthermore, the term "preventing" may also refer to the prophylactic administration of the combination to a patient in the pre-stage of the disease to be treated.
A therapeutically effective amount of each component of the combination of the application may be used simultaneously or in any order, and the components may be administered separately or as a fixed combination. The individual components of the combination may be administered separately at different times during the treatment or concurrently in divided or single combination forms. Furthermore, the term "use" also includes the use of prodrugs of any drugs that are convertible in vivo into the selected drug. Accordingly, the present application should be understood to include all such concurrent or alternating treatment regimens, and the term "use" should be interpreted accordingly.
The preferred route of administration of the dosage forms of the application is enteral or preferably oral. Tablets and capsules represent the best oral dosage unit form due to ease of administration.
The effective dosage of each active ingredient used in combination therapy may vary with the particular pharmaceutical composition employed, the manner of use, or the severity of the condition being treated.
Pharmaceutically acceptable carriers used in the medicament of the application include fillers, diluents, excipients, stabilizers, antioxidants, disintegrants, binders, lubricants, preservatives, colorants and the like.
Preferably, the filler is at least one selected from starch, pre-cross-linked starch, dextrin, chitosan, mannose, microcrystalline cellulose, polyanhydrides, polyphosphates, polyurethanes, fibrin, liposomes, polyethylene glycol, galactose, povidone.
Preferably, the diluent is at least one selected from mannitol, microcrystalline cellulose, lactose, starch, saccharin.
Preferably, the stabilizer is at least one selected from cyclodextrin and its derivatives, polyethylene glycol, tween, span, dextran, mannitol.
Preferably, the antioxidant is at least one selected from vitamin C, sodium metabisulfite, benzoic acid, citrate, sorbic acid, sodium sulfite, sodium bisulphite and sodium thiosulfate.
Preferably, the disintegrant is selected from croscarmellose sodium, crospovidone, hydroxypropyl cellulose, hydroxypropyl starch, polysorbate 80, sodium lauryl sulfate, and the like.
Preferably, the binder is selected from hydroxypropyl methylcellulose, povidone, starch, dextrin, microcrystalline cellulose, sodium alginate, methylcellulose, and the like.
Preferably, the lubricant is selected from stearic acid, magnesium stearate, talc, polyethylene glycol, sodium lauryl sulfate and the like.
Preferably, the preservative is selected from benzoic acid, nipagin, sorbic acid, ethanol and the like.
Detailed Description
Example 1: preparation of five cereal worm extract
The five-cereal worm extract is prepared according to the following method:
1. freeze drying artificial breeding five-cereal insects, pulverizing, sieving with 60 mesh sieve, supercritical extracting with carbon dioxide fluid at pressure of 25MPA and temperature of 50deg.C, and CO 2 The flow rate was 25L/h, and extraction was carried out for 2 hours to give a crude product.
2. Heating the crude product obtained in the step 1 to 80 ℃, adding distilled water with the temperature of 80 ℃ and the volume of 3 percent of the crude product, stirring for 30 minutes, and fully mixing; and (5) centrifugally separating at 5000r/min, and removing sediment to obtain the degummed oil.
3. Heating the degummed oil obtained in the step 2 to 60 ℃, adding 0.3% (w/w) sodium hydroxide, stirring for 1 hour, heating to 80 ℃, forming floccules, condensing, and centrifuging at 5000 r/min. Heating the supernatant to 80deg.C, adding 80-85deg.C distilled water 30% of the supernatant volume, stirring for 30min, standing, separating with separating funnel, heating the supernatant again, adding water, stirring, standing, measuring pH of the separated lower water, repeating for 3 times, and adding phenolphthalein into the lower water without color change. Taking the supernatant for later use.
4. Decoloring by using an adsorbent: adding activated carbon with volume of 4% of the supernatant, decolorizing at 90deg.C for 90min, and repeating for three times to obtain the final product.
Example 2: pharmacological test for improving sleep disorder
1. Test method
60 ICR mice, male, weighing 18-22 g,6-8 weeks old. The animals are placed at room temperature (22+/-1) DEG C, relative humidity of 65% and normal circadian rhythm regulation illumination time environment, and eat standard feed and drink water freely.
In the experiment, a fatigue insomnia model is caused by combining treadmill force training with intraperitoneal injection of PCPA (p-phenylalanine), and the sleeping function of a mice with the fatigue insomnia model is improved by exploring the five cereal worm extract.
In addition to the blank group, the other groups of mice were subjected to 30min of mouse treadmill training (25 m/min), 1 time a day, for 7 consecutive days. On day 8, PCPA (250 mg/kg) suspension was injected intraperitoneally, and after drug injection, mice developed contracture pain, and symptoms were relieved after 30-60 min. And evaluating whether the model is successful or not according to the sign change and the measurement index of the mice. After modeling for 2 days, the mice have sleep disorder, are easy to frighten and slow to move, which indicates that the model of consumptive disease and insomnia is successfully modeled.
80 mice were divided into 8 groups according to a random principle, each group of 10 mice, namely a blank group, a model group, a five-cereal worm extract group, a calcium left folinate group, a five-cereal worm extract+calcium left folinate group 1-3 and a positive control group. The five-cereal worm extract group (40 mg/kg), the left calcium folinate group (4 mg/kg), the five-cereal worm extract+the left calcium folinate group 1 (20 mg/kg+1 mg/kg), the five-cereal worm extract+the left calcium folinate group 2 (20 mg/kg+2 mg/kg), the five-cereal worm extract+the left calcium folinate group 3 (20 mg/kg+4 mg/kg) were respectively intragastized. The blank group and the model group are respectively irrigated with distilled water of the same volume, the positive control drug is diazepam, and the administration dosage of mice is 0.75mg/kg. The above groups were intragastric, 1 time daily, for 15 days.
Each group of mice was observed for feed intake/d, body weight, spirit, activity, posture, hair and serum 5-HT, DA and ACTH levels. Treatment 15d, mice in each group fasted for 12h, and blood was taken from the broken head. Standing blood at 4deg.C for 90min, centrifuging at 3500r/min for 10min, collecting serum, and storing at-20deg.C in refrigerator. Serum 5-HT, DA and ACTH levels were determined by enzyme-linked immunosorbent assay (ELISA) using serum.
2. Experimental results.
1. Mice signs change.
After administration, the feeding amount of mice starts to be recovered to be normal after the five-cereal worm extract group, the five-cereal worm extract and the calcium levofolinate 1-3 group and the positive control group are subjected to gastric lavage, the body weight is increased to different degrees, the actions are gradually normal, the body is stretched, the hair color is glossy, the skin mucosa is pink, compared with the normal mice, the mice have no difference, and the sleep rhythm is recovered to be normal.
Mice in the model group and the calcium levofolinate group still have sleep disorder, dry hair color and slow movement, and have no obvious improvement.
2. Effects on serum 5-HT, DA and ACTH levels
TABLE 1 influence on serum 5-HT, DA and ACTH levels
As can be seen from table 1, the serum 5-HT, DA and ACTH levels were significantly reduced in the mice of the model group (P < 0.01) compared to the blank group, indicating successful modeling; compared with the model group, the five-cereal worm extract plus the calcium levofolinate 1-3 group and the positive control group can obviously raise 5-HT, DA and ACTH (P < 0.01), which shows that the compound is effective for treating the sleep disorder of mice.
Example 3 evaluation of sleep improvement function Using sleep improvement function test method
1. Experimental method
ICR mice 120, male, weighing 18-22 g,6-8 weeks old. The animals are placed at room temperature (22+/-1) DEG C, relative humidity of 65% and normal circadian rhythm regulation illumination time environment, and eat standard feed and drink water freely.
60 mice were used for the direct sleep experiment and 60 mice were used for the barbituric sodium sleep latency experiment. Each experiment randomly divided animals into a five cereal worm extract group, a left calcium folinate group, a five cereal worm extract+left calcium folinate 1-3 group and a negative control group, each group of 10 animals. The amount of each drug was as in example 2, and the negative control group was given an equal amount of distilled water by oral gavage, 1 time a day, for 30 days.
The method is carried out according to the method of health food inspection and evaluation technical Specification of Ministry of health. Improving sleep function tests include: direct sleep experiments and barbital sodium sleep latency experiments.
(1) Direct sleep experiment: the animals in the administration group were observed for sleep after administration of the test sample and the negative control group was given the same volume of distilled water. Sleep is indicated by the disappearance of the eversion and the reflection. If the patient cannot turn over for more than 30-60s, the patient considers that the turning over and the reflection disappear and goes to sleep. The recovery of the regular reflection is the awakening, and the period from the disappearance of the regular reflection to the recovery is the sleeping time of the animal. The number of animals falling asleep and the sleep time of the negative control group and the administration group were recorded.
(2) Barbital sodium sleep latency experiment: pre-experiments are carried out before formal experiments are carried out, and the dosage of barbital sodium which enables the animal to fall asleep 100% but does not enable the animal to sleep for too long is determined, and the dosage is used for formal experiments. After 15min of the last administration of animals, each group of animals is injected with barbital sodium in the abdominal cavity (the experimental dose is 280 mg/kgBW), the injection amount is 0.1mL/10g BW, the disappearance of the everlasting reflection is taken as an index, and the influence of the sample on the sleeping latency of the barbital sodium is observed.
2. Experimental results.
(1) Direct sleep.
After administration, each group of mice shows symptoms of quietness, reduced autonomous activity and the like, and individual mice enter a sleep state, and particularly, the combined administration of the five-cereal worm extract and the calcium levofolinate has more sleep mice, which indicates that the combined administration has the effect of promoting sleep.
TABLE 2 influence on the direct sleep of mice
(2) Effect on pentobarbital sodium sleep time.
The sleep time of mice in each administration group is prolonged compared with that of mice in a negative control group under the hypnotic effect of pentobarbital sodium, wherein the combination administration group and the negative control group have a significant difference (P < 0.01), which indicates that the sample has the effect of prolonging the sleep time of pentobarbital sodium.
TABLE 3 influence on sodium pentobarbital sleep time
| Grouping | Number of mice (Only) | Sleep time (min) |
| Negative control group | 10 | 19 |
| Five cereal worm extract group | 10 | 28 |
| Calcium levofolinate group | 10 | 18 |
| Five cereal worm extract + calcium levofolinate group 1 | 10 | 37 |
| Five cereal worm extract+calcium levofolinate group 2 | 10 | 45 |
| Five cereal worm extract+calcium levofolinate 3 group | 10 | 46 |
3. Conclusion(s)
(1) The composition of the five-cereal worm extract and the calcium levofolinate can effectively promote the sleep of mice and prolong the sleeping time of pentobarbital sodium. In particular, the combined administration group of the five-cereal worm extract and the calcium levofolinate can significantly promote and prolong the sleep of mice, and has a synergistic effect compared with the single use of the five-cereal worm extract.
(2) The calcium levofolinate is used alone without a sleep-promoting effect, but the calcium levofolinate can obviously enhance the sleep-promoting effect of the five-cereal worm extract.
(3) The sleeping-promoting synergistic effect of the combination of the wugu chong extract and the calcium levofolinate is dose-independent.
Example 3: preparation of tablets
60g of five-cereal worm extract
Calcium levofolinate 3g
Taking the active ingredients, adding proper amount of conventional auxiliary materials for preparing tablets, uniformly mixing, and preparing 1000 tablets by a conventional tabletting machine.
Example 4: preparation of tablets
50g of five-cereal worm extract
Calcium levofolinate 5g
Taking the active ingredients, adding proper amount of conventional auxiliary materials for preparing tablets, uniformly mixing, and preparing 1000 tablets by a conventional tabletting machine.
Example 5: preparation of capsules
50g of five-cereal worm extract
Calcium levofolinate 10g
Mixing the above active ingredients with appropriate amount of conventional adjuvants for preparing capsule, and making into 1000 tablet.
Claims (6)
1. A pharmaceutical composition for improving, preventing and/or treating sleep disorders comprising a wu-chong extract and calcium levofolinate; wherein the mass ratio of the five cereal worm extract to the calcium levofolinate is 5-20:1; wherein the five cereal worm extract is prepared according to the following method:
(1) Freeze-drying artificially cultured five-cereal worms, crushing, sieving, and performing supercritical extraction with carbon dioxide fluid to obtain a crude product;
(2) Adding 3% distilled water into the crude product obtained in the step 1, and stirring and mixing; centrifuging to remove precipitate and obtain degummed oil;
(3) Adding sodium hydroxide into the degummed oil obtained in the step 2, stirring, condensing and centrifugally separating; adding distilled water into the supernatant, stirring, standing, separating, repeating for 1-3 times until the lower water and phenolphthalein are not discolored; taking supernatant for later use;
(4) Decolorizing the supernatant with activated carbon adsorbent: the addition amount of the active carbon is 4%, the decoloring temperature is 90 ℃, the decoloring time is 90 minutes, and the process is repeated three times to obtain the five-cereal worm extract.
2. The pharmaceutical composition of claim 1, wherein the mass ratio of the wuliangye extract to the calcium levofolinate is 20:1, 10:1 or 5:1.
3. The pharmaceutical composition of any one of claims 1-2, comprising a pharmaceutically acceptable carrier.
4. The pharmaceutical composition according to claim 3, which is a tablet, capsule, granule, injection, nose drops, inhalant, sustained-release preparation, aerosol or film.
5. Use of a pharmaceutical composition according to any one of claims 1-4 for the preparation of a medicament for improving, preventing and/or treating sleep disorders.
6. The use according to claim 5, wherein the sleep disorder is insomnia.
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