CN105902536B - Application of the loganin in the drug that preparation improves sleep - Google Patents
Application of the loganin in the drug that preparation improves sleep Download PDFInfo
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- CN105902536B CN105902536B CN201610375109.2A CN201610375109A CN105902536B CN 105902536 B CN105902536 B CN 105902536B CN 201610375109 A CN201610375109 A CN 201610375109A CN 105902536 B CN105902536 B CN 105902536B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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Abstract
The invention belongs to compound medicine fields, are related to the purposes of the new medicine use of loganin, especially loganin in the drug or health care product that preparation improves sleep.Loganin (Loganin) provided by the invention is one of the main chemical compositions of Cornaceae plant Fructus Corni (Cornus officinalis), chemical formula C17H26O10, molecular weight 390.38；Animal experiment proves that loganin extends mice sleep total duration in which can dramatically, and have the characteristics that dose-dependently to increase amount of sleep；Preliminary study on mechanism shows that loganin may be by increasing 5-HT level in mouse brain and carry out induced hypnotic.To sum up, loganin can be prepared into drug and health care product with sedative-hypnotic effect, and manufactured dosage form includes granule, tablet, capsule, granule, electuary, oral solution, dripping pill, pellet or injection.
Description
Technical field
The invention belongs to drug fields, and being related to the new medicine use of loganin, especially loganin in preparation improves sleep
Application in drug.
Technical background
The one third of life is spent in sleep, and only possessing good sleep could maintain normally to live, work
And study, it may be said that sleep is to maintain the premise and basis of mankind's activities.But more and more recently as social competition
Fierce and people's rhythm of life continuous quickening, sleep disturbance problem has been increasingly becoming the puzzlement of people, wherein performance outstanding
For insomnia.It is studied according to the World Health Organization, there are sleep disturbance by the people in the whole world current about 66%, and in China, insomnia rate is also high
Up to 10%~20%.Insomnia be not only easy to cause organic disease, can also make one immunity degradation, make people body consume compared with
Greatly, chronic insomnia more easily causes the damage of physiology and psychology.In short, insomnia has become the society for seriously affecting people's physical and mental health
One of problem.
The drug for treating insomnia mainly has barbiturates, Benzodiazepines, Non-benzodiazepine.The calmness of these early stages is urged
The long-term use of dormancy drug is easy to produce dependence, and larger dose can cause dizzy out of strength, dispersion attention, learning and memory energy often
Power decline, long-term administration hang-up will appear the adverse reactions such as rebound phenomenon or withrawal symptom.Therefore people have been devoted to pursue
Security window is bigger, smaller on sleep influence structure, the lighter novel sedative hypnotic drug of adverse reaction.
Many Chinese medicines have long-term clinical application history in terms of improving and treating sleep disturbance, these Chinese Herbs are true
It cuts, and adverse reaction is small, has become the hot spot of people's research.The study found that semen ziziphi spinosae, the seed of Oriental arborvitae, ganoderma lucidum, Schisandra chinensis etc.
Chinese medicine and its extract have the effect for improving significantly and promoting sleep.Therefore, finding to develop from Chinese medicine improves and treats
The new drug of sleep disturbance has great importance.
Loganin (Loganin) belongs to iridoid, is Cornaceae (Cornaceae) plant Fructus Corni
One of the principle active component of (Cornus officinalis).Studies have shown that loganin have it is hypoglycemic (Toxicology,
2011,290 (1): 14-21), anti-oxidant, anti-inflammatory (modern medicines and clinical, 2009,24 (5): 272-275) and other effects, can use
To improve the metabolic disorder of the organs such as liver, help to inhibit metabolic disease (such as hyperglycemia, hyperlipidemia), oxidative stress and inflammation
The formation (Drug Discov Ther, 2010,4 (4): 223-234.) of disease.However, loganin improve or treatment sleep disturbance,
The pharmacological action and clinical application for extending sleeping time etc., so far there is not yet any research.
The current Chinese invention patent in relation to loganin only visible preparation method (CN104447910A), content assaying method
(CN103808811A) and in terms of preparation treatment diabetes medicament (CN103110651A), have no any in terms of improving sleep
Report.
Summary of the invention
The object of the present invention is to provide a kind of new pharmaceutical usage of loganin, it is found that loganin has in terms of improving sleep
Good effect, the improvement sleep include hypnosis and improvement sleep quality.
Technical scheme is as follows:
The application of a kind of loganin in the drug that preparation improves sleep, which is characterized in that the loganin is such as following formula
(1) compound:
The English name of the loganin: loganin；Molecular weight: 390.38；Molecular formula: C17H26O10。
The improvement sleep includes syngignoscism and improvement sleep quality effect.
The improvement sleep effect is that the insomnia of 5-HT receptor antagonist PCPA induction is reversed to realize by loganin.
In specific application, the dosage of loganin is 5-80mg/kg, preferably 45-65mg/kg.
Further, in said medicine, one or more pharmaceutically acceptable carriers can be added as needed.
Further, said medicine can be prepared into granule, tablet, capsule, granule, electuary, oral solution, drop
Ball, pellet or injection.
For the medicine preparation at tablet, the tablet includes following component: loganin, microcrystalline cellulose, talcum powder, dimension life
Plain C, magnesium stearate, dehydrated alcohol, dosage of each component according to said preparation general dosage.
For the medicine preparation at capsule, the capsule includes following component: loganin, starch, pyrosulfurous acid hydrogen receives,
Magnesium stearate, dehydrated alcohol, dosage of each component according to said preparation general dosage.
For the medicine preparation at granule, the granule includes following component: loganin, starch, sodium hydrogensulfite, hard
Fatty acid magnesium, dehydrated alcohol, dosage of each component according to said preparation general dosage.
For the medicine preparation at pill, the pill includes following component: loganin, vitamin C, polyethylene glycol
6000, dosage of each component according to said preparation general dosage.
For the medicine preparation at micropill preparation, the micropill preparation includes following component: loganin, sucrose, sodium hydrogensulfite, hydroxyl
Third methylcellulose, talcum powder, dosage of each component according to said preparation general dosage.
For the medicine preparation at injection, the injection includes loganin, vitamin C, sodium chloride, sodium bicarbonate, note
Penetrate with water, dosage of each component according to said preparation general dosage.
Preferably, the medicine preparation is at oral solution, which is characterized in that includes following component in every 100ml oral solution:
Active constituent: loganin 90-110mg；
Stabilizer: benzyl alcohol 0.1-1.5ml；
Solubilizer: or mixtures thereof beta-cyclodextrin or lauryl sodium sulfate 0.1-1.5mg；
Corrigent: D-Glucose aldehydic acid-δ lactones 0.01-0.2mg；
Solvent: the aqueous solution of oxalic acid, wherein containing oxalic acid 0.75g in every 100ml water.
Preferably, the dosage of the loganin is 95-100mg；More preferable 98mg；
Preferably, the mixture that the solubilizer is beta-cyclodextrin and lauryl sodium sulfate weight ratio is 1:1；It is preferred that increasing
The dosage of solvent is 1mg.
Prepare the process of above-mentioned Strychnos nux-vomica glucoside oral liquid, comprising the following steps:
(1) the corrigent D-Glucose aldehydic acid-δ lactones is added in the aqueous solution of the solvent oxalic acid, stirs to complete
Portion's dissolution；
(2) it is subsequently added into the active constituent loganin, solubilizer, is stirred until homogeneous dissolution；
(3) the stabilizer benzyl alcohol is added, after mixing evenly, adds medicinal active carbon, institute is prepared after filtering
State Strychnos nux-vomica glucoside oral liquid.
About technical effect of the invention: by loganin to above threshold dose of sodium pentobarbitone induced mice sleeping time and
Sleep latency influences experiment, tests and with synergistic effect of the sub-threshold dose yellow Jackets to mouse sleep rate to the third ammonia of chlorobenzene
The intervention experiment of the insomnia model of sour (PCPA) induction, having investigated loganin improves the influence of sleeping animal sleep.
In addition, applicant is surprisingly found that, loganin, which is prepared by mixing into above-mentioned oral solution with specific auxiliary agent, to be made
The stability for obtaining loganin is improved, particularly, compared to addition other solubilizer such as polyvinylpyrrolidones or PEG-400
There is excellent stability Deng, the application.
Result of study shows that loganin can significantly shorten mice sleep incubation period and extend mice sleep total duration；And horse
The insomnia of 5-HT receptor antagonist PCPA induction can be reversed in money glycosides；As a result, it was confirmed that the loganin has tranquilizing soporific, improvement is slept
Dormancy obstructive action, induced hypnotic effect are closely related with 5-HT receptor.In addition loganin has from a wealth of sources, and hypotoxicity etc. is excellent
Point, therefore it has good application and development prospect in terms of preparing hypnotic drug.
Detailed description of the invention
Influence of Fig. 1 loganin to above threshold dose of sodium pentobarbitone induced mice Sleep latency
Influence of Fig. 2 loganin to above threshold dose of sodium pentobarbitone induced mice sleeping time
Influence of Fig. 3 loganin to PCPA inducing mouse insomnia model Sleep latency
Influence of Fig. 4 loganin to PCPA inducing mouse insomnia model sleeping time
Specific embodiment
It is right combined with specific embodiments below in order to make those skilled in the art more fully understand technical solution of the present invention
The present invention is described in further detail, but this does not imply that any restrictions of protection scope of the present invention.
Influence of 1 loganin of embodiment to above threshold dose of sodium pentobarbitone induced mice sleeping time and Sleep latency
Weight is taken (to be provided, moved by Beijing Vital River Experimental Animals Technology Co., Ltd. for the male ICR mouse of 20-24g
Object quality certification number: SCXK (capital) 2012-0001), it is randomly divided into blank solvent control group, estazolam by weight
(Estazolam is produced, lot number by Shandong Xin Yi Co., Ltd: 150910) 1.375mg/kg group, loganin 5mg/kg group,
20mg/kg group and 50mg/kg group, every group 15, gastric infusion, and administration time is recorded, above threshold dosage is injected intraperitoneally after 20min
Yellow Jackets (45mg/kg).Using righting reflex loss as time for falling asleep, righting reflex reverts to recovery time, records mouse
Sleep latency and sleep time.
Experimental result is as shown in table 1, when loganin 20,50mg/kg gastric infusion, can be obviously prolonged above threshold penta bar of dosage
It sleeps total duration (P < 0.05) than appropriate sodium induced mice, and is obviously shortened mice sleep incubation period, and be in dose-dependence.
Influence (Mean of 1 loganin of table to above threshold dose of sodium pentobarbitone induced mice sleeping time and Sleep latency
±S.E.M)
Note: * table not P < 0.05 compared with the control group
Influence of 2 loganin of embodiment to sub-threshold dose yellow Jackets intraperitoneal injection of mice sleep rate
Taking weight is the male ICR mouse of 20-24g, it is randomly divided into blank solvent control group, estazolam by weight
1.375mg/kg group, loganin 5mg/kg group, 20mg/kg group and 50mg/kg group, every group 20, gastric infusion, and record administration
Time is injected intraperitoneally sub-threshold dose yellow Jackets (22mg/kg) after 20min, observes and records mouse sleep situation.
Experimental result is as shown in table 2, loganin 20,50mg/kg gastric infusion, can obviously increase penta bar of sub-threshold dose ratio
Appropriate sodium induced mice sleep quantity (P < 0.05), the experimental results showed that, loganin has with sub-threshold dose yellow Jackets to be cooperateed with
The effect of hypnosis.
2 loganin of table is with sub-threshold dose yellow Jackets to the synergistic effect of mouse sleep rate
Note: * indicates P < 0.05 compared with the control group
Intervention of 3 loganin of embodiment to the PCPA insomnia model induced
Taking weight is the male ICR mouse of 20-24g, and it is (right that it by weight is randomly divided into blank solvent control group, PCPA
Chlorophenylalanine, be purchased from Sigma, 350mg/kg, i.p.) group, loganin (50mg/kg, i.g.) group and PCPA (350mg/kg,
I.p.)+loganin (50mg/kg, i.g.) group.Administration mode is continuous intraperitoneal injection first PCPA3 days, establishes mouse insomnia mould
Type, after PCPA 1h is injected intraperitoneally on day 3, loganin is given in stomach-filling, and the amobarbital of above threshold dosage is injected intraperitoneally after 20min
Sodium, using righting reflex loss as time for falling asleep, it is recovery time that righting reflex, which is replied, and record mice sleep incubation period holds with sleep
The continuous time.
Experimental result is as shown in table 3, and the insomnia model of PCPA induction, in PCPA model group, Strychnos nux-vomica can be reversed in loganin
Glycosides can dramatically increase the sleep total duration (P < 0.05) of mouse.The experimental results showed that loganin may be by increasing in mouse brain
5-HT level is to induced hypnotic.
Intervention (Mean ± S.E.M) of 3 loganin of table to the PCPA insomnia model induced
Note: * indicates that P < 0.05 compared with the control group, # indicate the P < 0.05 compared with PCPA model group
Preparation embodiment 1 prepares Strychnos nux-vomica glucoside oral liquid
The corrigent D-Glucose aldehydic acid-δ lactones, stirring to whole dissolutions are added in the aqueous solution of solvent oxalic acid；
It is subsequently added into the active constituent loganin, solubilizer, is stirred until homogeneous dissolution；The stabilizer benzyl alcohol is added, is stirred
After uniformly, add medicinal active carbon, the Strychnos nux-vomica glucoside oral liquid is prepared after filtering, in Strychnos nux-vomica glucoside oral liquid obtained,
Containing 98mg loganin, the mixture 1mg of 1ml benzyl alcohol, the beta-cyclodextrin of weight ratio 1: 1 and lauryl sodium sulfate,
D-Glucose aldehydic acid-δ the lactones of 0.1mg；In the aqueous solution of solvent oxalic acid, oxalic acid 0.75g, system are dissolved in every 100ml pure water
Obtain Strychnos nux-vomica glucoside oral liquid of the invention.
Embodiment 2
In addition to solubilizer is beta-cyclodextrin, remaining is the same as embodiment 1.
Embodiment 3
In addition to solubilizer is lauryl sodium sulfate, remaining is the same as embodiment 1.
Comparative example 1
In addition to without containing solubilizer, remaining is the same as embodiment 1.
Comparative example 2
In addition to solubilizer is polyvinylpyrrolidone, remaining is the same as embodiment 1.
Comparative example 3
In addition to solubilizer is PEG-400, remaining is the same as embodiment 1.
The test of loganin stability of Oral:
Appearance character detection carried out to the Strychnos nux-vomica glucoside oral liquid of production, observation at the beginning above-described embodiment 1-3 obtained and
Strychnos nux-vomica glucoside oral liquid obtained by comparative example 1-3, it is clear and bright to visually observe oral solution, no floating material, no deposited phenomenon；Then
Each sample is placed in low speed centrifuge, 1000rpm/min10 minutes, observes stability change；It is also carried out simultaneously by oral solution point
It is not placed 30 days in low temperature (4 DEG C), room temperature (25 DEG C), (45 DEG C) of high temperature, observes stability change；Specific observation index is as follows:
A --- naked-eye observation is clear and bright, no floating material, no deposited phenomenon；
B --- naked-eye observation substantially transparent, floating material are precipitated less than 5% less than 5%；
C --- naked-eye observation is muddy a little, floating material 5-15%, precipitates 5-15%；
D --- naked-eye observation is more muddy, floating material 15-25%, precipitates 15-25%；
4 loganin stability of Oral test result of table
| Embodiment | Centrifugation | Low temperature | Room temperature | High temperature |
| Embodiment 1 | A | A | A | A |
| Embodiment 2 | A | A | B | B |
| Embodiment 3 | A | B | B | B |
| Comparative example 1 | C | C | D | D |
| Comparative example 2 | B | B | B | C |
| Comparative example 3 | B | B | C | D |
As can be seen from Table 4, addition solubilizer is compared and is added without increasing in the Strychnos nux-vomica glucoside oral liquid of 1-3 of the embodiment of the present invention
The comparative example 1 of solvent, and the comparative example 2 and 3 of other solubilizer polyvinylpyrrolidones or PEG-400 is added in stabilization
Property aspect it is more excellent；Meanwhile when the mixture of beta-cyclodextrin and lauryl sodium sulfate that solubilizer is 1: 1, compared to addition
Individual beta-cyclodextrin or lauryl sodium sulfate are even better in terms of stability.
The application of loganin of the invention in the drug that preparation improves sleep has been retouched by specific example
It states, those skilled in the art can use for reference the content of present invention, and the links such as appropriate feed change, process conditions are corresponding other to realize
Purpose, correlation change all without departing from the contents of the present invention, and all similar substitutions and modifications are for those skilled in the art
For be it will be apparent that being considered as being included within the scope of the present invention.
Claims (2)
1. a kind of application of loganin in the drug that preparation improves sleep, which is characterized in that the loganin is such as following formula (1)
Compound:
The improvement sleep effect is that the insomnia of 5-HT receptor antagonist PCPA induction is reversed to realize by loganin；It is described
Medicine preparation includes following component in every 100ml oral solution at oral solution:
Active constituent: loganin 90-110mg；
Stabilizer: benzyl alcohol 0.1-1.5ml；
Solubilizer: 0.1-1.5mg；
Corrigent: D-Glucose aldehydic acid-δ lactones 0.01-0.2mg；
Solvent: the aqueous solution of oxalic acid, wherein containing oxalic acid 0.75g in every 100ml water；
The mixture that the solubilizer is beta-cyclodextrin and lauryl sodium sulfate weight ratio is 1: 1.
2. application according to claim 1, which is characterized in that the dosage of the loganin is 98mg.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1510037A (en) * | 2002-12-20 | 2004-07-07 | 首都医科大学宣武医院 | Cornel extractive, extracting method and use for preparing medicine and health food |
| CN1566124A (en) * | 2003-07-03 | 2005-01-19 | 和记黄埔医药企业有限公司 | Cornel extract and use thereof |
| CN1565469A (en) * | 2003-07-03 | 2005-01-19 | 和记黄埔医药企业有限公司 | Cornel extract oral medicine compositions low irritative to gastrointestinal tract and its preparation |
| CN101254185A (en) * | 2007-03-02 | 2008-09-03 | 首都医科大学宣武医院 | Use of cyclic enol ether terpenoid for producing promotive neurocyte proliferate and differentiation medicament |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007001972A (en) * | 2005-05-25 | 2007-01-11 | Mitsukan Group Honsha:Kk | Quiet sleep-inducing composition |
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- 2016-06-01 CN CN201610375109.2A patent/CN105902536B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1510037A (en) * | 2002-12-20 | 2004-07-07 | 首都医科大学宣武医院 | Cornel extractive, extracting method and use for preparing medicine and health food |
| CN1566124A (en) * | 2003-07-03 | 2005-01-19 | 和记黄埔医药企业有限公司 | Cornel extract and use thereof |
| CN1565469A (en) * | 2003-07-03 | 2005-01-19 | 和记黄埔医药企业有限公司 | Cornel extract oral medicine compositions low irritative to gastrointestinal tract and its preparation |
| CN101254185A (en) * | 2007-03-02 | 2008-09-03 | 首都医科大学宣武医院 | Use of cyclic enol ether terpenoid for producing promotive neurocyte proliferate and differentiation medicament |
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