CN108524500A - A kind of pharmaceutical composition for treating depression - Google Patents
A kind of pharmaceutical composition for treating depression Download PDFInfo
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- CN108524500A CN108524500A CN201710122624.4A CN201710122624A CN108524500A CN 108524500 A CN108524500 A CN 108524500A CN 201710122624 A CN201710122624 A CN 201710122624A CN 108524500 A CN108524500 A CN 108524500A
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- General Health & Medical Sciences (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a kind of pharmaceutical compositions for treating depression can improve the clinical cure rate of depression by using drug of the present invention, reduce disability rate and homicide rate to greatest extent, substantially eliminate clinical symptoms；Life quality is improved simultaneously, restores social function；It can most importantly be recurred with prevention of depression.The present invention relates to a kind of pharmaceutical composition for treating depression, described pharmaceutical composition includes：The compound of the present invention of 5 30mg, the filler of 50 1000mg, the corrigent of 20 200mg, 2 50mg adhesive and 1 5mg preservative.
Description
Technical field
The present invention relates to field of medicaments, and specifically, the present invention relates to a kind of pharmaceutical compositions for treating depression.
Background technology
Depression is also known as depressive disorder, low for main clinical characteristics with notable and lasting mental state, is mood disorder
Main Types.Clinical visible mental state is low unbecoming with its situation, and the downhearted of mood can be from depressed to extremely grieved, certainly
Inferior depression or even pessimistic and worldweary, can there is conamen or behavior；Even occur numb；Some cases have apparent anxiety and fortune
Dynamic property is intense；Severe patient may occur in which the psychotic symptoms such as illusion, vain hope.Even breaking-out continues at least 2 weeks or more, elder every time
Several years, majority of cases have the tendency that recurrent exerbation, and breaking-out is most of every time to alleviate, and can partly have residual symptoms or switch to slow
Property.The method for the treatment of depression mainly has drug therapy, psychotherapy, physiotherapy at present.Its drug treatment is most directly
Effective mode.
Invention content
The purpose of the present invention is to provide a kind of pharmaceutical compositions for treating depression.
In order to achieve the object of the present invention, the present invention provides a kind of pharmaceutical composition for treating depression, the medicine group
Closing object includes：The compound of the following structural of 5-30mg, the filler of 50-1000mg, the corrigent of 20-200mg, 2-50mg
Adhesive and 1-5mg preservative：
Wherein
R1 independently selected from：H, hydroxyl or alkyl.
Preferably, R1 is methyl.
Preferably, described pharmaceutical composition includes：The compound of the following structural of 20mg, the filler of 500mg, 80mg
Corrigent, the adhesive of 20mg and the preservative of 5mg：
Wherein
R1 independently selected from：H, hydroxyl or alkyl.
Preferably, R1 is methyl.
It is highly preferred that the filler can be lactose, mannitol, sucrose and their mixture.
It is highly preferred that the corrigent can be sweetener and various essence.
It is highly preferred that the adhesive can be starch slurry, polyvinylpyrrolidone, hydroxypropyl methyl cellulose.
It is highly preferred that the preservative can be chlorhexidine acetate, eucalyptus oil.
The present invention also provides purposes of the compound in the drug for preparing treatment depression, the compound has following knot
Structure：
Wherein
R1 independently selected from：H, hydroxyl or alkyl.
It is highly preferred that R1 is methyl.
By using drug of the present invention, depression clinical cure rate can be improved, reduces disability rate and suicide to greatest extent
Rate substantially eliminates clinical symptoms；Life quality is improved simultaneously, restores social function；It most importantly can be multiple with prevention of depression
Hair.
Description of the drawings
Fig. 1 is influence of the chronic stress to mouse syrup preference degree.
Fig. 2 is influence of the drug of the present invention to modeling mouse dead time in forced swimming test and qutstanding tail test.
A. forced swimming test；B. qutstanding tail test.
Fig. 3 is influence of the drug of the present invention to modeling mouse autonomic activities in open field test.
A. horizontal movement score；B. move vertically score.
Fig. 4 is influence of the drug of the present invention to cAMP contents in modeling Hippocampus of Mice.
Fig. 5 is the expression that drug of the present invention increases pCREB in modeling Hippocampus of Mice.
Fig. 6 is the expression that drug of the present invention increases BDNF in modeling Hippocampus of Mice.
Specific implementation mode
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
The characterization of 1 drug of the present invention of experimental example
1H NMR(500MHz,CDCl3) δ 1.05-1.27 (m, 3H), 1.50-1.77 (m, 5H), 1.99 (d, J=
12.51Hz, 2H), 2.46 (s, 3H), 2.66-2.78 (m, 7H), 7.35 (d, J=8.24Hz, 2H), 7.61 (s, 1H), 7.87
(d, J=8.24Hz, 2H), 8.89 (s, 1H), 9.90 (s, 1H), 10.65 (br.s, 1H)；13C NM R(126MHz,CDCl3)δ
21.7,25.9,26.2,32.0,38.6,46.1,101.7,110.9,127.2,129.2,129.8,131.3,133.0,
139.4,139.8,142.5,159.9,165.7。
Therapeutic effect of the drug of the present invention of 2 embodiment 1 of embodiment for depression
Male mouse of kunming is randomly divided into blank group, modeling group after adapting to environment.It is mild using chronic unpredictability
Modeling stress be carried out to model group, stress factor is such as：Folder tail 1min, it foot shock 10s, 4 DEG C of ice water swimming 5min, runs round the clock
, fasting for 24 hours, prohibit water for 24 hours, wet cage for 24 hours, tilt 45 ° of raisings for 24 hours etc..1~2 kind of Coping style is chosen daily, avoids repeating,
Continue 6 weeks.Carry out whether syrup preference experiment judgement modeling succeeds at the end of modeling.The successful animal of modeling is randomly divided into mould
Type group, Prozac administration group (10mg/kg), medicine group of the present invention (5mg/kg).It is administered by the dosage continuous gavage of 0.1mL/10g
28d。
Syrup preference experiment
Mouse 48h is first trained, mouse is made to adapt to drink syrup.All equal sub-cage rearings of mouse, 2 bottles of placement per cage, one bottle
Fill 1% sugar aqueous solution, another bottled pure water.1 vial position is changed per 12h.After having trained, the first 12h fasting for solids and liquids of animal, then give
Give 2 bottles of water that every cage mouse claimed weight in advance：1% sugar aqueous solution and pure water, free water 1h.Drinking-water is weighed after the test
The weight of bottle calculates syrup consumption, pure water consumption, then the preference percentage of mouse syrup is calculated by formula：Animal is to syrup
Preference percentage (%)=syrup consumption (g)/total liquid-consumed amount (syrup consumption (g)+pure water consumption (g)) ×
100%.
Forced swimming test
Bibliography (Porsolt RD, Le Pichon M, Jalfre M.Depression a new animal
Model sensitive to antidepressant treatments [J] .Nature, 1977,266 (564)：730-2.)
It is improved：Mouse is put into high 30cm, and the circular non-opaque plastic barrel of diameter 11cm, depth of water 15cm, 25 DEG C of water temperature, hind leg can not
Plastics bottom of the barrel is contacted, need to be bubbled through the water column by constantly struggling.Video record mouse swims in the water the behavior table of 6min
It is existing, the water surface, four limbs stopping struggle being floated on as motionless criterion with mouse, record starts the dead time of rear 4min.
Qutstanding tail test
Reference literature (Steru L, Chermat R, Thierry B, et al.The tail suspension test:a
New method for screening antidepressants in mice [J] .Psychopharmacology (Berl),
1985,85 (3)：367-70.) improved：It is sticked to mouse tail end with medical proof fabric, adhesive plaster is clamped with clip, makes mouse in
Outstanding state, the behavior expression of mouse, counts the dead time of 6min in video record 6min.It is perpendicular with stopping struggle, body
It hangs state by the feet, is stationary for criterion.
Open field test
It being carried out in the spacious case that length × width × height is 40cm × 40cm × 15cm, spacious case is divided into 5cm × 5cm equal portions,
Inner wall painted black.Mouse is put into the grid of centre when experiment, the activity condition of mouse in video record 5min.Statistics
The horizontal movement score (passing through grid number) and vertical movement score (upright number) of mouse.It is clear with alcohol after test every time
Clean box bottom surface.
Hippocampus cAMP assays
It removes hippocampal tissue rapidly on ice, rinses tissue sample with PBS, and press w (g)：V (mL)=1:5 systems are added
The HCL of 0.1mmoL, Ultrasonic Pulverization, 10000 × g centrifuge 15min (4 DEG C), abandon precipitation, take supernatant, and quantitative 1mmoL is added
Sodium hydroxide tune pH to 7 or so.It is operated by ELISA kit specification, by microplate reader determination sample absorbance value, calculates sample
Product cAMP contents.
Protein immunoblot
Take Hippocampus of Mice rapidly on ice, be placed in containing protease inhibitors, inhibitors of phosphatases RIPA lysates in
Homogenate, 16000 × g centrifuge 30min, take supernatant.According to BCA protein analytical methods determination sample protein contents.By V (albumen samples
Product solution)：V (5 × SDS-PAGE Loading Buffer)=4：1 is added 5 × SDS-PAGE sample-loading buffers.It is denatured by boiling
10min is saved backup.Each group sample carries out sds polyacrylamide gel electrophoresis, transfers on pvdf membrane, through 5% defatted milk
4 DEG C of overnight incubations of primary antibody are added after closing 2h in powder room temperature.Secondary antibody is added after TBST is rinsed, is incubated at room temperature 2h.Again after rinsing
ECL luminescent solutions exposure imaging in darkroom is added dropwise.Operating method bibliography (Zhang C, Cheng YF, Wang HT, et
al.RNA Interference-Mediated knockdown of Long-Form phospho diesterase-4D
(PDE4D)enzyme reverses amyloid-beta(42)-Induced memory deficits in mice[J].J
Alzheimers Dis, 2014,38 (2)：269-80.).
Statistical method
All experimental datas are all made of the expression of mean ± standard error, and single factor test side is carried out using 13.0 statistical softwares of SPSS
Difference analysis is counted.Between group between multiple samples two-by-two more first through homogeneity test of variance, if variance together if use Tukey's
Post-hoc methods use Dunnett's T if uneven3Method, P<0.05 has conspicuousness for difference.Block diagram uses
5 Software on Drawing of GraphPad Prism.
Influence of the chronic stress to mouse syrup preference degree
Anhedonia is the classical symptom of patients with depression, and the symptom of depressed mouse then shows as showing syrup preference
It writes and declines.We have a preference for experiment to investigate variation of the depressed mouse to syrup preference degree, to whether judge mouse with syrup
There is depressive symptom.After modeling, the syrup of verification 28 mouse of 8 mouse of blank group and modeling group has a preference for situation, as a result such as Fig. 1
Shown, compared with blank group, the syrup preference degree of model group mouse significantly reduces (P<0.01), show that we use chronic
Unpredictable mild stimulation depression model (modeling) is successfully established.On this basis, we divide 28 modeling group mouse at random
For model group (8), medicine group of the present invention (10) and Prozac administration group (10), subsequent experimental is carried out.
Influence of the drug of the present invention to modeling mouse dead time in forced swimming test and qutstanding tail test
Dead time in forced swimming test and qutstanding tail test can reflect the desperate state and depressive symptom of experimental animal,
Its dead time is longer, shows that its behavior is more desperate.The result of Fig. 2 shows that compared with blank group, model group mouse is forcing trip
Dead time in swimming experiment (Fig. 2A) and tail-suspention test (Fig. 2 B) significantly extends, and has statistical significance (P<0.01).And
Drug and positive control drug Prozac of the present invention can significantly shorten dead time (P of the mouse in the two experiments<0.01),
Show that drug of the present invention has antidepressant effect.
Influence of the drug of the present invention to modeling mouse autonomic activities in open field test
Spacious field experiment be evaluate animal independent behaviour, exploratory behaviour behaviouristics method, lattice are passed through by its horizontal movement
The standing number of the number and vertical movement of son, the independent behaviour and exploratory behaviour for observing mouse whether there is difference.As a result such as
Fig. 3 shows, each group mouse in 5min, horizontal movement score (Fig. 3 A) and vertical movement score (Fig. 3 B) compared with blank group,
There are no significant difference (P>0.05).Show that depression model, Prozac and drug administration of the present invention do not interfere with oneself of animal
Main motion activity and exploring ability.
Influence of the drug of the present invention to cAMP contents in Hippocampus of Mice
After behaviouristics, Hippocampus of Mice is taken to detect cAMP contents.The results are shown in Figure 4, model group hippocampus of mice
CAMP contents are significantly lower than blank group (P in tissue<0.01).And after giving drug and Prozac of the present invention respectively, modeling mouse
The content of cAMP significantly increases in hippocampus, and has significant difference (P<0.01).
Influence of the drug of the present invention to pCREB protein expressions in Hippocampus of Mice
Hippocampus of Mice albumen is taken to detect the phosphorylation level of CREB albumen by Western blot.As a result such as Fig. 5
Shown, pCREB protein levels are significantly lower than blank group (P in model group hippocampus of mice<0.01).And give drug and fluorine of the present invention
After Xi Ting, pCREB protein expressions significantly raise (P in hippocampus of mice<0.01).
The influence that drug of the present invention expresses bdnf protein in Hippocampus of Mice
Hippocampus of Mice albumen is taken to detect bdnf protein expression by Western blot, the results are shown in Figure 6,
Compared with blank group, bdnf protein expression significant decrease (P in model group hippocampus of mice<0.01).And give drug of the present invention and
After Prozac, in hippocampus of mice the expression of bdnf protein obviously raise (P<0.01).
Claims (10)
1. a kind of pharmaceutical composition for treating depression, which is characterized in that described pharmaceutical composition includes：The following knot of 5-30mg
The anti-corrosion of the compound of structure formula, the filler of 50-1000mg, the corrigent of 20-200mg, the adhesive of 2-50mg and 1-5mg
Agent：
Wherein
R1 independently selected from：H, hydroxyl or alkyl.
2. the pharmaceutical composition for the treatment of depression according to claim 1, which is characterized in that R1 is methyl.
3. the pharmaceutical composition for the treatment of depression according to claim 2, which is characterized in that described pharmaceutical composition packet
Contain：The compound of the following structural of 20mg, the filler of 500mg, the corrigent of 80mg, the adhesive of 20mg and 5mg it is anti-
Rotten agent：
Wherein
R1 independently selected from：H, hydroxyl or alkyl.
4. the pharmaceutical composition for the treatment of depression according to claim 3, which is characterized in that R1 is methyl.
5. the pharmaceutical composition for the treatment of depression according to claim 4, which is characterized in that the filler can be
Lactose, mannitol, sucrose and their mixture.
6. the pharmaceutical composition for the treatment of depression according to claim 4, which is characterized in that the corrigent can be
Sweetener and various essence.
7. the pharmaceutical composition for the treatment of depression according to claim 4, which is characterized in that the adhesive can be
Starch slurry, polyvinylpyrrolidone, hydroxypropyl methyl cellulose.
8. the pharmaceutical composition for the treatment of depression according to claim 4, which is characterized in that the preservative can be
Chlorhexidine acetate, eucalyptus oil.
9. purposes of the compound in the drug for preparing treatment depression, which is characterized in that the compound has having structure：
Wherein
R1 independently selected from：H, hydroxyl or alkyl.
10. the pharmaceutical composition for the treatment of depression according to claim 9, which is characterized in that R1 is methyl.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710122624.4A CN108524500A (en) | 2017-03-03 | 2017-03-03 | A kind of pharmaceutical composition for treating depression |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710122624.4A CN108524500A (en) | 2017-03-03 | 2017-03-03 | A kind of pharmaceutical composition for treating depression |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113181342A (en) * | 2021-05-19 | 2021-07-30 | 天津市宝恒生物科技有限公司 | Bacillus coagulans preparation for treating depression |
-
2017
- 2017-03-03 CN CN201710122624.4A patent/CN108524500A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113181342A (en) * | 2021-05-19 | 2021-07-30 | 天津市宝恒生物科技有限公司 | Bacillus coagulans preparation for treating depression |
| CN113181342B (en) * | 2021-05-19 | 2022-11-08 | 天津市宝恒生物科技有限公司 | Depression treating bacillus coagulans preparation |
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| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20180914 |
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| WW01 | Invention patent application withdrawn after publication |