CN104997791A - Application of 20(S)-protopanaxadiol in preparation of anxiolytic drugs - Google Patents
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Abstract
The invention relates to a new use of 20(S)-protopanaxadiol, and concretely relates to an application of 20(S)-protopanaxadiol in the preparation of anxiolytic drugs. An experiment result displays that the 20(S)-protopanaxadiol can treat anxiety, and has a better treatment effect than drugs in the prior art.
Description
Technical field
The present invention relates to the novelty teabag of 20 (S)-protopanoxadiols, specifically, relate to 20 (S)-protopanoxadiols and preparing the application in anxiolytic drugs.
Background technology
Protopanoxadiol is the interior metabolism product of glycol group ginsenoside, be divided into 20-(S) protopanoxadiol (20 (s)-protopanaxadiol, 20 (S)-dammarane-24-alkene-3 β, 12 β, 20-triol) and 20 (R)-protopanoxadiols (20 (R)-protopanaxadiol, 20 (R)-dammarane-24-alkene-3 β, 12 β, 20-triol), they are enantiomer each other, and its structure is as follows:
Progress (hair Jingjing etc. are studied carefully in the pharmacological action that prior art discloses 20 (S) protopanoxadiol, 20 (S)-protopanoxadiol Advance on Pharmacological Activities, Chinese experimental pharmacology of Chinese medical formulae magazine, the 24th volume in 2011) 20 (S)-protopanoxadiols have anticancer, antidepressant, activation chloride channel and suppress the unpolarized effect of sodium-ion channel, suppress many pharmacologically actives such as Human Embryonic Kidney HEK-293 cell and H. pylori bacteria growing.
(the Zhou Chenglin such as Zhou Chenglin, Ma Qiang, Xie Yeqi, Radix Panacis Quinquefolii glycol, triol group Saponin is to the experimentation of students intelligence and emotion influence, Journal of Shenyang Institute of Physical Education, 3rd phase in 1998, 11-14) disclose 20 (S)-protopanoxadiols to the impact of high school senior, clearly state this article the 11st page: " ruscogenin of dammarane type has two kinds, one is that 20 (S)-protopanoxadiol 20 (S)-panaxdiol are hereinafter referred to as glycol group and 20 (S)-Protopanaxatriol 20 (S)-proto-panaxdiol (hereinafter referred to as triol group) ".In this article 11 pages of forewords, author clearly states: " this test uses and is separated good glycol, triol group soap two affects research experiment to participating in college admission examination several psychological indicator and physical signs and Entrance Examination; its objective is that explanation takes Radix Panacis Quinquefolii glycol, triol group soap two to raising students intelligence level; stablize and improve total marks of the examination; reduce the anxiety level of student before examination, overcome student's tense situation and have positive facilitation ".And show in this article 13 pages of the 2nd section of contents: " with Radix Panacis Quinquefolii glycol, triol group Saponin on the experiment participating in the impact of college admission examination Anxiety pre-examination state; experimental result shows: take anxiety level before and after Radix Panacis Quinquefolii glycol, triol group; check through T; all do not reach significant level; but from the result of adding up, decrease than the anxiety level taking front student after taking Radix Panacis Quinquefolii glycol, triol group ".Therefore, the object of study of the document is Radix Panacis Quinquefolii glycol group and the intelligence of Radix Panacis Quinquefolii triol saponins on student and the impact of emotion.
Protopanoxadiol (PPD) is the aglycon of glycol group ginsenoside, is also the end product of glycol group ginsenoside after microorganism zymolysis.PPD has 20 (S), 20 (R) two kinds epimer, and they all belong to dammarane type four-ring triterpenoid compounds, and wherein, 20 (S)-PPD activity is the strongest.
Document " panaxdiols saponin (PDS) suppress NOS and p38 to alleviate LPS to suffer a shock brain injury ", in " panaxdiols saponin (PDS) is on the impact of blood fat, serum NO level, MDA content, SOD vigor " all by panaxdiols saponin referred to as PDS, i.e. (Panaxadiol saponins, PDS).
Anxiety neurosis, is called for short anxiety neurosis, is take anxiety as the neurosis of principal character.Show as without foundation of truth also without the on tenterhooks and frightened and restless mood of clear and definite objective objects and concrete idea content, also have vegetative nerve symptom and muscular tone, and mobility is uneasy.
Anxiety neurosis, the current cause of disease is still not clear.Research shows, anxiety neurosis and inherited genetic factors, characteristics of personality, adverse events, stressors, physical disease etc. all have relation, and these factors can cause body neuro-endocrine system to get muddled, and neurotransmitter is unbalance, thus cause the appearance of the symptoms such as anxiety.The various neurotransmitters such as anxiety patient often has 5-HT (5-hydroxy tryptamine), NE (norepinephrine) unbalance, and antianxiety drugs can make unbalance neurotransmitter trend normal, thus anxiety symptom is disappeared, emotion is recovered normally.
By up to the present, not yet about the patent report of 20 (S)-protopanoxadiol treatment anxiety neurosis aspects.
Summary of the invention
The object of this invention is to provide the novelty teabag of 20 (S)-protopanoxadiols.
Concrete, the present invention is to provide 20 (S)-protopanoxadiols and is preparing the application in anxiolytic drugs.
Described anxiety is anxiety neurosis, comprises generalized anxiety disorder, separation anxiety, elective mutism, panic disorder, social anxiety disorder, agoraphobia or special phobia.
Described generalized anxiety disorder (generalized anxiety disorder), show as extensive and lasting anxiety, degree is lighter than acute anxiety, and the persistent period reaches more than 3 months;
Described separation anxiety (Dissociative anxiety), refers to anxiety, uneasiness or offending emotional response that infant causes because being separated with relatives, also known as separation anxiety;
Described elective mutism, (Selective Mutism, SM), need the occasion of verbal communication (as school with infant at some, have stranger or the many environment etc. of people) enduringly " refusal " speak, and be normally a kind of clinical syndrome of feature in other occasion speeches;
Described panic disorder (panicdisorder) be called for short paranoid fears be repeatedly there is significant cardiopalmus, perspire, the autonomic nerve symptom such as to tremble, accompany by strong dying sense or sense out of control, fear to produce a kind of acute anxiety obstacle that the panic attack (panicattacks) of unfortunate consequence is feature;
Described social anxiety disorder is a kind of when associating with people, feels ill, nature, nervous even frightened emotional experience;
Described agoraphobia, its reveal any symptoms mainly comprises is afraid of to be alone leave home, and ducks into the store, place that people is many and public place, or used during taking train, bus or aircraft separately.
Described special phobia (Specific phobia), also known as simple phobia, shows as some the special object beyond to agoraphobia and social phobia two type, the fearing of sight or activity.
Described medicine is the preparation containing 20 (S)-protopanoxadiols, and described preparation is made up separately of 20 (S)-protopanoxadiols or is formed with pharmaceutically acceptable carrier.
Described preparation is injection, tablet, capsule, oral liquid, the agent of gas (powder) mist, patch, granule, Sublingual tablet or drop pill.
Described pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, is selected from one or more in filler, binding agent, disintegrating agent, lubricant, solubilizing agent, suspending agent, wetting agent, pigment, essence, solvent, surfactant or correctives.
Described filler is selected from starch, pregelatinized Starch, dextrin, glucose, sucrose, lactose, lactose, microcrystalline Cellulose, mannitol, sorbitol or xylitol, preferred sorbitol, microcrystalline Cellulose, lactose or pregelatinized Starch;
Described disintegrating agent is selected from cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium or starch, preferred polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose or carboxymethyl starch sodium;
Described lubricant is selected from magnesium stearate, Pulvis Talci, micropowder silica gel, PEG4000, PEG6000, sodium laurylsulfate, preferred magnesium stearate, Pulvis Talci;
Described binding agent is selected from sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, polyvidone, starch slurry, sucrose, Icing Sugar, rubber cement, gelatin, Polyethylene Glycol, preferred hydroxypropyl methylcellulose, polyvidone;
Described solubilizing agent is selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, meglumine, 1B, L-arginine, preferred sodium hydroxide, meglumine;
Described suspending agent is selected from micropowder silica gel, Cera Flava, cellulose, solid polyethylene glycol;
Described wetting agent is selected from glycerol, tween 80, ethoxy aluminium Oleum Ricini or lecithin;
Described solvent selected from ethanol, liquid polyethylene glycol, isopropyl alcohol, tween 80, glycerol, propylene glycol or vegetable oil, described vegetable oil is selected from soybean oil, Oleum Ricini, Oleum Arachidis hypogaeae semen, mediation wet goods;
Described surfactant is selected from smooth or Polysorbate (tween) of dodecylbenzene sodium sulfonate, stearic acid, Pluronic F68, fatty acid Pyrusussuriensis etc.;
Described correctives is selected from aspartame, Sucralose, essence, steviosin, acesulfame potassium, citric acid or saccharin sodium.
In application provided by the invention, the plan quantity of 20 (S)-protopanoxadiols is 1-500mg.
The novelty teabag of 20 (S)-protopanoxadiols provided by the invention has the following advantages:
1, (the Zhou Chenglin such as Zhou Chenglin, Ma Qiang, Xie Yeqi, Radix Panacis Quinquefolii glycol, triol group Saponin is to the experimentation of students intelligence and emotion influence, Journal of Shenyang Institute of Physical Education, 3rd phase in 1998, 11-14) disclose 20 (S)-protopanoxadiols to the impact of high school senior, although it is 20 (S)-panaxdiol that the document has write 20 (S)-protopanoxadiols exactly, but, in prior art, the English of 20 (S)-protopanoxadiols is 20 (s)-protopanaxadiol, form of presentation in the document and common practise are obviously different, therefore, those skilled in the art have no way of being learnt by the document: 20 (S)-protopanoxadiols (20 (s)-protopanaxadiol)-glycol group ginsenoside single sapogenin metabolite in vivo whether have to efficacy effect antianxity.In addition, document for be participate in student's Anxiety pre-examination of college entrance examination, be different from the neural anxiety disorders of the present invention, the latter is anxious sacred disease, and comparatively Anxiety pre-examination disease is more serious.
2, experimental result display: 20 (S)-protopanoxadiols have the effect of obviously antagonism mouse anxiety; Panoxadiol organizes total saponins (PDS) and has certain effect trend alleviating the behavior of model mice anxiety, and its effect is not as good as 20 (S)-protopanoxadiols.
Detailed description of the invention
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1: the effect detecting the mouse anxiety model that chlorobenzene piperazine (mCPP) is induced between 20 (S)-protopanoxadiol antagonism with Elevated plus-maze
1, laboratory animal: kunming mice, male, 25-30 gram, is provided by Shanghai Slac Experimental Animal Co., Ltd., credit number: SCXK (Shanghai) 2007-0005.
2, Experimental agents and preparation:
20 (S)-protopanoxadiols: Shanghai Chinese Medicine Creation Research Center, lot number 20050606-1, purity 94%; During experiment, prepare by the following method: take 20 (S)-protopanoxadiols, add specific solvent (ethanol: Oleum Ricini: the volume ratio of water is 1:10:89) and make suspension, be made into required concentration;
Panoxadiol organizes total saponins (PDS), Shanghai Chinese Medicine Creation Research Center, lot number 20070806, and during test, manner of formulation is with 20 (S)-protopanoxadiols; Diazepam, purchased from Shanghai Xinyi Pharmaceutical Factory, lot number 110801; 0.1mg/ml is made into CMC-Na;
Between chlorobenzene piperazine, purchased from sigma, lot number MKBK9966V; During experiment, be made into 0.4mg/ml with normal saline.
3, animal grouping, administering mode and dosage
By body weight by mice random packet, often organize 8, be specially:
Matched group: subcutaneous injection normal saline, 0.05ml/10g;
MCPP group (i.e. model group): subcutaneous injection, dosage is 2mg/kg;
Diazepam group: gastric infusion, dosage is 2mg/kg;
20 (S)-protopanoxadiol low dosages (L group): lumbar injection, dosage is 1.5mg/kg; Dosage (M group) in 20 (S)-protopanoxadiols: lumbar injection, dosage is 3mg/kg; 20 (S)-protopanoxadiol high doses (H group): lumbar injection, dosage is 7.5mg/kg.
Panoxadiol organizes total saponins (PDS) group with 20 (S)-protopanoxadiol groups.
Given low is 0.2ml/10g, and lumbar injection dosage is 0.1ml/10g, and subcutaneous doses is 0.05ml/10g.For keeping the concordance stimulated, each mice is stimulated with three: gavage, lumbar injection and subcutaneous injection.Mice is all carry out Elevated plus-maze detection after gavage one hour and lumbar injection half an hour, and 20 minutes subcutaneous injection mCPP carry out modeling before detection, and matched group is subcutaneous injection normal saline then.
4, experimental technique:
Employing plus maze is instrument, and Elevated plus-maze comprises two open arms, and two are closed arm, and there are an open portion in central authorities.Each group of mice detects and on Elevated plus-maze, adapts to 2 minutes/mice the previous day.Detect the same day, subcutaneous injection mCPP or coordinative solvent are after 20 minutes, and mice is placed in the flight data recorder of 60 × 60 × 35cm, allow it be familiar with environment after 5 minutes, and mice is placed in open portion of Elevated plus-maze central authorities, head is towards open arms.Image analysis system records the time that 5 minutes animals enter open arms (clear zone) automatically, distance, access times.Every mice is completed, and removes animal traces, carry out the test of next mice with dry cloth after cleaning with 10% alcoholic solution wiping labyrinth.
5, statistical disposition: adopt t inspection to carry out P value and calculate.
6, experimental result:
6.1 induce the impact of Anxiety Model mouse elevated plus-maze mice behavior to mCPP: the results are shown in Table 1
Table 1: the ethological impact of Anxiety Model mouse elevated plus-maze is induced on mCPP
Note: with mCPP model group ratio, * p<0.05, * p<0.01 (in addition, data in table: the time detected with mCPP Anxiety Model group mice, the initial data of Distance geometry access times, as the truth of a matter, is set as radix 1, the time that other group mices detect, the initial data of Distance geometry access times parameter corresponding to mCPP group is divided by, and obtains the data in form.)
Table 1 result shows:
Compared with normal group mice, subcutaneous injection mCPP modeling significantly can reduce the bright near-end of mice, the access time in bright far-end and whole clear zone, access Distance geometry access times, shows that mCPP can inducing mouse anxiety;
Compared with Anxiety Model group mice, diazepam significantly can reverse the behavior of mCPP modeling group mouse anxiety, 20 (S)-protopanoxadiols of L, M, H dosage also obviously can reverse the behavior of mCPP group model mouse anxiety, namely diazepam and as above three dosage 20 (S)-protopanoxadiols significantly can increase model mice in access time in bright near-end, bright far-end and whole clear zone, access Distance geometry access times, and compared with model group, there is significant difference.
Panoxadiol organizes total saponins (PDS) and has certain effect trend alleviating the behavior of mCPP group model mouse anxiety, the access times increase of middle dosage and the bright far-end of high dose group has meaning statistically, but there are no statistical difference in other group and access time and access distance.
Result shows: 20 (S)-protopanoxadiols have the effect of obviously antagonism mouse anxiety; Panoxadiol organizes total saponins (PDS) and has certain effect trend alleviating the behavior of model mice anxiety, and its effect is not as good as 20 (S)-protopanoxadiols.
6.2 other dosage induce the impact of Anxiety Model mouse elevated plus-maze mice behavior to mCPP: the results are shown in Table 2
Table 2: the key data of the effect of other dosage 20 (S)-protopanoxadiols antagonism mouse anxiety gathers:
Table 2 result shows: 0.125mg/kg, 0.25mg/kg, 0.5mg/kg, 15mg/kg, 20 (S)-protopanoxadiols of 30mg/kg and 60mg/kg dosage obviously can reverse the behavior of mCPP group model mouse anxiety, namely as above dosage PPD significantly can increase model mice in access time in bright near-end, bright far-end and whole clear zone, access Distance geometry access times, and compared with model group, has significant difference.
Result shows: 20 (S)-protopanoxadiols have the effect of obviously antagonism mouse anxiety.
Experimental example 2: the effect detecting the mouse anxiety model that chlorobenzene piperazine (mCPP) is induced between 20 (S)-protopanoxadiol antagonism with light and shade case
1, laboratory animal: with embodiment 1.
2, Experimental agents and preparation: with embodiment 1.
3, animal grouping, administering mode and dosage: with embodiment 1.
4, experimental technique:
Light and shade case comprises camera-lucida camera bellows, and there is spatial transition centre.Each group of mice detects and on light and shade case, adapts to 2 minutes/mice the previous day.Detect the same day, subcutaneous injection mCPP or coordinative solvent are after 20 minutes, and mice is placed in the camera-lucida district of light and shade case, and software analysis system automatically records animal in 5 minutes and enters the time of area pellucida and dark space, access times.
5, statistical disposition: adopt t inspection to carry out P value and calculate.
6, experimental result:
6.1 on the ethological impact of mCPP modeling mice light and shade case: the results are shown in Table 3
Table 3: on the ethological impact of mCPP modeling mice light and shade case
Note: with mCPP model group ratio, * p<0.05, * * p<0.01
Table 3 result shows: mCPP, under 2mg/kg dosage, adds up in the access times of camera-lucida and camera-lucida the effect having minimizing the access time to Kunming mouse, and compares with normal group and have significant difference (P<0.01).
The Anxiety Model Kunming mouse that the diazepam of 2mg/kg dosage significantly can increase mCPP induction adds up the access time in the access times of camera-lucida and camera-lucida, and has significant difference compared with model group.
Low, middle dosage, high dose 20 (S)-protopanoxadiol have the Anxiety Model mice increasing mCPP induction in the access times of camera-lucida and the effect of camera-lucida access time, and have significant difference compared with model group.
Panoxadiol organizes total saponins (PDS) and adds up that the access time does not have obvious effect to Kunming mouse in the access times of camera-lucida and camera-lucida, does not have the effect obviously alleviating the behavior of mCPP modeling mice light and shade case anxiety.
Result shows: 20 (S)-protopanoxadiols have the effect of obviously antagonism mouse anxiety; Panoxadiol organize effect that total saponins (PDS) alleviates the behavior of model mice anxiety not as good as 20 (S)-protopanoxadiol.
The key data of the effect of 6.2 other dosage 20 (S)-protopanoxadiols antagonism mouse anxieties gathers: in table 4
Table 4: other dosage are on the ethological impact of mCPP modeling mice light and shade case
Table 4 result shows: 0.125mg/kg, 0.25mg/kg, 0.5mg/kg, 15mg/kg, 20 (S)-protopanoxadiols of 30mg/kg and 60mg/kg dosage have the Anxiety Model mice that increases mCPP induction in the access times of camera-lucida and the effect of camera-lucida access time, and have significant difference compared with model group.
Result shows: 20 (S)-protopanoxadiols have the effect of obviously antagonism mouse anxiety.
Although above with general explanation, detailed description of the invention and test, the present invention is described in detail, and on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (6)
1.20 (S)-protopanoxadiols are preparing the application in anxiolytic drugs.
2. application according to claim 1, is characterized in that, described anxiety is anxiety neurosis, comprises generalized anxiety disorder, separation anxiety, elective mutism, panic disorder, social anxiety disorder, agoraphobia or special phobia.
3. application according to claim 1, is characterized in that, described medicine is the preparation containing 20 (S)-protopanoxadiols, and described preparation is made up separately of 20 (S)-protopanoxadiols or is formed with pharmaceutically acceptable carrier.
4. application according to claim 3, is characterized in that, described preparation is injection, tablet, capsule, oral liquid, aerosol, patch, granule, Sublingual tablet or drop pill.
5. application according to claim 3, it is characterized in that, described pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, is selected from one or more in filler, binding agent, disintegrating agent, lubricant, solubilizing agent, suspending agent, wetting agent, pigment, essence, solvent, surfactant or correctives.
6. the application according to any one of claim 1-5, is characterized in that, the plan quantity of 20 (S)-protopanoxadiols is 1-500mg.
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| CN111529539A (en) * | 2020-04-29 | 2020-08-14 | 海南亚洲制药股份有限公司 | Application of protopanoxadiol in preparing medicine |
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| CN101721439A (en) * | 2008-10-22 | 2010-06-09 | 云南金不换(集团)有限公司 | Notoginseng leaf triterpenes capsule and preparation thereof |
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| CN111529539A (en) * | 2020-04-29 | 2020-08-14 | 海南亚洲制药股份有限公司 | Application of protopanoxadiol in preparing medicine |
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