CN108619100A - Azaspiroanone medicine injection and preparation method and application thereof - Google Patents
Azaspiroanone medicine injection and preparation method and application thereof Download PDFInfo
- Publication number
- CN108619100A CN108619100A CN201710155536.4A CN201710155536A CN108619100A CN 108619100 A CN108619100 A CN 108619100A CN 201710155536 A CN201710155536 A CN 201710155536A CN 108619100 A CN108619100 A CN 108619100A
- Authority
- CN
- China
- Prior art keywords
- tandospirone
- injection
- acid
- group
- lyophilized
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
An azaspirone medicine injection and a preparation method and application thereof are characterized in that the azaspirone medicine injection comprises tandospirone active ingredients and a stabilizer. The azaspirone medicine injection has high stability and good anxiolytic effect, can meet the requirements of clinical patients, and can effectively solve the problem that children, patients (such as old patients and bedridden patients) with digestive system disorders, coma, convulsion and the like and dysphagia are not suitable for oral administration of tandospirone tablets or capsules. The azaspirone medicine injection also has the advantages of low cost, convenient use and the like. The solution of the azaspirone injection is clear, insoluble particles meet the standard, and the stability is good; no visible foreign matters and no abnormal toxicity; the concentration does not cause toxicity and significant irritation.
Description
Technical field
The present invention relates to a kind of azaspiro ketone drug injections and its preparation method and application.
Background technology
Anxiety is the center symptom of most common emotional responses and all kinds of neurosises.With the development and life of society
Tempo increase, demand of the people to anxiolytic drugs increasingly increase.Have by the 1st generation anxiolytic drugs of representative of Meprobamate
The 2nd generation anxiolytic drugs of drug resistance difference and serious withrawal symptom, Benzodiazepines has of flaccid muscles, spasm, ships certainly
Dynamic the problems such as waiting Psychomotor abilities obstacle, the discriminant function obstacle of memory, psychological and corporality to rely on.It is with Tandospirone
Represent the 3rd generation anxiolytic drugs selectively acting in intracerebral 5-HT1A receptors, site of action concentrate on emotion maincenter hippocampus,
The cerebral limbic systems such as amygdaloid nucleus are simultaneously projected to the nuclei of median raphe that 5-HT can be neural, pass through and activate presynaptic 5-HT1A receptor, inhibit
Neural spike train reduces the synthesis of 5-HT, while having partial agonist effect to the 5-HT1A receptors in postsynaptic, comprehensive to reach
The 5-HT functions of adjusting cynapse are closed, to play angst resistance effect, antidepressant effect can also be played simultaneously by being used for a long time.With 1
Generation, 2 generation drugs are compared, and highly selective due to Tandospirone, side effect is less, and sedative-hypnotic effect is weak, without of flaccid muscles
Effect, anti-spasm and inhibits autogenic movement effect, without according to lazyness and drug withdrawal withrawal symptom, in vivo without accumulation after prolonged application,
It has a extensive future in antianxiety field.
Tandospirone is the third generation novel anxiolytic succeeded in developing by SUMITOMO CHEMICAL Pharmaceutical Co., Ltd, and in 1996
Year is approved to list in Japan, initially enters Chinese market within 2004.The dosage form applied currently on the market only has oral tablet and glue
Wafer.For children, or there is digestive system obstacle, or the patient in the states such as stupor, twitch, convulsions and dysphagia
(such as gerontal patient, sickbed patients), tablets and capsules are unfavorable；These sufferers need more suitable for its physical condition or
The pharmaceutical dosage form of its illness, such as injection.
CN 101362751A disclose a kind of injection of Tandospirone, but Tandospirone disclosed in CN 101362751A
The stability of injection is poor, is unfavorable for storing, of high cost, and inventor's research finds the anxiolytic effect of the injection not
It is highly desirable.
Invention content
That there are stability the purpose of the present invention is being directed to Tandospirone pharmaceutical preparation in the prior art is poor, anxiolytic effect is poor
The problem of, a kind of novel Tandospirone injection is provided, and its preparation method and application, to solve existing Tandospirone drug
The technical problem of preparation stability difference and anxiolytic effect difference etc., improves the stability and anxiolytic effect of drug, to provide
It is a kind of to have both stability height and the good Tandospirone injection of anxiolytic effect.
The present invention is implemented by the following technical programs：
The present invention provides a kind of Tandospirone injection, which is characterized in that the Tandospirone injection includes smooth degree spiral shell
Ketone active constituent, stabilizer.
Preferably, above-mentioned Tandospirone injection, which is characterized in that the stabilizer is selected from hydrochloric acid, acetic acid, citron
It is one or more in acid, lactic acid, tartaric acid, dilute sulfuric acid, phosphoric acid, fumaric acid, succinic acid, malic acid, sodium hydroxide.
Preferably, above-mentioned Tandospirone injection, which is characterized in that the stabilizer is citric acid, hydrochloric acid and hydrogen-oxygen
Change one or more in sodium.
Preferably, above-mentioned Tandospirone injection, which is characterized in that when the Tandospirone injection shape soluble in water
When at aqueous solution, the pH value of the aqueous solution is 3.5~6.0.
Preferably, above-mentioned Tandospirone injection, which is characterized in that the Tandospirone active constituent is selected from citric acid
Tandospirone, hydrochloric acid Tandospirone, sulfuric acid Tandospirone, nitric acid Tandospirone, tartaric acid Tandospirone, oxalic acid Tandospirone,
Methanesulfonic acid Tandospirone, p-methyl benzenesulfonic acid Tandospirone, fumaric acid Tandospirone, maleic acid Tandospirone；Preferably, described smooth
Degree spiral shell ketone active constituent is tandospirone citrate.
Preferably, above-mentioned Tandospirone injection, which is characterized in that the Tandospirone injection includes liquid drugs injection, freezes
Dry powder needle, infusion.
Preferably, above-mentioned Tandospirone injection, which is characterized in that the Tandospirone injection further includes excipient
And/or water for injection；Preferably, the excipient is selected from lactose, fructose, glycine, sodium chloride, disodium hydrogen phosphate, phosphoric acid
It is one or more in sodium dihydrogen, mannitol, trehalose, sucrose, glucose, dextran, xylitol, sorbierite.
The present invention also provides a kind of methods preparing above-mentioned Tandospirone injection, which is characterized in that the method packet
It includes：It takes Tandospirone active constituent and stabilizer to be added in water for injection, be lyophilized or be not lyophilized, the Tandospirone note is made
Penetrate agent.
Preferably, above-mentioned method, which is characterized in that the method includes：Take Tandospirone active constituent and stabilizer
It is added in water for injection, adds needle-use activated carbon, filter, sterilizing or unsterilised is lyophilized or is not lyophilized, and the Tandospirone is made
Injection.
Preferably, the method includes：Excipient, Tandospirone active constituent, stabilizer is taken to be added in water for injection,
Stirring and dissolving adds needle-use activated carbon to adsorb, and filters, and sterilizing is lyophilized or is not lyophilized, and the Tandospirone injection is made.
The present invention also provides purposes of the above-mentioned Tandospirone injection in preparing anxiolytic drugs.
In injection of the present invention, Tandospirone active constituent can be configured in various concentration according to medication demand
Injection in range.Preferably, in the liquid drugs injection Tandospirone active constituent a concentration of 0.1mg/mL-20mg/mL；It is excellent
Selection of land, a concentration of 0.01mg/mL-1mg/mL of Tandospirone active constituent in the infusion solution；Preferably, the freeze-dried powder
The specification of Tandospirone active constituent is 0.1mg-20mg/ branch in agent.
Beneficial effects of the present invention：
The present inventor explores by continuous, is found surprisingly that, Tandospirone injection stability of the invention is high, anti-coke
It is good to consider effect, clinical patients demand can be met, can effectively solve children, or have digestive system obstacle, or in stupor, pumping
The patient (such as gerontal patient, sickbed patients) of states and dysphagia such as jerk, faint from fear should not take orally Tandospirone tablet or glue
The problem of wafer.The Tandospirone injection of the present invention also has many advantages, such as at low cost, easy to use.Especially when stabilizer is
When one or more in citric acid, hydrochloric acid and sodium hydroxide, the stability of the injection is obviously more preferable, has unexpected
Technique effect.The solution clarification of the Tandospirone injection of the present invention, particulate matter comply with standard, stability is good；It can not
See foreign matter, toxicity without exception；Its concentration does not cause toxicity and apparent irritation.
Specific implementation mode
The specific implementation mode of the present invention is described in detail below.It should be understood that described herein specific
Embodiment is merely to illustrate and explain the present invention, and is not intended to restrict the invention.
Embodiment 1
20mg tandospirone citrates are weighed, are added in appropriate water for injection, stirring to solution is clarified, and citric acid is added,
Again 200mL is settled to water for injection；Add needle-use activated carbon to adsorb, be filtered to remove activated carbon, sterilize, packs up to Tandospirone
Liquid drugs injection 100.
Embodiment 2
2g tandospirone citrates are weighed, are added in appropriate water for injection, stirring to solution is clarified, and hydrochloric acid is added, then use
Water for injection is settled to 200mL；Add needle-use activated carbon to adsorb, be filtered to remove activated carbon, sterilize, packs up to Tandospirone liquid drugs injection
100.
Embodiment 3
4g tandospirone citrates are weighed, are added in appropriate water for injection, stirring to solution is clarified, and sodium hydroxide is added,
Again 200mL is settled to water for injection；Add needle-use activated carbon to adsorb, be filtered to remove activated carbon, sterilize, packs up to Tandospirone
Liquid drugs injection 100.
Embodiment 4
2g tandospirone citrates are weighed, are added in appropriate water for injection, stirring to solution is clarified, and acetic acid is added, then use
Water for injection is settled to 200mL；Add needle-use activated carbon to adsorb, be filtered to remove activated carbon, sterilize, packs up to Tandospirone liquid drugs injection
100.
Embodiment 5
3g tandospirone citrates are weighed, are added in appropriate water for injection, stirring to solution is clarified, and malic acid is added, then
It is settled to 200mL with water for injection；Add needle-use activated carbon to adsorb, be filtered to remove activated carbon, sterilize, packs up to Tandospirone water
100, needle.
Embodiment 6
2.5g tandospirone citrates are weighed, are added in appropriate water for injection, stirring to solution is clarified, and citric acid is added,
Again 5000ml is settled to water for injection；Add needle-use activated carbon to adsorb, be filtered to remove activated carbon, sterilize, packs up to smooth degree spiral shell
Ketone is infused 100 bottles.
Embodiment 7
0.5g tandospirone citrates are weighed, are added in appropriate water for injection, stirring to solution is clarified, and tartaric acid is added,
Again 5000ml is settled to water for injection；Add needle-use activated carbon to adsorb, be filtered to remove activated carbon, sterilize, packs up to smooth degree spiral shell
Ketone is infused 100 bottles.
Embodiment 8
1g tandospirone citrates, 6g lactose are weighed, is added in appropriate water for injection, stirring to solution is clarified, and salt is added
Acid；Again 200mL is settled to water for injection；Add needle-use activated carbon to adsorb, be filtered to remove activated carbon, be lyophilized, packs up to smooth degree
100, spiral shell ketone powder needle.
Embodiment 9
0.5g tandospirone citrates, 10g mannitol are weighed, is added in appropriate water for injection, stirring to solution is clarified, and is added
Enter lactic acid；Again 200mL is settled to water for injection；Add needle-use activated carbon to adsorb, be filtered to remove activated carbon, be lyophilized, pack to obtain the final product
100, Tandospirone powder needle.
Comparative example 1
Tandospirone injection is prepared according to the method for embodiment 11 in patent CN 101362751A：
Tandospirone citrate 0.052mol (is approximately equivalent to 20g Tandospirones)
Water for injection 2000mL
It is dissolved with suitable water for injection, filtrate is filtered to clear and bright, 2000mL is injected water on filter, embedding is gone out
Bacterium is to get injection 1000.
Following " to 1 " are the abbreviation for the Tandospirone injection being prepared by comparative example 1；" example 1- examples 9 " be respectively by
The abbreviation for the Tandospirone injection that embodiment 1-9 is prepared.
Test example 1：Stability
(1) 60 DEG C of high-temperature stability experiment
High-temperature stability experiment is carried out under the conditions of the sample of 1 gained of embodiment 1-9 and comparative example is placed in 60 DEG C, as a result such as
Shown in the following table 1.
1 60 DEG C of high-temperature stability experiments of table
60 DEG C of high-temperature stability experimental results show that sample (not plus stabilizer) stability of comparative example 1 is poor, placement process
In related substance increase it is apparent, considerably beyond defined limit.Embodiment 4 (acetic acid), embodiment 5 (malic acid), embodiment 7
(tartaric acid) and the sample stability of embodiment 9 (lactic acid) are better than comparative example 1, and related substance is close to defined limit after 30 days.
Embodiment 1, embodiment 2, embodiment 3, embodiment 6 and embodiment 8 sample have excellent stability, related substance is without notable
Property variation.
(2) 40 DEG C of accelerated stability experiments
Accelerated stability experiment is carried out under the conditions of the sample of 1 gained of embodiment 1-9 and comparative example is placed in 40 DEG C, as a result such as
Shown in the following table 2.
2 40 DEG C of accelerated stability experiments of table
40 DEG C of accelerated stability experimental results show that the sample stability of comparative example 1 is poor, and related substance increases in placement process
It is long apparent, it has been more than defined limit.Embodiment 4, embodiment 5, embodiment 7 and embodiment 9 sample stability better than comparison
Example is increased after 1,6 months in relation to substance.The sample tool of embodiment 1, embodiment 2, embodiment 3, embodiment 6 and embodiment 8
There is excellent stability, related substance changes without conspicuousness.
(3) 5000lx light durabilities are tested
The sample of 1 gained of embodiment 1-9 and comparative example is placed under the conditions of 5000lx and carries out light durability experiment, as a result
As shown in table 3 below.
3 5000lx light durabilities of table are tested
5000lx light durability experimental results show that related substance is increased in the sample placement process of comparative example 1,
Have been approached defined limit.Embodiment 4, embodiment 5, the sample stability of embodiment 7 and embodiment 9 are preferable, and related substance omits
There is growth.Embodiment 1, embodiment 2, embodiment 3, embodiment 6 and embodiment 8 sample have excellent stability, related object
Matter changes without conspicuousness.
Test example 2：Antianxiety is tested
(1) wooden behavioral experiment
Estimate angst resistance effect by determining the use of the wooden behavior model of conditioned fear stress-induced.By 80 rats
It is randomly divided into 10 groups (physiological saline group, tandospirone citrate Capsules group, 1 group of comparative example, embodiment groups), every group 8, coverlet
It is solely placed in the impact test case of grid floor, and is given inevitable foot shock (total 2.5min) repeatedly, electricity
It is 30s to hit time interval, and total 5min is set as 0.6mA.24 hours after the single foot shock period, tandospirone citrate
Capsules group gives oral tandospirone citrate capsule, and physiological saline group gives intraperitoneal injection of saline, and 1 group of comparative example is given
1 gained Tandospirone injection of comparative example is injected intraperitoneally, embodiment group gives the smooth degree spiral shell obtained by intraperitoneal injection embodiment respectively
Ketone injection；After 0.5 hour, rat is again placed in impact test case, is not shocked by electricity, observation 5min (conditioned fear), knot
Fruit is shown in Table 4.
In the rat for giving foot shock, conditioned fear shows as wooden behavior, and wooden definition is a lack of any sight
Bone and the antenna activity observed, in addition to those related activities with breathing.Every other behavior is counted as activity.It is every according to it
Behavior during 10s, rat is classified as to show or wooden or active behavior.Percentage score (% is wooden) represents rat
Wooden period number during entire 10s.Wooden inhibition (IF%) is calculated using following equation：IF%=100-% is wooden.
P values, that is, probability reflect the possibility size that a certain event occurs.Statistics is according to obtained by significance test method
P values, generally with P<0.05 is notable, P<0.01 is highly significant, is meant that the difference between sample caused by sampling error
Probability be less than 0.05 or 0.01.
4 wooden behavioral experiment of table
| Group | Mouse number | Dosage mg/kg | Wooden Behavior inhibition rate |
| Physiological saline group | 8 | 10 | 42% |
| Tandospirone citrate capsule | 8 | 20 | 71% |
| 1 group of comparative example | 8 | 10 | 81% |
| 1 group of embodiment | 8 | 10 | 96%** |
| 2 groups of embodiment | 8 | 10 | 93%** |
| 3 groups of embodiment | 8 | 10 | 95%** |
| 4 groups of embodiment | 8 | 10 | 88%* |
| 5 groups of embodiment | 8 | 10 | 87%* |
| 8 groups of embodiment | 8 | 10 | 95%** |
| 9 groups of embodiment | 8 | 10 | 97%** |
Compared with the control group：*P<0.05, * * P<0.01.
Experimental result shows, 0.5h after the administration of single Tandospirone, give conditioned fear stress rat in observed by
To wooden Behavior inhibition rate increase.The wooden Behavior inhibition rate of embodiment group is higher than tandospirone citrate Capsules group and right
Ratio group.Therefore embodiment group can preferably improve the anxiety symptom of rat.
(2) elevated plus-maze test
80 rats are randomly divided into 10 groups, and (physiological saline group, 1 group of comparative example, is implemented tandospirone citrate Capsules group
Example group), every group 8.Tandospirone citrate Capsules group gives oral tandospirone citrate capsule, and physiological saline group gives abdomen
Chamber injecting normal saline, 1 group of comparative example give intraperitoneal injection 1 gained Tandospirone injection of comparative example, and embodiment group is given respectively
Give the Tandospirone injection obtained by intraperitoneal injection embodiment；Administration 5 days, 3 times/day, after sixty minutes in last dose, by rat
Being placed in Elevated plus-maze, (including two open arms (long 30cm, wide 6cm) close arm (long 30cm, wide 6cm) with two, close the upper of arm
Portion is opened wide, and there are one the opening of 5*5cm, labyrinths to close arm apart from the open portion in the high centers 50cm in ground, head court in center.Experiment exists
The morning 8:00-14:It is carried out between 00.Animal in 5 minutes is automatically recorded by DigBehv animal behaviors analysis system 2.0 to enter
It open arms number and closes arm number and the residence time and is closing the residence time in arm in open arms.Then with into open arms number and always
Entering the percentage of arm number, when run duration closes the percentage of total run duration in arm as antianxiety work with open arms in open arms
Use index.Wiped clean labyrinth after the completion of test every time, then tested next time.Into open arms number and residence time with
The anxiety of rat is negatively correlated, and fewer into open arms number, the residence time is shorter, illustrates that the anxiety of mouse is tighter
Weight, the results are shown in Table 5.
Test data mean+SDIt indicates, data analysis is carried out with SPSS11.5 softwares.Compare between group
Compared with using one-way analysis of variance (One-Way ANOVA).
5 elevated plus-maze test of table
| Group | Mouse number | Dosage mg/kg | Into open arms percentage of time (%) | Into open arms percentage of time (%) |
| Physiological saline group | 8 | 10 | 3.89±1.07 | 18.70±3.23 |
| Tandospirone citrate capsule | 8 | 20 | 8.37±1.84 | 22.34±4.21 |
| 1 group of comparative example | 8 | 10 | 12.03±2.15 | 28.04±2.57 |
| 1 group of embodiment | 8 | 10 | 19.69±2.58** | 38.04±2.48** |
| 2 groups of embodiment | 8 | 10 | 19.02±1.35** | 38.64±2.51** |
| 3 groups of embodiment | 8 | 10 | 19.73±3.01** | 38.95±2.17** |
| 4 groups of embodiment | 8 | 10 | 16.03±1.15* | 34.04±2.07* |
| 5 groups of embodiment | 8 | 10 | 16.55±1.97* | 34.25±2.14* |
| 8 groups of embodiment | 8 | 10 | 18.85±1.97** | 37.75±2.14** |
| 9 groups of embodiment | 8 | 10 | 19.35±2.15** | 37.98.04±2.84** |
Compared with the control group：* P ﹤ 0.05, * * P ﹤ 0.01
Experimental result is shown, after giving Tandospirone, all rats enter open arms percentage of time and enter open arms number
Percentage increases.The entrance open arms percentage of time of embodiment group is more than tandospirone citrate Capsules group and comparative example group,
The entrance open arms percentage of time of embodiment group is longer than tandospirone citrate Capsules group and comparative example group.Therefore embodiment group
The anxiety symptom of rat can preferably be improved.
(3) light and shade case is tested
80 rats are randomly divided into 10 groups, and (physiological saline group, 1 group of comparative example, is implemented tandospirone citrate Capsules group
Example group), every group 8.Tandospirone citrate Capsules group gives oral tandospirone citrate capsule, and physiological saline group gives abdomen
Chamber injecting normal saline, 1 group of comparative example give intraperitoneal injection 1 gained Tandospirone injection of comparative example, and embodiment group is given respectively
Give the Tandospirone injection obtained by intraperitoneal injection embodiment；Administration 5 days, 3 times/day, after sixty minutes in last dose, into every trade
It is tested to learn, all experiments are 8:00-14:It is carried out between 00.First rat is placed individually into plastic casing before test, is allowed to freedom
Activity 5 minutes, then by rat head back to camera bellows direction be placed in camera-lucida center, recorded after release worn in 5 minutes case number and
The residence time in camera-lucida.Wiped clean light and shade case after the completion of test every time, then tested next time, the results are shown in Table 6.
Test data mean+SDIt indicates, data analysis is carried out with SPSS11.5 softwares.Compare between group
Compared with using one-way analysis of variance (One-Way ANOVA).
6 light and shade case of table is tested
| Group | Mouse number | Dosage mg/kg | Wear case number | The camera-lucida activity time (S) |
| Physiological saline group | 8 | 10 | 12.23±1.87 | 147.01±8.56 |
| Tandospirone citrate capsule | 8 | 20 | 20.76±2.14 | 172.62±14.35 |
| 1 group of comparative example | 8 | 10 | 25.35±1.05 | 183.03±10.58 |
| 1 group of embodiment | 8 | 10 | 34.23±2.18 | 206.64±1.35 |
| 2 groups of embodiment | 8 | 10 | 33.23±2.18 | 202.64±1.35 |
| 3 groups of embodiment | 8 | 10 | 32.34±1.57 | 203.72±8.76 |
| 4 groups of embodiment | 8 | 10 | 29.07±1.08 | 195.37±9.57 |
| 5 groups of embodiment | 8 | 10 | 28.78±2.17 | 191.87±8.37 |
| 8 groups of embodiment | 8 | 10 | 33.23±2.18 | 202.64±1.35 |
| 9 groups of embodiment | 8 | 10 | 33.98±1.47 | 202.64±1.05 |
Experimental result shows that the case number of wearing of embodiment group is more than tandospirone citrate Capsules group and comparative example group, real
The camera-lucida activity time for applying example group is longer than tandospirone citrate Capsules group and comparative example group.Therefore embodiment group can be more preferable
Improvement rat anxiety symptom.
(4) social interaction is tested
80 rats are randomly divided into 10 groups, and (physiological saline group, 1 group of comparative example, is implemented tandospirone citrate Capsules group
Example group), every group 8.Tandospirone citrate Capsules group gives oral tandospirone citrate capsule, and physiological saline group gives abdomen
Chamber injecting normal saline, 1 group of comparative example give intraperitoneal injection 1 gained Tandospirone injection of comparative example, and embodiment group is given respectively
Give the Tandospirone injection obtained by intraperitoneal injection embodiment；Administration 5 days, 3 times/day.In after the last administration, by rat individually every
From placing 1 hour, then two rats are placed in an opening plastic casing (22cm*15cm*12cm), observe them 5 minutes
The interior social exploratory behaviour (smell, climb, drill body, lick companion's neck, fight) to companion, the results are shown in Table 7.
Test data mean+SDIt indicates, data analysis is carried out with SPSS11.5 softwares.Between group
Compare and uses one-way analysis of variance (One-Way ANOVA).
7 social interaction of table is tested
| Group | Mouse number | Dosage mg/kg | The social interaction cumulative time (S) |
| Physiological saline group | 8 | 10 | 119.35±11.37 |
| Tandospirone citrate capsule | 8 | 20 | 149.21±9.27 |
| 1 group of comparative example | 8 | 10 | 176.85±15.67 |
| 1 group of embodiment | 8 | 10 | 196.85±10.28 |
| 2 groups of embodiment | 8 | 10 | 193.27±14.39 |
| 3 groups of embodiment | 8 | 10 | 195.72±9.28 |
| 4 groups of embodiment | 8 | 10 | 185.59±11.87 |
| 5 groups of embodiment | 8 | 10 | 183.59±13.65 |
| 8 groups of embodiment | 8 | 10 | 194.59±9.78 |
| 9 groups of embodiment | 8 | 10 | 194.59±15.67 |
Experimental result shows that the social interaction cumulative time of embodiment group is longer than tandospirone citrate Capsules group and comparison
Example group.Therefore embodiment group can preferably improve the anxiety symptom of rat.
In summary, Tandospirone injection stability of the invention and anxiolytic effect are significantly better than conventional smooth degree spiral shell
Ketone injection, and the anxiolytic effect of the Tandospirone injection of the present invention is also significantly better than conventional Tandospirone oral capsule
Agent can effectively solve children, or have digestive system obstacle, or the trouble in the states such as stupor, twitch, convulsions and dysphagia
The problem of person (such as gerontal patient, sickbed patients) should not take orally Tandospirone tablet or capsule.Especially when stabilizer is Chinese holly
When one or more in rafter acid, hydrochloric acid and sodium hydroxide, the injection has apparent more excellent stability.
The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above
Detail can carry out a variety of simple variants to technical scheme of the present invention within the scope of the technical concept of the present invention, this
Kind simple variant all belongs to the scope of protection of the present invention.
Claims (10)
1. a kind of Tandospirone injection, which is characterized in that the Tandospirone injection includes Tandospirone active constituent, steady
Determine agent.
2. Tandospirone injection according to claim 1, which is characterized in that the stabilizer be selected from hydrochloric acid, acetic acid,
It is one or more in citric acid, lactic acid, tartaric acid, dilute sulfuric acid, phosphoric acid, fumaric acid, succinic acid, malic acid, sodium hydroxide.
3. Tandospirone injection according to claim 1 or 2, which is characterized in that the stabilizer is citric acid, hydrochloric acid
With it is one or more in sodium hydroxide.
4. Tandospirone injection according to any one of claim 1-3, which is characterized in that when the Tandospirone is noted
When penetrating agent formation aqueous solution soluble in water, the pH value of the aqueous solution is 3.5~6.0.
5. the Tandospirone injection according to any one of claim 1-4, which is characterized in that the Tandospirone activity
Ingredient be selected from tandospirone citrate, hydrochloric acid Tandospirone, sulfuric acid Tandospirone, nitric acid Tandospirone, tartaric acid Tandospirone,
Oxalic acid Tandospirone, methanesulfonic acid Tandospirone, p-methyl benzenesulfonic acid Tandospirone, fumaric acid Tandospirone, maleic acid Tandospirone；
Preferably, the Tandospirone active constituent is tandospirone citrate.
6. Tandospirone injection according to any one of claims 1-5, which is characterized in that the Tandospirone injection
Agent includes liquid drugs injection, freeze-dried powder, infusion.
7. the Tandospirone injection according to any one of claim 1-6, which is characterized in that the Tandospirone injection
Agent further includes excipient and/or water for injection；Preferably, the excipient is selected from lactose, fructose, glycine, sodium chloride, phosphorus
One kind in sour disodium hydrogen, sodium dihydrogen phosphate, mannitol, trehalose, sucrose, glucose, dextran, xylitol, sorbierite
Or it is a variety of.
8. a kind of method preparing the Tandospirone injection described in any one of claim 1-7, which is characterized in that the side
Method includes：It takes Tandospirone active constituent and stabilizer to be added in water for injection, be lyophilized or be not lyophilized, the smooth degree spiral shell is made
Ketone injection.
9. according to the method described in claim 8, it is characterized in that, the method includes：Take Tandospirone active constituent and steady
Determine agent to be added in water for injection, add needle-use activated carbon, filter, sterilizing or unsterilised is lyophilized or is not lyophilized, and the smooth degree is made
Spiral shell ketone injection；
Preferably, the method includes：It takes excipient, Tandospirone active constituent, stabilizer to be added in water for injection, stirs
Dissolving, adds needle-use activated carbon to adsorb, and filters, and sterilizing is lyophilized or is not lyophilized, and the Tandospirone injection is made.
10. purposes of the Tandospirone injection in preparing anxiolytic drugs described in any one of claim 1-7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710155536.4A CN108619100B (en) | 2017-03-16 | 2017-03-16 | Azaspirone medicine injection and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710155536.4A CN108619100B (en) | 2017-03-16 | 2017-03-16 | Azaspirone medicine injection and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108619100A true CN108619100A (en) | 2018-10-09 |
| CN108619100B CN108619100B (en) | 2022-05-13 |
Family
ID=63686352
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710155536.4A Active CN108619100B (en) | 2017-03-16 | 2017-03-16 | Azaspirone medicine injection and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108619100B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101322684A (en) * | 2007-06-11 | 2008-12-17 | 海南中和药业股份有限公司 | Acetic acid desmopressin injection prescription and preparation technique thereof |
| CN101362751A (en) * | 2007-08-10 | 2009-02-11 | 成都市律凯医药科技有限公司 | Tandospirone citrate, preparation method thereof, formulations and quality control method |
| CN102264344A (en) * | 2008-12-22 | 2011-11-30 | 爱尔康研究有限公司 | Compositions of topical ocular solutions to deliver effective concentrations of active agent to posterior segment of eye |
| CN105218528A (en) * | 2014-06-06 | 2016-01-06 | 四川科瑞德制药有限公司 | A kind of L-TARTARIC ACID Tandospirone compound |
-
2017
- 2017-03-16 CN CN201710155536.4A patent/CN108619100B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101322684A (en) * | 2007-06-11 | 2008-12-17 | 海南中和药业股份有限公司 | Acetic acid desmopressin injection prescription and preparation technique thereof |
| CN101362751A (en) * | 2007-08-10 | 2009-02-11 | 成都市律凯医药科技有限公司 | Tandospirone citrate, preparation method thereof, formulations and quality control method |
| CN102264344A (en) * | 2008-12-22 | 2011-11-30 | 爱尔康研究有限公司 | Compositions of topical ocular solutions to deliver effective concentrations of active agent to posterior segment of eye |
| CN105218528A (en) * | 2014-06-06 | 2016-01-06 | 四川科瑞德制药有限公司 | A kind of L-TARTARIC ACID Tandospirone compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108619100B (en) | 2022-05-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Nikkhah et al. | Dopaminergic microtransplants into the substantia nigra of neonatal rats with bilateral 6-OHDA lesions. II. Transplant-induced behavioral recovery | |
| CN102245615A (en) | Methods of treating hepatic encephalopathy | |
| CN106511366B (en) | Treat drug of ischemia apoplexy and preparation method thereof and purposes | |
| CN108012527A (en) | Benzimidizole derivatives are used for the purposes of Control of Nocturnal Gastric Acid Breakthrough | |
| CN106389479A (en) | Application of bacillus coagulans in preparing preparation for preventing or treating autism | |
| WO2023237124A1 (en) | Crocin suspension and use thereof in preparation of rapid-acting antidepressant drug | |
| CN110151823A (en) | A kind of application of cinnamon essential oil | |
| Lehmann | Therapeutic results with chlorpromazine (Largactil) in psychiatric conditions | |
| CN108143733A (en) | A kind of narcotic analgesics compositions and preparation method thereof | |
| CN107417556A (en) | L aspartase calciums and preparation method thereof | |
| CN107126510B (en) | Traditional Chinese medicine composition for treating children tic disorder syndrome and application thereof | |
| CN1961879B (en) | Pharmaceutical composition for nose administered in-situ gel spray of Huperzine A, preparation process and use thereof | |
| CN101780227B (en) | Traditional Chinese medicine composition for treating acute stroke and preparation method thereof | |
| Allen et al. | Excitotoxic lesions of the pedunculopontine tegmental nucleus disinhibit orofacial behaviours stimulated by microinjections of d-amphetamine into rat ventrolateral caudate-putamen | |
| CN114699424B (en) | New application of bacteroides fragilis zwitterionic capsular polysaccharide and/or modified zwitterionic capsular polysaccharide | |
| CN108619100A (en) | Azaspiroanone medicine injection and preparation method and application thereof | |
| CN101559046A (en) | Therapeutic action of micromolecule sugar alcohol composite on nasal disease | |
| KR0185539B1 (en) | Complex coughing drug and their preparation method | |
| US5527825A (en) | Method of treating schizophrenia, tourette's syndrome, mania, autism, and obsessive compulsive disorder with inhibitors of brain nitric oxide synthase | |
| CN108210879A (en) | A kind of pharmaceutical composition for treating acute Cerebral bleeding and its application | |
| CN109200268A (en) | The composition and its long-time service method of weight gain compound | |
| US8916607B2 (en) | Use of piperphentonamine or salts thereof in manufacture of medicaments for treating brain diseases | |
| CN110279734A (en) | A kind of application of angelica essential oil | |
| CN1840121A (en) | Medicine for treating cough and preparation method thereof | |
| WO2014038878A2 (en) | Composition for brain-neuron protection and brain-disease prevention, alleviation or treatment comprising muskrat musk |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |