CN108619100B - Azaspirone medicine injection and preparation method and application thereof - Google Patents
Azaspirone medicine injection and preparation method and application thereof Download PDFInfo
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- 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
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- 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
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- 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
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- 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
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 invention relates to an azaspirone medicine injection and a preparation method and application thereof.
Background
Anxiety is the most common emotional response and is also the central symptom of various types of neurosis. With the development of society and the pace of life increasing, people are increasingly demanding anxiolytic drugs. The 1 st generation anxiolytic drugs represented by meprobamate have poor drug resistance and serious withdrawal symptoms, and the 2 nd generation anxiolytic drugs of benzodiazepines have problems of psychomotor dysfunction such as muscle relaxation, spasm and spontaneous movement, memory discrimination dysfunction, psychology and physical dependence and the like. The 3 rd generation anxiolytic represented by tandospirone selectively acts on 5-HT1A receptors in brain, the acting part is concentrated on the cerebral marginal system of hippocampus, amygdala and the like of emotional center and projects to the midriff of 5-HT nervously, by activating presynaptic 5-HT1A receptors, neuronal discharge is inhibited, 5-HT synthesis is reduced, and partial agonism is performed on postsynaptic 5-HT1A receptors, so that 5-HT function of synapsis is comprehensively regulated, and the anxiolytic effect is exerted, and the antidepressant effect can be exerted when the anxiolytic is used for a long time. Compared with the 1 generation and 2 generation medicaments, the tandospirone has less side effect due to high selectivity of tandospirone, has weak sedative hypnotic effect, no muscle relaxation effect, anti-spasm and spontaneous movement inhibition effect, no dependence and withdrawal symptoms after stopping medicament, no accumulation in vivo after long-term application, and wide application prospect in the field of antianxiety.
Tandospirone is a third generation of novel anxiolytic drug developed successfully by sumitomo pharmaceutical corporation in japan and approved for the market in 1996 in japan, and began to enter the chinese market in 2004. The only dosage forms currently available on the market are oral tablets and capsules. For children, patients with digestive system disorders, coma, convulsion, dysphagia (such as elderly patients, bedridden patients), tablets and capsules are not suitable; these patients need pharmaceutical dosage forms, such as injections, that are more suitable for their physical condition or their disorder.
CN 101362751a discloses an injection of tandospirone, but CN 101362751a discloses an injection of tandospirone, which has poor stability, is not favorable for storage, and has high cost, and the inventor finds that the anxiolytic effect of the injection is not ideal.
Disclosure of Invention
The invention aims to solve the problems of poor stability and poor anxiolytic effect of a tandospirone medicinal preparation in the prior art, and provides a novel tandospirone injection, a preparation method and application thereof, so that the technical problems of poor stability, poor anxiolytic effect and the like of the existing tandospirone medicinal preparation are solved, the stability and the anxiolytic effect of a medicament are improved, and the tandospirone injection with high stability and good anxiolytic effect is provided.
The invention is implemented by the following technical scheme:
the invention provides a tandospirone injection, which is characterized by comprising a tandospirone active ingredient and a stabilizer.
Preferably, the tandospirone injection is characterized in that the stabilizer is one or more selected from hydrochloric acid, acetic acid, citric acid, lactic acid, tartaric acid, dilute sulfuric acid, phosphoric acid, fumaric acid, succinic acid, malic acid and sodium hydroxide.
Preferably, the tandospirone injection is characterized in that the stabilizer is one or more of citric acid, hydrochloric acid and sodium hydroxide.
Preferably, the tandospirone injection is characterized in that when the tandospirone injection is dissolved in water to form an aqueous solution, the pH value of the aqueous solution is 3.5-6.0.
Preferably, the tandospirone injection is characterized in that the tandospirone active ingredient is selected from tandospirone citrate, tandospirone hydrochloride, tandospirone sulfate, tandospirone nitrate, tandospirone tartrate, tandospirone oxalate, tandospirone mesylate, tandospirone p-toluenesulfonate, tandospirone fumarate and tandospirone maleate; preferably, the active component of tandospirone is tandospirone citrate.
Preferably, the tandospirone injection is characterized by comprising a water injection, a freeze-dried powder injection and an infusion solution.
Preferably, the tandospirone injection is characterized by further comprising an excipient and/or water for injection; preferably, the excipient is one or more selected from lactose, fructose, glycine, sodium chloride, disodium hydrogen phosphate, sodium dihydrogen phosphate, mannitol, trehalose, sucrose, glucose, dextran, xylitol, and sorbitol.
The present invention also provides a method for preparing the tandospirone injection, which is characterized in that the method comprises the following steps: and adding the tandospirone active ingredient and the stabilizer into water for injection, and freeze-drying or not, thus preparing the tandospirone injection.
Preferably, the method as described above, wherein the method comprises: adding the tandospirone active ingredient and the stabilizer into water for injection, adding activated carbon for injection, filtering, sterilizing or not sterilizing, and freeze-drying or not freeze-drying to prepare the tandospirone injection.
Preferably, the method comprises: adding excipient, tandospirone active ingredient and stabilizer into water for injection, stirring for dissolving, adding active carbon for injection for adsorption, filtering, sterilizing, and lyophilizing or not lyophilizing to obtain the tandospirone injection.
The invention also provides application of the tandospirone injection in preparing an anxiolytic drug.
In the injection, injection with tandospirone active ingredients in different concentration ranges can be prepared according to the medication requirements. Preferably, the concentration of the tandospirone active ingredient in the water injection is 0.1mg/mL-20 mg/mL; preferably, the concentration of the tandospirone active ingredient in the infusion solution is 0.01mg/mL-1 mg/mL; preferably, the specification of the tandospirone active ingredient in the freeze-dried powder injection is 0.1mg-20 mg/injection.
The invention has the beneficial effects that:
the inventor finds that the tandospirone injection has high stability and good anxiolytic effect, can meet the requirements of clinical patients, and can effectively solve the problem that children, patients with digestive system disorders, coma, convulsion and the like, and patients with dysphagia (such as old patients and bedridden patients) are not suitable for orally taking tandospirone tablets or capsules. The tandospirone injection also has the advantages of low cost, convenient use and the like. Particularly, when the stabilizer is one or more of citric acid, hydrochloric acid and sodium hydroxide, the injection has obviously better stability and unexpected technical effect. The solution of the tandospirone 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.
Detailed Description
The following describes in detail specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
Example 1
Weighing 20mg of tandospirone citrate, adding a proper amount of water for injection, stirring until the solution is clear, adding citric acid, and then adding the water for injection to a constant volume of 200 mL; adding active carbon for adsorption, filtering to remove active carbon, sterilizing, and packaging to obtain 100 tandospirone water needles.
Example 2
Weighing 2g of tandospirone citrate, adding a proper amount of water for injection, stirring until the solution is clear, adding hydrochloric acid, and then adding the water for injection to a constant volume of 200 mL; adding active carbon for adsorption, filtering to remove active carbon, sterilizing, and packaging to obtain 100 tandospirone water needles.
Example 3
Weighing 4g of tandospirone citrate, adding a proper amount of water for injection, stirring until the solution is clear, adding sodium hydroxide, and then adding the water for injection to a constant volume of 200 mL; adding active carbon for adsorption, filtering to remove active carbon, sterilizing, and packaging to obtain 100 tandospirone water needles.
Example 4
Weighing 2g of tandospirone citrate, adding a proper amount of water for injection, stirring until the solution is clear, adding acetic acid, and then adding the water for injection to a constant volume of 200 mL; adding active carbon for adsorption, filtering to remove active carbon, sterilizing, and packaging to obtain 100 tandospirone water needles.
Example 5
Weighing 3g of tandospirone citrate, adding a proper amount of water for injection, stirring until the solution is clear, adding malic acid, and then adding the water for injection to a constant volume of 200 mL; adding active carbon for adsorption, filtering to remove active carbon, sterilizing, and packaging to obtain 100 tandospirone water needles.
Example 6
Weighing 2.5g of tandospirone citrate, adding a proper amount of water for injection, stirring until the solution is clear, adding citric acid, and then adding the water for injection to reach the constant volume of 5000 ml; adding active carbon for injection, filtering to remove active carbon, sterilizing, and packaging to obtain tandospirone infusion 100 bottles.
Example 7
Weighing 0.5g of tandospirone citrate, adding a proper amount of water for injection, stirring until the solution is clear, adding tartaric acid, and then adding the water for injection to fix the volume to 5000 ml; adding active carbon for injection, filtering to remove active carbon, sterilizing, and packaging to obtain tandospirone infusion 100 bottles.
Example 8
Weighing 1g of tandospirone citrate and 6g of lactose, adding a proper amount of water for injection, stirring until the solution is clear, and adding hydrochloric acid; then the volume is determined to 200mL by using the water for injection; adding active carbon for adsorption, filtering to remove active carbon, lyophilizing, and packaging to obtain 100 tandospirone powder for injection.
Example 9
Weighing 0.5g of tandospirone citrate and 10g of mannitol, adding a proper amount of water for injection, stirring until the solution is clear, and adding lactic acid; then the volume is determined to 200mL by using the water for injection; adding active carbon for adsorption, filtering to remove active carbon, lyophilizing, and packaging to obtain 100 tandospirone powder for injection.
Comparative example 1
Tandospirone injection was prepared according to the method of example 11 in patent CN 101362751 a:
0.052mol of tandospirone citrate (about 20g of tandospirone)
2000mL of water for injection
Dissolving with appropriate amount of water for injection, filtering the filtrate to be clear, adding water for injection to 2000mL, bottling, and sterilizing to obtain 1000 injectable preparations.
The following "pair 1" is an abbreviation for tandospirone injection prepared from comparative example 1; "examples 1 to 9" are abbreviations for tandospirone injections prepared in examples 1 to 9, respectively.
Test example 1: stability of
(1) High temperature stability test at 60 deg.C
The samples obtained in examples 1 to 9 and comparative example 1 were subjected to a high temperature stability test at 60 ℃ and the results are shown in Table 1 below.
TABLE 160 ℃ high temperature stability test
The results of the 60 ℃ high temperature stability experiments show that the sample of comparative example 1 (without the stabilizer) has poor stability, and the growth of related substances is obvious during the placement process and far exceeds the specified limit. The samples of example 4 (acetic acid), example 5 (malic acid), example 7 (tartaric acid) and example 9 (lactic acid) were more stable than comparative example 1, and the substances were close to the specified limits after 30 days. The samples of example 1, example 2, example 3, example 6 and example 8 have excellent stability, and the relevant substances have no significant change.
(2) Accelerated stability test at 40 deg.C
The samples obtained in examples 1 to 9 and comparative example 1 were subjected to accelerated stability test at 40 c, and the results are shown in table 2 below.
Table 240 ℃ accelerated stability test
The results of the accelerated stability test at 40 ℃ show that the sample of comparative example 1 has poor stability and the growth of the related substances during the standing process is obvious and exceeds the specified limit. The stability of the samples of example 4, example 5, example 7 and example 9 is better than that of the comparative example 1, and the related substances are increased after 6 months. The samples of example 1, example 2, example 3, example 6 and example 8 have excellent stability, and the relevant substances have no significant change.
(3)5000lx light stability test
The samples obtained in examples 1 to 9 and comparative example 1 were subjected to a light stability test under 5000lx conditions, and the results are shown in the following Table 3.
TABLE 35000 lx light stability test
The 5000lx light stability test results show that the samples of comparative example 1 have increased related substances during the standing process and are close to the specified limits. The samples of example 4, example 5, example 7 and example 9 were more stable with a slight increase in the amount of the substance involved. The samples of example 1, example 2, example 3, example 6 and example 8 have excellent stability, and the relevant substances have no significant change.
Test example 2: anxiolytic test
(1) Experiment of catalepsy
Anxiolytic effects were estimated by determining a model of catatonic behaviour induced by conditioned fear stress. 80 rats were randomly divided into 10 groups (saline group, tandospirone citrate capsule group, comparative example 1 group, example group), 8 rats each were individually placed in a shock test chamber with a grid floor, and were repeatedly given an inevitable foot shock (total 2.5min) with a shock time interval of 30s for 5min set at 0.6 mA. 24 hours after a single foot electric shock period, the tandospirone citrate capsule group is administered with an oral tandospirone citrate capsule, the normal saline group is administered with an intraperitoneal injection of normal saline, the comparative example 1 group is administered with an intraperitoneal injection of the tandospirone injection obtained in the comparative example 1, and the example groups are respectively administered with the intraperitoneal injection of the tandospirone injections obtained in the examples; after 0.5 hours, the rats were again placed in the shock chamber without shock and observed for 5min (conditioned fear), the results of which are shown in table 4.
In rats given a foot shock, conditioned fear manifests as catastrophe behavior, defined as a lack of any observed skeletal and tentacle activity, except those associated with respiration. All other behaviors are counted as activities. Rats were classified as exhibiting either catalepsy or voluntary behavior according to their behavior every 10s period. The percentage score (% catalepsy) represents the number of periods of catalepsy throughout the 10s period in the rat. The inhibition of freezing (IF%) was calculated using the following formula: IF% ═ 100-% stiffness.
The P value, i.e., the probability, reflects the magnitude of the likelihood of an event occurring. Statistics the P values obtained from the significance test method are generally significant with P <0.05 and very significant with P <0.01, meaning that the probability of sample-to-sample differences due to sampling errors is less than 0.05 or 0.01.
TABLE 4 Stiff behavior test
| Group of | Number of mice | Dosage mg/kg | Rate of inhibition of freezing behaviour |
| Physiological saline group | 8 | 10 | 42％ |
| Tandospirone citrate capsule | 8 | 20 | 71％ |
| Comparative example 1 group | 8 | 10 | 81％ |
| EXAMPLE 1 group | 8 | 10 | 96％** |
| EXAMPLE 2 group | 8 | 10 | 93％** |
| EXAMPLE 3 group | 8 | 10 | 95％** |
| EXAMPLE 4 group | 8 | 10 | 88％* |
| EXAMPLE 5 group | 8 | 10 | 87％* |
| EXAMPLE 8 group | 8 | 10 | 95％** |
| EXAMPLE 9 group | 8 | 10 | 97％** |
Compared with the control group: p <0.05, P < 0.01.
The experimental results show that the inhibition rate of catatonic behaviour observed in rats given conditioned fear stress is increased 0.5h after a single administration of tandospirone. The inhibition rate of the freezing behavior of the example group is higher than that of the tandospirone citrate capsule group and the comparative example group. Therefore, the anxiety symptom of the rat can be improved better by the embodiment group.
(2) Elevated cross maze experiment
80 rats were randomly divided into 10 groups (saline group, tandospirone citrate capsule group, comparative example 1 group, example group) of 8 rats each. The tandospirone citrate capsule group is used for oral administration of tandospirone citrate capsules, the normal saline group is used for intraperitoneal injection of normal saline, the comparative example 1 group is used for intraperitoneal injection of the tandospirone injection obtained in the comparative example 1, and the example groups are respectively used for intraperitoneal injection of the tandospirone injection obtained in the example; after 5 days and 3 times/day of administration, 60 minutes after the last administration, the rat was placed in an elevated plus maze comprising two open arms (30 cm long and 6cm wide) and two closed arms (30 cm long and 6cm wide), the upper part of the closed arms being open, with a 5 x 5cm open area in the center, the maze being 50cm high from the ground and the central open part being open, the head facing the closed arms, the experiment was performed at 8:00-14:00 am, the number of times the animal entered the open arms and the number of times the animal entered the closed arms and the retention time in the closed arms were automatically recorded by the DigBehv animal behavior analysis system 2.0 for 5 minutes, the percentage of the number of times the animal entered the open arms and the total movement time in the closed arms were used as anxiolytic indicators, the maze was wiped after each test was completed, the number of times the open arms entered and the retention time were negatively correlated with the mood of the anxiety in the rat, the smaller the number of arm entries, the shorter the retention time, indicating that the anxiety of the rats was more severe, and the results are shown in Table 5.
Mean. + -. standard deviation of test data
Data analysis was performed using SPSS11.5 software. Group(s)The comparisons were performed using One-Way analysis of variance (One-Way ANOVA).
TABLE 5 elevated Cross maze experiment
| Group of | Number of mice | Dosage mg/kg | Percentage of time to arm opening (%) | Percentage of arm-opening entries (%) |
| 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 |
| Comparative example 1 group | 8 | 10 | 12.03±2.15 | 28.04±2.57 |
| EXAMPLE 1 group | 8 | 10 | 19.69±2.58** | 38.04±2.48** |
| EXAMPLE 2 group | 8 | 10 | 19.02±1.35** | 38.64±2.51** |
| EXAMPLE 3 group | 8 | 10 | 19.73±3.01** | 38.95±2.17** |
| EXAMPLE 4 group | 8 | 10 | 16.03±1.15* | 34.04±2.07* |
| EXAMPLE 5 group | 8 | 10 | 16.55±1.97* | 34.25±2.14* |
| EXAMPLE 8 group | 8 | 10 | 18.85±1.97** | 37.75±2.14** |
| Examples9 groups of | 8 | 10 | 19.35±2.15** | 37.98.04±2.84** |
Compared with the control group: p <0.05 > and P <0.01
The results of the experiments show that all rats had an increase in the percentage of open arm entry time and the percentage of open arm entry times after tandospirone administration. The percentage of arm-entering time of the example group is more than that of the tandospirone citrate capsule group and that of the comparative example group, and the percentage of arm-entering times of the example group is more than that of the tandospirone citrate capsule group and that of the comparative example group. Therefore, the group of examples can improve the anxiety symptom of rats better.
(3) Light and shade box experiment
80 rats were randomly divided into 10 groups (saline group, tandospirone citrate capsule group, comparative example 1 group, example group) of 8 rats each. The tandospirone citrate capsule group is used for oral administration of tandospirone citrate capsules, the normal saline group is used for intraperitoneal injection of normal saline, the comparative example 1 group is used for intraperitoneal injection of the tandospirone injection obtained in the comparative example 1, and the example groups are respectively used for intraperitoneal injection of the tandospirone injection obtained in the example; the administration was 5 days, 3 times per day, and behavioral testing was performed 60 minutes after the last administration, all tests were performed between 8:00 and 14: 00. Before testing, the rat is put into a plastic box independently and allowed to move freely for 5 minutes, then the rat is placed in the center of the open box in the direction that the head of the rat faces back to the dark box, and after release, the number of times of penetrating the box within 5 minutes and the residence time in the open box are recorded. After each test, the light and dark box was wiped clean, and the next test was performed, with the results shown in table 6.
Mean. + -. standard deviation of test data
Data analysis was performed using SPSS11.5 software. Comparison between groups Using Single factorAnalysis of variance (One-Way ANOVA).
TABLE 6 light and shade box experiment
| Group of | Number of mice | Dosage mg/kg | Number of box passes | Open case 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 |
| Comparative example 1 group | 8 | 10 | 25.35±1.05 | 183.03±10.58 |
| EXAMPLE 1 group | 8 | 10 | 34.23±2.18 | 206.64±1.35 |
| EXAMPLE 2 group | 8 | 10 | 33.23±2.18 | 202.64±1.35 |
| EXAMPLE 3 group | 8 | 10 | 32.34±1.57 | 203.72±8.76 |
| EXAMPLE 4 group | 8 | 10 | 29.07±1.08 | 195.37±9.57 |
| EXAMPLE 5 group | 8 | 10 | 28.78±2.17 | 191.87±8.37 |
| EXAMPLE 8 group | 8 | 10 | 33.23±2.18 | 202.64±1.35 |
| EXAMPLE 9 group | 8 | 10 | 33.98±1.47 | 202.64±1.05 |
The experimental result shows that the number of the box-through times of the example group is more than that of the tandospirone citrate capsule group and the comparative example group, and the open box activity time of the example group is longer than that of the tandospirone citrate capsule group and the comparative example group. Therefore, the group of examples can improve the anxiety symptom of rats better.
(4) Social interaction experiment
80 rats were randomly divided into 10 groups (saline group, tandospirone citrate capsule group, comparative example 1 group, example group) of 8 rats each. The tandospirone citrate capsule group is used for oral administration of tandospirone citrate capsules, the normal saline group is used for intraperitoneal injection of normal saline, the comparative example 1 group is used for intraperitoneal injection of the tandospirone injection obtained in the comparative example 1, and the example groups are respectively used for intraperitoneal injection of the tandospirone injection obtained in the example; the administration is carried out for 5 days and 3 times per day. After the last dose, rats were kept in isolation for 1 hour, and then two rats were placed in an open plastic box (22cm x 15cm x 12cm) and observed for their social exploration behavior (sniffing, climbing, drilling, licking the neck of the partner, and fighting) for the partner within 5 minutes, with the results shown in table 7.
Mean. + -. standard deviation of test data
Data analysis was performed using SPSS11.5 software. Group comparisons were performed using One-Way analysis of variance (One-Way ANOVA).
TABLE 7 social interaction experiment
| Group of | Number of mice | Dosage mg/kg | Cumulative social interaction time (S) |
| Physiological saline group | 8 | 10 | 119.35±11.37 |
| Tandospirone citrate capsule | 8 | 20 | 149.21±9.27 |
| Comparative example 1 group | 8 | 10 | 176.85±15.67 |
| EXAMPLE 1 group | 8 | 10 | 196.85±10.28 |
| EXAMPLE 2 group | 8 | 10 | 193.27±14.39 |
| EXAMPLE 3 group | 8 | 10 | 195.72±9.28 |
| EXAMPLE 4 group | 8 | 10 | 185.59±11.87 |
| EXAMPLE 5 group | 8 | 10 | 183.59±13.65 |
| EXAMPLE 8 group | 8 | 10 | 194.59±9.78 |
| EXAMPLE 9 group | 8 | 10 | 194.59±15.67 |
The experimental results show that the cumulative social interaction time of the example group is longer than that of the tandospirone citrate capsule group and the comparative example group. Therefore, the group of examples can improve the anxiety symptom of rats better.
In conclusion, the stability and the anxiolytic effect of the tandospirone injection are obviously better than those of the conventional tandospirone injection, the anxiolytic effect of the tandospirone injection is also obviously better than that of the conventional tandospirone oral capsule, and the problem that children, patients with digestive system disorders, coma, convulsion and the like, and patients with dysphagia (such as old patients and bedridden patients) are not suitable for orally taking tandospirone tablets or capsules can be effectively solved. Particularly, when the stabilizer is one or more of citric acid, hydrochloric acid and sodium hydroxide, the injection has obviously more excellent stability.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and such simple modifications are within the protective scope of the present invention.
Claims (7)
1. The tandospirone injection is characterized by consisting of tandospirone citrate, a stabilizer, an excipient and/or water for injection;
the stabilizer is one or more selected from hydrochloric acid, acetic acid, citric acid, lactic acid, tartaric acid, malic acid and sodium hydroxide;
the excipient is one or more selected from lactose and mannitol;
when the tandospirone injection is dissolved in water to form an aqueous solution, the pH value of the aqueous solution is 3.5-6.0.
2. The tandospirone injection according to claim 1, wherein the stabilizer is one or more of citric acid, hydrochloric acid and sodium hydroxide.
3. The tandospirone injection according to claim 1 or 2, characterized in that the tandospirone injection comprises water injection, lyophilized powder injection, and infusion solution.
4. A method for preparing the tandospirone injection of any one of claims 1-3, comprising: and adding the tandospirone citrate and the stabilizer into water for injection, and freeze-drying or not, thus preparing the tandospirone injection.
5. The method of claim 4, wherein the method comprises: adding tandospirone citrate and a stabilizer into water for injection, adding activated carbon for injection, filtering, sterilizing or not sterilizing, and freeze-drying or not freeze-drying to prepare the tandospirone injection.
6. The method of claim 4, wherein the method comprises: adding excipient, tandospirone citrate and stabilizer into water for injection, stirring for dissolving, adding active carbon for injection for adsorption, filtering, sterilizing, and lyophilizing or not to lyophilize to obtain the tandospirone injection.
7. Use of the tandospirone injection according to any one of claims 1-3 for the preparation of an anxiolytic medicament.
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| 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 |
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| 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 |
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