CN108567971A - A kind of carbetocin injection - Google Patents
A kind of carbetocin injection Download PDFInfo
- Publication number
- CN108567971A CN108567971A CN201810608204.1A CN201810608204A CN108567971A CN 108567971 A CN108567971 A CN 108567971A CN 201810608204 A CN201810608204 A CN 201810608204A CN 108567971 A CN108567971 A CN 108567971A
- Authority
- CN
- China
- Prior art keywords
- carbetocin
- injection
- acid
- sodium
- amount
- 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
- NSTRIRCPWQHTIA-DTRKZRJBSA-N carbetocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSCCCC(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(OC)C=C1 NSTRIRCPWQHTIA-DTRKZRJBSA-N 0.000 title claims abstract description 105
- 108700021293 carbetocin Proteins 0.000 title claims abstract description 105
- 229960001118 carbetocin Drugs 0.000 title claims abstract description 105
- 239000007924 injection Substances 0.000 title claims abstract description 99
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
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- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims abstract description 14
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
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Classifications
-
- 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
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Abstract
The invention belongs to pharmaceutical technology fields, are related to a kind of carbetocin injection.The infusion pump contains carbetocin, poly uronic acid derivative, vitamin D and water for injection.The amount of carbetocin is 50 80 μ g in per 2mL carbetocin injections, the amount of poly uronic acid derivative is 5 8mg, the amount of vitamin D is 1 5mg.
Description
Technical field
The invention belongs to pharmaceutical technology fields, are related to a kind of carbetocin injection.
Background technology
During Livestock Production, production efficiency is improved, production cost is reduced, is the target that aquaculture is pursued always.And divide
Childbirth is an important link in cattle breeding reproductive process, and in modern aquaculture model, the childbirth of generally existing dam is powerless, produces
The problems such as journey is long, postpartum hemorrhage, causes to seriously endanger, be brought to animal farm serious to the life security of dam and newborn animal
Economic loss influences the development of animal husbandry.The domestic animal of scientific and reasonable management childbirth can greatly improve livestock reproduction efficiency, in advance
Anti- domestic animal childbirth is dead, to also improve the production capacity of entire poultry field.
Stages of labor is long when domestic animal is given a birth, and can lead to dam sharp ache, be also easy to produce fatigue or even in the flue.It gave a birth
Cheng Zhong, maternal uterine, which is constantly shunk, causes uterus drawing long, causes uterine wall long, excessively thin, uterine smooth muscle flexibility decrease,
It is be easy to cause endometrial impairment and postpartum uterine contractions fatigue, makes domestic animal birth canal massive haemorrhage, oedema and hemotoncus etc., even
Cause dam uterus, vagina abjection, or even dead.And stages of labor is long while can cause damages to newborn animal.When uterine contractile, son
Fetal circulation in utero can be interrupted briefly, and it is to cause domestic animal birth process to neutralize to divide as a result to cause anoxic, childbirth asphyxia
The main reason for puerperium is immediately dead.And due to prolonged labor, piglet struggles in birth canal and consumes more energy, and postpartum is young
Pig vigor is poor, eats less than sufficient colostrum, and body obtains breast milk protection deficiency, may cause under nursery-age pig growth performance
Drop, the harm such as survival rate reduction.
It is the problem of for domestic animal labor progress, clinically existing mostly to reinforce uterine contractile using oxytocic drug, accelerate stages of labor.
Carbetocin is a kind of long-acting oxytocins nonapeptide analog with agonist characteristics of synthesis, can be with uterine smooth muscle
Ocytocin receptor combine, so that uterine contractile is synchronized, regularization, reinforce domestic animal uterine contractile, prevent postpartum hemorrhage, effectively
Shortening labor.Individual carbetocin injection is used widely in domestic animal industry, but is single use the contracting of card shellfish
The effect of palace element is limited, and if dealt with improperly, and the fierce of uterus is caused to shrink the childbirth asphyxia amount for increasing newborn animal.
Invention content
It is an object of the present invention to be directed to domestic animal, a kind of carbetocin injection of safe promotion childbirth is provided, is led to
The synergistic effect between carbetocin, poly uronic acid derivative and vitamin D components is crossed, promotes uterine contractile, shorten production
Journey prevents postpartum hemorrhage, improves livestock reproduction efficiency.
In order to reach foregoing invention purpose, the present invention uses following technical scheme：A kind of carbetocin injection, it is described
Infusion pump contains carbetocin, poly uronic acid derivative, vitamin D and water for injection.
Normal muscle shrinks the free calcium that need to be relied in sarcoplasm, therefore calcium ion is the activation of muscle excitation-contraction coupling
Agent, carbetocin is combined with the ocytocin receptor of uterine smooth muscle, and calcium ion is promoted to be flowed into myocyte, increased calcium
It can be combined with calmodulin, stimulation myosin light chain kinase (MLCK) generates uterine contractile function.Under non pregnant state, son
The ocytocin receptor content in palace is very low, reaches peak in gestation increase, childbirth.Therefore carbetocin is to non-pregnant son
Palace does not act on, but the uterus and the uterus that has just produced to gestation are with effective uterine contractile effect.
Poly uronic acid derivative can be from by D-MANNOSE aldehydic acid and/or D- galacturonic acids and/or L- gulose aldehyde
It is selected in the polyuronic acid derivative group that acid and/or D-Glucose aldehydic acid and/or some miscellaneous sugars are constituted.Poly uronic acid derivative
Carboxyl and hydroxyl easily form a kind of void structure being suitable for the calcium binding with polyvalent cation, particularly divalent, when
In the presence of having calcium ion, this void structure is complexed with calcium ion, can the calcium ion that generated in tissue fluid be carried along into myocyte
It is interior, and vitamin D can promote the poly uronic acid derivative of complexing calcium ions to enter cell.Poly uronic acid derivative is as high
On the one hand the injection that Molecularly Imprinted Polymer has the stickiness for improving injection, and is within the scope of suitable stickiness can carry
The material stability of high injection, extends the shelf life；On the other hand, after the injection injection muscle of suitable stickiness, active ingredient
Cell is slowly entered, the function and effect of carbetocin are extended.Vitamin D is preferably calciferol, and calciferol can also exist
In the void structure of poly uronic acid derivative, by calciferol, Ca2+, poly uronic acid derivative formed complex thorn
Swash internal blood platelet largely to assemble, increases hemoglutination, to prevent postpartum hemorrhage.
Preferably, the poly uronic acid derivative is pectin, sodium alginate, glycosaminoglycan, poly uronic acid half fiber
It is one or more in dimension element.
Further preferably, the poly uronic acid derivative is pectin, and esterification degree ＜ 50%, molecular weight is 5-15 ten thousand.
Preferably, the amount of carbetocin is 50-80 μ g in per 2mL carbetocin injections, poly uronic acid spreads out
The amount of biology is 5-8mg, the amount of vitamin D is 1-5mg.
In carbetocin injection, carbetocin is active constituent, supplemented by poly uronic acid derivative and vitamin D
Co-ingredients, the content and its relationship of three need strictly to control in the present invention, form suitable proportioning.The card shellfish of high-content contracts
Palace element makes domestic animal childbirth uterus excess shrinkage early period, and later stage childbirth is powerless, easily causes difficult labour；And the poly uronic acid of high-content
Derivative makes injection fluid viscosity excessive, and the effect for influencing active ingredient plays.
Wherein water for injection is existing for the solvent as injection, and amount is usually such that injection volume augmentation to rule
Definite value, therefore those skilled in the art are usually not specifically described, or refer to only in the amount of the water in describing injection
It is appropriate to go out its amount, either points out that its amount is " surplus " or points out that its amount is " in right amount, to add to the similar statement such as 2ml ".
Further preferably, the amount of carbetocin is 70 μ g, poly uronic acid derivative in every 2mL carbetocin injections
The amount of object is 6mg, the amount of vitamin D is 3mg.
Preferably, the carbetocin injection of the present invention further includes pH adjusting agent, selected from hydrochloric acid, citric acid, apple
Tartaric acid, acetic acid, lactic acid, phosphoric acid, citric acid, tartaric acid, sodium hydroxide, triethylamine, glutamic acid, arginine, sodium carbonate, bicarbonate
Sodium and disodium hydrogen phosphate it is one or more, dosage is to adjust the pH value of injection to 4.0 ± 0.2.By acid regulator or/
The pH value that carbetocin is controlled with alkali conditioning agent is 4.0 ± 0.2, and carbetocin injectable liquefied composition property at this ph is steady
It is fixed, injection storage life can be extended；Injection chemism at this ph is good, and curative effect is more preferably.
Preferably, the present invention carbetocin injection further include bacteriostatic agent, selected from sodium nitrite, benzyl alcohol,
It is one or more in benzalkonium chloride, benzalkonium bromide, chloreresol, anesin, phenol and cresols.The effect of bacteriostatic agent is to kill
It goes out and microorganism living in injection or inhibits growth breeding, improve preparation stability.Because carbetocin injection clinic is answered
Used time is directly injected into animal body tissue, blood vessel or intraorganic with liquid condition, and the requirement to its safety is than other dosage forms
Strictly, the selection of bacteriostatic agent is added in strict accordance with standards of pharmacopoeia.
Preferably, the amount of bacteriostatic agent is 1-3mg in per 2mL carbetocin injections.If the content mistake of bacteriostatic agent
Few, sterilization functions are limited, and part, which is killed, kills microorganism residual microbial or regeneration microbiological effect note in the either short time
Penetrate the preservation term of liquid；If the content of bacteriostatic agent is excessive, the bacteriostatic agent of high-content can reduce the safety of injection.It is further excellent
It selects, the amount of bacteriostatic agent is 1.9mg in every 2mL carbetocin injections.
Preferably, the present invention carbetocin injection further include buffer salt, selected from sodium acetate, sodium citrate,
Sodium succinate or disodium hydrogen phosphate.
Preferably, the amount of buffer salt is 20-30mg in per 2mL carbetocin injections.Further preferably, per 2mL
The amount of buffer salt is 27mg in carbetocin injection.
Another object of the present invention provides the method for preparing carbetocin injection comprising following steps：
In the water for injection to material-compound tank for weighing 80-90% recipe quantities, be added recipe quantity poly uronic acid derivative and
Vitamin D, or bacteriostatic agent or/and buffer salt are added, after dissolving mixing pH value is adjusted with pH adjusting agent to 4.0 ± 0.2, so
After carbetocin is added, under the conditions of 40~60 DEG C with 50-80rpm rotating speeds stir 20-40min, dissolve mixing after, be cooled to
30 DEG C or less add water for injection constant volume, detect and close through 0.45 μm, 0.22 μm of poly (ether sulfone) film secondary filtration to visible foreign matters after constant volume
Lattice, filling, as of the invention carbetocin injection.
The present invention has the advantages that with the prior art：
The carbetocin infusion pump of the present invention contains carbetocin, poly uronic acid derivative and vitamin D, blocks shellfish
Oxytocin, which is cooperateed with as active constituent, poly uronic acid derivative and vitamin D as auxiliary element, between three's ingredient, to be made
With raising carbetocin prevents postpartum hemorrhage to uterotonic effect.The carbetocin injection application of the present invention
Dam after delivery starting can shorten farrowing internal and stages of labor, improve Livestock Production efficiency and improve female newborn animal life security.
Specific implementation mode
Explanation is further described to technical scheme of the present invention below by specific embodiment.If without specified otherwise,
Raw material employed in the embodiment of the present invention is raw material commonly used in the art, and the method employed in embodiment is this
The conventional method in field.
Embodiment 1
The carbetocin injection of the present embodiment, including carbetocin, sodium alginate, calciferol, benzyl alcohol and
Sodium acetate, the group per 2mL carbetocin injections become：The content of carbetocin is 70 μ g, sodium alginate content is
6mg, calciferol content are 3mg, benzyl alcohol content is 1.9mg and the content 27mg of sodium acetate, are adjusted using acetic acid as pH
Agent, it is 4.0 to adjust pH, and surplus is water for injection.
In the water for injection to material-compound tank for weighing 90% recipe quantity, the sodium alginate, calciferol, benzene first of recipe quantity is added
Alcohol and sodium acetate, dissolve mixing after with vinegar acid for adjusting pH value to 4.0, carbetocin is then added, under the conditions of 50 DEG C with
80rpm rotating speeds stir 40min, after dissolving mixing, are cooled to 25 DEG C plus water for injection constant volume, through 0.45 μm, 0.22 μm after constant volume
It is qualified that poly (ether sulfone) film secondary filtration to visible foreign matters detect, filling, and filling specification is 2ml mono-, and every carbetocin contains
Amount is 70 μ g.The as carbetocin injection of the present embodiment.
Embodiment 2
The carbetocin injection of the present embodiment, including carbetocin, pectin (esterification degree 65%, molecular weight 15
Ten thousand), calciferol, benzyl alcohol and sodium acetate, the group per 2mL carbetocin injections become：The content of carbetocin is
(esterification degree 65%, molecular weight are that 15 ten thousand) content is 6mg, calciferol content is 3mg, benzyl alcohol content is for 70 μ g, pectin
The content 27mg of 1.9mg and sodium acetate, using acetic acid as pH adjusting agent, using acetic acid as pH adjusting agent, adjusting pH is
4.0, surplus is water for injection.
In the water for injection to material-compound tank for weighing 90% recipe quantity, be added the pectin of recipe quantity, calciferol, benzyl alcohol and
Sodium acetate is used vinegar acid for adjusting pH value to 4.0, carbetocin is then added, turned with 80rpm under the conditions of 50 DEG C after dissolving mixing
Speed stirring 40min after dissolving mixing, is cooled to 25 DEG C plus water for injection constant volume, through 0.45 μm, 0.22 μm of poly (ether sulfone) film after constant volume
It is qualified that secondary filtration to visible foreign matters detect, filling, and filling specification is 2ml mono-, and the content of every carbetocin is 70 μ g.
The as carbetocin injection of the present embodiment.
Embodiment 3
The carbetocin injection of the present embodiment, including carbetocin, pectin (esterification degree 40%, molecular weight 15
Ten thousand), calciferol, benzyl alcohol and sodium acetate, the group per 2mL carbetocin injections become：The content of carbetocin is
70 μ g, pectin esterification degree 40%, molecular weight are that 15 ten thousand) content is 6mg, calciferol content is 3mg, benzyl alcohol content is
The content 27mg of 1.9mg and sodium acetate, using acetic acid as pH adjusting agent, using acetic acid as pH adjusting agent, adjusting pH is
4.0, surplus is water for injection.
In the water for injection to material-compound tank for weighing 90% recipe quantity, be added the pectin of recipe quantity, calciferol, benzyl alcohol and
Sodium acetate is used vinegar acid for adjusting pH value to 4.0, carbetocin is then added, turned with 80rpm under the conditions of 50 DEG C after dissolving mixing
Speed stirring 40min after dissolving mixing, is cooled to 25 DEG C plus water for injection constant volume, through 0.45 μm, 0.22 μm of poly (ether sulfone) film after constant volume
It is qualified that secondary filtration to visible foreign matters detect, filling, and filling specification is 2ml mono-, and the content of every carbetocin is 70 μ g.
The as carbetocin injection of the present embodiment.
Embodiment 4
The carbetocin injection of the present embodiment, including carbetocin, pectin (esterification degree 35%, molecular weight 10
Ten thousand), calciferol, chloreresol and sodium citrate, the group per 2mL carbetocin injections become：The content of carbetocin
For 60 μ g, pectin content 5mg, calciferol content be 3mg, chloreresol content is 3mg and the content 20mg of sodium citrate, make
Use lactic acid as pH adjusting agent, it is 4.0 to adjust pH, and surplus is water for injection.
In the water for injection to material-compound tank for weighing 90% recipe quantity, be added the pectin of recipe quantity, calciferol, chloreresol and
Sodium citrate uses vinegar acid for adjusting pH value to 4.0, carbetocin is then added, with 60rpm under the conditions of 40 DEG C after dissolving mixing
Rotating speed stirs 40min, after dissolving mixing, is cooled to 22 DEG C plus water for injection constant volume, through 0.45 μm, 0.22 μm of polyether sulfone after constant volume
It is qualified that film secondary filtration to visible foreign matters detect, filling, and filling specification is 2ml mono-, and the content of every carbetocin is 60 μ
g.The as carbetocin injection of the present embodiment.
Embodiment 5
The carbetocin injection of the present embodiment, including carbetocin, pectin (esterification degree 35%, molecular weight 10
Ten thousand), calciferol, anesin and sodium succinate, the group per 2mL carbetocin injections become：Carbetocin
Content is 70 μ g, pectin content 6mg, calciferol content are 3mg, anesin content is 1.9mg and sodium succinate
Content 27mg, using citric acid as pH adjusting agent, it is 4.0 to adjust pH, and surplus is water for injection.
In the water for injection to material-compound tank for weighing 90% recipe quantity, the tertiary fourth of pectin, calciferol, trichlorine of recipe quantity is added
Alcohol and sodium succinate, dissolve mixing after with vinegar acid for adjusting pH value to 4.0, carbetocin is then added, under the conditions of 50 DEG C with
80rpm rotating speeds stir 40min, after dissolving mixing, are cooled to 25 DEG C plus water for injection constant volume, through 0.45 μm, 0.22 μm after constant volume
It is qualified that poly (ether sulfone) film secondary filtration to visible foreign matters detect, filling, and filling specification is 2ml mono-, and every carbetocin contains
Amount is 70 μ g.The as carbetocin injection of the present embodiment.
Comparative example 1
The carbetocin injection of this comparative example and embodiment 3 difference lies in, do not include pectin in comparative example 1,
It is same as Example 3, does not repeat herein.
Comparative example 2
Difference lies in do not include vitamin in comparative example 2 to the carbetocin injection of this comparative example with embodiment 3
D2, it is other same as Example 3, it does not repeat herein.
Comparative example 3
Difference lies in do not include pectin and dimension in comparative example 3 to the carbetocin injection of this comparative example with embodiment 3
Raw element D2, it is other same as Example 3, it does not repeat herein.
Comparative example 4
Difference lies in comparative example 4 uses L- guluronic acids to the carbetocin injection of this comparative example with embodiment 3
Tetrose replaces pectin.It is other same as Example 3, it does not repeat herein.
Comparative example 5
Difference lies in the pectin content of comparative example 5 is the carbetocin injection of this comparative example with embodiment 3
12mg, it is other same as Example 3, it does not repeat herein.
Comparative example 6
The carbetocin injection of this comparative example and embodiment 3 difference lies in, the pectin content of comparative example 6 is 2mg,
It is other same as Example 3, it does not repeat herein.
Comparative example 7
Difference lies in the calciferol content of comparative example 7 is the carbetocin injection of this comparative example with embodiment 3
8mg, it is other same as Example 3, it does not repeat herein.
Comparative example 8
Difference lies in the calciferol content of comparative example 8 is the carbetocin injection of this comparative example with embodiment 3
0.5mg, it is other same as Example 3, it does not repeat herein.
In order to inquire into stability and the safety of carbetocin of the invention, accelerated test, irritation test are devised
And safety testing.
Accelerated test
What this experiment carried out under conditions of acceleration, the purpose is to the chemically or physically variation by pharmaceutical preparation, predictions
The stability of pharmaceutical preparation provides necessary data for formulation design, packaging, transport, storage.Injection of the present invention belongs to temperature
More sensitive drug is spent, according to《Chinese veterinary pharmacopoeia》Veterinary drug stability test guideline (one annex 9001 of version in 2015) is advised
Fixed, the injection of Example 3-5 is placed 6 months in stability test case, the temperature of control stability chamber for 25 ±
2 DEG C, relative humidity be 60% ± 10%.January, 2 months, the sampling of March and 6 months are primary after on-test respectively, are detected.
Test result is shown in Table 1.
1 accelerated test result of table
Table 1 can illustrate the carbetocin of the present invention after accelerated test 6 months, and character, pH value of sample etc. are without bright
Aobvious variation；Though the measurement result in relation to the detections such as substance and assay has slightly variation but unobvious, in controllable model
In enclosing, meet quality standard draft regulation, illustrates that property is stablized under this product acceleration environment.
Irritation test and hemolytic experiment
It is directly injected into animal body tissue, blood vessel or organ with liquid condition when carbetocin injection clinical application
, it absorbs soon, effect is rapid.Therefore, stringenter than other dosage forms to the requirement of its safety.Mainly for the agent in this experiment
Type carries out some safety examinations, including irritation test and hemolytic experiment.
Healthy rabbits 9 similar in weight are taken, are divided into 3 groups, every group 3,3 groups of injections for injecting embodiment 3-5 respectively,
Every rabbit is injected in the quadriceps muscle of thigh of side hind leg for reagent product 1.0ml, and same agent is injected with the corresponding position of other side hind leg
The physiological saline of amount is as a contrast.It is administered to after 48h if health is normal, auricular vein injects air and puts to death experimental rabbit and to note
Penetrate position dissect, take out quadriceps muscle of thigh, it is longitudinally slit, pay attention to will on surface it is observed that variation highlight, in this way
It is no to have bleeding, white variation, brown variation etc..Intramuscular injection site muscle groups are observed according to injection stimulate the reaction standards of grading
Be woven with stimulates phenomenon without hyperemia, oedema, denaturation and necrosis etc., and is converted into corresponding score value according to the degree of stimulate the reaction.Thorn
It is as shown in table 2 to swash property test result.
2 injection muscle irritation test result of table
After injecting drug and physiological saline 48h, rabbit activity is normal, and auricular vein injects air and puts to death rabbit, dissect stock
Musculus quadriceps, longitudinally slit, the muscle color of injection site and non-injection position muscle color contrast unobvious visually observe injection
Quadriceps muscle of thigh surface has no that apparent hyperemia, oedema, denaturation and necrosis etc. stimulate phenomenon, standards of grading knot after drug and physiological saline
9 rabbit reaction score value of fruit display injection embodiment 3-5 injections and injecting normal saline is 0 point, is not stimulated substantially
Property.Experimental group and saline control group result are without significant difference.
Hemolytic is tested, and Rabbit Heart blood sampling takes rabbit blood 15mL, is removed fibrinogen with glass bar agitation blood, is made
At defibrinated blood.About 10 times of amounts of 0.9% sodium chloride solution are added, shake up, 1000r/min is centrifuged 15 minutes, removes supernatant, is sunk
The red blood cell in shallow lake is washed 2~3 times with 0.9% sodium chloride solution as stated above again, until the not aobvious red of supernatant.By gained
Red blood cell is diluted to the suspension of 2% (v/v) with 0.9% sodium chloride injection, is for experiment.
Clean tube 11 is taken, is numbered, No. 1-3 pipe is the injection of embodiment 3, and No. 4-6 pipe is the note of embodiment 4
Liquid is penetrated, No. 7-9 pipe is the injection of embodiment 5, and No. 10 pipes are negative control pipe, and No. 11 pipes are positive control pipe.Shown in table 3
It sequentially adds 2% red cell suspension, 0.9% sodium chloride solution or distilled water, after mixing, is immediately placed in 37 DEG C of water-baths and keeps the temperature,
Start every 15min observations once, is observed 1 time every 1h after 1h, 3h is observed continuously.Hemolytic test result is shown in Table 3.
3 hemolytic test result of table
According to the hemolytic test result of table 3：The 1st~No. 9 test tube of tested material is showed no haemolysis, and No. 7 pipe is completely molten
Blood, i.e. card shellfish uterine contraction element injection of the invention do not generate haemocylolysis, are used for intramuscular injection.
Safety testing
The recommended dose of the carbetocin injection administration of the present invention is 1ml, in order to evaluate the card shellfish contracting palace of the present invention
Whether plain injection generates harmful effect during handling sow, to pig physical signs, production performance, implements this examination
It tests.This test objective is to inject the carbetocin injection of 0,1,3 and 5 times of recommended dose to sow respectively, evaluates it and is pushing away
Recommend the safety to sow under use condition.
40 health pigs are randomly divided into 4 groups, every group 10, that is, test I group, II group, III group and IV group.Test I group, II
Group and III group of pig are injected 1 times of group (35 μ g/) of recommended dose, 3 times of groups (105 μ g/) of recommended dose and are recommended respectively
5 times of groups (175 μ g/) of dosage, IV group of pig inject 1ml physiological saline.Experiment grouping and dosage regimen are shown in Table 4.
4 safety testing dosage of table and experiment are grouped
The time for carrying out drug injection is referred to as " the 1st day ", is administered three times respectively at the 1st, the 2nd and the 3rd day.
Test pig appearance, behavior, heat situation, allergic reaction are observed, body temperature, Respiration Rate, heart rate, blood biochemical is measured and refers to
Mark.The injection same day is denoted as the 1st day (D1), and in the above indices, body temperature, Respiration Rate, heart rate, blood parameters are after injection
0th (D0), 2 (D2), 4 (D4) and 10 days (D10) are respectively observed or are measured once, shown in test result table 5.The pig of drug for injection
Started to acquire blood sample in D0, D2, D4 and D10 days at 7 points in the mornings, detection, blood routine and blood parameters inspection are completed in 3 hours
It surveys the results detailed in Table 6.
Table 5 tests pig body temperature, breathing and pulse measuring result
As known from Table 5, before drug-treated, during processing and after processing, body temperature, IE ratio and the arteries and veins of all experiment pigs
Frequency of fighting changes less.It tests I group, II group of experiment, test between III group and IV group of negative control group group of experiment without significance difference
It is different.
Table 6 tests pig blood routine and blood parameters measurement result
As known from Table 6, before drug-treated, during processing and after processing, the blood routine data variation of all experiment pigs is not
Greatly.It tests I group, II group of experiment, test between III group and IV group of negative control group group of experiment without significant difference.
By accelerated test, irritation test and safety testing it is found that having for the carbetocin of the present invention is good
Good stability and safety, will not bring insecurity after intramuscular injection.
Clinical test
Clinical test is carried out to the embodiment of the present invention 1-5 and comparative example 1-8, inquires into injection heterogeneity or content
Influence to Farrowing.
130 sows are randomly divided into 13 groups (every group 10), 1-13 groups.It is injected after experiment 1 piglet of Farrowing
Carbetocin injection 1ml/ heads, 1-13 groups inject embodiment 1, embodiment 2, embodiment 3, embodiment 4, embodiment respectively
5, the card shellfish contracting palace of comparative example 1, comparative example 2, comparative example 3, comparative example 4, comparative example 5, comparative example 6, comparative example 7 and comparative example 8
Plain injection.The time that every piglet is given birth to is recorded in detail, and afterbirth efflux time calculates farrowing internal, every sow of statistics
Nest litter size, artificial aiding-birth head number (artificial aiding-birth standard：First 5 of childbirth, if more than the 45 points kinds in interval, are manually helped
Production, interval was more than 30 minutes later, progress artificial aiding-birth), dead son's number and the mummification of fetus.Birth process is dead young for fresh and development
Good dead son, the extremely young color of During Pregnancy is gloomy or develops abnormal piglet (being known as the mummification of fetus).Use weight method：Point
Dressing weight=blood loss before dressing weight-childbirth, calculates the amount of bleeding during sows farrowing before childbirth.Test result refers to table 7.
The comparison of table 7 each group farrowing internal, afterbirth efflux time, Cluth size, amount of bleeding
1-13 groups inject embodiment 1, embodiment 2, embodiment 3, embodiment 4, embodiment 5, comparative example 1, comparison respectively
The carbetocin injection of example 2, comparative example 3, comparative example 4, comparative example 5, comparative example 6, comparative example 7 and comparative example 8, from table 7
It is found that embodiment 3-4 is shorter relative to the farrowing internal time of embodiment 1-2 and comparative example 1-8 and afterbirth efflux time, help
Production head number is less, and the extremely young number of nest and nest mummy number are low, and childbirth blood loss is few, overall that good promotion childbirth effect is presented.
Therefore the present invention carbetocin injection is with good stability and safety, flesh is carried out to childbirth dam
After meat injection, can effectively shorten stages of labor, improve newborn animal survival rate and dam life security, and uneasiness will not be brought to domestic animal
Total factor.
In addition, right in place of the non-limit of claimed technical scope midrange and in embodiment technical solution
The same replacement of single or multiple technical characteristics is formed by new technical solution, equally all in claimed model
In enclosing；Simultaneously the present invention program it is all enumerate or unrequited embodiment in, parameters in the same embodiment are only
Indicate an example (i.e. a kind of feasible scheme) for its technical solution.
Specific embodiment described herein is only an example for the spirit of the invention.Technology belonging to the present invention is led
The technical staff in domain can do various modifications or supplement to described specific embodiment or substitute by a similar method, but simultaneously
The spirit or beyond the scope defined by the appended claims of the present invention is not deviated by.
Claims (9)
1. a kind of carbetocin injection, which is characterized in that the infusion pump is containing carbetocin, poly uronic acid derivative
Object, vitamin D and water for injection.
2. a kind of carbetocin injection according to claim 1, which is characterized in that the poly uronic acid derivative
It is one or more in pectin, sodium alginate, glycosaminoglycan, poly uronic acid hemicellulose.
3. a kind of carbetocin injection according to claim 1, which is characterized in that the poly uronic acid derivative
For pectin, esterification degree ＜ 50%, molecular weight is 5-15 ten thousand.
4. a kind of carbetocin injection according to claim 1, which is characterized in that per 2mL carbetocin injections
The amount of carbetocin is 50-80 μ g in liquid, the amount of poly uronic acid derivative is 5-8mg, the amount of vitamin D is 1-5mg.
5. a kind of carbetocin injection according to claim 1, which is characterized in that further include pH adjusting agent, choosing
From hydrochloric acid, citric acid, malic acid, acetic acid, lactic acid, phosphoric acid, citric acid, tartaric acid, sodium hydroxide, triethylamine, glutamic acid, smart ammonia
Acid, sodium carbonate, sodium bicarbonate and disodium hydrogen phosphate it is one or more, dosage be adjust the pH value of injection to 4.0 ±
0.2。
6. a kind of carbetocin injection according to claim 1, which is characterized in that further include bacteriostatic agent, be selected from
It is one or more in sodium nitrite, benzyl alcohol, benzalkonium chloride, benzalkonium bromide, chloreresol, anesin, phenol and cresols.
7. a kind of carbetocin injection according to claim 6, which is characterized in that per 2mL carbetocin injections
The amount of bacteriostatic agent is 1-3mg in liquid.
8. a kind of carbetocin injection according to claim 1, which is characterized in that further include buffer salt, be selected from
Sodium acetate, sodium citrate, sodium succinate or disodium hydrogen phosphate.
9. a kind of carbetocin injection according to claim 8, which is characterized in that per 2mL carbetocin injections
The amount of buffer salt is 20-30mg in liquid.
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| CN110404050A (en) * | 2019-07-26 | 2019-11-05 | 翔宇药业股份有限公司 | The preparation process of carbetocin injection |
| CN111249231A (en) * | 2020-03-18 | 2020-06-09 | 成都市海通药业有限公司 | Oxytocin injection taking ethanol as chlorobutanol solvent and preparation method thereof |
| CN114191388A (en) * | 2021-12-27 | 2022-03-18 | 苏州天马医药集团天吉生物制药有限公司 | Preparation method of carbetocin preparation |
| CN115531517A (en) * | 2022-10-26 | 2022-12-30 | 海南皇隆制药股份有限公司 | Carbetocin injection and preparation method thereof |
| CN116143880A (en) * | 2022-11-28 | 2023-05-23 | 深圳新声药业有限公司 | The preparation method of oxytocin injection |
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| CN116143880A (en) * | 2022-11-28 | 2023-05-23 | 深圳新声药业有限公司 | The preparation method of oxytocin injection |
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| CN108567971B (en) | 2021-09-28 |
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