CN108236716A - A kind of pharmaceutical composition containing oxytocin analog and its preparation method and application - Google Patents
A kind of pharmaceutical composition containing oxytocin analog and its preparation method and application Download PDFInfo
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- CN108236716A CN108236716A CN201611203711.4A CN201611203711A CN108236716A CN 108236716 A CN108236716 A CN 108236716A CN 201611203711 A CN201611203711 A CN 201611203711A CN 108236716 A CN108236716 A CN 108236716A
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- CN
- China
- Prior art keywords
- oxytocin
- calcium
- divalent metal
- zinc
- pharmaceutical composition
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 38
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- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229940030508 uterotonics Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 235000016804 zinc Nutrition 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/095—Oxytocins; Vasopressins; Related peptides
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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
- 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
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
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- Gastroenterology & Hepatology (AREA)
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- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Dermatology (AREA)
- Reproductive Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Peptides Or Proteins (AREA)
Abstract
The present invention relates to a kind of pharmaceutical compositions containing oxytocin analog and its preparation method and application.Described pharmaceutical composition includes oxytocin analog, excipient and divalent metal cation salt.Divalent metal cation salt is selected from the solution of one or more of calcium chloride, calcium acetate, calcium citrate, calcium tartrate, zinc chloride, zinc gluconate, calcium gluconate, calcium sulfate, zinc sulfate, zinc acetate, zinc citrate combination.The pharmaceutical composition of the present invention can eliminate uterine sensibility difference and in 30 DEG C of stabilizations preserved for a long time of energy.
Description
Technical field
The present invention relates to drug fields, and in particular to a kind of pharmaceutical composition containing oxytocin analog.
Background technology
Oxytocin, also known as oxytocins are a kind of uterotonics, can be extracted from animal posterior pituitary or chemistry closes
Into synthetic is free of pitressin, no boosting, and the selective excitation to uterine smooth muscle is strengthened its contraction, faced
Produce surviving of son palace is most sensitive to oxytocin (estrogen secretion increase), and rudimentry uterus is to this product anergy, First Trimester or mid-term
Uterus is relatively low to the reactivity of oxytocins, and latter half of gestation then gradually increases, until just before giving birth preceding reach highest.Low dose can strengthen the fundus of uterus
The rhythm and pace of moving things of portion's smooth muscle is shunk, and strengthens its convergent force, and contraction frequency is accelerated, and retractable property is similar with spontaneous labor, and keeps
Polarity and symmetry, therefore be clinically used for hastening parturition, induced labor.
Because individual difference is big when oxytocin preparation uses, individual uterus has differences the sensibility of oxytocin, can cause
Part maternal uterine contraction is weak, is easy to cause postpartum haemorrhage.If incorrect, timely processing, easily increase difficult labour and midwifery machine
Meeting increases operation production and infection chance, is easy to cause prolonged labor, and consumption puerpera's muscle power causes postpartum hemorrhage, produces fetus
Wound increases, and fetal distress easily occurs, and influences neonatal prognosis.
China is vast in territory, summer other than the Qinghai-Tibet Platean of high-land and Tianshan Mountains etc., the greater part at 20 DEG C or more,
The many places in south are at 28 DEG C or more.Therefore need to develop a kind of can eliminate uterine sensibility difference and be preserved for a long time at 30 DEG C steady
The Pharmaceutical composition of fixed oxytocin.
The storage condition of the commercially available injection oxytocin of 2015 editions regulations of Chinese Pharmacopoeia and oxytocin injection is cool
Dark place preserves, and cool dark place preservation refers to shading and stored below 20 DEG C.Carbetocin parenteral solution is 2-8 DEG C of storage.
China is vast in territory, summer other than the Qinghai-Tibet Platean of high-land and Tianshan Mountains etc., the greater part at 20 DEG C or more,
The many places in south are at 28 DEG C or more.Therefore need to develop a kind of can eliminate uterine sensibility difference and be preserved for a long time at 30 DEG C steady
The Pharmaceutical composition of fixed oxytocin analog.
Invention content
In view of this, the present invention provides a kind of stabilization containing oxytocin analog for the Pharmaceutical composition of active constituent and
Preparation method.The composition can for a long time place at 30 DEG C, the advantage for having quality more stable, curative for effect.
The first technical problem to be solved by the present invention is long-term at 30 DEG C for oxytocin analog Pharmaceutical composition
In storage a kind of above-mentioned class containing oxytocin of offer is provided the technical issues of generation deamidation impurity, hydrolysis impurity, unknown impuritie
Like the Pharmaceutical composition and preparation method of object.
The second technical problem to be solved by the present invention is that the Pharmaceutical composition for being directed to oxytocin analog is in use
The technical issues of uterus is insensitive and composition and the preparation that a kind of Pharmaceutical composition for providing above-mentioned oxytocin analog is provided
Method.
The Pharmaceutical composition of the present invention unexpectedly obtains and a kind of can eliminate uterine sensibility difference and 30 DEG C long-term can protect
It deposits, reduces the technique effect that deamidation impurity, hydrolysis impurity, unknown impuritie are generated in long-term storage.
The present invention is found surprisingly that the sample prepared using divalent metal cation salt can solve medicinal group of oxytocin medicine analog
It is insensitive that conjunction object leads to the problem of deamidation impurity, hydrolysis impurity, unknown impuritie and elimination uterus in 30 DEG C long-term storage
Problem.
One aspect of the invention provides a kind of pharmaceutical composition containing oxytocin analog, similar it includes oxytocin
Object, excipient and divalent metal cation salt.
In embodiments of the invention, oxytocin analog is selected from oxytocin, carbetocin, Nacartocin, card
The combination of one or more of ancient oxytocin.
In embodiments of the invention, divalent metal cation salt is selected from calcium ion salts or zinc ion salt, preferably chlorination
Calcium, calcium acetate, calcium citrate, calcium tartrate, zinc chloride, zinc gluconate, calcium gluconate, calcium sulfate, zinc sulfate, acetic acid
The solution of one or more of zinc, zinc citrate combination.
In embodiments of the invention, excipient is selected from mannitol, lactose, glucose, sucrose, sodium chloride, sorbierite
One or more of combination.
In embodiments of the invention, the content of each component is：Per 5000IU-20000IU oxytocins, correspondence includes
The divalent metal cation salt of 0.1mol-3mol and 20g-100g excipient；
Or per 0.1g carbetocins, the corresponding divalent metal cation salt comprising 0.1mol-3mol and 20g-100g are assigned
Shape agent.
In embodiments of the invention, preparation is selected from powder ampoule agent for injection.
Another aspect of the invention provides the preparation method of pharmaceutical composition of the present invention, includes the following steps:
1) 0.1mol/L-3mol/L divalent metal ion salt solutions are prepared；
2) excipient, oxytocin analog are added in and is uniformly mixed；
3) divalent metal ion salt solution is continuously added to total volume；
4) it is lyophilized after the prepared solution sterilization of step 3)；
Optionally, regulating step 1) in divalent metal ion salt solution pH value to 3.5-6.9.
Preferably, it is lyophilized to be cooled to -40 DEG C hereinafter, and opening the heating of vacuum laggard stroke sequence.
Preferably, each component concentration ratio in step 3) acquired solution is every 5000IU/L-20000IU/L oxytocins,
It is corresponding to include the divalent metal cation salt of 0.1mol/L-3mol/L and 20g/L-100g/L excipient；Or per 0.1g/L card shellfishes
Oxytocin, it is corresponding comprising the divalent metal cation salt of 0.1mol/L-3mol/L and 20g/L-100g/L excipient.
In the specific technical solution of the present invention, freeze-drying program is cools the temperature to -40 DEG C hereinafter, keeping the temperature 1.5-3 hours；
Vacuum is opened, -35 DEG C~-25 DEG C is warming up to and keeps the temperature 2-10 hours, -20 DEG C~-10 DEG C keep the temperature 2-10 hours, -5 DEG C~5 DEG C guarantors
2-10 hours warm, 10 DEG C~35 DEG C keep the temperature 5-10 hours.
In one embodiment of the invention, oxytocin powder needle is prepared according to following ratio：
Divalent metal ion salt solution (optionally, adjusting pH value to 3.5-6.9) is prepared, adds in excipient, oxytocin dissolving
Mixing；Divalent metal ion salt solution is continuously added to total volume；By prepared solution through 0.22 μm of filter aseptic filtration,
Packing, freeze-drying.
In one embodiment of the invention, carbetocin powder needle is prepared according to following ratio：
Divalent metal ion salt solution (optionally, adjusting pH value to 3.5-6.9) is prepared, adds in excipient, oxytocin dissolving
Mixing；Divalent metal ion salt solution is continuously added to total volume；By prepared solution through 0.22 μm of filter aseptic filtration,
Packing, freeze-drying.
In one embodiment of the invention, oxytocin powder needle is prepared according to following ratio：
0.1mol/L calcium gluconate solutions are prepared, with glucose acid for adjusting pH to pH3.5, add in mannitol, oxytocin
Dissolve mixing；Calcium gluconate solution is continuously added to total volume；By prepared solution through 0.22 μm of filter aseptic filtration,
It is dispensed with 1.0ml/ branch；Freeze-drying.
In one embodiment of the invention, oxytocin powder needle is prepared according to following ratio：
0.5mol/L calcium chloride solutions are prepared, add in mannitol, oxytocin dissolving mixing.Continuously add 0.5mol/L chlorinations
Calcium solution is to total volume；By prepared solution through 0.22 μm of filter aseptic filtration, dispensed with 0.5ml/ branch.Freeze-drying.
In one embodiment of the invention, oxytocin powder needle is prepared according to following ratio：
1.5mol/L solution of zinc sulfate is prepared, with apple acid for adjusting pH to 5.0, adds in lactose, oxytocin dissolving mixing；After
The continuous solution of zinc sulfate that adds in is to total volume；By prepared solution through 0.22 μm of filter aseptic filtration, dispensed with 5.0ml/ branch；
Freeze-drying.
In one embodiment of the invention, oxytocin powder needle is prepared according to following ratio：
2mol/L calcium sulphate solns are prepared, with winestone acid for adjusting pH to 5.5, add in sucrose, oxytocin dissolving mixing.Continue
Calcium sulphate soln is added in total volume；By prepared solution through 0.22 μm of filter aseptic filtration, dispensed with 10.0ml/ branch.
Freeze-drying.
In one embodiment of the invention, oxytocin powder needle is prepared according to following ratio：
0.1mol/L calcium citrate solutions are prepared, with vinegar acid for adjusting pH to pH6.9, add in mannitol, oxytocin dissolving mixes
It is even；Calcium citrate solutions are continuously added to total volume；By prepared solution through 0.22 μm of filter aseptic filtration, with 1.0ml/
Branch dispenses；Freeze-drying.
In one embodiment of the invention, carbetocin powder needle is prepared according to following ratio：
0.1mol/L calcium citrate solutions are prepared, with vinegar acid for adjusting pH to pH4.5, it is molten to add in mannitol, carbetocin
Solve mixing；Calcium citrate solutions are continuously added to total volume；By prepared solution through 0.22 μm of filter aseptic filtration, with
1.0ml/ branch dispenses；Freeze-drying.
The pharmaceutical composition that another aspect of the present invention provides the present invention is being prepared for uterine contractile or uterine hemostasis
Drug in purposes.
The pharmaceutical composition that another aspect of the present invention provides the present invention is being prepared for improving uterine sensibility or disappear
Except the purposes in the drug of uterine sensibility difference.
In the inventive solutions, the pH adjusting agent used in divalent metal ion salt solution pH value to 3.5-6.9 is selected from
Gluconic acid, grape acid lactone, malic acid, citric acid, acetic acid, tartaric acid；
Its divalent metal ion solution is selected from calcium chloride, calcium acetate, calcium citrate, calcium tartrate, zinc chloride, gluconic acid
In zinc, calcium gluconate, calcium sulfate, zinc sulfate, zinc acetate, the solution of one or more kinds of combinations of zinc citrate；
Advantageous effect
Pharmaceutical composition of the present invention can eliminate uterine sensibility difference and in the technology effect of 30 DEG C of stabilizations preserved for a long time of energy
Fruit.
Pharmaceutical composition stability of the present invention is high, can store for a long time, deamidation impurity, hydrolysis impurity, unknown impuritie energy
Enough control is in low-level.
Specific embodiment
It is further illustrated the present invention below with embodiment, but the present invention is not intended to be limited thereto.
Embodiment 1 uses prior art preparation oxytocin powder needle.
Oxytocin 10000IU
Mannitol 50.0g
Inject water to total volume 1000ml
Supplementary material is weighed by recipe quantity, with water for injection by mannitol, oxytocin dissolving mixing continuously adds appropriate injection
With water to total volume；By prepared solution through 0.22 μm of filter aseptic filtration, dispensed with 1.0ml/ branch.Freeze-drying.
Plate layer temperature is down to -40 DEG C hereinafter, heat preservation 3 hours in 1 hour.Vacuum is opened, is started to warm up, -25 DEG C of guarantors
Temperature 2 hours, -20-10 DEG C keep the temperature 2 hours, and -5 DEG C keep the temperature 2 hours, and 10 DEG C keep the temperature 5 hours, and 35 DEG C keep the temperature 5 hours.
Embodiment 2 uses prior art preparation oxytocin powder needle.
Supplementary material is weighed by recipe quantity, dissolves oxytocin, mannitol, and mixing respectively with water for injection.With citric acid tune
PH to 3.5 is saved, continues to add injection to total volume, 0.2um filterings are dispensed with 1.0ml/ branch.Freeze-drying.
Plate layer temperature is down to -40 DEG C hereinafter, heat preservation 1.5-3 hours in 1 hour.Vacuum is opened, is started to warm up, -35
~-25 DEG C keep the temperature 2 hours, and -20~-10 DEG C keep the temperature 2 hours, and -5~5 DEG C keep the temperature 2 hours, and 10~35 DEG C keep the temperature 5 hours.
Embodiment 3 uses the oxytocin powder needle of prior art preparation.
Supplementary material is weighed by recipe quantity, dissolves oxytocin, mannitol, cysteine hydrochloride respectively with water for injection, and
Mixing.Continue to add injection to total volume, 0.2um filterings are dispensed with 1.0ml/ branch.Freeze-drying.
Plate layer temperature is down to -40 DEG C hereinafter, heat preservation 1.5-3 hours in 1 hour.Vacuum is opened, is started to warm up, -35
~-25 DEG C keep the temperature 2 hours, and -20~-10 DEG C keep the temperature 2 hours, and -5~5 DEG C keep the temperature 2 hours, and 10~35 DEG C keep the temperature 5 hours.
The oxytocin powder needle of 4 present invention of embodiment
0.1mol/L calcium gluconate solutions are prepared, with glucose acid for adjusting pH to pH3.5, add in mannitol, oxytocin
Dissolve mixing.Calcium gluconate solution is continuously added to total volume；By prepared solution through 0.22 μm of filter aseptic filtration,
It is dispensed with 1.0ml/ branch.Freeze-drying.
Plate layer temperature is down to -40 DEG C hereinafter, heat preservation 1.5-3 hours in 1 hour.Vacuum is opened, is started to warm up, -35
~-25 DEG C keep the temperature 2 hours, and -20~-10 DEG C keep the temperature 2 hours, and -5~5 DEG C keep the temperature 2 hours, and 10~35 DEG C keep the temperature 5 hours.
The oxytocin powder needle of 5 present invention of embodiment
0.5mol/L calcium chloride solutions are prepared, add in mannitol, oxytocin dissolving mixing.Continuously add 0.5mol/L chlorinations
Calcium solution is to total volume；By prepared solution through 0.22 μm of filter aseptic filtration, dispensed with 0.5ml/ branch.Freeze-drying.
Plate layer temperature is down to -40 DEG C hereinafter, heat preservation 1.5-3 hours in 1 hour.Vacuum is opened, is started to warm up, -35
~-25 DEG C keep the temperature 2 hours, and -20~-10 DEG C keep the temperature 2 hours, and -5~5 DEG C keep the temperature 2 hours, and 10~35 DEG C keep the temperature 5 hours.
The oxytocin powder needle of 6 present invention of embodiment
1.5mol/L solution of zinc sulfate is prepared, with apple acid for adjusting pH to 5.0, adds in lactose, oxytocin dissolving mixing.After
The continuous solution of zinc sulfate that adds in is to total volume；By prepared solution through 0.22 μm of filter aseptic filtration, dispensed with 5.0ml/ branch.
Freeze-drying.
Plate layer temperature is down to -40 DEG C hereinafter, heat preservation 1.5-3 hours in 1 hour.Vacuum is opened, is started to warm up, -35
~-25 DEG C keep the temperature 5 hours, and -20~-10 DEG C keep the temperature 5 hours, and -5~5 DEG C keep the temperature 5 hours, and 10~35 DEG C keep the temperature 8 hours.
The oxytocin powder needle of 7 present invention of embodiment
2mol/L calcium sulphate solns are prepared, with winestone acid for adjusting pH to 5.5, add in sucrose, oxytocin dissolving mixing.Continue
Calcium sulphate soln is added in total volume；By prepared solution through 0.22 μm of filter aseptic filtration, dispensed with 10.0ml/ branch.
Freeze-drying.
Plate layer temperature is down to -40 DEG C hereinafter, heat preservation 1.5-3 hours in 1 hour.Vacuum is opened, is started to warm up, -35
~-25 DEG C keep the temperature 5 hours, and -20~-10 DEG C keep the temperature 10 hours, and -5~5 DEG C keep the temperature 10 hours, and 10~35 DEG C keep the temperature 10 hours.
The oxytocin powder needle of 8 present invention of embodiment
0.1mol/L calcium citrate solutions are prepared, with vinegar acid for adjusting pH to pH6.9, add in mannitol, oxytocin dissolving mixes
It is even.Calcium citrate solutions are continuously added to total volume；By prepared solution through 0.22 μm of filter aseptic filtration, with 1.0ml/
Branch dispenses.Freeze-drying.
Plate layer temperature is down to -40 DEG C hereinafter, heat preservation 1.5-3 hours in 1 hour.Vacuum is opened, is started to warm up, -35
~-25 DEG C keep the temperature 2 hours, and -20~-10 DEG C keep the temperature 2 hours, and -5~-5 DEG C keep the temperature 2 hours, and 10~35 DEG C keep the temperature 5 hours.
The carbetocin powder needle of 9 present invention of embodiment
0.1mol/L calcium citrate solutions are prepared, with vinegar acid for adjusting pH to pH4.5, it is molten to add in mannitol, carbetocin
Solve mixing；Calcium citrate solutions are continuously added to total volume；By prepared solution through 0.22 μm of filter aseptic filtration, with
1.0ml/ branch dispenses；Freeze-drying.
Plate layer temperature is down to -40 DEG C hereinafter, heat preservation 1.5-3 hours in 1 hour.Vacuum is opened, is started to warm up, -35
~-25 DEG C keep the temperature 2 hours, and -20~-10 DEG C keep the temperature 2 hours, and -5~5 DEG C keep the temperature 2 hours, and 10~35 DEG C keep the temperature 5 hours.
10 stability test of embodiment
By embodiment 1-9 samples and commercially available oxytocin injectionAt 30 DEG C ± 2 DEG C, 65%RH ± 5%RH's
Under the conditions of place for a long time.As a result referring to table 1.
1 30 DEG C of storage ability data of table
Research finds that when preparing oxytocin powder needle embodiment 1-3 is using the oxytocin powder needle of prior art preparation at 0 month
After Shi Youguan substances are larger, and 30 DEG C are placed 36 months, hydrolysis impurity 1.6-2.7%, deamidation impurity is 1.2-1.8.%, not
Impurity is known for 1.5-2.0%, it is total miscellaneous for 8.3-8.9%, deamidation impurity, hydrolysis impurity, unknown impuritie and total miscellaneous significantly increase
Add；Content is 84-85%, is significantly degraded.
(oxytocin injection) is placed 36 months at 30 DEG C, and deamidation impurity is 1.5%, and unknown impuritie is
3.6%, it is total it is miscellaneous is 13.0%, deamidation impurity, hydrolysis impurity, unknown impuritie and total miscellaneous increase considerably；Content is 88.2%,
Significantly degrade.
Related substance is small during the embodiment of the present invention 4-9 samples 0 month, and after 30 DEG C are placed 36 months, deamidation impurity, water
Impurity, unknown impuritie are solved no more than 0.2%, deamidation impurity, hydrolysis impurity and unknown impuritie are without dramatically increasing；It is always miscellaneous not surpass
0.55% is crossed, content still has 98%.
It can be seen that the oxytocin analog pharmaceutical compositions of the present invention can be placed 36 months 30 DEG C long-term.
Oxytocin analog composition provided by the invention is in water for injection, 0.9% sodium chloride injection or 5% glucose
It can be dissolved rapidly in parenteral solution, solution achromaticity and clarification free from admixture precipitates after dissolving.And oxytocin powder needle provided by the invention and card
Shellfish oxytocin powder needle all shows stable property under conditions of 30 DEG C of long-time stability data.
By 6 months under conditions of 40 DEG C of ± 2 DEG C/65%RH ± 5%RH of embodiment 4-9 samples, as a result referring to table 2.
2 40 DEG C of table accelerates stability data in June
Embodiment 11：Oxytocin analog Pharmaceutical composition animal safety experiment prepared by 4-9 of the embodiment of the present invention
1st, vascular stimulation tests
The undamaged healthy rabbits 36 of ears are chosen, it is (each real that left side auricular vein injects the embodiment of the present invention respectively
Apply example 6) prepare oxytocin analog Pharmaceutical composition 1ml, auris dextra injection etc. capacity 5% glucose injection, daily 1
It is secondary, continuous injection 7 days.
During injection, the irritative response of auricular vein is observed in timing daily.It puts to death rabbit within 8th day, takes bilateral ear edge quiet
Arteries and veins and surrounding tissue, are fixed with formaldehyde, be respectively 11 away from injection site, 21, the proximal part of 31mm make conventional organization slice, light
Microscopic observation whether there is pathological change.Observation index and criterion are shown in Table 3.
3 blood vessel irritation of table scores and criterion
According to the method described above and the scoring of table 3 and criterion, 4-9 points of the rabbit auricular vein injection embodiment of the present invention
The oxytocin analog Pharmaceutical composition not prepared, irritation is compared with 5% glucose injection, no significant difference.Visually
Observation, has no the inflammatory reactions such as the congestion of blood vessel, peripheral tissue edema.Histotomy inspection has no blood vessel structure exception, interior skin lesion
Wound, thrombosis and other pathological changes.The blood vessel of its naked eyes and om observation, the accumulation score of surrounding tissue are respectively less than 0.5,
Show that oxytocin powder needle that 4-9 of the embodiment of the present invention prepared respectively and carbetocin powder are nonirritant for blood vessel.
2nd, muscle irritation is tested
Healthy rabbits 36 are taken, every rabbit left side quadriceps muscle of thigh injects 4-9 of the embodiment of the present invention (each embodiments respectively
6) prepare oxytocin analog Pharmaceutical composition 1ml, right side injection same volume physiological saline.Injection site is observed after injection
Muscle whether there is the reactions such as hyperemia, oedema, and (the 3rd day) sacrificed by exsanguination after half animal 48h, longitudinally slit skin visually observes two
Side injection position whether there is the reactions such as hyperemia, oedema, and its tissue is taken to do pathologic finding.Then the medicine is evaluated by the standard of table 4
Stimulate the reaction.Remaining animal continues to observe 14d, and aforesaid operations are repeated after the 18th day sacrificed by exsanguination, and evaluation criterion is shown in Table 4.
4 muscle irritation reaction evaluating standard of table
| Rank | Stimulate the reaction phenomenon |
| 0 grade | Medicine-feeding part is without significant reaction. |
| 1 grade | Medicine-feeding part mild hyperaemia, diameter are less than 0.15cm. |
| 2 grades | Medicine-feeding part moderate is congested, diameter 0.15-1.0cm. |
| 3 grades | Medicine-feeding part severe is congested, red and swollen, and muscle has denaturation. |
| 4 grades | There is the denaturation of muscle brown, necrosis. |
| 5 grades | There is large area necrosis in muscle serious degenerative. |
According to the method described above and the evaluation criterion of table 3, injection 4-9 systems of the embodiment of the present invention in quadriceps muscle of thigh on the left of rabbit
After standby oxytocin powder needle and carbetocin powder needle, injection site muscle is visually observed without the reactions such as hyperemia, oedema, pathologic group
It knits inspection and also has no the explicitlies stimulate the reaction such as tissue degeneratiaon or necrosis, there was no significant difference compared with physiological saline side.
3rd, to the sensitization test (STT) of cavy
Healthy guinea pig 48 is chosen, cavy is randomly divided into test group, negative control group and positive controls, negative control
Group gives the solvent of same volume；Positive controls give sensitization positive material known to bovine serum albumin(BSA)；Every abdominal cavity of test group
Inject 4-9 of the embodiment of the present invention (each embodiment 6) prepare oxytocin acceptable analogues composition 1.0ml, the next day inject 1
It is secondary, co-injection 3 times.Then each point 2 groups random, respectively 14 days or 21 days after the 1st administration, intravenous parenteral solution observes cavy
Whether there is the allergic symptoms such as excited uneasiness, expiratory dyspnea.
The result shows that the activity of test group cavy is normal, has no adnormal respiration etc., do not there is allergic reaction.
4th, hemolysis in vitro is tested
Prepare 2% rabbit red cell suspension.Every group takes 7, test tube, and various liquid are added in by table 5.Each test tube is gently shaken
It is even, it puts in 37 DEG C of waters bath with thermostatic control and is incubated, the result of observation 0.5,1,2,3,6 hour.The judgement of red blood cell agglutination in vitro and haemolysis
Standard is shown in Table 6.Oxytocin powder needle and carbetocin powder needle prepared by embodiment 4-9 is dissolved respectively with water for injection.
The outer hemolytic test sample-adding table of 5 injecting fluid of table
6 red blood cell hemolysis in vitro of table and agglutination test criterion
According to the method described above and the criterion of table 6, distilled water control tube was in complete hemolysis in 0.5 hour.Physiological saline
With 4-9 of embodiment of the present invention oxytocin powder needles and carbetocin powder needle in 3 hours without haemolysis.Gently shake, it is raw
Reason brine and the red blood cell of oxytocin powder needle and carbetocin powder needle tubing bottom sediments can be completely dispersed, and show contracting palace of the invention
Plain analog Pharmaceutical composition is reacted without red blood cell condensation.
5th, acute systemic toxicity
Healthy mice 35 is taken, mouse is randomly divided into test group and control group, mouse is put into fixator.Test group
Oxytocin analog Pharmaceutical composition test liquid (each embodiment 5 of 4-9 of embodiment of the present invention preparations is injected separately into from tail vein
Only), control group injection blank control liquid, injection speed 0.1ml/s, injection dosage 50ml/kg.After injection, observation
Mouse immediate reaction, and in 4,24,48 and 72 hours, observation and general state, the toxicity of record test group and control animals
Performance and dead animal number.
Reaction of animals observation index after table 7 is injected
According to the method described above and the observation index of table 7, within 72 hour observation period, the reaction of test group animal is not more than
Control animals, animal is without toxic reaction, and no animal dead, weight is without significant change.
In conclusion oxytocin analog Pharmaceutical composition prepared by injection embodiment of the present invention 4-9 has good group
Knit compatibility.Show that oxytocin analog Pharmaceutical composition safety prepared by the present invention is good, used for clinical injection.
12 isolated uterine animal experiment of embodiment
Take that (ip stilbestrol parenteral solutions 0.5ml/ on the 2nd only, can promote to make it into before experiment in estrous female rats
Estrus) 9, rabbit 9, cervical dislocation cuts off abdominal cavity after putting to death, and finds out uterus, gently removes；Under the connecting place of two jiaos of uterus
End is cut, and is taken out uterus, is placed in the culture dish of nutritious liquid.Two jiaos of uterus connecting place is cut off, takes one jiao, clip 2cm, one
End is with being fixed on bath bottom on sample hook hook, the other end is with line with being fixed on bath bottom, other end line on sample hook hook
Ligation is connected with sensor.The nutrient solution of bath is advisable with that can submerge uterus.Bath temperature is 37 ± 0.5 DEG C, stands 15min,
After adapting to after uterus, start to test.BL-420F biological functional systems are opened, start to test.Distinguished with 1ml waters for injection
Embodiment 1-9 is dissolved, and starts to be administered.Calculate uterotonic intensity, frequency and uterine contractile vigor.
8 uterotonic intensity of table, frequency and uterine contractile vigor result table
The result shows that the embodiment of the present invention 4-9 has apparent excitation to rat, rabbit isolated uterine smooth muscle,
The amplitude of contraction increases, and frequency is accelerated, and tension increases, and in dose-effect relationship；The embodiment of the present invention 4-9 can be to different uterus
Identical excitation is generated, to individual to no effect difference.
And embodiment 1-3 has Isolated Rat Uterus smooth muscle excitation, but to the excitement of rabbit isolated uterine smooth muscle
Effect is weaker, and there are individual differences.
Claims (10)
1. a kind of pharmaceutical composition containing oxytocin analog, it includes oxytocin analog, excipient and divalent metal ions
Salt.
2. pharmaceutical composition according to claim 1, wherein, oxytocin analog be selected from oxytocin, carbetocin, that
The combination of one or more of card oxytocin, cargutocin.
3. according to claim 1-2 any one of them pharmaceutical compositions, wherein, divalent metal cation salt be selected from calcium ion salts or
Zinc ion salt, preferably calcium chloride, calcium acetate, calcium citrate, calcium tartrate, zinc chloride, zinc gluconate, calcium gluconate,
The solution of one or more of calcium sulfate, zinc sulfate, zinc acetate, zinc citrate combination.
4. according to claim 1-3 any one of them pharmaceutical compositions, wherein, excipient is selected from mannitol, lactose, grape
The combination of one or more of sugar, sucrose, sodium chloride, sorbierite.
5. according to any one of claim 2-4 described pharmaceutical compositions, wherein, the content of each component is：Per 5000IU-
20000IU oxytocins, it is corresponding comprising the divalent metal cation salt of 0.1mol-3mol and 20g-100g excipient；Or per 0.1g
Carbetocin, it is corresponding comprising the divalent metal cation salt of 0.1mol-3mol and 20g-100g excipient.
6. according to claim 1-5 any one of them pharmaceutical compositions, preparation is selected from injection powder needle.
7. according to the preparation method of any one of claim 1-6 described pharmaceutical compositions, include the following steps:
1) 0.1mol/L-3mol/L divalent metal ion salt solutions are prepared；
2) excipient, oxytocin analog are added in and is uniformly mixed；
3) divalent metal ion salt solution is continuously added to total volume；
4) it is lyophilized after prepared solution sterilization；
Optionally, regulating step 1) in divalent metal ion salt solution pH value to 3.5-6.9.
8. preparation method according to claim 7, wherein, each component concentration ratio of step 3) acquired solution is：Often
5000IU/L-20000IU/L oxytocins, the corresponding divalent metal cation salt and 20g/L- for including 0.1mol/L-3mol/L
100g/L excipient；
Or per 0.1g/L carbetocins, the corresponding divalent metal cation salt and 20g/L- for including 0.1mol/L-3mol/L
100g/L excipient.
9. the drug for uterine contractile or uterine hemostasis is being prepared according to claim 1-6 any one of them pharmaceutical composition
In purposes.
It is 10. sub for improving uterine sensibility or elimination preparing according to claim 1-6 any one of them pharmaceutical composition
Purposes in the drug of palace sensitivity differences.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611203711.4A CN108236716A (en) | 2016-12-23 | 2016-12-23 | A kind of pharmaceutical composition containing oxytocin analog and its preparation method and application |
| PCT/CN2017/092717 WO2018113272A1 (en) | 2016-12-23 | 2017-07-13 | Pharmaceutical composition comprising oxytocin analog, preparation method therefor, and use thereof |
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| CN201611203711.4A CN108236716A (en) | 2016-12-23 | 2016-12-23 | A kind of pharmaceutical composition containing oxytocin analog and its preparation method and application |
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| CN201611203711.4A Pending CN108236716A (en) | 2016-12-23 | 2016-12-23 | A kind of pharmaceutical composition containing oxytocin analog and its preparation method and application |
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| CN (1) | CN108236716A (en) |
| WO (1) | WO2018113272A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111012739A (en) * | 2019-12-04 | 2020-04-17 | 长春圣金诺生物制药有限公司 | Injection containing carbetocin and stabilizer and capable of being stored at normal temperature |
| CN111184687A (en) * | 2018-10-29 | 2020-05-22 | 厦门紫旭医药科技有限公司 | Oxytocin injection and preparation method thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109745544B (en) * | 2018-11-23 | 2024-11-08 | 南京新百药业有限公司 | Stable oxytocin pharmaceutical composition and preparation method thereof |
| EP4288078A4 (en) * | 2021-02-03 | 2024-12-11 | Sun Pharmaceutical Industries Ltd | READY-TO-INFUSE PHARMACEUTICAL FORM OF OXYTOCIN |
| CN114983935B (en) * | 2022-06-15 | 2024-01-26 | 上海上药第一生化药业有限公司 | Uterine contraction injection and its preparation process |
| WO2023247760A1 (en) * | 2022-06-24 | 2023-12-28 | Xellia Pharmaceuticals Aps | Oxytocin formulation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102146122A (en) * | 2010-11-12 | 2011-08-10 | 深圳市健元医药科技有限公司 | Process for producing medicament with uterine contraction effect |
| CN103830720A (en) * | 2014-03-25 | 2014-06-04 | 深圳翰宇药业股份有限公司 | Medicine composition containing oxytocin |
| CN105451716A (en) * | 2013-07-18 | 2016-03-30 | 曼金德公司 | Thermally stable dry powder pharmaceutical compositions and methods |
-
2016
- 2016-12-23 CN CN201611203711.4A patent/CN108236716A/en active Pending
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2017
- 2017-07-13 WO PCT/CN2017/092717 patent/WO2018113272A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102146122A (en) * | 2010-11-12 | 2011-08-10 | 深圳市健元医药科技有限公司 | Process for producing medicament with uterine contraction effect |
| CN105451716A (en) * | 2013-07-18 | 2016-03-30 | 曼金德公司 | Thermally stable dry powder pharmaceutical compositions and methods |
| CN103830720A (en) * | 2014-03-25 | 2014-06-04 | 深圳翰宇药业股份有限公司 | Medicine composition containing oxytocin |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111184687A (en) * | 2018-10-29 | 2020-05-22 | 厦门紫旭医药科技有限公司 | Oxytocin injection and preparation method thereof |
| CN111012739A (en) * | 2019-12-04 | 2020-04-17 | 长春圣金诺生物制药有限公司 | Injection containing carbetocin and stabilizer and capable of being stored at normal temperature |
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| Publication number | Publication date |
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| WO2018113272A1 (en) | 2018-06-28 |
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