CN102580057A - Medicine composition containing ergometrine and oxytocin analogue and preparation method - Google Patents
Medicine composition containing ergometrine and oxytocin analogue and preparation method Download PDFInfo
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- CN102580057A CN102580057A CN2012100660981A CN201210066098A CN102580057A CN 102580057 A CN102580057 A CN 102580057A CN 2012100660981 A CN2012100660981 A CN 2012100660981A CN 201210066098 A CN201210066098 A CN 201210066098A CN 102580057 A CN102580057 A CN 102580057A
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- China
- Prior art keywords
- ergometrine
- oxytocin
- antioxidant
- pharmaceutical composition
- composition according
- Prior art date
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Links
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical class 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](CSSC[C@H](N)C(=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(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 title claims abstract description 90
- WVVSZNPYNCNODU-CJBNDPTMSA-N Ergometrine Natural products C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@@H](CO)C)C2)=C3C2=CNC3=C1 WVVSZNPYNCNODU-CJBNDPTMSA-N 0.000 title claims abstract description 69
- 229960001405 ergometrine Drugs 0.000 title claims abstract description 69
- WVVSZNPYNCNODU-XTQGRXLLSA-N Lysergic acid propanolamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)C)C2)=C3C2=CNC3=C1 WVVSZNPYNCNODU-XTQGRXLLSA-N 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 239000000203 mixture Substances 0.000 title claims abstract description 27
- 239000003814 drug Substances 0.000 title abstract description 15
- 229940079593 drug Drugs 0.000 title abstract description 5
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- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 3
- 101800000989 Oxytocin Proteins 0.000 claims description 80
- XNOPRXBHLZRZKH-UHFFFAOYSA-N Oxytocin Natural products N1C(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CC(C)C)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C(C(C)CC)NC(=O)C1CC1=CC=C(O)C=C1 XNOPRXBHLZRZKH-UHFFFAOYSA-N 0.000 claims description 79
- 229960001723 oxytocin Drugs 0.000 claims description 79
- 239000003963 antioxidant agent Substances 0.000 claims description 57
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 42
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 21
- 238000005516 engineering process Methods 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 10
- 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 claims description 9
- 229960001118 carbetocin Drugs 0.000 claims description 9
- 108700021293 carbetocin Proteins 0.000 claims description 9
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- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
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- 239000000600 sorbitol Substances 0.000 claims description 4
- YHKWDHMRGAMOKU-YGMDSVBLSA-N (2s,5s,8r,11r,14s)-11-(2-amino-2-oxoethyl)-n-[2-[[(2s)-1-[(2-amino-2-oxoethyl)amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]-8-(3-amino-3-oxopropyl)-5-[(2s)-butan-2-yl]-2-[(4-hydroxyphenyl)methyl]-3,6,9,12,20-pentaoxo-1,4,7,10,13-pentazacycloicosane- Chemical compound N1C(=O)CCCCC[C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@@H](CCC(N)=O)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]1CC1=CC=C(O)C=C1 YHKWDHMRGAMOKU-YGMDSVBLSA-N 0.000 claims description 3
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 235000001014 amino acid Nutrition 0.000 claims description 3
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- 235000010355 mannitol Nutrition 0.000 claims description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- UNBRKDKAWYKMIV-QWQRMKEZSA-N (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)CC)C2)=C3C2=CNC3=C1 UNBRKDKAWYKMIV-QWQRMKEZSA-N 0.000 claims description 2
- YREISLCRUMOYAY-BKQYHRSVSA-N (6ar)-n-(1-hydroxypropan-2-yl)-7-methyl-6,6a,8,9-tetrahydro-4h-indolo[4,3-fg]quinoline-9-carboxamide;(z)-but-2-enedioic acid Chemical compound OC(=O)\C=C/C(O)=O.C1=CC(C=2[C@H](N(C)CC(C=2)C(=O)NC(CO)C)C2)=C3C2=CNC3=C1 YREISLCRUMOYAY-BKQYHRSVSA-N 0.000 claims description 2
- NSENZNPLAVRFMJ-UHFFFAOYSA-N 2,3-dibutylphenol Chemical compound CCCCC1=CC=CC(O)=C1CCCC NSENZNPLAVRFMJ-UHFFFAOYSA-N 0.000 claims description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 229920001503 Glucan Polymers 0.000 claims description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 2
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- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
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- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 2
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- 229940049920 malate Drugs 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
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- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
The invention relates to a medicine composition, which is characterized by consisting of oxytocin analogue, ergometrine or salt acceptable in pharmacy, a carrier acceptable in preparation process or excipient, antioxygen, a potential of hydrogen (pH)conditioning agent, solubilizer and other auxiliary materials. The medicine composition is used for prevention and cure of postpartum hemorrhage caused by uterine contraction and atony and active management at the third stage of childbirth and is contribute to postpartum functional recovery. The ergometrine and the oxytocin analogue are combined to increase the curative effect and reduce the untoward effect. The dosage form is a freeze-drying mode or a sterile split package mode, high temperature sterilization is avoided in the preparation process, the medicines are stored in a solid state, the integrated antioxygen is added, impurities are decreased, the medicine composition is stable, and storage and transportation at the room temperature are facilitated.
Description
Technical field
The present invention relates to prevent and treat, belong to medical technical field because the pharmaceutical composition of functional recovery in puerperal is managed and helped to weak postpartum hemorrhage that causes of uterine contraction and the activity of childbirth phase III.
Background technology
Oxytocin is mainly used in induced labor, antenatal inertia of uterus, postpartum hemorrhage and subinvolution of uterus clinically.
Oxytocin can be shunk by the indirect stimulation uterine smooth muscle, simulates eutocous uterine contraction effect, causes cervical dilatation, and the uterus reaches the peak to increasing gradually in the pregnant process of being reflected at of oxytocin when mature.Can also stimulate the smooth muscle contraction of mammary gland, help milk to discharge, but not increase the galactopoiesis amount of mammary gland from breast.
The special construction of oxytocin serotonergic neuron on dissecting makes oxytocin have the dual function of hormone and neurotransmitter.The main effect of oxytocin is to promote uterine contraction.In uterine contraction, the mutual relation of oxytocin and oxytocin receptor has determined the population equilibrium of uterine activity.Keeping the uterus tranquillization or impelling in its contraction, if oxytocin receptor number just needs more oxytocin to produce uterine contraction less, and gestation promptly is like this in early days.Latter half of gestation then antithesis.This has just constituted basis to oxytocin sensitivity in the whole pregnant process, human body uterus.Oxytocin also can impel uterine contraction through the activation of the calcium channel related with receptor and the release of sarcoplasmic reticulum calcium.Estrogen can increase oxytocin expression of gene in rat uterus and people's amniotic membrane, chorion, the decidua culture.Thymosin also has certain regulating action to oxytocin, because contain the thymus fragment reaction in the oxytocin gene, thymosin can make the level of oxytocin in mRNA expression and blood, the hypophysis of hypothalamus oxytocin significantly increase.
Many researchs show that oxytocin is through (oxytocinreceptor OTR) combines to work with the oxytocin receptor.When oxytocin and oxytocin receptor after external the combination, stimulate the proteic allos subunit of G α that GTP is hydrolyzed into GDP, and discharge β, the γ subunit stimulates phospholipase C, phospholipase is converted into diglyceride and inositoltriphosphoric acid (IP3).Diglyceride SP kinase c is active, and then makes its substrate phosphorylation, causes some reactions of specific cells.IP
3Can stimulate Ca
2+Through the flow of calcium channel entering endochylema, these Ca
2+Mainly from sarcoplasmic reticulum, but some are also arranged from the extracellular.The calcium that increases can combine with calmodulin, CaM, stimulates MLCK (MLCK) to produce the uterine contraction function.In decidua, what the Ca2+ of increase reacted is the synthetic and release of prostaglandin.
Oxytocin is oral very easily to be destroyed by Digestive system, and intramuscular injection was onset in 3～5 minutes, and effect continues 30～60 minutes; Intravenous drip is onset immediately, and uterotonic frequency and intensity increase gradually in 15～60 minutes, and is stable then; Instillation finished back 20 minutes, and its effect is decrescence moved back.Half-life was generally 1～6 minute.These article are through liver, kidney metabolism, and through renal excretion, minute quantity is the original shape thing.
Carbetocin is for being the oxytocin analog, and by Canadian Duratocin, Ferring Inc develops, and import is Chinese.Half-life is 40min, than long 4～10 times of oxytocin.Multicenter randomized control study external and China shows that all carbetocin (100 μ g intravenous injection) is hemorrhage effective equally with oxytocin behind controlled selection property cesarean section, and the two safety is similar.Its pharmacological action is similar with oxytocin, and the oxytocin receptors bind on carbetocin and the uterine smooth muscle causes uterus rhythmicity contraction and strengthens existing contraction frequency, increases uterus tension force.Quiet notes and the onset of intramuscular injection carbetocin are very fast, promptly have the uterus active in the 2min.Single intravenous injection carbetocin can keep uterine contraction (60 ± 18) min, and (119 ± 69) min that holds time of intramuscular injection is 4 times that the intramuscular injection oxytocin is held time.
Ergometrine is that effect is the strongest in the Ergota composition, and minimum a kind of of toxic reaction is uterotonic, can obviously increase uterine activity, can directly act on uterine smooth muscle, and effect is strong and lasting.
Heavy dose can make the tetanic contraction of uterus muscle, can make Placenta Hominis plantation virgin palace intramuscular blood vessel oppressed and stop blooding, and the sensitivity in the latter half of gestation uterus to the palace medicine that contracts increases.Mainly be used in puerperal or post-abortion the prevention and the treatment since inertia of uterus or contract again bad due to metrorrhagia.Be used for the uterus meromorphosis in puerperal, quicken uterine involution.
Its contraction frequency or intensity increase when low dose of, normally loosen then; Dosage strengthens then uterine contraction reinforcement and prolongs, and resting tension improves, even forms lasting contraction.Hypomere and palace body muscle shrink simultaneously, are unfavorable for that fetus gives birth to, so can only be used for puerperal.Ergometrine directly acts on uterine smooth muscle; Increase tension force, frequency and amplitude that the rhythm and pace of moving things shrinks, pretend, can make uterus muscle that the contraction of tetanic property takes place with rapid, strong and lasting; Make Placenta Hominis adhere in place's flesh layer blood vessel and oppressed and stop blooding, shorten third stage of labor and reduce hemorrhage.
The Cornocentin raw material is included in European Pharmacopoeia and American Pharmacopeia, and in Europe and U.S.'s listing, the dosage form of mainly going on the market is an oral cavity disintegration tablet.
There are ergometrine injection and oxytocin inj to use separately respectively at present clinically.There is the people that compound injection is processed in the ergometrine oxytocin abroad; Wherein contain two kinds of medicines of Cornocentin and oxytocin, the two share the obvious synergy that increased, and convenient; Its regular size is: 1ml contains ergometrine 500ug, oxytocin 5 units (IU).Commodity are called Syntometrine, are produced without competition and are sold by Novartis Co.,Ltd, go on the market in states such as Ireland, Australia, Britain, Malaysia, South Africa and New Zealand.This compound preparation has combined the rapid-action advantage with the ergometrine long action time of oxytocin, and the slight vasodilatory effect of oxytocin has relaxed the blood vessel function that contracts that ergometrine causes.The system evaluation of Cochrane thinks, compares with using traditional oxytocin (5IU or 10IU), and Syntometrine has reduced the risk of hemorrhage postpartum hemorrhage at 500～1000mL, but the hemorrhage risk that surpasses 1000mL is at two groups comparing difference not statistically significant.
Syntometrine has combined the quick uterotropic effect of oxytocin, and oxytocin is discharged by the posthypophysis secretion, and contains a kind of nonapeptide hormone that continues uterine contraction effect ergometrine.According to the situation of intramuscular injection, the incubation period that the uterine contraction of use Syntometrine (about 21/2 minute) takes place will be much smaller than independent use ergometrine (about 7 minutes).And only can continue to compare in 1/2-1 hour with independent use oxytocin, Syntometrine can keep several hours uterine contraction effect.
This performance of Syntometrine makes its activity management of phase III that is suitable for giving a birth, and can prevent or treat postpartum hemorrhage, especially since any factor cause can't intravenous situation under.It is used to prevent and the usage of treating postpartum hemorrhage is: after Placenta Hominis is discharged, and intramuscular injection 1ml Syntometrine when generation is hemorrhage maybe.If necessary, the injection of 1ml maybe duplicate injection in being no less than 2 hours interval.Must be no more than 3ml at 24 integral doses in as a child.Can implement intravenous injection Syntometrine (injecting 0.5-1ml slowly), but not recommend such use.Blood pressure is monitored in suggestion when implementing intravenous injection.
Domestic to use maximum in the market be folk prescription oxytocin injection, and price is lower, uses very extensive.Ergometrine is because raw material has only Hebei to open one tame enterprise of medicine group in production, and domestic use is also few.
After 2～3 minutes, uterine contraction promptly comes into effect the compound preparation of oxytocin and ergometrine in intramuscular injection, and effect continues 3 hours, and quiet notes take effect immediately, and act on 45 minutes, and the contraction of rhythmicity is sustainable to reach 3 hours.Therefore the two compound recipe has: the long characteristics of the phase of keeping that combined the rapid-action and ergometrine of oxytocin; Oxytocin simultaneously is owing to there is certain vasodilator effect; Strengthened the probability of postpartum hemorrhage, behind the coupling ergometrine, ergometrine has vasoconstrictive active; Can reduce the effect of postpartum hemorrhage and uterus functional recovery greatly, have clinically than the independent use incomparable advantage of ergometrine.
As stated, China does not also have the aqueous injection of compound recipe oxytocin and ergometrine to go on the market at present.Though the Syntometrine listing is abroad arranged, and there is more serious defective in this aqueous injection:
Operations such as sterilization need carry out disinfection in the preparation process of aqueous injection.It is F to the terminally sterilised specification requirement of small-volume injection that China's existing medicine registration rules and technology are evaluated guideline
0＞8.Reaches such requirement, must carry out the sterilization treatment of temperature requirement more than 100 ℃, and under this condition of high temperature, oxytocin is owing to be special polypeptide structure that structure is the peptide chain that contains 9 aminoacid compositions of disulfide bond: H-Cys-Tyr-Ile-Glu (NH
2)-Asp (NH
2)-Cys-Pro-Leu-Gly-NH
2, being easy to be destroyed generation impurity, main impurity is related substance and related peptides and polymer etc., thereby reduces drug effect or produce serious adverse reaction, these untoward reaction mainly show as severe anaphylactic reaction, feel sick, vomiting and skin Pruritus etc.So these article cannot high temperature sterilize, external what adopt is aseptic filtration degerming technology.
As take the degerming of aseptic filtration method; Requirement to working condition is very harsh; Depollution of environment rank and production line automation degree require high; Equipment drops into huge, and the workshop is in the isolation of Strict aseptic, and China does not also have the aseptic filtration liquid drugs injection production line of a family through FDA or European Union's Valuation Standard at present.High by this explained hereafter cost, clinical beyond affordability.
In addition; Compound recipe oxytocin and ergometrine aqueous injection are very unstable; It is had relatively high expectations to preservation condition: even the product that adopts the filtration sterilization explained hereafter to come out is also wanted lucifuge, 2～8 ℃ of storage and transport; This brings huge inconvenience for clinical use, and production and cost of transportation have limited the clinical practice of these article aqueous injection.
For overcoming above defective; We have developed a kind of stable pharmaceutical composition that contains ergometrine and oxytocin analog on the basis of big quantity research; This kind pharmaceutical composition stable in properties; Can room temperature storage and transportation, said composition can be prepared into freeze-drying preparation for injection or sterile packaged preparation.
Research shows that oxytocin is responsive to oxygen under high temperature, illumination state, therefore, adds a certain amount of compound antioxygen composition in the compositions and helps to increase stability.
Do not need the condition of high temperature in the lyophilized formulations technical process, adopt filtering with microporous membrane technology, workshop only needs the regional area purification to get final product; Avoided high temperature to destroy the impurity of being introduced, made that the purity of product active substance is higher, medicine is deposited and is transported with solid forms; Much stable than solution state, on this basis, the antioxidant composition that is added in the compositions; Make product more stable in the process that keeps sample for a long time, and convenient store (room temperature), transport and use more convenient.Has incomparable advantage clinically.
Summary of the invention
The present invention has overcome the defective of prior art and provides a kind of and can effectively prevent and treat because weak postpartum hemorrhage that causes of uterine contraction and the activity management of childbirth phase III and help the pharmaceutical composition of functional recovery in puerperal; Compared with prior art, stability of drug, effectiveness, safety, ease of use are obviously improved.
Pharmaceutical composition of the present invention is characterized in that being made up of adjuvants such as acceptable carrier or excipient, composite antioxidant (antioxidant and collaborative antioxidant are formed), PH regulator, solubilizing agent in oxytocin analog and ergometrine or its pharmaceutically acceptable salt and the preparation process.
Research shows that oxytocin is responsive to oxygen under the condition of high temperature, therefore, adds a certain amount of compound antioxygen composition in the compositions and helps to increase stability, can tolerate room temperature preservation.
Pharmaceutical composition of the present invention on the basis that has added a certain amount of antioxidant and collaborative antioxidant composition, adopts lyophilized formulations technology, can significantly reduce related substance and produce, and increases stability.
The freeze-dry process flow process:
The first step: join adjuvant solution: take by weighing the adjuvant of recipe quantity, place the container of sterilizing, add an amount of water for injection, after stirring and the dissolving, add needle-use activated carbon, stir, use the filter membrane of warp sterilization to take off charcoal;
Second step: add antioxidant: the composite antioxidant of weighing recipe quantity adds above-mentioned filtrating of taking off behind the charcoal, and makes it to dissolve fully;
The 3rd step: preparation principal agent: the principal agent composition that takes by weighing recipe quantity adds wherein, fully stirs and makes dissolving, adds the injection water to scale;
The 4th step: degerming lyophilizing: the filtering with microporous membrane degerming, be sub-packed in the cillin bottle by the loading amount requirement, send into the freezer dryer lyophilizing, add a cover, labelling promptly gets.
Need to prove: the adding of antioxidant must be adsorbed antioxidant or collaborative antioxidant composition otherwise the active carbon meeting is a large amount of after first step adjuvant solution takes off charcoal, descend thereby cause antioxidation to render a service, and then cause stability decreases.The adding of antioxidant must be before principal agent dissolving, and is promptly protected in course of dissolution to guarantee principal agent.
Pharmaceutical composition of the present invention, oxytocin analog can be selected from oxytocin Oxytocin, carbetocin Carbetocin, nacartocin Nacartocin, cargutocin Cargutocin etc.
Pharmaceutical composition of the present invention, ergometrine pharmaceutically acceptable salt are selected from pharmaceutically acceptable salt such as ergometrine maleate, ergometrine benzene sulfonate, ergometrine arginine salt, ergometrine mesylate, methylergometrine malate.
Pharmaceutical composition of the present invention is characterized in that, the content of oxytocin is 1～20 unit (IU) in the described compositions.
Pharmaceutical composition of the present invention wherein is preferably 5～10 units (IU) with oxytocin content.
Pharmaceutical composition of the present invention is 0.10mg～5.00mg in the content of ergometrine ergometrine pharmaceutically acceptable salt.
Pharmaceutical composition of the present invention, wherein the content in ergometrine ergometrine pharmaceutically acceptable salt is preferably 0.25mg～1.00mg.
Pharmaceutical composition of the present invention; Must contain the composite antioxidant composition of being made up of antioxidant and synergist and just can reach the steady statue to heat and oxygen, its specific antioxidant that contains is selected from one or more in sodium sulfite, sodium pyrosulfite, sodium sulfite, sodium thiosulfate or amino acids, vitamin C, dibutyl phenol, the butylated hydroxyarisol.Though compound recipe contains the existing listing of hydro-acupuncture preparation of the pharmaceutical composition of oxytocin analog and ergometrine abroad; But it can not bear and surpass 2～8 ℃ of extraneous storage requirement storage and transport; And pharmaceutical composition of the present invention can tolerate room temperature preservation, and stability can reach more than 2 years.2～8 ℃ of needs cold chain transportations have also increased the weight of circulation cost.
Pharmaceutical composition of the present invention, its antioxidant content are 0.01mg～0.50mg.
Pharmaceutical composition of the present invention, the composite antioxidant that it contained select for use collaborative antioxidant comprise: one or more of citric acid, citric acid, tartaric acid, cysteine etc.
Pharmaceutical composition of the present invention, its collaborative antioxidant content is 0.01mg～0.50mg.
Pharmaceutical composition of the present invention is characterized in that, dosage form can be made into freeze-drying preparation for injection (or aseptic subpackaged), and medicine is stored and transportation with solid state, and can be made into normal saline or glucose injection during use needs concentration vein or intramuscular administration.
Pharmaceutical composition of the present invention; Pharmaceutic adjuvants such as its acceptable carrier or excipient are selected from: mannitol, lactose, inositol, glucosan, glycine, dextran, sorbitol, L cysteine etc., PH regulator: one or more in citric acid, lactic acid, sodium hydroxide, sodium citrate, the sodium bicarbonate etc.
Any one Pharmaceutical composition that the present invention relates to; Can be used for preventing and treat because weak postpartum hemorrhage that causes of uterine contraction and the management of the activity of childbirth phase III and help the pharmaceutical composition of functional recovery in puerperal, and select the Pharmaceutical composition of different UDs according to the state of an illness.
Pharmaceutical composition involved in the present invention can be used for human or animal's individuality.
Description of drawings
Do not have
The specific embodiment
Embodiment 1:
The contrast of the pharmaceutical composition of injection use compound oxytocin and analog thereof and ergometrine pharmaceutically acceptable salt and ergometrine oxytocin inj its related substances and stability
Test sample and reference substance:
External reference substance: Syntometrine injection (ergometrine oxytocin inj), the 10IU/ml/ bottle, Zuellig Pharma company provides, and Novartis company produces;
Test sample A: the ergometrine oxytocin inj, simulate external Syntometrine injection formula, do not contain antioxidant, adopt the aseptic filtration explained hereafter, handle Xianyu Science and Technology Co., Ltd., Nanjing's self-control without high temperature sterilize;
Test sample B: the ergometrine oxytocin inj, simulate external Syntometrine injection formula, do not contain antioxidant, adopt high temperature sterilize to handle, Xianyu Science and Technology Co., Ltd., Nanjing provides;
Test sample C: the oxytocin of injection ergometrine, do not contain antioxidant, after aseptic filtration, adopt the preparation of lyophilizing production technology, Xianyu Science and Technology Co., Ltd., Nanjing provides;
Test sample D: the oxytocin of injection ergometrine, contain antioxidant, after aseptic filtration, adopt the preparation of lyophilizing production technology, Xianyu Science and Technology Co., Ltd., Nanjing provides;
Test sample E: the oxytocin of injection ergometrine, contain antioxidant and collaborative antioxidant, after aseptic filtration, adopt the preparation of lyophilizing production technology, Xianyu Science and Technology Co., Ltd., Nanjing provides;
Oxytocin content and determination of related substances method:
It is lower that biologic assay is measured sensitivity, operates numerous rope, and the present invention adopts the HPLC method:
Assay: measure according to HPLC (pharmacopeia appendix VD).
Chromatographic condition: (25cm * 0.46cm, 5 μ m) are filler with octadecyl silane; With the 0.1mol/L sodium dihydrogen phosphate is mobile phase A, and water-acetonitrile (1: 1) is a Mobile phase B, carries out gradient elution in accordance with the law; get an amount of mobile phase A that adds of these article and process certain density solution, get 100 μ l sample introductions, the detection wavelength is 220nm; the record chromatogram, other gets the standard substance of these article, measures with method;, promptly get in peak area content by external standard method.
The determination of related substances method: it is an amount of to get test sample; Add mobile phase A and process the solution that contains certain unit concentration among every 1ml, according to content assaying method, in the need testing solution chromatogram as show impurity peaks; Desolventize outside the peak, calculate maximum single impurity and total impurities by area normalization method.
10 days illumination study on the stability:
Above-mentioned each test sample is put (4500 ± 500Lx) high light held 10 days is measured 0,5,10 day oxytocin content and related substance respectively, and relatively investigates its stability under illumination condition with 0 day result.
Pharmaceutical composition and its injection influence factor (high light 4500 ± 500Lx) result of the tests of the injection ergometrine oxytocin of several kinds of different prescriptions of table 1
Reference substance: Syntometrine injection (ergometrine oxytocin inj)
Test sample A: the ergometrine oxytocin inj, do not contain antioxidant, handle without high temperature sterilize;
Test sample B: the ergometrine oxytocin inj, do not contain antioxidant, adopt high temperature sterilize to handle;
Test sample C: the oxytocin of injection ergometrine, do not contain antioxidant, adopt the freeze-dry process preparation;
Test sample D: the oxytocin of injection ergometrine, contain antioxidant, adopt the freeze-dry process preparation;
Test sample E: the oxytocin of injection ergometrine, contain antioxidant and collaborative antioxidant, adopt the freeze-dry process preparation.
Table 1 is the result show, these article are responsive to illumination, and external reference substance is without high-temperature process; Similar with the situation of change of self-control test sample A, test sample B is because through high-temperature process, and active ingredient is destroyed significantly; It is meaningless to investigate the impurity variation, has confirmed under the oxytocin condition of high temperature unstable;
The injection preparation that lyophilizing makes after the degerming of test sample C employing aseptic filtration method does not add any antioxidant, from stability change in the prescription; Compare with reference substance, test sample A in the time of 10 days; Content all descends to some extent, single assorted and all risings to some extent of total impurities, but the impurity increasing degree is starkly lower than reference substance and test sample A; Explain that the prepared test sample medicine of lyophilized formulations technology is in solid state, stability will obviously be superior to injection;
Added antioxidant in the prescription of test sample D, content just has reduction slightly in the time of 10 days, and maximum single impurity and total impurities slightly raise, and explains that antioxidant is effective to guarantor's effect of medicine;
Not only added antioxidant but also added collaborative antioxidant in the prescription of test sample E, protection intensity is bigger, and from testing result, content and related substance be no change almost.Total impurities content is lower than reference substance more than 10 times in the time of 10 days, explains that pharmaceutical composition of the present invention and prescription thereof, technology are far superior to external reference substance.
Avoid that high temperature destroys, the solid state storage, and factor such as associating antioxidant product stability has all been played important effect.Based on the conclusion of this research,, also can reach the requirement of stability if preparation of pharmaceutical compositions of the present invention is become sterile packaged preparation.
The high temperature accelerated stability was investigated in 6 months:
Through factors influencing; These article are except responsive to illumination; Also, unstable under the condition of high temperature to responsive to temperature, so the Syntometrine injection needs 2～8 ℃ of cryopreservation; For further investigating the long-time stability of sample under different dosage forms and the different prescription condition, design experiment is following:
Above-mentioned each test sample is put 40 ± 2 ℃ high temperature held 6 months, measure 0,1,2,3,6 month oxytocin content and related substance respectively, and relatively investigate its stability under hot conditions with 0 day result.
Pharmaceutical composition and its injection stability (40 ± 2 ℃ of high temperature) of the injection ergometrine oxytocin of several kinds of different prescriptions of table 2 are investigated the result
Reference substance: Syntometrine injection (ergometrine oxytocin inj)
Test sample A: the ergometrine oxytocin inj, do not contain antioxidant, handle without high temperature sterilize;
Test sample C: the oxytocin of injection ergometrine, do not contain antioxidant, adopt the freeze-dry process preparation;
Test sample D: the oxytocin of injection ergometrine, contain antioxidant, adopt the freeze-dry process preparation;
Test sample E: the oxytocin of injection ergometrine, contain antioxidant and anti-same antioxidant, adopt the freeze-dry process preparation;
Table 2 is the result show: under 40 ± 2 ℃ of states of high temperature; During reference substance and test sample A (ergometrine oxytocin inj) high temperature accelerated stability test to 6 month; Content has been reduced to about 60%; And corresponding impurity also produces very significantly, and near 40%, it also is the main cause that causes serious adverse reaction clinically that impurity produces;
The stability of employing lyophilizing preparation technology's composition for injection C, D, E obviously is superior to the ergometrine oxytocin inj, explains that under this condition injection ergometrine oxytocin stability obviously is superior to injection; Therefore, the injection ergometrine oxytocin of different prescriptions can tolerate the room temperature long preservation;
Test sample C: though content descends to some extent, total impurities also raises with single mixing to some extent, and amplitude is starkly lower than hydro-acupuncture preparation! Yet,, still not in acceptability limit, explain that not adding antioxidant product does not still reach under the long-term room temperature preservation condition and stablize qualified requirement by the limit of Chinese Pharmacopoeia regulation (singly assortedly is not more than 1.5%, total assorted be not more than 5%);
Test sample D: the basic no change of content, related substance slightly raises, and the limit of stipulating by pharmacopeia meets basically;
Test sample E: the basic no change of content, related substance does not produce basically, and constant product quality property is best.
Embodiment 2:
The oxytocin of injection use compound benzenesulfonic acid ergometrine
(1) prescription
(2) preparation technology
Take by weighing recipe quantity mannitol, add the water for injection of 4/5 amount, stir and make dissolving fully.
Between the hydrochloric acid adjust pH 3-8 with 1.0mol/L, add water for injection again and be settled to 1000ml.
Add 0.5～1g active carbon, stir the 15min after-filtration and take off charcoal, add recipe quantity oxytocin, benzenesulfonic acid acid ergometrine, sodium sulfite and cysteine, with the membrane filtration degerming of 0.22um.
Measure the content of intermediate principal agent, confirm loading amount.
Lid is filled in, is rolled in lyophilizing, button.
Embodiment 3:
Injection use compound carbetocin Cornocentin
(1) prescription
(2) preparation technology
Take by weighing dextran, the glycine of recipe quantity, add in the water for injection of full dose 90%, adopt 78HW-1 digital display constant temperature blender with magnetic force stirring and dissolving, get solution (1).
Take by weighing 0.1% (W/V) active carbon, join and stir 15min in the above-mentioned medicinal liquid (1), cross the hourglass filter and take off charcoal, with 0.22um filter membrane fine straining.
Get the associating antioxidant sodium pyrosulfite and the citric acid of recipe quantity, slowly add in 5% the water for injection, stir and make dissolving, solution (2).
Ergometrine and the carbetocin of getting recipe quantity slowly add (2), stir simultaneously to make dissolving fully.
Solution (2) is added solution (1), stir, transfer PH to 4～6.Be settled to scale with water for injection, measure content, confirm loading amount, fill is in cillin bottle.
Get in the LGJ-18 freezer dryer freezing trap freezingly after the sample packing, kept several hours, open vacuum pump and be evacuated to 10pa, near lowest total of the melting point, keep a period of time, the maintenance several hours that heats up, is jumped a queue, outlet, is rolled lid at tamponade.
Embodiment 4:
The oxytocin of injection use compound Cornocentin
(1) prescription
(2) preparation technology
Join adjuvant solution: take by weighing the adjuvants such as lactose, sorbitol of recipe quantity, place the container of sterilizing, add an amount of water for injection, stir and dissolving after, add needle-use activated carbon, stir, take off charcoal, the aseptic filter membrane fine straining of 0.22um with filter membrane through sterilization;
Add antioxidant: the composite antioxidant of weighing recipe quantity adds above-mentioned filtrating of taking off behind the charcoal, and makes it to dissolve fully;
The preparation principal agent: the principal agent composition that takes by weighing recipe quantity adds wherein, fully stirs and makes dissolving, transfers PH, adds the injection water to scale;
The degerming lyophilizing: the filtering with microporous membrane degerming, measure content, be sub-packed in the cillin bottle by the loading amount requirement, send into the freezer dryer lyophilizing, add a cover, labelling promptly gets.
Embodiment 5:
Injection use compound Cornocentin oxytocin (aseptic subpackaged)
(1) prescription
(2) preparation technology
Take by weighing the aseptic rank oxytocin of recipe quantity, be sub-packed in cillin bottle behind Cornocentin, sorbitol, lactose Vit C, the tartaric acid mixing, promptly get.
The personnel of pharmaceutical field should be appreciated that the present invention can not only limit to specific embodiment described herein, and can carry out various changes and modification and the essence of the present invention and the scope that do not exceed claim and limited to it.
Claims (13)
1. a pharmaceutical composition is characterized in that being made up of acceptable carrier or excipient, antioxidant and collaborative antioxidant, PH regulator, solubilizing agent in oxytocin analog and ergometrine or its pharmaceutically acceptable salt and the preparation process.
2. according to claims 1 described pharmaceutical composition, the oxytocin analog can be selected from oxytocin, carbetocin or nacartocin, cargutocin etc.
3. pharmaceutical composition according to claim 1, ergometrine pharmaceutically acceptable salt are selected from ergometrine maleate, ergometrine benzene sulfonate, ergometrine arginine salt, ergometrine mesylate, methylergometrine malate.
4. pharmaceutical composition according to claim 2 is characterized in that, the content of oxytocin is 1～20 unit (IU) in the described compositions.
5. pharmaceutical composition according to claim 4, wherein oxytocin content is preferably 5～10 units (IU).
6. pharmaceutical composition according to claim 3 is characterized in that, the content in ergometrine ergometrine pharmaceutically acceptable salt in the described compositions is 0.10mg～5.00mg.
7. pharmaceutical composition according to claim 6, wherein the content in ergometrine ergometrine pharmaceutically acceptable salt is preferably 0.25mg～1.00mg.
8. pharmaceutical composition according to claim 1; Must contain the composite antioxidant composition of being made up of antioxidant and synergist and just can reach the steady statue to heat and oxygen, its specific antioxidant that contains is selected from one or more in sodium sulfite, sodium pyrosulfite, sodium sulfite, sodium thiosulfate or amino acids, vitamin C, dibutyl phenol, the butylated hydroxyarisol.
9. pharmaceutical composition according to claim 8, its antioxidant content are 0.01mg～0.50mg.
10. pharmaceutical composition according to claim 1, the composite antioxidant that it contained select for use collaborative antioxidant comprise: one or more of citric acid, citric acid, tartaric acid etc.
11. pharmaceutical composition according to claim 10, its collaborative antioxidant content is 0.01mg～0.50mg.
12. pharmaceutical preparation according to claim 1; Its acceptable carrier or excipient are selected from: mannitol, lactose, inositol, glucosan, glycine, dextran, sorbitol, L cysteine, the PH regulator is selected from: one or more in citric acid, lactic acid, sodium hydroxide, sodium citrate, the sodium bicarbonate.
13., it is characterized in that according to the described pharmaceutical composition of claim 1～12, on the basis that has added a certain amount of antioxidant and collaborative antioxidant composition, adopt lyophilizing or sterile packaged preparation technology, can significantly reduce related substance and produce, increase stability.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104189886A (en) * | 2014-09-22 | 2014-12-10 | 南京济群医药科技有限公司 | Compound drug composition for delivery and application of compound drug composition |
| CN105055361A (en) * | 2015-08-19 | 2015-11-18 | 河北智同医药控股集团有限公司 | Methyl ergometrine maleate tablets and preparation method thereof |
| WO2016053092A1 (en) * | 2014-10-01 | 2016-04-07 | Oxytone Bioscience B.V. | Orally disintegrating solid pharmaceutical dosage unit containing a partus control substance |
| CN107106640A (en) * | 2014-10-01 | 2017-08-29 | 奥克希托恩生物科学公司 | Oral solid pharmaceutical dosage unit containing birth control device |
| CN109172530A (en) * | 2018-11-23 | 2019-01-11 | 南京新百药业有限公司 | Pharmaceutical composition and preparation method thereof containing oxytocin |
| CN110308222A (en) * | 2019-07-17 | 2019-10-08 | 武汉赛沃医药科技有限公司 | A kind of related substance detecting method of carbetocin bulk pharmaceutical chemicals |
| CN114712483A (en) * | 2022-05-12 | 2022-07-08 | 成都倍特药业股份有限公司 | Ergometrine compound injection and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0784475B1 (en) * | 1994-09-27 | 2001-01-17 | University College London | Prostagladin analogues by the oral or vaginal route for the routine management of the third stage of labour |
| CN102144965A (en) * | 2010-10-29 | 2011-08-10 | 深圳市健元医药科技有限公司 | More-stable carbetocin acetate injection |
-
2012
- 2012-03-14 CN CN201210066098.1A patent/CN102580057B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0784475B1 (en) * | 1994-09-27 | 2001-01-17 | University College London | Prostagladin analogues by the oral or vaginal route for the routine management of the third stage of labour |
| CN102144965A (en) * | 2010-10-29 | 2011-08-10 | 深圳市健元医药科技有限公司 | More-stable carbetocin acetate injection |
Non-Patent Citations (1)
| Title |
|---|
| COOK MSC ET AL: "A Randomized Clinical Trial Comparing Oral Misoprostol With Synthetic Oxytocin or Syntometrine in the Third Stage of Labour", 《AUST NZ J OBSTET GYNAECOL》, vol. 39, no. 4, 31 December 1999 (1999-12-31), pages 414 - 419 * |
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