CN102580057B - 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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- CN102580057B CN102580057B CN201210066098.1A CN201210066098A CN102580057B CN 102580057 B CN102580057 B CN 102580057B CN 201210066098 A CN201210066098 A CN 201210066098A CN 102580057 B CN102580057 B CN 102580057B
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- ergometrine
- oxytocin
- antioxidant
- content
- injection
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- 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
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 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
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
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- 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
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- -1 ergometrine arginine salt Chemical class 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 prevention and treat postpartum hemorrhage and the management of the activity of childbirth phase III causing because uterine contraction is weak and the pharmaceutical composition that contributes to functional recovery in puerperal, belong to medical technical field.
Background technology
Oxytocin is mainly used in induced labor, antenatal inertia of uterus, postpartum hemorrhage and subinvolution of uterus clinically.
Oxytocin can indirect stimulation uterine myometrium, simulates eutocous uterine contraction effect, causes cervical dilatation, and uterus increases in During Pregnancy gradually to the reaction of oxytocin, reaches peak when mature.Can also sting mammotropic smooth muscle contraction, contribute to milk to discharge from breast, but not increase the galactopoiesis amount of mammary gland.
The special construction of oxytocin serotonergic neuron on dissecting makes oxytocin have the dual function of hormone and neurotransmitter.The Main Function 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.Maintaining uterus tranquillization or impelling in its contraction, if oxytocin receptor number is less, just need more oxytocin to produce uterine contraction, First Trimester is like this.Latter half of gestation antithesis.This has just formed basis to oxytocin sensitivity in whole During Pregnancy, human body uterus.Oxytocin also can impel uterine contraction by the activation of the calcium channel associated with receptor and the release of sarcoplasmic reticulum calcium.Estrogen can increase the expression of oxytocin gene in rat uterus and people's amniotic membrane, chorion, decidua culture.Thymosin also has certain regulating action to oxytocin, because contain thymus fragment reaction in oxytocin gene, thymosin can make the level of oxytocin in the mrna expression of hypothalamus oxytocin and blood, hypophysis significantly increase.
Much research shows, oxytocin by with oxytocin receptor (oxytocinreceptor, OTR) in conjunction with working.After oxytocin is combined in vitro with oxytocin receptor, stimulate the allos subunit α of G albumen that GTP is hydrolyzed into GDP, and discharge β, γ subunit stimulation phospholipase C, phospholipase is converted into diglyceride and inositoltriphosphoric acid (IP3).Diglyceride stimulatory protein(SP) kinase c is active, and then makes its substrate phosphorylation, causes some reactions of specific cells.IP
3can stimulate Ca
2+by calcium channel, enter the flow of endochylema, these Ca
2+mainly from sarcoplasmic reticulum, but also there are some from extracellular.The calcium increasing can be combined with calmodulin, CaM, stimulates myosin light chain kinase (MLCK) to produce uterine contraction function.In decidua, what the Ca2+ of increase reacted is the synthetic and release of prostaglandin.
The oral very easily digested liquid of oxytocin destroys, and intramuscular injection was onset in 3～5 minutes, and effect continues 30～60 minutes, intravenous drip is onset immediately, and in 15～60 minutes, uterotonic frequency and intensity increase gradually, then stable, after instillation 20 minutes, its effect was decrescence moved back.Half-life is generally 1～6 minute.This product is through liver, kidney metabolism, and through renal excretion, minute quantity is original shape thing.
Carbetocin is for being oxytocin analog, and by Canadian Duratocin, Ferring Inc develops, and import is Chinese.Half-life is 40min, compared with long 4～10 times of oxytocin.Multicenter randomized control clinical trial research external and China all shows, carbetocin (100 μ g intravenous injection) is hemorrhage and oxytocin is effective equally after controlling Selective cesarean section, and the two safety is similar.Its pharmacological action is similar to oxytocin, and the oxytocin receptor of carbetocin on uterine smooth muscle is combined and caused that uterus rhythmicity shrinks and strengthen existing contraction frequency, increases uterus tension force.Quiet note and the onset of intramuscular injection carbetocin are very fast, have uterus active in 2min.Single dose intravenous is injected carbetocin can keep uterine contraction (60 ± 18) min, and (119 ± 69) min that holds time of intramuscular injection, is 4 times that intramuscular injection oxytocin is held time.
Ergometrine is that in Ergota composition, effect is the strongest, and toxic reaction minimum a kind of, 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 be oppressed and stop blooding, in the sensitivity increase of Dui Suo palace, latter half of gestation uterus medicine.Mainly be used in the prevention of puerperal or post-abortion and treatment due to inertia of uterus or contracting multiple bad due to metrorrhagia.For uterus meromorphosis in puerperal, accelerate uterine involution.
When low dose of, its contraction frequency or strength increase, then normally loosen; Dosage strengthens uterine contraction to be strengthened and extends, and resting tension improves, and even forms and continues to shrink.Hypomere and palace body muscle shrink simultaneously, are unfavorable for delivery of baby, therefore can only be 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 with rapid, strong and lasting, can make uterus muscle that tetanic property occurs and shrink, make Placenta Hominis adhere to blood vessel in place's flesh layer and oppressed and stop blooding, shorten third stage of labor and reduce hemorrhage.
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 oral cavity disintegration tablet.
There are clinically at present ergometrine injection and oxytocin inj to use separately respectively.There is people that ergometrine oxytocin is made to compound injection abroad, wherein contain two kinds of medicines of Cornocentin and oxytocin, Papillary has obviously increased synergy, and convenient, its regular size is: 1ml is containing ergometrine 500ug, oxytocin 5 units (IU).Commodity are called Syntometrine, are produced without competition and are sold, in state's listings such as Ireland, Australia, Britain, Malaysia, South Africa and New Zealand by Novartis Co.,Ltd.This compound preparation combines the advantage of the rapid-action and ergometrine long action time of oxytocin, and the slight vasodilatory effect of oxytocin has relaxed the contracting blood vessel function that ergometrine causes.The system evaluation of Cochrane is thought, compare with the traditional oxytocin of application (5IU or 10IU), Syntometrine has reduced the risk of the hemorrhage postpartum hemorrhage at 500～1000mL, but the hemorrhage risk over 1000mL is at the comparing difference not statistically significant of two groups.
Syntometrine combines the quick uterotropic effect of oxytocin, and oxytocin is discharged by 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) occurs will be much smaller than independent use ergometrine (about 7 minutes).And only can continue to compare for 1/2-1 hour with independent use oxytocin, Syntometrine can maintain the uterine contraction effect of a few hours.
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 due to any factor, cause cannot intravenous situation under.It for the usage of preventing and treat postpartum hemorrhage is: after Placenta Hominis is discharged, and intramuscular injection 1ml Syntometrine when generation is hemorrhage maybe.If necessary, the injection of 1ml may duplicate injection within being no less than the interval of 2 hours.Integral dose 24 in as a child must be no more than 3ml.Can implement intravenous injection Syntometrine (injecting slowly 0.5-1ml), but not recommend such use.Blood pressure is monitored in suggestion when implementing intravenous injection.
Domestic to apply in the market maximum be folk prescription oxytocin injection, and price is lower, uses very extensive.Ergometrine is being produced because raw material only has Hebei Yi Jia enterprise of Zhang Yao group, and domestic use is also few.
The compound preparation of oxytocin and ergometrine is in intramuscular injection after 2～3 minutes, and uterine contraction comes into effect, and effect continues 3 hours, and quiet note takes effect immediately, and acts on 45 minutes, and the contraction of rhythmicity is sustainable reaches 3 hours.Therefore the two compound recipe has: combine the feature that oxytocin maintenance phase rapid-action and ergometrine is grown, oxytocin is simultaneously owing to there being certain vasodilator effect, strengthened the probability of postpartum hemorrhage, after coupling ergometrine, ergometrine has vasoconstrictive active, can greatly reduce the effect that postpartum hemorrhage and uterus function recover, have clinically than the unrivaled advantage of the independent use of ergometrine.
As mentioned above, China does not also have the aqueous injection of compound recipe oxytocin and ergometrine to go on the market at present.Although having Syntometrine listing abroad, there is more serious defect in this aqueous injection:
In the preparation process of aqueous injection, need the operations such as sterilizing that carry out disinfection.The existing medicine Registration regulations of China and drug evaluation guideline are F to the terminally sterilised specification requirement of small-volume injection
0> 8.Reach such requirement, must carry out the sterilization treatment of 100 ℃ of above temperature requirements, and under this condition of high temperature, oxytocin is owing to be special polypeptide structure, and structure is the peptide chain of 9 aminoacid compositions containing disulfide bond: H-Cys-Tyr-Ile-Glu (NH
2)-Asp (NH
2)-Cys-Pro-Leu-Gly-NH
2, being easy to 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 main manifestations are serious anaphylaxis, feel sick, vomiting and skin Pruritus etc.So this product cannot high temperature sterilize, external what adopt is aseptic filtration degerming technique.
As take the degerming of aseptic filtration method, very harsh to the requirement of working condition, depollution of environment rank and production line automation degree require high, equipment investment is huge, workshop is in strict aseptic isolation, and China does not also have one at present by the aseptic filtration liquid drugs injection production line of FDAHuo European Union Valuation Standard.High, clinical beyond affordability by this explained hereafter cost.
In addition, compound recipe oxytocin and ergometrine aqueous injection are very unstable, it is had relatively high expectations to preservation condition: even adopt filtration sterilization explained hereafter product out, also want lucifuge, 2～8 ℃ of storage and transport, this brings huge inconvenience to clinical use, and production and cost of transportation have limited the clinical practice of this product aqueous injection.
For overcoming above defect, we have developed a kind of stable pharmaceutical composition that contains ergometrine and oxytocin analog on the basis of large quantity research, this kind of 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, oxytocin is responsive to oxygen under high temperature, illumination state, therefore, adds a certain amount of compound antioxygen composition to contribute to increase stability in compositions.
In lyophilized formulations technical process, do not need the condition of high temperature, adopt filtering with microporous membrane technique, workshop only needs regional area to purify, and has avoided high temperature to destroy the impurity of introducing, make the purity of product active substance higher, medicine is deposited and is transported with solid forms, much stable compared with solution state, on this basis, the antioxidant composition adding in 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.There is clinically unrivaled advantage.
Summary of the invention
The present invention has overcome the defect of prior art and a kind of can effectively prevent and treat postpartum hemorrhage and the management of the activity of childbirth phase III causing because uterine contraction is weak and the pharmaceutical composition that contributes to functional recovery in puerperal is provided, compared with prior art, the stability of medicine, effectiveness, safety, ease of use are obviously improved.
Pharmaceutical composition of the present invention, is characterized in that in oxytocin analog and ergometrine or its pharmaceutically acceptable salt and preparation process the adjuvants such as acceptable carrier or excipient, composite antioxidant (antioxidant and collaborative antioxidant form), PH regulator, solubilizing agent form.
Research shows, oxytocin is responsive to oxygen under the condition of high temperature, therefore, adds a certain amount of compound antioxygen composition to contribute to increase stability in compositions, can tolerate room temperature preservation.
Pharmaceutical composition of the present invention, is adding on the basis of a certain amount of antioxidant and collaborative antioxidant composition, adopts lyophilized formulations technique, can greatly reduce related substance and produce, and increases stability.
Freeze-dry process flow process:
The first step: join adjuvant solution: take the adjuvant of recipe quantity, be placed in the container of sterilizing, add appropriate water for injection, after stirring and dissolving, add needle-use activated carbon, stir, use the de-charcoal of filter membrane through sterilizing;
Second step: add antioxidant: weigh the composite antioxidant of recipe quantity, add the filtrate after above-mentioned de-charcoal, and make it to dissolve completely;
The 3rd step: preparation principal agent: the principal agent composition that takes recipe quantity adds wherein, is fully stirred to dissolve, and injects water to scale;
The 4th step: degerming lyophilizing: filtering with microporous membrane degerming, by loading amount requirement, be sub-packed in cillin bottle, send into freezer dryer lyophilizing, add a cover, label and get final product.
It should be noted that: adding of antioxidant must, after the de-charcoal of first step adjuvant solution, be adsorbed antioxidant or collaborative antioxidant composition otherwise active carbon meeting is a large amount of, thereby cause antioxidation effect to decline, and then cause stability decreases.Adding of antioxidant must be before principal agent dissolves, 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 is selected from the 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, in described compositions, the content of oxytocin is 1～20 unit (IU).
Pharmaceutical composition of the present invention, is wherein preferably 5～10 units (IU) with oxytocin content.
Pharmaceutical composition of the present invention, the content of ergometrine ergometrine pharmaceutically acceptable salt of take is 0.10mg～5.00mg.
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 being comprised of antioxidant and synergist and just can reach the steady statue to heat and oxygen, its specific antioxidant containing is selected from one or more in sodium sulfite, sodium pyrosulfite, sodium sulfite, sodium thiosulfate or amino acids, vitamin C, dibutyl phenol, butylated hydroxyarisol.Although the hydro-acupuncture preparation of the pharmaceutical composition that compound recipe contains oxytocin analog and ergometrine is existing listing 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, 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 is 0.01mg～0.50mg.
Pharmaceutical composition of the present invention, its contained composite antioxidant selected 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, during use, can be made into and need concentration vein or intramuscular administration with normal saline or glucose injection.
Pharmaceutical composition of the present invention, the 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, sodium bicarbonate etc.
Any one Pharmaceutical composition the present invention relates to, the pharmaceutical composition of functional recovery in puerperal is managed and contributed to postpartum hemorrhage and the activity of childbirth phase III that can be used for preventing and treatment causes because uterine contraction is weak, and according to the state of an illness, select the Pharmaceutical composition of different unit dose.
Pharmaceutical composition involved in the present invention can be used for human or animal's individuality.
Accompanying drawing explanation
Nothing
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), 10IU/ml/ bottle, Zuellig Pharma company provides, and Novartis company produces;
Test sample A: ergometrine oxytocin inj, simulate external Syntometrine injection formula, not containing antioxidant, adopt aseptic filtration explained hereafter, without high temperature sterilize, process Xianyu Science and Technology Co., Ltd., Nanjing's self-control;
Test sample B: ergometrine oxytocin inj, simulate external Syntometrine injection formula, not containing antioxidant, adopt high temperature sterilize to process, Xianyu Science and Technology Co., Ltd., Nanjing provides;
Test sample C: the oxytocin of injection ergometrine, not containing 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, containing 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, containing 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 related substances determination method:
It is lower that biologic assay is measured sensitivity, operates numerous rope, and the present invention adopts HPLC method:
Assay: measure according to high performance liquid chromatography (pharmacopeia appendix VD).
Chromatographic condition: be filler with octadecyl silane (25cm * 0.46cm, 5 μ m); Take 0.1mol/L sodium dihydrogen phosphate as mobile phase A, water-acetonitrile (1: 1) is Mobile phase B, carry out gradient elution in accordance with the law, get this product and add in right amount mobile phase A to make certain density solution, get 100 μ l sample introductions, detection wavelength is 220nm, record chromatogram, separately get the standard substance of this product, be measured in the same method, by external standard method, in peak area content, obtain.
Determination of related substances method: get test sample appropriate, add mobile phase A and make the solution that contains certain unit concentration in every 1ml, according to content assaying method, in need testing solution chromatogram as aobvious impurity peaks, desolventize outside peak, by area normalization method, calculate maximum single contaminant and total impurities.
10 days illumination study on the stability:
Above-mentioned each test sample is put under the high light of (4500 ± 500Lx) and placed 10 days, measure respectively 0,5,10 day oxytocin content and related substance, and relatively investigate its stability under illumination condition with 0 day result.
Pharmaceutical composition and its injection influence factor (high light 4500 ± 500Lx) result of the test of the injection ergometrine oxytocin of several different prescriptions of table 1
Reference substance: Syntometrine injection (ergometrine oxytocin inj)
Test sample A: ergometrine oxytocin inj,, containing antioxidant, without high temperature sterilize, do not process;
Test sample B: ergometrine oxytocin inj, not containing antioxidant, adopts high temperature sterilize to process;
Test sample C: the oxytocin of injection ergometrine, not containing antioxidant, adopts freeze-dry process preparation;
Test sample D: the oxytocin of injection ergometrine, containing antioxidant, adopts freeze-dry process preparation;
Test sample E: the oxytocin of injection ergometrine, containing antioxidant and collaborative antioxidant, adopts freeze-dry process preparation.
Table 1 result shows, this product is responsive to illumination, and external reference substance is without high-temperature process, similar to the situation of change of self-control test sample A, test sample B is because through high-temperature process, active ingredient is significantly destroyed, investigate impurity variation meaningless, confirmed under the oxytocin condition of high temperature unstable;
The injection preparation that after the degerming of test sample C employing aseptic filtration method, lyophilizing makes, in prescription, do not add any antioxidant, from stability change, in the time of 10 days, compare with reference substance, test sample A, content all declines to some extent, single assorted and all risings to some extent of total impurities, but impurity increasing degree is starkly lower than reference substance and test sample A, illustrate that the prepared test sample medicine of lyophilized formulations technique is in solid state, stability will obviously be better than injection;
In the prescription of test sample D, added antioxidant, in the time of 10 days, content is in a slight decrease, and maximum single contaminant and total impurities slightly raise, and illustrates that antioxidant is effective to guarantor's effect of medicine;
In the prescription of test sample E, not only added antioxidant but also added collaborative antioxidant, protection intensity is larger, and from testing result, content and related substance are almost unchanged.In the time of 10 days, total impurities content more than 10 times, illustrates that pharmaceutical composition of the present invention and prescription thereof, technique are far superior to external reference substance lower than reference substance.
Avoid the factors such as high temperature destruction, solid state storage and associating antioxidant all to play very important effect to product stability.Conclusion based on this research, if pharmaceutical composition of the present invention is prepared into sterile packaged preparation, also can reach the requirement of stability.
Within 6 months, high temperature accelerated stability is investigated:
Through factors influencing, this product is except responsive to illumination, also to responsive to temperature, unstable under the condition of high temperature, therefore Syntometrine injection needs 2～8 ℃ of cryopreservation, for further investigating the long-time stability of sample under different dosage forms and different prescription condition, design experiment is as follows:
Above-mentioned each test sample is put under the high temperature of 40 ± 2 ℃ and placed 6 months, measure respectively 0,1,2,3,6 month oxytocin content and related substance, 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 different prescriptions of table 2 are investigated result
Reference substance: Syntometrine injection (ergometrine oxytocin inj)
Test sample A: ergometrine oxytocin inj,, containing antioxidant, without high temperature sterilize, do not process;
Test sample C: the oxytocin of injection ergometrine, not containing antioxidant, adopts freeze-dry process preparation;
Test sample D: the oxytocin of injection ergometrine, containing antioxidant, adopts freeze-dry process preparation;
Test sample E: the oxytocin of injection ergometrine, containing antioxidant and anti-same antioxidant, adopts freeze-dry process preparation;
Table 2 result shows: 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 60% left and right, and corresponding impurity also produces very significantly, approach 40%, it is also the main cause that causes clinically serious adverse reaction that impurity produces;
Adopt lyophilizing preparation technology's composition for injection C, D, the stability of E to be obviously better than ergometrine oxytocin inj, illustrate under this condition, injection ergometrine oxytocin stability is obviously better than injection; Therefore the injection ergometrine oxytocins that, difference is write out a prescription can tolerate room temperature and preserve for a long time;
A test sample C: though content declines to some extent, total impurities and single mixing also raise to some extent, and amplitude is starkly lower than hydro-acupuncture preparation! Yet, by the limit of Chinese Pharmacopoeia regulation (is singly assortedly not more than 1.5%, total assorted be not more than 5%), still not in acceptability limit, illustrate that not adding antioxidant product does not still reach under long-term room temperature preservation condition and stablize qualified requirement;
Test sample D: content is substantially unchanged, and related substance slightly raises, meets substantially by the limit of pharmacopeia regulation;
Test sample E: content is substantially unchanged, and related substance does not produce substantially, and constant product quality is best.
Embodiment 2:
The oxytocin of injection use compound benzenesulfonic acid ergometrine
(1) prescription
(2) preparation technology
Take recipe quantity mannitol, add the water for injection of 4/5 amount, stir and make to dissolve completely.
Between hydrochloric acid adjust pH 3-8 with 1.0mol/L, then add water for injection to be settled to 1000ml.
Add 0.5～1g active carbon, filtering decarbonization after stirring 15min, adds 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, determine loading amount.
Lyophilizing, lid is filled in, rolled to button.
Embodiment 3:
Injection use compound carbetocin Cornocentin
(1) prescription
(2) preparation technology
Take 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, obtain solution (1).
Take 0.1% (W/V) active carbon, join in above-mentioned medicinal liquid (1) and stir 15min, cross the de-charcoal of hourglass filter, with 0.22um filter membrane fine straining.
Get associating antioxidant sodium pyrosulfite and the citric acid of recipe quantity, slowly add in 5% water for injection, be stirred to dissolve, obtain solution (2).
Ergometrine and the carbetocin of getting recipe quantity slowly add (2), stir and make to dissolve completely simultaneously.
Solution (2) is added to solution (1), stir, adjust PH to 4～6.With water for injection, be settled to scale, measure content, determine loading amount, fill is in cillin bottle.
After sample subpackage, enter in LGJ-18 freezer dryer freezing trap freezingly, keep a few hours, open vacuum pump and be evacuated to 10pa, near lowest total of the melting point, keep a period of time, heat up and keep a few hours, tamponade, jump a queue, outlet, roll lid.
Embodiment 4:
The oxytocin of injection use compound Cornocentin
(1) prescription
(2) preparation technology
Join adjuvant solution: take the adjuvants such as lactose, sorbitol of recipe quantity, be placed in the container of sterilizing, add appropriate water for injection, after stirring and dissolving, add needle-use activated carbon, stir, use the de-charcoal of filter membrane through sterilizing, the aseptic filter membrane fine straining of 0.22um;
Add antioxidant: weigh the composite antioxidant of recipe quantity, add the filtrate after above-mentioned de-charcoal, and make it to dissolve completely;
Preparation principal agent: the principal agent composition that takes recipe quantity adds wherein, is fully stirred to dissolve, and adjusts PH, injects water to scale;
Degerming lyophilizing: filtering with microporous membrane degerming, measure content, by loading amount requirement, be sub-packed in cillin bottle, send into freezer dryer lyophilizing, add a cover, label and get final product.
Embodiment 5:
Injection use compound Cornocentin oxytocin (aseptic subpackaged)
(1) prescription
(2) preparation technology
Take the aseptic rank oxytocin of recipe quantity, Cornocentin, sorbitol, lactose Vit C, tartaric acid are sub-packed in cillin bottle after mixing, and obtain.
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 not exceed the spirit and scope of the invention that claim limits it.
Claims (4)
1. a pharmaceutical composition, is characterized in that composed of the following components: 1) oxytocin or oxytocin analog; 2) ergometrine or its pharmaceutically acceptable salt; 3) acceptable carrier or excipient in preparation process; 4) antioxidant; 5) collaborative antioxidant; 6) pH adjusting agent; 7) solubilizing agent,
Wherein oxytocin analog is selected from carbetocin;
Ergometrine pharmaceutically acceptable salt is selected from ergometrine maleate, ergometrine benzene sulfonate, ergometrine arginine salt, ergometrine mesylate, methylergometrine malate;
Antioxidant is selected from one or more in sodium sulfite, sodium pyrosulfite, sodium sulfite, sodium thiosulfate or vitamin C;
Collaborative antioxidant is selected from citric acid or tartaric acid;
PH adjusting agent is selected from one or more in citric acid, lactic acid, sodium hydroxide, sodium citrate, sodium bicarbonate; Pharmaceutically acceptable carrier or excipient are selected from mannitol, lactose, inositol, glucosan, glycine, dextran, sorbitol or L cysteine;
In compositions, the content of oxytocin is 1～20IU,
Or the content of oxytocin analog is 20IU;
The content of ergometrine ergometrine pharmaceutically acceptable salt of take in compositions is 0.10mg～5.00mg;
In compositions, antioxidant content is 0.01mg～0.50mg;
In compositions, collaborative antioxidant content is 0.01mg～0.50mg.
2. pharmaceutical composition according to claim 1, wherein oxytocin content is 5～10IU.
3. pharmaceutical composition according to claim 1, the content of ergometrine ergometrine pharmaceutically acceptable salt of wherein take is 0.25mg～1.00mg.
4. according to the pharmaceutical composition described in claim 1-3 any one, it is characterized in that, adding on the basis of a certain amount of antioxidant and collaborative antioxidant composition, adopt lyophilizing or sterile packaged preparation technique.
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| PL3200764T3 (en) | 2014-10-01 | 2020-12-28 | Oxytone Bioscience B.V. | Orally disintegrating solid pharmaceutical dosage unit containing a partus control substance |
| JP6607509B2 (en) * | 2014-10-01 | 2019-11-20 | オキシトーン バイオサイエンス ビー．ブイ． | Orally disintegrating solid pharmaceutical dosage unit containing parturition control substances |
| CN105055361B (en) * | 2015-08-19 | 2018-02-23 | 河北智同医药控股集团有限公司 | A kind of methylergonovine maleate tablet and preparation method thereof |
| CN109172530B (en) * | 2018-11-23 | 2021-10-01 | 南京新百药业有限公司 | Medicine composition containing oxytocin and preparation method thereof |
| 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 |
| CN114712483B (en) * | 2022-05-12 | 2023-09-29 | 成都倍特药业股份有限公司 | Ergot neomycin and oxytocin compound injection and preparation method and application thereof |
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