CN106075393A - A kind of isophthalic oxytocin injection and preparation method thereof - Google Patents
A kind of isophthalic oxytocin injection and preparation method thereof Download PDFInfo
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- CN106075393A CN106075393A CN201610404804.7A CN201610404804A CN106075393A CN 106075393 A CN106075393 A CN 106075393A CN 201610404804 A CN201610404804 A CN 201610404804A CN 106075393 A CN106075393 A CN 106075393A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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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
- 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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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
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Abstract
The invention provides a kind of isophthalic oxytocin injection, Main Ingredients and Appearance is: oxytocin, 0.2g containing phloroglucin comprise water for injection 100ml in every 100ml, for induced labor, hasten parturition, postpartum and post-abortion answer uterine hemorrhage that is bad and that cause because of uterine atony or contracting.The invention also discloses the preparation method of a kind of isophthalic oxytocin injection, its quality meets that " notice with regard to issuing chemicals injection and multicomponent Biochemical Drugs injection main technique requirements " specify, smooth muscle spasm, oedema can be released, make the elastic increase of uterine neck, it is easy to expansion, make both drug effect synergies.
Description
Technical field
The present invention relates to pharmaceutical field, particularly relate to chemicals injection.
Background technology
Oxytocin (Oxytocin), is also called oxytocins, be a kind of that be made up of 9 amino acid residues, there is biological living
The polypeptide amino acid product of property.
Oxytocin injection is peptide hormone uterotonics, stimulates uterine myometrium, simulates eutocous
Uterine contractile effect, causes cervical dilatation, and the reaction to oxytocin for the uterus is gradually increased in During Pregnancy, reaches height when mature
Peak, stings mammotropic smooth muscle contraction, contributes to milk and freely stitches eliminating, but does not increase the amount of milk secretion of mammary gland.Isophthalic
Triphenol can directly act on the smooth muscle of intestines and stomach and urogenital tract, is parent's flesh, non-atropine, non-opium poppy bases smooth muscle
Antispasmodic.It compared with other smooth muscle spasmolysis medicines, is characterized in not having cholinolytic effect, releasing the same of smooth muscle spasm
When, a series of cholinolytic sample side effect will not be produced, the symptoms such as low blood pressure, increased heart rate, arrhythmia cordis will not be caused, to painstaking effort
Pipe function does not affect.All intramuscular injection, quiet push away, patient that intravenous infusion is administered, long-term or high dose compliance is good.Nowadays, I
In phloroglucinol injection add oxytocin injection composition, to further up to release smooth muscle spasm, oedema, make
Uterine neck is elastic to be increased, it is easy to expansion, makes both work in coordination with.
Content of the invention
The present invention is applied to chemicals injection.The purpose of the present invention uses method below to be achieved.
A kind of isophthalic-oxytocin injection, its chemical constitution is the peptide chain of 9 amino acid compositions containing disulfide bond, bag
Containing following component: every 10000ml parenteral solution includes: oxytocin solution 100ml；0.2g containing phloroglucin；Water for injection adds to
10000ml；Wherein, 1ml parenteral solution contains 10 unit oxytocin solution Main Ingredients and Appearances and is: oxytocin, contains isophthalic three in every 100ml
Phenol 0.2g simultaneously comprises water for injection 100ml, consists of H-Cys-Tyr-Ile-Glu (NH2)-Asp (NH2)-Cys-Pro-Leu-
Gly-NH2, molecular formula: C43H66N12O12S2, for induced labor, hasten parturition, postpartum and post-abortion because of uterine atony or contracting multiple bad
And the uterine hemorrhage causing.
The purpose of the present invention realizes also by following manner.
The preparation method of a kind of isophthalic-oxytocin injection, comprises the steps:
(1) for raw material, resorcinol is placed in reaction vessel with resorcinol, adds reaction dissolvent to dissolve, dissolve
After be added drop-wise to bromo-succinimide solution in reaction vessel, control time for adding is about half an hour, and temperature is controlled in half
Between hour to three hours, after reactant liquor pretreatment, obtain bromine resorcinol；
(2) solid obtaining step (1) adds in reaction vessel, is subsequently adding reaction dissolvent, highly basic and catalyst,
It is warming up to 140 DEG C, take backflow manipulation 6 hours, after reaction, product is cooled to less than 60 DEG C, and adds aqueous solvent to stir
It is cooled to room temperature, filter and remove catalyst, stratification, take aqueous phase after layering, phloroglucin mixed salt solution can be obtained；
(3) intermediate a, b, i.e. Boc-C*s-T*r-Ile-G*n-OH and H-A*n-C* are prepared respectively
S-Pro-Leu-Gly-NH, in preparation process, employing 3-(diethoxy phosphoryl oxy)-1,2,3-phentriazines-
4-ketone is as condensing agent；With azido diphenyl phosphate as condensing agent, at DMF, DPPA, dioxane, piperidines, TFA and DCM
Under conditions of existence, reacting with intermediate a and intermediate b, controlling reaction temperature-20～40 DEG C, reaction 10～40 is little
When, it is being passed through after air oxidation reaction completes, the solvent in vacuum dried removing reaction system, obtain oxytocin；
(4) under step (2) gained variable concentrations, phloroglucin salting liquid and gained oxytocin premix in step 3 enter anti-
Answering in container, being added to the water fully dissolving, institute's amount of water is 3-5 times of solute, is warming up to 100 DEG C, adds activated carbon after dissolving
Backflow decolouring, is that 0.5-0.8mol/L hydrochloric acid regulates its pH value to 1-3 by concentration respectively, after carry out heat filtering, filtrate is naturally cold
But crystallization, separates out solid, filters to obtain crude product under the conditions of this.
(5) variable concentrations isophthalic-oxytocin can be obtained after the steps such as crude product carries out re-dissolved, decolouring, cooling, cleaning, drying
Injection products.
Preferably, the ratio of resorcinol and the reaction dissolvent addition therebetween of variable concentrations distribution in step (1)
It can be 1:3 group；1:5 group or 1:6 group, i.e. 1g:3ml；1g:5ml or 1g:6ml.
Preferably, in step (1), bromo-succinimide solution and reaction dissolvent ratio are 1:0.8；1:1 or 1:1.2.
Preferably, in step (1), resorcinol and bromo-succinimide solution proportion are 1:1.5；1:1.6 or 1:1.8.
Preferably, the raw material according to gained variable concentrations in described step (1), the phloroglucin salt that can obtain variable concentrations is molten
Liquid, it is preferred that concentration is 1.02mol/L, 1.1mol/L or 1.15mol/L.
The positive effect of the present invention: it is " chemical with regard to issuing that the parenteral solution of offer can guarantee that oxytocin injection quality meets
Drug injection agent and the notice of multicomponent Biochemical Drugs injection main technique requirements " specify, smooth muscle convulsion can be released simultaneously
Contraction, oedema, make the elastic increase of uterine neck, it is easy to expansion, makes both drug effects synergies.
Detailed description of the invention
The invention discloses a kind of isophthalic-oxytocin injection and preparation method thereof, those skilled in the art can use for reference
Present disclosure, is suitably modified technological parameter and realizes.Special needs to be pointed out is, all similar replacements and change are to this area skill
Being apparent from for art personnel, they are considered as within the scope of the present invention.The method of the present invention and application are
Through being described by preferred embodiment, related personnel substantially can be to this in without departing from present invention, spirit and scope
Methods and applications described in Wen are modified or suitably change and combination, realize and apply the technology of the present invention.
Isophthalic-contracting palace parenteral solution that the present invention provides and preparation thereof, raw materials used medicine or auxiliary material all can be by preparation method
Market is buied.
Below in conjunction with embodiment, the present invention is expanded on further: control variable concentrations raw material distribution is the main of the present invention
Feature, will systematically discuss below and prepare phloroglucin and oxytocin under concentration control and temperature control.
A kind of isophthalic-oxytocin injection, its chemical constitution is the peptide chain of 9 amino acid compositions containing disulfide bond, bag
Containing following component: every 10000ml parenteral solution includes: oxytocin solution 100ml；0.2g containing phloroglucin；Water for injection adds to
10000ml；Wherein, 1ml parenteral solution contains 10 unit oxytocin solution, consists of H-Cys-Tyr-Ile-Glu (NH2)-Asp
(NH2)-Cys-Pro-Leu-Gly-NH2, molecular formula: C43H66N12O12S2, for induced labor, hasten parturition, postpartum and post-abortion because of
Uterine atony or the uterine hemorrhage that is multiple bad and that cause that contracts；Understand placenta reserve function by oxytocin challenge test (OCT).
The preparation method of a kind of isophthalic-oxytocin injection, comprises the steps:
(1) for raw material, resorcinol is placed in reaction vessel with resorcinol, adds reaction dissolvent to dissolve, dissolve
After be added drop-wise to bromo-succinimide solution in reaction vessel, control time for adding is about half an hour, and temperature is controlled in half
Between hour to three hours, after reactant liquor pretreatment, obtain bromine resorcinol；Preferably, variable concentrations distribution resorcinol with
The ratio of reaction dissolvent addition therebetween can be 1:3 group；1:5 group；1:6 group, i.e. 1g:3ml；1g:5ml；1g:6ml, bromo
Succimide solution and reaction dissolvent ratio are 1:0.8；1:1；1:1.2, resorcinol and bromo-succinimide solution ratio
Example is 1:1.5；1:1.6；1:1.8；
(2) solid obtaining step (1) adds in reaction vessel, is subsequently adding reaction dissolvent, highly basic and catalyst,
It is warming up to 140 DEG C, take backflow manipulation 6 hours, after reaction, product is cooled to less than 60 DEG C, and adds aqueous solvent to stir
It is cooled to room temperature, filter and remove catalyst, stratification, take aqueous phase after layering, phloroglucin mixed salt solution can be obtained, according to step
(1) raw material of gained variable concentrations in, can obtain the phloroglucin salting liquid of variable concentrations, it is preferred that concentration is 1.02mol/L,
1.1mol/L or 1.15mol/L；
(3) intermediate a, b, i.e. Boc-C*s-T*r-Ile-G*n-OH and H-A*n-C* are prepared respectively
S-Pro-Leu-Gly-NH, in preparation process, employing 3-(diethoxy phosphoryl oxy)-1,2,3-phentriazines-
4-ketone is as condensing agent；With azido diphenyl phosphate as condensing agent, at DMF, DPPA, dioxane, piperidines, TFA and DCM
Under conditions of existence, reacting with intermediate a and intermediate b, controlling reaction temperature-20～40 DEG C, reaction 10～40 is little
When, it is being passed through after air oxidation reaction completes, the solvent in vacuum dried removing reaction system, obtain oxytocin；
(4) under step (2) gained variable concentrations, phloroglucin salting liquid and gained oxytocin premix in step 3 enter anti-
Answering in container, being added to the water fully dissolving, institute's amount of water is 3-5 times of solute, is warming up to 100 DEG C, adds activated carbon after dissolving
Backflow decolouring, is that 0.5-0.8mol/L hydrochloric acid regulates its pH value to 1-3 by concentration respectively, after carry out heat filtering, filtrate is naturally cold
But crystallization, separates out solid, filters to obtain crude product under the conditions of this.
(5) variable concentrations isophthalic-oxytocin can be obtained after the steps such as crude product carries out re-dissolved, decolouring, cooling, cleaning, drying
Injection products.
Take 3 kinds of variable concentrations isophthalic-contracting palace product, every part of 1ml, do following process respectively:
We are existing is divided into 3 parts of experimental group and 1 part of control group, and close observation in clinical stages of labor by 192 case childbirths,
Being embodied within the following manner, test result indicate that, isophthalic-contracting palace product can ease the pain, and shortens first stage of labor, and does not affects
Postpartum hemorrhage amount and neonatal Apgar score.
According to above-mentioned clinical testing data feedback, under strict controlled temperature conditions, we are by the resorcinol of variable concentrations distribution
Ratio control with reaction dissolvent addition therebetween is 1:5 group, i.e. 1g:5ml, and bromo-succinimide solution is molten with reaction
Agent ratio is 1:1, and resorcinol and bromo-succinimide solution proportion are 1:1.6, can obtain isophthalic-contracting palace concentration under the conditions of this
For 1.1mol/L, being applied to curative effect in clinic good, side effect is little.
Claims (6)
1. isophthalic-oxytocin injection, it is characterised in that comprise following component:
Every 10000ml parenteral solution includes:
Oxytocin solution 100ml
0.2g containing phloroglucin
Water for injection adds to 10000ml
Wherein, 1ml parenteral solution contains 10 unit oxytocin solution.
2. a preparation method for isophthalic-oxytocin injection as claimed in claim 1, comprises the steps:
(1) for raw material, resorcinol is placed in reaction vessel with resorcinol, adds reaction dissolvent to dissolve, will after dissolving
Bromo-succinimide solution is added drop-wise in reaction vessel, and control time for adding is about half an hour, and temperature is controlled in half an hour
Between three hours, after reactant liquor pretreatment, obtain bromine resorcinol；
(2) solid obtaining step (1) adds in reaction vessel, is subsequently adding reaction dissolvent, highly basic and catalyst, heats up
To 140 DEG C, take backflow manipulation 6 hours, after reaction, product is cooled to less than 60 DEG C, and add aqueous solvent stirring cooling
To room temperature, filter and remove catalyst, stratification, take aqueous phase after layering, phloroglucin mixed salt solution can be obtained；
(3) intermediate a, b, i.e. Boc-C*s-T*r-Ile-G*n-OH and H-A*n-C*s-are prepared respectively
Pro-Leu-Gly-NH, in preparation process, uses 3-(diethoxy phosphoryl oxy)-1,2,3-phentriazine-4-
Ketone is as condensing agent；With azido diphenyl phosphate as condensing agent, exist at DMF, DPPA, dioxane, piperidines, TFA and DCM
Under conditions of, react with intermediate a and intermediate b, control reaction temperature-20～40 DEG C, react 10～40 hours,
It is passed through after air oxidation reaction completes, the solvent in vacuum dried removing reaction system, obtain oxytocin；
(4) under step (2) gained variable concentrations, phloroglucin salting liquid and gained oxytocin premix in step 3 enter reaction appearance
In device, being added to the water fully dissolving, institute's amount of water is 3-5 times of solute, is warming up to 100 DEG C, adds activated carbon backflow after dissolving
Decolouring, is that 0.5-0.8mol/L hydrochloric acid regulates its pH value to 1-3 by concentration respectively, after carry out heat filtering, filtrate cools down analysis naturally
Crystalline substance, separates out solid, filters to obtain crude product under the conditions of this.
(5) variable concentrations isophthalic-oxytocin injection can be obtained after the steps such as crude product carries out re-dissolved, decolouring, cooling, cleaning, drying
Liquid product.
3. preparation method according to claim 2, it is characterised in that: the resorcinol of variable concentrations distribution in step (1)
Ratio with reaction dissolvent addition therebetween can be 1:3 group；1:5 group or 1:6 group, i.e. 1g:3ml；1g:5ml or 1g:6ml.
4. preparation method according to claim 2, it is characterised in that: in step (1) bromo-succinimide solution with anti-
Solvent ratios is answered to be 1:0.8；1:1 or 1:1.2.
5. preparation method according to claim 2, it is characterised in that: in step (1), resorcinol is sub-with bromo succinyl
Amine aqueous solution ratio is 1:1.5；1:1.6 or 1:1.8.
6. the preparation method according to right wants 3-5, it is characterised in that: according to gained variable concentrations in described step (1)
Raw material, can obtain the phloroglucin salting liquid of variable concentrations, it is preferred that concentration is 1.02mol/L, 1.1mol/L or 1.15mol/L.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610404804.7A CN106075393A (en) | 2016-06-11 | 2016-06-11 | A kind of isophthalic oxytocin injection and preparation method thereof |
| PCT/CN2016/093515 WO2017210989A1 (en) | 2016-06-11 | 2016-08-05 | Phloroglucinol-oxytocin injection and preparation method therefor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610404804.7A CN106075393A (en) | 2016-06-11 | 2016-06-11 | A kind of isophthalic oxytocin injection and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN106075393A true CN106075393A (en) | 2016-11-09 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610404804.7A Pending CN106075393A (en) | 2016-06-11 | 2016-06-11 | A kind of isophthalic oxytocin injection and preparation method thereof |
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| WO (1) | WO2017210989A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101235081A (en) * | 2008-03-10 | 2008-08-06 | 无锡市凯利药业有限公司 | Method for preparing oxytocin |
| CN103641687A (en) * | 2013-11-30 | 2014-03-19 | 开封明仁药业有限公司 | Preparation method of phloroglucinol |
-
2016
- 2016-06-11 CN CN201610404804.7A patent/CN106075393A/en active Pending
- 2016-08-05 WO PCT/CN2016/093515 patent/WO2017210989A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101235081A (en) * | 2008-03-10 | 2008-08-06 | 无锡市凯利药业有限公司 | Method for preparing oxytocin |
| CN103641687A (en) * | 2013-11-30 | 2014-03-19 | 开封明仁药业有限公司 | Preparation method of phloroglucinol |
Non-Patent Citations (3)
| Title |
|---|
| 周金枝: "注射用间苯三酚联合缩宫素在产妇产程中的作用", 《实用临床医学》 * |
| 唐春艳: "间苯三酚联合缩宫素对产程的影响观察", 《中国当代医药》 * |
| 郑兴宗: "产程活跃期应用间苯三酚联合缩宫素的疗效观察", 《全科医学临床与教育》 * |
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| WO2017210989A1 (en) | 2017-12-14 |
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