CN102525890A - Milrinone injection and preparation method thereof - Google Patents
Milrinone injection and preparation method thereof Download PDFInfo
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- CN102525890A CN102525890A CN2010105947391A CN201010594739A CN102525890A CN 102525890 A CN102525890 A CN 102525890A CN 2010105947391 A CN2010105947391 A CN 2010105947391A CN 201010594739 A CN201010594739 A CN 201010594739A CN 102525890 A CN102525890 A CN 102525890A
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Abstract
The invention provides milrinone injection and a preparation method thereof and belongs to the technical field of chemical medicine preparations. The milrinone injection adopts one or more of acetic acid, phosphoric acid and sulfuric acid as a pH regulator and adopts glucose as an osmotic pressure regulator. The milrinone injection has a simple and convenient preparation process, high stability, low content of milrinone related substances and a good clinical using effect and is low in cost.
Description
Technical field
The present invention relates to a kind of milrinone injection and preparation method thereof, belong to technical field of medicine.
Background technology
Milrinone (Milrinone) is a kind of cardiac tonic, is phosphodiesterase inhibitor, is the succedaneum of amrinone, but its effect is strong 10～30 times than amrinone, and toleration is better.Milrinone is oral all effective with intravenous injection, but untoward reaction is heavier when oral.Milrinone has positive inotropic action and vasorelaxation action concurrently.Its positive inotropic action mainly is through suppressing phosphodiesterase, interior cyclic adenosine monophosphate (cAMP) concentration of myocardial cell being increased, intracellular Ca2+ increase, myocardial contraction reinforcement, cardiac output increase.Its vasorelaxation action possibly be to directly act on due to the small artery, thereby can reduce the forward and backward load of heart, reduces left ventricular filling pressure, improves left chamber function, increases cardiac index, but mean arterial pressure and heart rate are not had obvious influence.The cardiovascular effect of milrinone is relevant with dosage; Mainly show as positive inotropic action when low dose of, when dosage strengthens, when reaching the maximum positive inotropic effect of stable state gradually; Mainly show as vasorelaxation action, its blood vessel dilating effect also can be strengthened with the increase of dosage gradually.Milrinone is safer to the patient with conduction block.
Milrinone is gone on the market in the Europe and the U.S. in 1989 by the research and development of Sanofi-Aventis company, and its injection formula is milrinone, lactic acid, glucose, water for injection.Wherein, adjuvant lactic raw material cost is higher.
Chinese patent 200710112913.2 discloses a kind of milrinone injection, comprises in the disclosed prescription among the embodiment that principal agent milrinone, isoosmotic adjusting agent sodium chloride, water for injection, pH regulator agent are a kind of in acetic acid, phosphoric acid or the sulphuric acid.This prescription finds that through test sodium chloride is as the isoosmotic adjusting agent of Corotrope with the isoosmotic adjusting agent of sodium chloride as injection, and after placement or high temperature or the illumination, related substance (being impurity) content rises to some extent.
Summary of the invention
The present invention provides a kind of new milrinone injection and preparation method thereof.Milrinone injection preparation technology of the present invention is easy, cost is low, good stability, low, the clinical result of use of milrinone its related substances are good.
Comprise principal agent milrinone, isoosmotic adjusting agent glucose and water for injection in the milrinone injection formula of the present invention, the pH regulator agent is one or more in acetic acid, phosphoric acid and the sulphuric acid.The effect of glucose is as osmotic pressure regulator, is used for osmotic pressure with injection and is adjusted to consistently with the human body osmotic pressure, prevents the damage to human body of hypotonic or hyperosmotic solution.Acetic acid, phosphoric acid or vitriolic effect are as injection pH value regulator, regulate the pH scope between 2.8～4.0.
The concentration range of milrinone in injection is preferably 0.2～1mg/ml, further is preferably 1mg/ml.
The concentration range of glucose in injection is preferably 44.6～49.4mg/ml, further is preferably 47mg/ml.
The method for preparing of milrinone injection according to the invention is milrinone to be dissolved with water for injection, with one or more regulator solution pH value to 2.8～4.0 in acetic acid, phosphoric acid and the sulphuric acid; Dissolve in glucose again; Add injection water standardize solution, mixing, encapsulation sterilization behind the filtering with microporous membrane.
Milrinone injection provided by the present invention has following advantage:
(1) preparation technology is easy;
(2) compare with the milrinone lactate of Sai Nuofei-Sanofi-Aventis's development, Corotrope of the present invention is guaranteeing that cost is lower under the prerequisite that stability is high, its related substances is low;
(3) compare with Chinese patent 200710112913.2, Corotrope of the present invention adopts glucose as isoosmotic adjusting agent, and its related substances is lower, and quality is higher, and stability is better;
(4) clinical easy to use, therapeutic effect is good.
The specific embodiment
Embodiment 1:
Milrinone 5 grams
Acetic acid is an amount of
Glucose 235 grams
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone, add 3 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add glucose, be stirred to complete dissolving, add 5 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, 1000 bottles of fills, sterilization with 0.5M acetic acid regulator solution pH value to 3.5.
Embodiment 2:
Milrinone 1 gram
Acetic acid is an amount of
Glucose 235 grams
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone, add 3 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add glucose, be stirred to complete dissolving, add 5 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, fill, sterilization with 0.5M acetic acid regulator solution pH value to 3.0.
Embodiment 3:
Milrinone 5 grams
Acetic acid is an amount of
Glucose 223 grams
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone, add 3 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add glucose, be stirred to complete dissolving, add 5 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, fill, sterilization with 0.5M acetic acid regulator solution pH value to 4.0.
Embodiment 4:
Milrinone 5 grams
Acetic acid is an amount of
Glucose 247 grams
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone, add 3 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add glucose, be stirred to complete dissolving, add 5 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, fill, sterilization with 0.5M acetic acid regulator solution pH value to 2.8.
Embodiment 5:
Milrinone 5 grams
Phosphoric acid is an amount of
Glucose 235 grams
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone, add 3 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add glucose, be stirred to complete dissolving, add 5 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, 1000 bottles of fills, sterilization with 0.5M phosphoric acid regulator solution pH value to 3.5.
Embodiment 6:
Milrinone 1 gram
Phosphoric acid is an amount of
Glucose 235 grams
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone, add 3 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add glucose, be stirred to complete dissolving, add 5 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, fill, sterilization with 0.5M phosphoric acid regulator solution pH value to 3.0.
Embodiment 7:
Milrinone 5 grams
Phosphoric acid is an amount of
Glucose 223 grams
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone, add 3 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add glucose, be stirred to complete dissolving, add 5 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, fill, sterilization with 0.5M phosphoric acid regulator solution pH value to 4.0.
Embodiment 8:
Milrinone 5 grams
Phosphoric acid is an amount of
Glucose 247 grams
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone, add 3 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add glucose, be stirred to complete dissolving, add 5 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, fill, sterilization with 0.5M phosphoric acid regulator solution pH value to 2.8.
Embodiment 9:
Milrinone 5 grams
Sulphuric acid is an amount of
Glucose 235 grams
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone, add 3 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add glucose, be stirred to complete dissolving, add 5 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, 1000 bottles of fills, sterilization with 0.5M sulfuric acid regulation solution pH value to 3.5.
Embodiment 10:
Milrinone 1 gram
Sulphuric acid is an amount of
Glucose 235 grams
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone, add 3 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add glucose, be stirred to complete dissolving, add 5 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, fill, sterilization with 0.5M sulfuric acid regulation solution pH value to 3.0.
Embodiment 11:
Milrinone 5 grams
Sulphuric acid is an amount of
Glucose 223 grams
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone, add 3 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add glucose, be stirred to complete dissolving, add 5 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, fill, sterilization with 0.5M sulfuric acid regulation solution pH value to 4.0.
Embodiment 12:
Milrinone 5 grams
Sulphuric acid is an amount of
Glucose 247 grams
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone, add 3 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add glucose, be stirred to complete dissolving, add 5 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, fill, sterilization with 0.5M sulfuric acid regulation solution pH value to 2.8.
The comparative study of milrinone injection of the present invention and Chinese patent 200710112913.2 milrinone injection:
1, EXPERIMENTAL DESIGN: milrinone injection of the present invention (comprises milrinone, glucose, water for injection; Also contain a kind of in acetic acid, phosphoric acid or the sulphuric acid or several) (comprise milrinone, sodium chloride, water for injection with Chinese patent 200710112913.2 milrinone injection; Also contain a kind of in acetic acid, phosphoric acid or the sulphuric acid or several) after supplementary material prepares by recipe quantity; With each sample 60 ℃ of high temperature or 4500LX illumination condition held 10 days, respectively at its related substances of measuring each sample in 0,5,10 day.
2, assay method:
The mensuration of related substance: measure according to HPLC (two appendix VD of Chinese Pharmacopoeia version in 2010 method).
Chromatographic condition: with octyl silane group silica gel is filler; With phosphoric acid hydrogen dimethylamino solution (get dipotassium hydrogen phosphate 2.7g, add water 800ml dissolving after, add triethylamine 2.4ml, regulate pH to 7.5 with phosphoric acid)-acetonitrile (volume ratio 80: 20) is a mobile phase, the detection wavelength is 220nm.
Related substance: milrinone related substance A (impurity A) [1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridines)-5-amide]
3, two prescription determination of related substances results relatively: table 1～table 3 is results that the present invention and Chinese patent 200710112913.2 prepared milrinone injection detect related substance after illumination and hot conditions held.
Table 1: the embodiment of the invention 1 and Chinese patent 200710112913.2 embodiment 1 prepared injection contrast
Table 2: the embodiment of the invention 5 and Chinese patent 200710112913.2 embodiment 2 prepared injection contrasts
Table 3: the embodiment of the invention 9 and Chinese patent 200710112913.2 embodiment 3 prepared injection contrasts
Above-mentioned test shows, adopts Corotrope prescription its related substances of the present invention significantly to reduce, and product quality significantly improves.
Claims (8)
1. a milrinone injection is characterized in that, is made up of milrinone, pH regulator agent, glucose and water for injection, and wherein said pH regulator agent is a section in acetic acid, phosphoric acid and the sulphuric acid or multiple.
2. milrinone injection according to claim 1 is characterized in that, the concentration range of said milrinone in injection is 0.2～1mg/ml.
3. milrinone injection according to claim 2 is characterized in that, the concentration of said milrinone in injection is 1mg/ml.
4. milrinone injection according to claim 2 is characterized in that, the concentration of said milrinone in injection is 0.2mg/ml.
5. milrinone injection according to claim 1 is characterized in that, the concentration range of said glucose in injection is 44.6～49.4mg/ml.
6. milrinone injection according to claim 5 is characterized in that, the concentration of said glucose in injection is 47mg/ml.
7. according to any described milrinone injection in the claim 1～6, it is characterized in that the pH value scope of said injection is 2.8～4.0.
8. the method for preparing of any said milrinone injection in the claim 1～6; Milrinone is dissolved with water for injection; With one or more regulator solution pH value to 2.8～4.0 in acetic acid, phosphoric acid and the sulphuric acid, dissolve in glucose again, add injection water standardize solution; Mixing, encapsulation sterilization behind the filtering with microporous membrane.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105947391A CN102525890A (en) | 2010-12-17 | 2010-12-17 | Milrinone injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010105947391A CN102525890A (en) | 2010-12-17 | 2010-12-17 | Milrinone injection and preparation method thereof |
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| CN102525890A true CN102525890A (en) | 2012-07-04 |
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| CN2010105947391A Pending CN102525890A (en) | 2010-12-17 | 2010-12-17 | Milrinone injection and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104739759A (en) * | 2015-04-02 | 2015-07-01 | 海南合瑞制药股份有限公司 | Pharmaceutical composition containing milrinone compound |
| CN108158988A (en) * | 2018-02-27 | 2018-06-15 | 河北化工医药职业技术学院 | The preparation method of Milrinone injection |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1559613A (en) * | 2004-03-10 | 2005-01-05 | 杨喜鸿 | Medicinal invert sugar injection |
| CN1879622A (en) * | 2005-06-13 | 2006-12-20 | 信谊药厂 | Milrinone lyophilized powder for injection and preparation method thereof |
-
2010
- 2010-12-17 CN CN2010105947391A patent/CN102525890A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1559613A (en) * | 2004-03-10 | 2005-01-05 | 杨喜鸿 | Medicinal invert sugar injection |
| CN1879622A (en) * | 2005-06-13 | 2006-12-20 | 信谊药厂 | Milrinone lyophilized powder for injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 刘争建等: "高海拔地区心先安联合米力农治疗心衰伴缓慢心律失常临床观察", 《西南国防医药》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104739759A (en) * | 2015-04-02 | 2015-07-01 | 海南合瑞制药股份有限公司 | Pharmaceutical composition containing milrinone compound |
| CN104739759B (en) * | 2015-04-02 | 2018-03-02 | 海南合瑞制药股份有限公司 | A kind of pharmaceutical composition containing milrinone compound |
| CN108158988A (en) * | 2018-02-27 | 2018-06-15 | 河北化工医药职业技术学院 | The preparation method of Milrinone injection |
| CN108158988B (en) * | 2018-02-27 | 2021-03-23 | 河北化工医药职业技术学院 | Preparation method of milrinone injection |
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Application publication date: 20120704 |
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