CN103655562A - Stable milrinone medicament composition for injection - Google Patents
Stable milrinone medicament composition for injection Download PDFInfo
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- CN103655562A CN103655562A CN201210363429.8A CN201210363429A CN103655562A CN 103655562 A CN103655562 A CN 103655562A CN 201210363429 A CN201210363429 A CN 201210363429A CN 103655562 A CN103655562 A CN 103655562A
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Abstract
The invention discloses a novel stable milrinone medicament composition for treating congestive heart-failure, and a preparation method of the milrinone medicament composition. The milrinone medicament composition consists of milrinone, cysteine hydrochloride, sodium calcium edentate and water for injection. The medicament composition disclosed by the invention is high in stability, simple in preparation process, convenient in clinical application and easy to achieve industrial implementation.
Description
Technical field
The present invention relates to the medicine in field of medicaments, especially relate to milrinone pharmaceutical composition of a kind of injection and preparation method thereof.
Background technology
Common name: milrinone
English name: Milrinone;
Chemical name is: 2-methyl-6-oxygen-1,6-dihydro-[3,4 ' two pyridines]-5 formonitrile HCNs;
Molecular formula: C
12h
9n
3o;
Molecular weight: 211.22;
Pharmacological action: this product is phosphodiesterase inhibitor, is the similar drugs of amrinone, and the mechanism of action is identical with amrinone.Oral and quiet note is all effective, has positive inotropic action and vasorelaxation action concurrently.But its effect is strong 10～30 times compared with amrinone.Toleration is better.This product positive inotropic action is mainly by suppressing phosphodiesterase, makes cyclic adenosine monophosphate (cAMP) Enrichment in myocardial cell, and intracellular Ca2+ increases, and myocardial contraction is strengthened, and cardiac output increases.And it is irrelevant with epinephrine β1receptor or myocardial cell Na+, K+-ATP enzyme.Its vasorelaxation action may be to directly act on due to 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 had no significant effect.The cardiovascular effect of milrinone is relevant with dosage, and when low dose of, main manifestations is positive inotropic action, and when dosage strengthens, while reaching gradually the maximum positive inotropic effect of stable state, its blood vessel dilating effect also can be strengthened gradually with the increase of dosage.
Pharmacokinetics: intravenously administrable rises and comes into force for 5～15 minutes, removing the half-life is 2～3 hours.Protein binding rate 70%.
Indication: be applicable to acute and chronic intractable congestive heart failure that a variety of causes that Folium Digitalis Purpureae, diuretic, vasodilation are failed to respond to any medical treatment or effect is not good enough is caused.
Usage and dosage: intravenous injection: loading 25～75ug/ ㎏, 5 ~ 10 minutes slow quiet notes, later 0.25～1.0ug/ ㎏ per minute maintains.Every day, maximal dose was no more than 1.13mg/ ㎏.Oral: a 2.5～7.5mg, every day 4 times.
Application number is that the invention of CN200410030826.9 relates to and the invention discloses a kind of milrinone sodium chloride injection for the treatment of congestive heart failure and preparation method thereof, it is characterized in that the content of each component in every 100ml injection is: rice power 15 ~ 30mg; Sodium chloride 830 ~ 920mg; Lactic acid 26 ~ 32mg.In preferred every 100ml injection, the content of each component is: milrinone 20mg; Sodium chloride 872mg; Lactic acid 28mg.
Application number is CN200710112913.2 Milrinone injection of disclosing a kind of new treatment congestive heart failure and preparation method thereof, it is characterized in that it also contains a kind of in acetic acid, phosphoric acid or sulphuric acid, and regulate the pH value scope of injection between 2.8-3.5.It is high that injection provided by the present invention has stability, and preparation technology is simple, the clinical easy to use and good advantage of therapeutic effect.
Application number is CN200710301504.7 hydrochloric acid Milrinone injection of disclosing a kind of new treatment congestive heart failure and preparation method thereof, it is characterized in that containing milrinone, hydrochloric acid, sodium chloride and water for injection, and hydrochloric acid regulates the pH value scope of injection between 2.8-3.5.It is high that injection provided by the present invention has purity, and preparation technology is simple, the clinical easy to use and good advantage of therapeutic effect.
Application number is that CN201010594750.8 discloses a kind of Milrinone injection and preparation method thereof, belongs to chemicals medicine technical field.Milrinone injection of the present invention be take hydrochloric acid as pH adjusting agent, and glucose is osmotic pressure regulator, and its preparation technology is easy, cost is low, good stability, low, the clinical result of use of milrinone its related substances are good.
The inventor is through studying for a long period of time, unexpected discovery, injection milrinone pharmaceutical composition prepared by application cysteine hydrochloride and calcium disodium edetate, good stability, not only successfully solved the problem of the poor stability of milrinone, and production cost reduction, easy to implement, can realize industrialization, remarkable in economical benefits.
Summary of the invention
The first object of the present invention is to provide a kind of milrinone pharmaceutical composition of injection, injection milrinone pharmaceutical composition, and good stability, is better applied to clinically, has more obvious advantage.
The second object of the present invention is to provide the preparation method of the milrinone pharmaceutical composition of injection of the present invention, and the method is simple, easy to implement, can realize industrialization.
For realizing the first object of the present invention, the present invention adopts following technical scheme:
A milrinone pharmaceutical composition for injection, the milrinone pharmaceutical composition described in every 1000, its formula consists of:
Milrinone pharmaceutical composition of the present invention is adopted preparation with the following method:
Get recipe quantity water for injection 90%, temperature, at 75-85 ℃, adds recipe quantity cysteine hydrochloride and calcium disodium edetate, after stirring and dissolving; Record original ph, according to original ph, with 10% CYSTEAMINE HCL acid solution, regulate pH value scope at 2.5-3.0; The milrinone that adds recipe quantity, is stirred to and dissolves completely; To solution, add medicinal charcoal, stir; Sucking filtration, adds water for injection to full dose, and mix homogeneously is measured pH value; Fine straining; Fill; Sterilizing; Lamp inspection; Warehouse-in; Obtain milrinone pharmaceutical composition.
In the present invention, the consumption of described medicinal charcoal is 0.05%.
In the present invention, described stirring is at 50-60 ℃, to stir 30 minutes.
In the present invention, described sterilising conditions is: 121 ℃, 20 minutes.
For realizing the present invention, below to the more detailed elaboration of the present invention:
Traditional milrinone pharmaceutical composition, milrinone is water-soluble hardly, and traditional solubilizing agent and cosolvent can only guarantee the quality of injection short time, and the shelf-life is short, and in industrialization process, production environment requires harshness, for industrialization brings very big inconvenience.
In the present invention, in the stability study process to milrinone solution, find to select a certain amount of cysteine hydrochloride to congratulate calcium disodium edetate, after the pH value of regulator solution, then dissolve milrinone, can effectively make milrinone dissolve rapidly.Through the screening of test recipe and the summary of test data of tens of times, optimized its recipe quantity, not only solved the problem of poor stability, and made product quality more stable.
The milrinone pharmaceutical composition of a kind of injection of the present invention, the milrinone pharmaceutical composition described in every 1000, its formula consists of:
The inventor finds through a large amount of experimental study, and milrinone pharmaceutical composition is above-mentioned while more having apolegamy side, described pharmaceutical composition the best in quality, and stability is best.
Another aspect of the present invention provides the preparation method of milrinone pharmaceutical composition of the present invention, and the method is simple, prepared milrinone pharmaceutical composition good stability.
Preparation method provided by the present invention comprises: get recipe quantity water for injection 90%, temperature, at 75-85 ℃, adds recipe quantity cysteine hydrochloride and calcium disodium edetate, after stirring and dissolving; Record original ph, according to original ph, with 10% CYSTEAMINE HCL acid solution, regulate pH value scope at 2.5-3.0; The milrinone that adds recipe quantity, is stirred to and dissolves completely; To solution, add medicinal charcoal, stir; Sucking filtration, adds water for injection to full dose, and mix homogeneously is measured pH value; Fine straining; Fill; Sterilizing; Lamp inspection; Warehouse-in; Obtain milrinone pharmaceutical composition.
The milrinone pharmaceutical composition making according to the inventive method is through industrial amplification production and study on the stability, proves that product is stable, and through pharmacology, toxicological test, solution is non-stimulated to blood vessel, without anaphylaxis, also without haemolysis, to human body without injury.
In preparation method of the present invention, the consumption of described medicinal charcoal is 0.05%.
In preparation method of the present invention, described stirring is at 50-60 ℃, to stir 30 minutes.
In preparation method of the present invention, sterilising conditions is: 121 ℃, 20 minutes.
Add appropriate medicinal charcoal can improve the clarity of solution, can adsorb thermal source, pigment again, medicinal charcoal there is no absorption to milrinone, and the inventor adopts UV-VIS spectrophotometry to measure the content of milrinone, has investigated medicinal charcoal, temperature, the impact of adsorption time on milrinone content in injection.Result shows, medicinal charcoal consumption is 0.1%, and adsorption time was at 30 minutes, and adsorption temp is at 50-60 ℃, and best results, is shown in test example.
Compared with prior art, tool of the present invention has the following advantages:
1) new milrinone compositions provided by the present invention has thoroughly solved milrinone stability problem.
2) milrinone pharmaceutical composition provided by the present invention has improved the yield of this product, the market risk of reduction product, and being better applied to clinical treatment has very large help.
3) new milrinone compositions provided by the present invention, through industrialized great production and study on the stability, proves constant product quality, and through pharmacology, toxicological test, solution is non-stimulated to blood vessel, without anaphylaxis, also without haemolysis, to human body without injury.
4) preparation method of new milrinone compositions provided by the present invention, the method is simple, prepared milrinone pharmaceutical composition good stability.
The specific embodiment
Below in conjunction with embodiment, the present invention is described in further detail
Embodiment 1
Milrinone pharmaceutical composition described in every 1000, its formula consists of:
Preparation technology: get recipe quantity water for injection 90%, temperature, at 75-85 ℃, adds recipe quantity cysteine hydrochloride and calcium disodium edetate, after stirring and dissolving; Record original ph, according to original ph, with 10% CYSTEAMINE HCL acid solution, regulate pH value scope at 2.5-3.0; The milrinone that adds recipe quantity, is stirred to and dissolves completely; To solution, add 0.05% medicinal charcoal, stir; Sucking filtration, adds water for injection to full dose, and mix homogeneously is measured pH value; Fine straining; Fill; Sterilizing; Lamp inspection; Warehouse-in; Obtain milrinone pharmaceutical composition.
Test example 1
Chelating agen and the screening of pH adjusting agent consumption
Consider do not add or add not commensurability different types of anti-chelating agen and pH adjusting agent, be placed in the illumination of 4500LX ± 500LX and the calorstat of 60 ℃ ± 2 ℃ of high temperature 10 days, respectively at 5,10 days, its appearance luster, pH value and related substance are checked.
Prescription 1 prescription 2
Prescription 3 prescriptions 4
Prescription 5 prescriptions 6
By above result of the test, shown: in prescription 1 and prescription 2 layoutprocedures, separate out; After prescription 3 calorstats at 4500LX ± 500LX illumination condition, 60 ℃ ± 2 ℃ of high temperature are placed and are placed for 5 days, outward appearance, color and luster, pH value have no significant change, related substance impurity speckle is not obvious, up to specification, it is against regulation that prescription 4-6 places 10 days related substances at the calorstat of 4500LX ± 500LX illumination condition, 60 ℃ ± 2 ℃ of high temperature, from result of the test, observe, prescription 3 is better than other prescription, so we select to write out a prescription and 3 carry out the screening of test example 2.
Test example 2
This test example is to investigate medicinal charcoal consumption, temperature, the impact of adsorption time on milrinone content in injection.
The preparation of 1 milrinone sample solution: precision takes milrinone 5g and is placed in 5000ml volumetric flask, dilute with water scale, shakes up, and measures content, as reserve liquid.
The impact of 2 different time different amounts medicinal charcoal on milrinone absorption: get respectively 12 parts of reserve liquid 300ml, every 4 parts is one group, add respectively medicinal charcoal 0,0.05%, 0.1%, 0.15%, in 60 ℃ of thermostat water baths, work overtime 15,30,35 minutes respectively for 4 parts in every group, be cooled to room temperature, get subsequent filtrate according to measuring trap containing under quantifier, calculate content, the results are shown in Table:
Medicinal charcoal different amounts and difference stir your impact on milrinone content
From showing, can find out, the consumption of medicinal charcoal is larger, and adsorption time is longer, and content declines more obvious, and therefore in preparation process, medicinal charcoal consumption is 0.05%, and adsorption time was at 30 minutes.
Claims (5)
1. a milrinone pharmaceutical composition for injection, is characterized in that, the milrinone pharmaceutical composition described in every 1000, and its formula consists of:
2. the preparation method of milrinone pharmaceutical composition according to claim 1, is characterized in that, the method comprises the steps:
Get recipe quantity water for injection 90%, temperature, at 75-85 ℃, adds recipe quantity cysteine hydrochloride and calcium disodium edetate, after stirring and dissolving; Record original ph, according to original ph, with 10% CYSTEAMINE HCL acid solution, regulate pH value scope at 2.5-3.0; The milrinone that adds recipe quantity, is stirred to and dissolves completely; To solution, add medicinal charcoal, stir; Sucking filtration, adds water for injection to full dose, and mix homogeneously is measured pH value; Fine straining; Fill; Sterilizing; Lamp inspection; Warehouse-in; Obtain milrinone pharmaceutical composition.
3. the preparation method of milrinone pharmaceutical composition according to claim 2, is characterized in that, the consumption of described medicinal charcoal is 0.05%.
4. the preparation method of milrinone pharmaceutical composition according to claim 2, is characterized in that, described stirring is at 50-60 ℃, to stir 30 minutes.
5. the preparation method of milrinone pharmaceutical composition according to claim 2, is characterized in that, described sterilising conditions is: 121 ℃, 20 minutes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210363429.8A CN103655562A (en) | 2012-09-25 | 2012-09-25 | Stable milrinone medicament composition for injection |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210363429.8A CN103655562A (en) | 2012-09-25 | 2012-09-25 | Stable milrinone medicament composition for injection |
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| CN103655562A true CN103655562A (en) | 2014-03-26 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN118415977A (en) * | 2024-07-03 | 2024-08-02 | 山东新时代药业有限公司 | Milrinone injection and application thereof |
-
2012
- 2012-09-25 CN CN201210363429.8A patent/CN103655562A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN118415977A (en) * | 2024-07-03 | 2024-08-02 | 山东新时代药业有限公司 | Milrinone injection and application thereof |
| CN118415977B (en) * | 2024-07-03 | 2024-08-23 | 山东新时代药业有限公司 | Milrinone injection and application thereof |
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Application publication date: 20140326 |