CN100389768C - Milrinone composition for injection and its prepn - Google Patents
Milrinone composition for injection and its prepn Download PDFInfo
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- CN100389768C CN100389768C CNB2004100539865A CN200410053986A CN100389768C CN 100389768 C CN100389768 C CN 100389768C CN B2004100539865 A CNB2004100539865 A CN B2004100539865A CN 200410053986 A CN200410053986 A CN 200410053986A CN 100389768 C CN100389768 C CN 100389768C
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- milrinone
- acidic materials
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- injection
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Abstract
The present invention provides a milrinone freeze drying powder injection which has high concentration and is used for injection and a preparation method thereof. The freeze drying powder injection contains the following ingredients: 2 to 10 parts of milrinone by weight, acidic material which is acceptable on pharmacy, and 15 to 100 parts of carrier which is acceptable on pharmacy by weight, wherein the weight ratio of the acidic material to the milrinone is from 0.25:1 to 1:0.25, and the acidic material is selected from L-aspartic acid, tartaric acid, citric acid, glutamic acid, or a mixture. The freeze drying powder injection is dissolved in water, and the injection whose milrinone concentration is from 2 to 10 mg/ml can be obtained. Therefore, the medicine volume for injection can be reduced, the stability is good, the clinical medication is convenient, and the storage and the transportation of medicine are convenient.
Description
Technical field
The present invention relates to a kind of field of pharmaceutical preparations, relate more specifically to milrinone composition for injection and preparation method thereof.
Background technology
Milrinone belongs to phosphodiesterase inhibitor, is applicable to the 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.Because milrinone is insoluble in water, so the milrinone injection concentration of clinical practice is less, only is 1mg/ml, regular size is 5ml: 5mg and 10ml: 10mg, and the drug administration by injection liquor capacity is bigger.Still the development report that does not have the milrinone powder ampoule agent for injection both at home and abroad.
Therefore, this area presses for higher injection of exploitation milrinone concentration and preparation method thereof.
Summary of the invention
Purpose of the present invention just provides the higher injection of a kind of milrinone concentration, lyophilized injectable powder and preparation method thereof.
In a first aspect of the present invention, a kind of Corotrope is provided, it contains following component:
(a) milrinone of 2-10mg/ml is by the cumulative volume of dissolving back injection;
(b) pharmaceutically acceptable acidic materials, the weight ratio of acidic materials and milrinone are 0.25: 1 to 1: 0.25, and described acidic materials are selected from: L-aspartic acid, tartaric acid, citric acid, glutamic acid or its combination;
(c) pharmaceutically acceptable carrier; With
(d) pharmaceutically acceptable diluent.
In another preference, described diluent is a water.
In another preference, described acidic materials are selected from: L-aspartic acid, tartaric acid, citric acid or its combination.
In another preference, the pH value of described injection is 2.5-5.
In a second aspect of the present invention, a kind of Milrione lyophilied powder injection is provided, contain following component:
(a) 2-10 weight portion milrinone;
(b) pharmaceutically acceptable acidic materials, the weight ratio of acidic materials and milrinone are 0.25: 1 to 1: 0.25, and described acidic materials are selected from: L-aspartic acid, tartaric acid, citric acid, glutamic acid or its combination;
(c) 15-100 weight portion pharmaceutically acceptable carrier,
Wherein, described lyophilized injectable powder is water-soluble, and forming milrinone concentration is the injection of 2-10mg/ml.
In another preference, described acidic materials are selected from: L-aspartic acid, tartaric acid, citric acid or its combination.More preferably, described acidic materials are L-aspartic acid or tartaric acid.
In another preference, described carrier is selected from: mannitol, lactose or its combination.
Preparation method in another preference, this method may further comprise the steps:
(a) mix 2-10 weight portion milrinone, pharmaceutically acceptable acidic materials and 500-1000 weight portion aqueous solvent, make the milrinone dissolving form solution, the weight ratio of its middle acid substance and milrinone is 0.25: 1 to 1: 0.25, and described acidic materials are selected from: L-aspartic acid, tartaric acid, citric acid, glutamic acid or its combination;
(b) the pharmaceutically acceptable carrier of 15-100 weight portion is joined in the solution of step (a) stirring and dissolving;
(c) solution of step (b) is removed pyrogen and sterilization;
(d) solution to step (c) carries out lyophilization, obtains Milrione lyophilied powder injection.
In another preference, sterilization is the cellulose esters micro-filtration membrane filtration by 0.22 micron in the step (c); Perhaps
Be that pharmaceutically acceptable acidic materials are earlier soluble in water in the step (a), and then add milrinone.
The specific embodiment
The inventor finds through further investigation, though present milrinone preparation adopts lactic acid as its cosolvent, yet solubilization-aid effect is poor, commercially available milrinone injection concentration low (1mg/ml), therefore through groping in a large number, find that some pharmaceutically acceptable acidic materials (for example L-aspartic acid, tartaric acid, citric acid etc.) are suitable as the cosolvent of milrinone very much, by adding these specific acidic materials, can obtain the Corotrope that concentration improves (as 2-10mg/ml) greatly as cosolvent.
On the one hand, pharmaceutical composition of the present invention contains:
(a) 2-10mg/ml milrinone is in the cumulative volume after the composition dissolves;
(b) pharmaceutically acceptable acidic materials, the weight ratio of milrinone and acidic materials are 0.25: 1-1: 0.25;
(c) pharmaceutically acceptable carrier; With
(d) solvent.
Acidic materials used in the present invention should be selected pharmaceutical field acidic materials commonly used for use.Representational example comprises: L-aspartic acid, tartaric acid, citric acid, glutamic acid or its combination.Preferred example be the L-aspartic acid (the L-aspartic acid be a kind of pharmacy allow can intravenous aminoacid, record in Chinese Pharmacopoeia and other various countries' pharmacopeia), tartaric acid or its combination.Test shows that L-aspartic acid and tartaric acid can significantly increase the dissolubility of milrinone in water, and makes pH value reach the acid range of 2.5-5.0.
In addition, compare,, therefore when lyophilization, be difficult to remove fully because lactic acid is liquid component with using lactic acid.In contrast, L-aspartic acid, citric acid, tartaric acid etc. all are solid acids, and is therefore very easy when lyophilizing, and help to significantly improve the stability of solid composite.
The amount of middle acid substance of the present invention reaches clinical desired drug level for making the milrinone dissolving, as 2-10mg/ml or higher.Usually, the weight ratio of milrinone and acidic materials is 0.25: 1 to 1: 0.25, preferably 0.5: 1-1: 0.5, and more preferably be 0.8: 1-1: 0.8.
Pharmaceutical composition of the present invention also can contain materia medica various additives commonly used, as long as this additive does not hinder the function of milrinone.Representational additive comprises (but being not limited to): caffolding agent, antioxidant, pH additive etc.
Usually, the pH value after the present composition dissolving is 2.5-5.0, more preferably is 3.0-3.5.
The above-mentioned fluid composition of the present invention can be made lyophilized injectable powder with conventional drying means (as lyophilization, vacuum drying etc.).
Usually, the present invention's method of preparing Milrione lyophilied powder injection may further comprise the steps:
(a) mix 2-10 weight portion milrinone, pharmaceutically acceptable acidic materials and 500-1000 weight portion aqueous solvent, make the milrinone dissolving form solution, the weight ratio of its middle acid substance and milrinone is 0.25: 1 to 1: 0.25;
(b) the pharmaceutically acceptable carrier of 15-100 weight portion is joined in the solution of step (a) stirring and dissolving;
(c) solution of step (b) is removed pyrogen and sterilization;
(d) solution to step (c) carries out lyophilization, obtains Milrione lyophilied powder injection.Be generally the white crystals block.
In another preference, can earlier pharmaceutically acceptable acidic materials and milrinone be dissolved in the water for injection, form solution; Then, in the solution that the carrier above-mentioned steps of adding pharmacy permission forms.
At present need to adopt 5-10ml can finish the intravenous administration of 5-10mg milrinone clinically, and lyophilized injectable powder of the present invention is owing to dissolve back milrinone concentration height fast, only need to finish intravenously administrable below the 1-2.5ml, therefore compared with prior art, lyophilized injectable powder of the present invention has following main beneficial effect:
(a) can reduce the injecting drug use volume;
(b) be convenient to lyophilizing, and stability is better;
(c) effect duration is longer;
(d) make things convenient for the storage and the transportation of clinical application and medicine.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.
Embodiment 1
Under the condition of cleaning, 2g L-aspartic acid is dropped in the dosing utensil, add stirring and dissolving among 50 ℃ of water for injection 800ml, be cooled to room temperature, add 2g milrinone stir about and made it molten entirely in 30 minutes, drop into the dissolving of 40g mannitol, add 0.3% pin with the charcoal absorption pyrogen that stirs, filtering decarbonization adds water to capacity, through the 0.22um filtering with microporous membrane, obtain 2mg/ml milrinone solution.Packing 2.5ml is in cillin bottle, and aseptic freeze-dried injectable powder was made in lyophilization in 72 hours.Specification is the 5mg/ bottle.
Embodiment 2
Dosing utensil in cleaning, 2g tartaric acid is dissolved in stirring and dissolving in the 800ml water for injection, add 2g milrinone stir about and made it molten entirely in 1 hour, drop into 20g lactose stirring and dissolving, add 0.3% pin with the charcoal absorption pyrogen that stirs, filtering decarbonization adds water to capacity, through the 0.22um filtering with microporous membrane, obtain 2mg/ml milrinone solution.Packing 2.5ml is in cillin bottle, and aseptic freeze-dried injectable powder was made in lyophilization in 72 hours.Specification is the 5mg/ bottle.
Embodiment 3
Under the condition of cleaning, 2.5g L-aspartic acid is dropped in the dosing utensil, add stirring and dissolving among 50 ℃ of water for injection 800ml, be cooled to room temperature, add 2.5g milrinone stir about and made it molten entirely in 30 minutes, drop into the dissolving of 50g mannitol, add 0.3% pin with the charcoal absorption pyrogen that stirs, filtering decarbonization adds water to capacity, through the 0.22um filtering with microporous membrane, obtain 2.5mg/ml milrinone solution.Packing 2ml is in cillin bottle, and aseptic freeze-dried injectable powder was made in lyophilization in 72 hours.Specification is the 5mg/ bottle.
Embodiment 4
Under the condition of cleaning, 4g L-aspartic acid is added in the dosing utensil, add stirring and dissolving among the water for injection 750ml, be cooled to room temperature, add 4g milrinone stir about and made it molten entirely in 30 minutes, drop into the dissolving of 35g mannitol, add 0.3% pin with the charcoal absorption pyrogen that stirs, filtering decarbonization adds water to capacity, through the 0.22um filtering with microporous membrane, obtain 4mg/ml milrinone solution.Packing 2.5ml is in the 10ml cillin bottle, and aseptic freeze-dried injectable powder was made in lyophilization in 72 hours.Specification is the 10mg/ bottle.
Embodiment 5
Under the condition of cleaning, the 15g citric acid is added in the dosing utensil, add stirring and dissolving among the water for injection 800ml, be cooled to room temperature, add 10g milrinone stir about and made it molten entirely in 30 minutes, drop into the dissolving of 30g mannitol, add 0.3% pin with the charcoal absorption pyrogen that stirs, filtering decarbonization adds water to capacity, through the 0.22um filtering with microporous membrane, obtain 10mg/ml milrinone solution.Packing 1.0ml is in the 10ml cillin bottle, and aseptic freeze-dried injectable powder was made in lyophilization in 36 hours.Specification is the 10mg/ bottle.
Embodiment 6
Performance test
(a) stability result
Adopt embodiment 1 sample to carry out accelerated test (40 ℃, 75%RH) six months, the result compared with 0 month, and content, pH value, related substance and other indexs all do not have significant change.
(b) anaphylaxis, hemolytic, blood vessel irritation result of the test
After 10mg/1ml specification injection of the present invention (embodiment 5) adds 1ml water for injection, be injected in and be applied to rabbit (accumulated dose is respectively 10mg and 20mg).Simultaneously, the contrast injection of 5mg/5ml is injected in is applied to rabbit (accumulated dose is respectively 10mg and 20mg), observe the reaction of rabbit then.
The result shows that the product of the present invention of 10mg/1ml is 0～1 grade to the average response level that the rabbit quadriceps femoris stimulates, and does not have anaphylaxis, hemolytic, and the pain of rabbit performance obviously is less than matched group.
Each lyophilized injectable powder to embodiment 1-4, behind same procedure interpolation 1ml water for injection, also be injected in and be applied to rabbit (accumulated dose is 10mg), the result is identical with the lyophilized injectable powder of embodiment 5, the average response level that the rabbit quadriceps femoris is stimulated is 0～1 grade, and do not have anaphylaxis, hemolytic, and the pain of rabbit performance obviously is less than matched group.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. a Corotrope is characterized in that, contains following component:
(a) milrinone of 2-10mg/ml is by the cumulative volume of injection;
(b) pharmaceutically acceptable acidic materials, the weight ratio of acidic materials and milrinone are 0.25: 1 to 1: 0.25, and described acidic materials are selected from: L-aspartic acid, tartaric acid, citric acid, glutamic acid or its combination;
(c) pharmaceutically acceptable carrier, wherein said carrier is selected from: mannitol, lactose or its combination; With
(d) pharmaceutically acceptable diluent, wherein said diluent is a water.
2. Corotrope as claimed in claim 1 is characterized in that, the weight ratio of acidic materials and milrinone is 0.5: 1 to 1: 0.5.
3. Corotrope as claimed in claim 1 is characterized in that, described acidic materials are selected from: L-aspartic acid, tartaric acid, citric acid or its combination.
4. Corotrope as claimed in claim 1 is characterized in that, the pH value of described injection is 2.5-5.
5. a Milrione lyophilied powder injection is characterized in that, contains following component:
(a) 2-10 weight portion milrinone;
(b) pharmaceutically acceptable acidic materials, the weight ratio of acidic materials and milrinone are 0.25: 1 to 1: 0.25, and described acidic materials are selected from: L-aspartic acid, citric acid, glutamic acid, tartaric acid or its combination;
(c) 15-100 weight portion pharmaceutically acceptable carrier, described carrier is selected from: mannitol, lactose or its combination.
6. Milrione lyophilied powder injection as claimed in claim 5 is characterized in that, described acidic materials are selected from: L-aspartic acid, citric acid, tartaric acid or its combination.
7. Milrione lyophilied powder injection as claimed in claim 6 is characterized in that, described acidic materials are L-aspartic acid or tartaric acid.
8. Milrione lyophilied powder injection as claimed in claim 5 is characterized in that, the weight ratio of acidic materials and milrinone is 0.5: 1 to 1: 0.5.
9. the preparation method of Milrione lyophilied powder injection as claimed in claim 5 is characterized in that, this method may further comprise the steps:
(a) mix 2-10 weight portion milrinone, pharmaceutically acceptable acidic materials and 500-1000 weight portion aqueous solvent, make the milrinone dissolving form solution, the weight ratio of its middle acid substance and milrinone is 0.25: 1 to 1: 0.25, and described acidic materials are selected from: L-aspartic acid, tartaric acid, citric acid, glutamic acid or its combination;
(b) the pharmaceutically acceptable carrier of 15-100 weight portion is joined in the solution of step (a), stirring and dissolving, wherein said carrier is selected from: mannitol, lactose or its combination;
(c) solution of step (b) is removed pyrogen and sterilization;
(d) solution to step (c) carries out lyophilization, obtains Milrione lyophilied powder injection.
10. method as claimed in claim 9 is characterized in that, sterilization is the cellulose esters micro-filtration membrane filtration by 0.22 micron in the step (c); Perhaps
Be that pharmaceutically acceptable acidic materials are earlier soluble in water in the step (a), and then add milrinone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100539865A CN100389768C (en) | 2004-08-25 | 2004-08-25 | Milrinone composition for injection and its prepn |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100539865A CN100389768C (en) | 2004-08-25 | 2004-08-25 | Milrinone composition for injection and its prepn |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1739512A CN1739512A (en) | 2006-03-01 |
| CN100389768C true CN100389768C (en) | 2008-05-28 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB2004100539865A Expired - Fee Related CN100389768C (en) | 2004-08-25 | 2004-08-25 | Milrinone composition for injection and its prepn |
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102727431B (en) * | 2012-07-12 | 2013-11-06 | 南京正大天晴制药有限公司 | Injecta containing milrinone and preparation method thereof |
| CN103372013A (en) * | 2013-06-28 | 2013-10-30 | 上海交通大学医学院附属瑞金医院 | Application of milrinone in preparation of medicine for treating diabetic foot ulcer |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993024122A1 (en) * | 1992-05-29 | 1993-12-09 | Board Of Regents, The University Of Texas System | Use of cardiotonic drugs and inhibitors of nitric oxide synthesis to alleviate pathologic hypotension |
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- 2004-08-25 CN CNB2004100539865A patent/CN100389768C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993024122A1 (en) * | 1992-05-29 | 1993-12-09 | Board Of Regents, The University Of Texas System | Use of cardiotonic drugs and inhibitors of nitric oxide synthesis to alleviate pathologic hypotension |
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| CN1739512A (en) | 2006-03-01 |
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