CN100581546C - Medicament compound containing milrinone - Google Patents
Medicament compound containing milrinone Download PDFInfo
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- CN100581546C CN100581546C CN200710301504A CN200710301504A CN100581546C CN 100581546 C CN100581546 C CN 100581546C CN 200710301504 A CN200710301504 A CN 200710301504A CN 200710301504 A CN200710301504 A CN 200710301504A CN 100581546 C CN100581546 C CN 100581546C
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- milrinone
- injection
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- hydrochloric acid
- sodium chloride
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Abstract
The invention discloses novel hydrochloride milrinone injection for treating congestive heart failure and a preparation method of the hydrochloride milrinone injection. The invention is characterized in that the invention contains milrinone, hydrochloride, sodium chloride and water for injection; and the range of pH value of the injection that the hydrochloride adjusts is between 2.8 to 3.5. The injection provided by the invention has the advantages of high purity, simple preparation process, convenient using in clinic and good efficacy.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains milrinone, be used for the treatment of congestive heart failure, belong to field of medicaments.
Background technology
Milrinone (milrinone) is a kind of cardiac tonic, belong to the phosphodiesterase iii inhibitor, substitute products for amrinone, its activity is 10～30 times of amrinone, the heart failure patient that is used for the treatment of obstinate heart failure and second generation digitalism, can obviously improve the various parameters of heart failure patient systemic blood flow kinetics, no platelet reduces and the hypotension side effect.At first ratified by FDA in the U.S. in 1987,1992 at U.S.'s official listing, thereafter successively in national list marketings such as Britain, France, Germany, Holland, Belgium and Brazil.
Studies show that milrinone lactate also can be used for hanging down heart row syndrome after the Cardiac Surgery extracorporeal circulation, removes the bridge blood vessel spasm, improves heart orthotopic transplantation patient's cardiac function and anti-inflammatory response, improves visceral bloodflow perfusion etc., main adverse reactions is that a few patients can have hypotension, sinus tachycardia, ventricular arrhythmia, platelet count reduces, abnormal liver function, renal dysfunction and headache, dizziness, vomiting etc.
Milrinone is compared with the effect of dobutamine and be experimental results show that: dobutamine reduces the effect of ventricular diastole final end pressure and systemic vascular resistance less than milrinone; Dobutamine more can increase coronary blood flow than milrinone, but has also increased myocardial oxygen consumption simultaneously, and milrinone is then denied.
Heart failure is that sickness rate few in number is up to now still continuing one of cardiovascular disease that increases, according to scholarly forecast, Energostim thing market will be with the speed increment in year 10.9%, sales volume in 2005 is about 6,000,000,000 dollars, and French Sai Nuofei-Sheng Delabao company milrinone sales volume in 2000 just reaches 1.8 hundred million Euros.
Because the untoward reaction of tablet is too big, eliminated by market, milrinone is applied to the patient with injection class dosage form basically at present.Chinese patent CN1679566 discloses a kind of milrinone injection and preparation method thereof, has adopted lactic acid as cosolvent and pH value regulator.Chinese patent CN1621834 discloses a kind of high-efficient liquid phase determining method of milrinone related substance, has adopted a kind of high performance liquid chromatogram method milrinone to be carried out the mensuration of related substance.
Summary of the invention
The invention provides a kind of new milrinone injecta composition and preparation method thereof.
Injection of the present invention mainly is made up of milrinone, hydrochloric acid, sodium chloride and water for injection.The effect of hydrochloric acid is the pH value that is used to regulate injection on the one hand, make its pH value scope between 2.8-3.5, on the other hand as the cosolvent of milrinone in water, adopt when regulating the hydrochloric acid of which kind of concentration to regulate just for operational convenience, be adjusted to the pH value scope between 2.8-3.5 the time milrinone be complete molten in the injection for preparing.The effect of sodium chloride is as osmotic pressure regulator, and the osmotic pressure that is used to regulate injection is to close with the osmotic pressure of the blood of human body, and generally being adjusted to concentration is between the 0.8%-1.0%.The concentration range of milrinone in solution is 0.1 grams per liter-10 grams per liter, is preferably 0.5 grams per liter-5 grams per liter, and more preferably 1 grams per liter-5 grams per liter is further elected 1 grams per liter more again as.
Hydrochloric acid milrinone injection provided by the present invention has the following advantages:
(1) compares the injection purity height that utilizes the present invention to prepare with the milrinone lactate injection.
(2) preparation technology is simple.
(3) clinical easy to use, therapeutic effect is good.
The specific embodiment
Embodiment 1
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 40g
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone 5 grams, add 3 liters of waters for injection, stir, with 0.5M hydrochloric acid conditioning solution pH value to 2.9, it is molten entirely to continue to be stirred to solution, adds sodium chloride 40 grams, stirs moltenly entirely, adds water for injection to 5 liter, mixing, 0.45 μ m filtering with microporous membrane, 1000 bottles of fills, sterilization.
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 42g
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone 5 grams, add 2 liters of waters for injection, stir, with 0.2M hydrochloric acid conditioning solution pH value to 3.0, add sodium chloride 42 grams, stir moltenly entirely, add water for injection to 5 liter, it is molten entirely to continue to be stirred to solution, mixing, 0.45 μ m filtering with microporous membrane, 1000 bottles of fills, sterilization.
Embodiment 3
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 45g
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone 5 grams, add 4.5 liters of waters for injection, stir, with 1M hydrochloric acid conditioning solution pH value to 3.1, it is molten entirely to continue to be stirred to solution, adds sodium chloride 45 grams, stirs moltenly entirely, adds water for injection to 5 liter, mixing, 0.45 μ m filtering with microporous membrane, 1000 bottles of fills, sterilization.
Embodiment 4
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 45g
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone 5 grams, add 4.5 liters of waters for injection, stir, with 2M hydrochloric acid conditioning solution pH value to 3.2, it is molten entirely to continue to be stirred to solution, adds sodium chloride 45 grams, stirs moltenly entirely, adds water for injection to 5 liter, mixing, 0.45 μ m filtering with microporous membrane, 1000 bottles of fills, sterilization.
Embodiment 5
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 48g
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone 5 grams, add 4.5 liters of waters for injection, stir, with 1.5M hydrochloric acid conditioning solution pH value to 3.3, it is molten entirely to continue to be stirred to solution, adds sodium chloride 48 grams, stirs moltenly entirely, adds water for injection to 5 liter, mixing, 0.45 μ m filtering with microporous membrane, 1000 bottles of fills, sterilization.
Embodiment 6
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 50g
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone 5 grams, add 4.5 liters of waters for injection, stir, with 0.5M hydrochloric acid conditioning solution pH value to 3.4, it is molten entirely to continue to be stirred to solution, adds sodium chloride 50 grams, stirs moltenly entirely, adds water for injection to 5 liter, mixing, 0.45 μ m filtering with microporous membrane, 1000 bottles of fills, sterilization.
Embodiment 7
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 45g
Water for injection adds to 5 liters of cumulative volumes
Take by weighing milrinone 5 grams, add 4.5 liters of waters for injection, stir, with 0.5M hydrochloric acid conditioning solution pH value to 3.5, it is molten entirely to continue to be stirred to solution, adds sodium chloride 45 grams, stirs moltenly entirely, adds water for injection to 5 liter, mixing, 0.45 μ m filtering with microporous membrane, 1000 bottles of fills, sterilization.
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 40g
Water for injection adds to 2.5 liters of cumulative volumes
Take by weighing milrinone 5 grams, add 1.5 liters of waters for injection, stir, with 0.5M hydrochloric acid conditioning solution pH value to 2.9, it is molten entirely to continue to be stirred to solution, adds sodium chloride 40 grams, stirs moltenly entirely, adds water for injection to 2.5 liter, mixing, 0.45 μ m filtering with microporous membrane, 500 bottles of fills, sterilization.
Embodiment 9
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 8g
Water for injection adds to 1 liter of cumulative volume
Take by weighing milrinone 5 grams, add 0.6 liter of water for injection, stir, with 0.5M hydrochloric acid conditioning solution pH value to 3.0, it is molten entirely to continue to be stirred to solution, adds sodium chloride 8 grams, stirs moltenly entirely, adds water for injection to 1 liter, mixing, 0.45 μ m filtering with microporous membrane, 200 bottles of fills, sterilization.
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 20g
Water for injection adds to 2.5 liters of cumulative volumes
Take by weighing milrinone 5 grams, add 1.5 liters of waters for injection, stir, with 0.5M hydrochloric acid conditioning solution pH value to 3.1, add sodium chloride 20 grams, stir moltenly entirely, add water for injection to 2.5 liter, it is molten entirely to continue to be stirred to solution, mixing, 0.45 μ m filtering with microporous membrane, 500 bottles of fills, sterilization.
Embodiment 11
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 40g
Water for injection adds to 10 liters of cumulative volumes
Take by weighing milrinone 5 grams, add 7 liters of waters for injection, stir, with 0.5M hydrochloric acid conditioning solution pH value to 3.1, add sodium chloride 40 grams, stir moltenly entirely, add water for injection to 10 liter, it is molten entirely to continue to be stirred to solution, mixing, 0.45 μ m filtering with microporous membrane, 1000 bottles of fills, sterilization.
Embodiment 12
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 225g
Water for injection adds to 25 liters of cumulative volumes
Take by weighing milrinone 5 grams, add 20 liters of waters for injection, stir, with 0.5M hydrochloric acid conditioning solution pH value to 3.5, it is molten entirely to continue to be stirred to solution, adds sodium chloride 225 grams, stirs moltenly entirely, adds water for injection to 25 liter, mixing, 0.45 μ m filtering with microporous membrane, 5000 bottles of fills, sterilization.
Embodiment 13
Milrinone 5 grams
Hydrochloric acid is an amount of
Sodium chloride 450g
Water for injection adds to 50 liters of cumulative volumes
Take by weighing milrinone 5 grams, add 35 liters of waters for injection, stir, with 0.5M hydrochloric acid conditioning solution pH value to 3.3, it is molten entirely to continue to be stirred to solution, adds sodium chloride 450 grams, stirs moltenly entirely, adds water for injection to 50 liter, mixing, 0.45 μ m filtering with microporous membrane, 10000 bottles of fills, sterilization.
Embodiment 14
Hydrochloric acid is an amount of
Sodium chloride 8.5g
Water for injection adds to 1 liter of cumulative volume
Take by weighing milrinone 10 grams, add 0.6 liter of water for injection, stir, with 0.5M hydrochloric acid conditioning solution pH value to 3.1, it is molten entirely to continue to be stirred to solution, adds sodium chloride 8.5 grams, stirs moltenly entirely, adds water for injection to 1 liter, mixing, 0.45 μ m filtering with microporous membrane, fill, sterilization.
Embodiment 15
According to the injection of embodiment 3 preparations, adopt the collection of illustrative plates of the HPLC chromatography determination related substance in the up-to-date national new drug quality standard, its spectrum data such as table 1.As can be seen, its related substances of the injection of embodiment 3 preparation is extremely low, milrinone as principal agent composition purity up to 99.8995%.
The chromatographic data of the injection of table 1 embodiment 3 preparations
Sigal 1:vwd1 A wavelength=220nm
Embodiment 16
According to the method among the embodiment 3, just adopt lactic acid to substitute hydrochloric acid, the injection of other steps and the identical preparation of operation is according to the collection of illustrative plates of the high effective liquid chromatography for measuring related substance in the up-to-date national new drug quality standard, its spectrum data such as table 2.As can be seen, its related substances that lactic acid substitutes the injection for preparing behind the hydrochloric acid raises to some extent, and milrinone is 98.6796% as principal agent composition purity.
Table 2 embodiment 3 lactic acid substitute the chromatographic data of the injection behind the hydrochloric acid
Sigal 1:vwd1 A wavelength=220nm
Embodiment 17 milrinone compositionss are to the influence of rat heart failure model
1 modeling and grouping
40 of Wistar healthy rats, male and female half and half are got 8 at random as normal group (male and female half and half).All the other rats give doxorubicin hydrochloride (Zhejiang Haizheng Pharmaceutical Co product dilutes with normal saline) lumbar injection, 2mg/kg, and injection in preceding 5 times per 3 days was once injected once in then per later on 7 days, accumulative total consumption 20mg/kg; Normal group is then used normal saline and is in kind injected.The rat echocardiography of the 10th week the amycin qtd of cardiomyopathy group being randomly drawed shows that parameters of left ventricular function is unusual, LVEDV and LVESV obviously increase, EF is normal, and matched group obviously reduces, and the 10th all normal control rats echocardiographies are not all found core function abnormality.With 3 groups of amycin cardiomyopathy components: model group, matched group, experimental group, 8 every group, male and female half and half.
2 medications
Animal model begins administration after setting up successfully, matched group lumbar injection milrinone lactate injection (according to the disclosed milrinone injection preparation of Chinese patent CN1679566 embodiment 1 self-control), 7mg/kg, 1 time/day; The hydrochloric acid milrinone injection that the experimental group rats by intraperitoneal injection embodiment of the invention 1 is prepared, 7mg/kg, 1 time/day; The normal saline of normal group and model group lumbar injection equal volume, 1 time/day.More than four groups of equal 5 weeks of administration.
3 detect index
3.1 parameters of left ventricular function
During the administration, the 1st weekend, the 2nd weekend and the 5th weekend, ultrasonic with the M type with HP toy ultrasonic probe (15MHz) at the rat parasternal, normal group, model group, matched group and experimental group rat are carried out cardiac function to be detected, comprise left chamber end-diastolic volume (LVEDV), left chamber end systolic volume (LVESV), left ventricular ejection mark (LVEF), LVEF=(left ventricular end diastolic volume-left ventricular end-systolic volume)/left ventricular end diastolic volume * 100%, result such as table 1.
Table 1 is respectively organized the parameters of left ventricular function of rat after the 1st, 2,5 weeks of administration
Compare △ p＞005 with normal group; Compare #p＜001 with model group; Compare * p＜0.05 with matched group
3.2 ventricular rhythm index
After administration finishes, adopt dynamic ecg that experimental group and control rats are carried out 24h ambulatory electrocardiogram (DCG) inspection, write down every DCG result that rat is complete, calculate the not normal number of times of each time period chamber property ectopic cardiac rhythm of matched group and experimental group rat (with one hour as a time period, write down the not normal number of times of each time period chamber property ectopic cardiac rhythm of every rat, averaging can get), and data are imported the Excel worksheet make point and line chart, as accompanying drawing 1.
The result of these pharmacodynamics tests shows, hydrochloric acid milrinone injection has better treatment advantage to the heart failure of caused by doxorubicin than milrinone lactate, in the medication process of short-term, the curative effect of the two does not almost have difference, but through behind the long-term prescription, the advantageous effect of hydrochloric acid milrinone injection just seems fairly obvious, and in preparation research, the hydrochloric acid milrinone is higher than the stability of milrinone lactate, and its related substances after the long term test in the hydrochloric acid milrinone injection significantly reduces than the content of milrinone lactate injection.
Description of drawings
Accompanying drawing 1: the not normal number of times of chamber property ectopic cardiac rhythm of treatment back matched group and experimental group changes.
Claims (8)
1. pharmaceutical composition that is used for the treatment of congestive heart failure is characterized in that it contains milrinone and hydrochloric acid, and described pharmaceutical composition is an injection.
2. pharmaceutical composition as claimed in claim 1 is characterized in that it contains sodium chloride.
3. pharmaceutical composition as claimed in claim 1 is characterized in that it contains water.
4. pharmaceutical composition as claimed in claim 1 is characterized in that its pH value scope is 2.8-3.5.
5. pharmaceutical composition as claimed in claim 1 is characterized in that wherein the concentration range of milrinone in solution is: 0.1 grams per liter-10 grams per liter.
6. pharmaceutical composition as claimed in claim 5 is characterized in that wherein the concentration range of milrinone in solution is: 0.5 grams per liter-5 grams per liter.
7. pharmaceutical composition as claimed in claim 6 is characterized in that wherein the concentration range of milrinone in solution is: 1 grams per liter-5 grams per liter.
8. pharmaceutical composition as claimed in claim 7 is characterized in that wherein the concentration of milrinone in solution is: 1 grams per liter.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710301504A CN100581546C (en) | 2007-09-06 | 2007-12-25 | Medicament compound containing milrinone |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200710112914.7 | 2007-09-06 | ||
| CN200710112914 | 2007-09-06 | ||
| CN200710301504A CN100581546C (en) | 2007-09-06 | 2007-12-25 | Medicament compound containing milrinone |
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| Publication Number | Publication Date |
|---|---|
| CN101199524A CN101199524A (en) | 2008-06-18 |
| CN100581546C true CN100581546C (en) | 2010-01-20 |
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| CN102579329B (en) * | 2012-03-06 | 2013-04-17 | 北京六盛合医药科技有限公司 | Milrinone lactate injection and preparation method thereof |
| CN103664773A (en) * | 2013-12-18 | 2014-03-26 | 南京易亨制药有限公司 | Preparing method and refining method for milrinone |
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| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Lunan Beite Pharmaceutical Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2010370000513 Denomination of invention: Medicament compound containing milrinone Granted publication date: 20100120 License type: Exclusive License Open date: 20080618 Record date: 20100909 |
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| EC01 | Cancellation of recordation of patent licensing contract |
Assignee: Lunan Beite Pharmaceutical Co., Ltd. Assignor: Lunan Pharmaceutical Group Co., Ltd. Contract record no.: 2010370000513 Date of cancellation: 20131016 |
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| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model |