CN101305984A - Medicaments solution - Google Patents
Medicaments solution Download PDFInfo
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- CN101305984A CN101305984A CNA2007100223940A CN200710022394A CN101305984A CN 101305984 A CN101305984 A CN 101305984A CN A2007100223940 A CNA2007100223940 A CN A2007100223940A CN 200710022394 A CN200710022394 A CN 200710022394A CN 101305984 A CN101305984 A CN 101305984A
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- levosimendan
- polyvidone
- maleic acid
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- drug solution
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Abstract
The invention discloses a pharmaceutical solution which takes levosimendan or medicine salt thereof as an active ingredient, takes absolute ethyl alcohol as a solvent, and also comprises maleic acid and solubilizer polyvidone. The pH valve of the pharmaceutical solution ranges from 3 to 4; wherein, the weight-to-volume ratio of the levosimendan or the medicine salt thereof is 0.2 to 0.3 percent, and 0.25 percent is optimized; the weight-to-volume ratio of the maleic acid is 0.001 to 0.01 percent, and the range from 0.005 to 0.009 percent is optimized; the weight-to-volume ratio of the polyvidone is 0.5 to 2 percent, and 1 percent is optimized. A stability experiment shows that pharmaceutical solution has better stability.
Description
Technical field
The present invention relates to medical technical field, being specifically related to a kind of is the drug solution of active ingredient with levosimendan or its pharmaceutical salts.
Background technology
Levosimendan (Levosimendan) is a kind of heart failure therapy medicine of newtype---cardiomyopathy flesh power medicine claims calcium sensitizer again.Research and develop by Finland Orion Corporation, go on the market in Switzerland first in October, 2000, be applicable to the back short-term intravenous injection treatment of being in hospital of acute decompensation serious symptom chronic heart failure, when conventional medicine used curative effect not enough separately, he was used as the additivity treatment.The listing dosage form is an injection, trade name Simdax, and specification is 5ml:12.5mg and 10ml:25mg.This medical instrument has unique dual function pattern, can increase heart output, and distend the blood vessels, and does not increase heart rate when improving cardiac pumping function, and effectively relief of symptoms improves prognosis; This product also can make vein, tremulous pulse and cerebral vasodilators, reduces preload and afterload, improves coronary blood flow.Acute myocardial infarction patients is used this product, and its hematodinamics and clinical symptoms all can obtain obvious improvement.This product does not influence myocardial relaxation, does not increase malignant arrhythmia danger yet.When myocardial ischemia and reperfusion injury, has cardioprotection.This product well-tolerated, with other medicines for cardiovascular system such as beta-blocker, during couplings such as ACE inhibitor, calcium antagonist, nitrate esters medicine, digoxin, warfarin, aspirin, generally safer.Zoopery shows that left Xi Mengtan can increase heart rate, cardiac output, systolic blood flow rate, reduces LVEDP, reduces systemic vascular resistance and average arteria coronaria diastole impedance of blood flow.Show that with the control experiment of milrinone left Xi Mengtan is obvious than milrinone aspect the increase myocardial contraction, and can significantly reduce myocardial oxygen consumption, the cardiac arrhythmia incidence rate also obviously reduces.The result of external multinomial clinical research shows that also levosimendan is remarkable to the serious symptom chronic heart failure effect for the treatment of acute compensatory imbalance, the more similar medicine of hemodynamic change is remarkable, side effect is littler, can reduce the heart failure mortality rate and reach 43%, being first medicine of the treatment heart failure of newtype, also is one of best medicine of this indication curative effect.
The technology of the drug solution of the open levosimendan of Chinese patent CN0081245.3, this patent disclosure be solvent with ethanol, adding PKa is organic acid and the solubilizing agent of 2-4, this patent has been carried out preparation research at the physics and the chemical property of levosimendan to a certain extent, but its organic acid w/v is 0.03%-0.6%, consumption is more, as everyone knows, when adding more organic acid in the vein input pharmaceutical preparation, bring huge zest can for patient's blood vessel, and human body need carry out metabolism to these organic acid, though these organic acid are harmless to human body, but neither be useful, the amount that adds invalid components is many more, and patient's burden is just big more; This patent is not selected solubilizing agent at the chemical property of levosimendan, just hope certain determining, and less than the molecular property at levosimendan, carry out deep research, these defectives have caused levosimendan or this unstable material of its pharmaceutical salts, because the untoward reaction that the reason of preparation causes a large amount of untoward reaction, particularly levosimendan or its pharmaceutical salts catabolite to produce.
Summary of the invention
The objective of the invention is to overcome above-mentioned shortcoming, research by experiment find that the operating weight volume ratio is that 0.001%～0.01% maleic acid can promote levosimendan or its pharmaceutical salts to have stability, and the use amount of maleic acid has reduced more than 30 times; In the process of selecting solubilizing agent, we find that more unexpectedly when adding polyvidone, the stability of effective ingredient has increased, and carries out confirmatory experiment, use polyvidone to use other solubilizing agent as the solubilizing agent ratio, and stability fully improves.
Purpose of the present invention can reach by following measure:
A kind of drug solution is an active component with levosimendan or its pharmaceutical salts, is solvent with the dehydrated alcohol, also comprises maleic acid and solubilizing agent polyvidone in the drug solution.
The pH value of this drug solution is 3～4.
Wherein the w/v of levosimendan or its pharmaceutical salts is 0.2%～0.3%; Preferred levosimendan or its pharmaceutical salts w/v are 0.25%.
Wherein the maleic acid w/v is 0.001%～0.01%.
Preferred maleic acid w/v is 0.005%～0.009%.
Wherein the polyvidone w/v is 0.5%～2%.
Preferred polyvidone w/v is 1%.
Dehydrated alcohol among the present invention refers to the dehydrated alcohol in the Pharmacopoeia of the People's Republic of China (issuing in 2005); Or water content is not higher than 0.3% straight alcohol by weight.
W/v of the present invention refers to the ratio of solute weight and drug solution volume, is called w/v.
Maleic acid of the present invention is a butene dioic acid, colourless monoclinic prism, 139～140 ℃ of fusing points, density 1.590 gram per centimeters
3(20 ℃).Soluble in water, ethanol, acetone, its pKa value is 1.92.
Levosimendan physicochemical property of the present invention: levosimendan is a yellow crystalline powder; Water soluble; Chemical stability at least 4 hours; Degraded rapidly in strong base solution; Octane and water are than (being the profit partition coefficient)=10; PKa=6.3.The pH of levosimendan solution is not 4.75 when adding the pH regulator agent, and molecular formula is:
Described levosimendan pharmaceutical salts is the pharmaceutically acceptable salt by the levosimendan of known method preparation.Its pharmaceutically acceptable salt need be effectively, the salt that preferred levosimendan and alkali metal or alkaline-earth metal form.
The molecular formula of the application's polyvidone is:
The test of the dependency of the solution pH value that the ethanol solution of levosimendan or its pharmaceutical salts is carried out shows that along with levosimendan solution pH value reduces, its physical stability is improved.And first enhancing of its chemical stability afterwards reduces, and stability is maximum when pH3-4, and it is constant substantially when this pH to show as its related substances.Determining to make its solution-stabilized pH scope in view of the above is 3～4.Regulate pH value to 3～4 of medicinal liquid, the consumption of maleic acid counts 0.001%～0.01% according to w/v, regulates the pH value to 3.5 of medicinal liquid, and the consumption of maleic acid counts 0.005%～0.009% according to w/v.Maleic acid can be used as the additives of venoclysis drug solution, and addition is few, safety non-toxic.
Because related levosimendan drug solution must be diluted with water to more and use behind the small concentration, still keeps fine solubility in order to guarantee levosimendan after dilution, we have also added water solubilizer in related levosimendan drug solution.For following consideration, our preferred polyvidone of related water solubilizer:
(1) polyvidone has good solubilization;
(2) may form intermolecular hydrogen bonding between polyvidone and the levosimendan, thereby be beneficial to the stable of levosimendan drug solution, can not destroy its stability at least.
The levosimendan molecular formula:
The polyvidone structural formula:
Prescription analysis:
(3) according to the w/v meter, the polyvidone consumption can meet the demands at 0.5%-2% in related levosimendan drug solution, and preferred polyvidone consumption is 1%.
Stability experiment research
1. maleic acid is to levosimendan or its pharmaceutical salts chemically stable Journal of Sex Research
Experimental technique: get levosimendan or its pharmaceutical salts 20～30 grams respectively, dissolving becomes 10000ml solution fully in dehydrated alcohol, the maleic acid that adds the Different Weight volume ratio respectively, analyze the amount of catabolite, catabolite is: (4-ethyoxyl-6-imino group-5-{[4-(4-methyl-6-oxo-1,4,5,6-tetrahydrochysene-pyridazine-3-yl)-and phenyl] hydrazono-}-5,6-phenodiazine-1 (H)-pyrimidine-2-subunit)-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydrochysene-pyridazine-3-yl)-phenylazo] acetonitrile.Experimental result sees Table 1:
Table 1 maleic acid is to effective ingredient chemically stable Journal of Sex Research
Experiment conclusion: show that by above-mentioned experiment when the maleic acid w/v was 0.001%～0.01%, levosimendan and pharmaceutical salts stability thereof were better, it is not 0.005%～0.009% that preferred maleic acid weight is promoted to a higher rank.
2. the solubilizing agent polyvidone is to levosimendan or its pharmaceutical salts chemically stable Journal of Sex Research
Experimental technique: get levosimendan or its pharmaceutical salts 20～30 grams respectively, dissolving becomes solution 10000ml fully in dehydrated alcohol, the maleic acid that adds w/v 0.007%, the polyvidone that adds the Different Weight volume ratio again, analyze the amount of catabolite, catabolite is (4-ethyoxyl-6-imino group-5-{[4-(4-a methyl-6-oxo-1,4,5,6-tetrahydrochysene-pyridazine-3-yl) phenyl] hydrazono-}-5,6-phenodiazine-1 (H)-pyrimidine-2-subunit)-[4-(4-methyl-6-oxo-1,4,5,6-tetrahydrochysene-pyridazine-3-yl)-phenylazo] acetonitrile.Experimental result sees Table 2:
Table 2 solubilizing agent polyvidone is to the chemical stability of levosimendan or its pharmaceutical salts
Experiment conclusion: show that by above-mentioned experiment the solubilizing agent polyvidone has good stability to levosimendan or its pharmaceutical salts.
3. the different pH value of the levosimendan ethanol solution investigation of stability down
Get levosimendan 0.2507g, 0.2514g, 0.2530g, 0.2520g, 0.2511g and place the 100ml measuring bottle respectively, add the 50ml anhydrous alcohol solution.With reference to the pH value scope of foreign data, select Pka for use
1Be 1.92 maleic acids that are as the pH value regulator, pH value is adjusted to 1.04,2.01,3.10,4.08,5.03,6.13,7.02 respectively.The same operation of the filtration of medicinal liquid, fill and lamp inspection.
0 day related substance of working sample.Get the sample that wherein clarity is qualified and placed the situation of change of the color of investigation sample, outward appearance, clarity, related substance 10 days in 25 ℃.The results are shown in Table 3, table 4.
The different pH value levosimendan of table 3 ethanol solution physical stability result
The different pH value levosimendan of table 4 ethanol solution chemical stability result
| The pH value | 0 day determination of related substances is % as a result | 10 days determination of related substances are % as a result | The variation % of related substance |
| 1.04 | 0.15 | 0.32 | +0.17 |
| 2.01 | 0.15 | 0.37 | +0.22 |
| 3.10 | 0.15 | 0.14 | -0.01 |
| 4.08 | 0.15 | 0.15 | 0 |
| 5.03 | 0.15 | 0.37 | +0.22 |
| 6.13 | 0.15 | 1.05 | +0.90 |
| 7.02 | 0.15 | 1.30 | +1.15 |
Annotate: change above-mentioned levosimendan or its pharmaceutical salts weight into different gram numbers, above-mentioned experimental result changes little.
Interpretation of result: experimental result as seen, pH value is higher than 5.0, the sample instability, related substance increases by 6～8 times, pH value is lower than 2.0, the sample related substance is little increase, sample is stable in the scope of pH value 3.0～4.0, the basic no change of related substance.Determine that by last experiment the pH value scope of levosimendan injection is 3～4.
The specific embodiment
The present invention's concrete technical scheme required for protection is not limited to the concrete combination of the expressed technical scheme of following embodiment.
Embodiment 1
Levosimendan 25 grams, maleic acid 0.1 gram, polyvidone 50 grams are got dehydrated alcohol and are prepared 10000ml, 1000 of preparation ejection preparations.
Embodiment 2
Levosimendan 25 grams, maleic acid 1 gram, polyvidone 200 grams are got dehydrated alcohol and are prepared 10000ml, 1000 of preparation ejection preparations.
Embodiment 3
Levosimendan 25 grams, maleic acid 0.5 gram, polyvidone 100 grams are got dehydrated alcohol and are prepared 10000ml, 1000 of preparation ejection preparations.
Embodiment 4
Levosimendan 25 grams, maleic acid 0.9 gram, polyvidone 70 grams are got dehydrated alcohol and are prepared 10000ml, 1000 of preparation ejection preparations.
Embodiment 5
Levosimendan 25 grams, maleic acid 0.4 gram, polyvidone 150 grams are got dehydrated alcohol and are prepared 10000ml, 1000 of preparation ejection preparations.
Embodiment 6
Levosimendan sodium salt 25 grams, maleic acid 0.8 gram, polyvidone 180 grams are got dehydrated alcohol and are prepared 10000ml, 1000 of preparation ejection preparations.
Embodiment 7
Levosimendan 20 grams, maleic acid 0.1 gram, polyvidone 50 grams are got dehydrated alcohol and are prepared 10000ml, 1000 of preparation ejection preparations.
Embodiment 8
Levosimendan 30 grams, maleic acid 1 gram, polyvidone 200 grams are got dehydrated alcohol and are prepared 10000ml, 1000 of preparation ejection preparations.
Embodiment 9
Levosimendan 22 grams, maleic acid 0.5 gram, polyvidone 100 grams are got dehydrated alcohol and are prepared 10000ml, 1000 of preparation ejection preparations.
Embodiment 10
Levosimendan 28 grams, maleic acid 0.9 gram, polyvidone 70 grams are got dehydrated alcohol and are prepared 10000ml, 1000 of preparation ejection preparations.
Embodiment 11
Levosimendan 25 grams, maleic acid 0.4 gram, polyvidone 150 grams are got dehydrated alcohol and are prepared 10000ml, 1000 of preparation ejection preparations.
Embodiment 12
Levosimendan 27 grams, maleic acid 0.8 gram, polyvidone 180 grams are got dehydrated alcohol and are prepared 10000ml, 1000 of preparation ejection preparations.
Claims (8)
1. a drug solution is an active component with levosimendan or its pharmaceutical salts, is solvent with the dehydrated alcohol, also comprises maleic acid and solubilizing agent polyvidone in the drug solution.
2. drug solution according to claim 1, its pH value are 3～4.
3. drug solution according to claim 1, wherein the w/v of levosimendan or its pharmaceutical salts is 0.2%～0.3%.
4. drug solution according to claim 1, wherein the w/v of levosimendan or its pharmaceutical salts is 0.25%.
5. drug solution according to claim 1, wherein the w/v of maleic acid is 0.001%～0.01%.
6. drug solution according to claim 1, wherein the w/v of maleic acid is 0.005%～0.009%.
7. drug solution according to claim 1, wherein the w/v of polyvidone is 0.5%～2%.
8. drug solution according to claim 1, wherein the w/v of polyvidone is 1%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100223940A CN101305984A (en) | 2007-05-16 | 2007-05-16 | Medicaments solution |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100223940A CN101305984A (en) | 2007-05-16 | 2007-05-16 | Medicaments solution |
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| Publication Number | Publication Date |
|---|---|
| CN101305984A true CN101305984A (en) | 2008-11-19 |
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| CNA2007100223940A Pending CN101305984A (en) | 2007-05-16 | 2007-05-16 | Medicaments solution |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108289832A (en) * | 2015-11-06 | 2018-07-17 | 卡利努法姆股份有限公司 | For carrying out the Levosimendan of intravenously administrable with infusion or injection form and being transfused the improvement formula of concentrate |
| CN111514147A (en) * | 2020-05-12 | 2020-08-11 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium medicinal composition for acute decompensated heart failure symptoms and preparation method thereof |
| CN111548310A (en) * | 2020-05-12 | 2020-08-18 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium crystal form and preparation method thereof |
| CN111718299A (en) * | 2020-07-23 | 2020-09-29 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium crystal form B and preparation method thereof |
-
2007
- 2007-05-16 CN CNA2007100223940A patent/CN101305984A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108289832A (en) * | 2015-11-06 | 2018-07-17 | 卡利努法姆股份有限公司 | For carrying out the Levosimendan of intravenously administrable with infusion or injection form and being transfused the improvement formula of concentrate |
| CN108289832B (en) * | 2015-11-06 | 2021-08-31 | 卡利努法姆股份有限公司 | Improved formulations of levosimendan and infusion concentrates for intravenous administration in infusion or injection form |
| CN111514147A (en) * | 2020-05-12 | 2020-08-11 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium medicinal composition for acute decompensated heart failure symptoms and preparation method thereof |
| CN111548310A (en) * | 2020-05-12 | 2020-08-18 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium crystal form and preparation method thereof |
| CN111548310B (en) * | 2020-05-12 | 2021-07-02 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium crystal form and preparation method thereof |
| CN111718299A (en) * | 2020-07-23 | 2020-09-29 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium crystal form B and preparation method thereof |
| CN111718299B (en) * | 2020-07-23 | 2023-03-10 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium crystal form B and preparation method thereof |
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Open date: 20081119 |