CN1611219A - Levosimendan medicinal composition and its preparing method - Google Patents
Levosimendan medicinal composition and its preparing method Download PDFInfo
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- CN1611219A CN1611219A CN 200310102271 CN200310102271A CN1611219A CN 1611219 A CN1611219 A CN 1611219A CN 200310102271 CN200310102271 CN 200310102271 CN 200310102271 A CN200310102271 A CN 200310102271A CN 1611219 A CN1611219 A CN 1611219A
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Abstract
The present invention relates to a medicine composition containing levosimondan as effective component and its perparation method. In the concrete, said invention relates to a powder injection containing levosimondan as effective component and its preparation method. As compared with existent similar injection said invented powder injection has the advantages of good stability, long storage period and convenient transportation, storage and application, etc.
Description
Technical field
Levosimendan powder of the present invention is medicinal, and main route of administration is intravenous injection.Sterile injection powder of the present invention has good stable, and they are specially adapted to transfusion.Levosimendan, chemical name (R)-(-)-2-[4 (4-methyl-6 oxo-1,4,5,6-tetrahydro pyridazine-3)-Ji-phenyl hydrazono-] Cyanoacetyl-Cyacetazid, be used for the treatment of congestive heart failure clinically.
The background of invention
Levosimendan is (-)-2-[4 (4-methyl-6 oxo-1,4,5,6-tetrahydro pyridazine-3)-Ji-phenyl hydrazono-] levo form of Cyanoacetyl-Cyacetazid, EP 565546 B1 and WO97/35841 disclose preparation method.Levosimendan is effectively to the treatment heart failure, is significant dependency with combining of troponin.The structural formula of levosimendan is as follows:
Levosimendan is published at Am.J.Cardiol.1995 by people such as Sundberg S. in the blood flow effect of human body; 75:1061～1066.Levosimendan is published in J.Cardiovasc.Pharmacol. at the pharmacokinetics of intravenous injection and oral back human body by people such as Sandell E-P., 26 (Suppl.1), and S57-S62,1995. levosimendans are used for the treatment of myocardial ischemia and are disclosed in WO93/21921.The percutaneous drug administration preparation of levosimendan is disclosed in WO98/01111.Clinical research has confirmed the favourable effect of levosimendan to patients with heart failure.
By the blood vessel administration, for example, intravenous injection is mainly comprised by many advantages: (1) intravenous injection or venous transfusion almost can obtain response immediately; (2) the treatment response is easier to control by vascular drug delivery; (3) because of loss of consciousness can't oral drugs the patient can pass through vascular drug delivery, or influence absorption because of the gastrointestinal tract inactivation.
The preparation of levosimendan injection solution is disclosed in WO01/19334, and injection particularly is suitable for the injection of intravenous route, relates to the many problems owing to the levosimendan stability that chemistry and physical factor are caused.Levosimendan solution is more responsive to chemical factor, has so just limited the shelf life of solution, produces unnecessary catabolite.Levosimendan is insoluble in water, is easy to be precipitated out from aqueous solution.In a single day it is very dangerous producing precipitation in the used for intravenous injection solution, because granule may be blocked blood vessel.When pH value when neutrality begins to descend, the dissolubility of levosimendan reduces rapidly, therefore, low pH value is disadvantageous to dissolubility in principle.Like this, being necessary to improve the levosimendan aqueous solution preparation can all stablize chemical factor, physical factor in the long term store process, and is suitable for intravenously administrable.
Patent specification in full
Levosimendan at room temperature is a crystalline powder, and pKa is 6.26.At room temperature, the dissolubility of levosimendan in phosphate buffer is 0.4mg/ml (pH7.4), 0.03mg/ml (pH6) and 0.02mg/ml (pH2).As seen, the dissolubility of levosimendan in water descends rapidly along with pH drops to below the neutrality.But found that the pH that can prepare medicinal acceptance is lower than 5.5 levosimendan aqueous solution.Such solution carries out lyophilization at long lay up period chemistry and physically stable with this solution, is particularly suitable for medicinal.
On the one hand, the invention provides the salt that contains levosimendan or the pharmaceutically acceptable acceptance powder as active component, the pH of its aqueous solution is lower than 5.5, preferably is lower than 5 or lower, and optimum is about 3～4.5.The preparation of invention can be used for various medicinal applications, must exist with powder type at lay up period.
Preparation of the present invention contains in the treatment of levosimendan the effectively route of administration of amount and preparation, and Therapeutic Method is with relevant by the situation of therapist.Usually, in the preparation weight range of levosimendan at 0.001～5mg/ml.The human dosage range of levosimendan preferably is about 0.2～20mg at 0.1～50mg, and is relevant with route of administration, age, body weight and patient disease situation.Scope was at 1～300ng/ml when optimum blood peak concentration of drug reached stable state in the congestive heart failure treatment, and that more excellent is 10～150ng/ml, between particularly about 20～60ng/ml.The speed of levosimendan intravenously administrable is 0.005～100 μ g/kg/min, typically is 0.01～10 μ g/kg/min, more typically 0.02～1 μ g/kg/min.Speed for the suitable continuous infusion of patients with heart failure treatment levosimendan is 0.05～0.4 μ g/kg/min.
Levosimendan salt can prepare with known method.Medicinal acceptable salt is as active medicine.But preferred salt is alkali metal or alkali salt.
Controlling suitable pH is very important for keeping the levosimendan stability of formulation.Therefore, allow to use suitable medicinal acceptable acid compound or buffer system.Preferred acid compound comprises the organic acid of medicinal acceptable pKa between 2～4, and these acid comprise the acid of 2-hydroxyl alkanol, as citric acid, lactic acid, tartaric acid or malic acid.As use medicinal acceptable buffer system, and from the buffer agent classification, select can to keep pH effectively below 5.5, preferably below 5 or lower, most preferably in 3～4.5 scopes, the method known to the preparation of buffer agent is to use widely.
Preparation of the present invention also contains dissolubility improving agent (solubilizing agent) simultaneously, can increase the dissolubility of levosimendan, makes it keep dissolved state in aqueous solution, and prevents levosimendan crystallization in water, or crystalline growth.The dissolubility improving agent that is suitable for comprises cosolvent, for example ethanol or propylene glycol, surfactant and polymer substance such as poly yamanashi esters, poly-alkyl alcohols (as Polyethylene Glycol), poloxamer or polyvidone and fatty acid and single or two glyceride, for example linoleic acid or glyceryl monolaurate.Usually, the consumption of dissolubility improving agent is preferably 0.005～10% 0.001～80% of the preparation total amount, most preferably 0.01～5%.When being used for intravenous injection, alternative adjuvant is just limited, and polyvidone or ethanol or its mixture are preferred dissolubility improving agent, and wherein polyvidone is most preferred.Molecular weight is better suited at the polyvidone below 40000, and what be more suitable for is below 5000, particularly is about 2500.Preferably use the polyvidone of BASF AG, commodity are called Kollidone PF12.
The present invention also contains scalable etc. and oozes the filler that plays the skeleton supporting role simultaneously in freeze-drying process, lactose, mannitol, glycine etc., and more excellent with lactose, mannitol, mannitol is more excellent.Consumption more preferably is 1%～8%, optimally 3%～6% at 0.5%～10% (w/v) of the heavy molten back of powder solution.
The normal various adjuvants that use in the injection, for example antiseptic etc. also can use in preparation of the present invention.
On the other hand, the invention provides the water-soluble injection freeze-dried powder that contains levosimendan or its salt.The pH value of its powder aqueous solution should be lower than 5.5, more preferably should be lower than 5, optimally should hang down between 3～4.5.The aqueous solution of venoclysis can be injection or transfusion.Sterile injection powder of the present invention is chemically stable and physically stable in secular storage process.More excellent sterile injection powder is easy to heavily dissolve with water for injection, and is used for venous transfusion or disposable injection.
The amount of the levosimendan that comprises in the preparation of the present invention is relevant with therapeutic process and patient's situation.But normally treatment is effectively measured.This amount can preferably be about 0.005～0.5mg/ml at 0.001～1.0mg/ml, more preferably is about 0.01～0.1mg/ml.
Keep the acid compound of the required medicinal acceptance of pH of the heavy molten rear solution of preparation of the present invention or the consumption of buffer, in above relevant portion introduction.
Preparation of the present invention can be used for increasing levosimendan and can keep the amount of dissolved state at aqueous solution by adding dissolubility improving agent (solubilizing agent), comprises preventing levosimendan crystallization or crystalline growth in solution.The pharmaceutic adjuvant that can be used for venoclysis is more limited, and polyvidone and ethanol or its mixture are more excellent solubilizing agents, and polyvidone is most preferred.The solubilizing agent amount ranges is usually in 0.001～20% of total amount in the sterile injection powder preparation, and preferably 0.01～10% of the powder total amount.Most preferred amount is 0.1～5% of a powder total amount.
Preparation of the present invention is that sterilized powder by dissolving levosimendan and other adjuvants is in aseptic water for injection.Preparation technology is as follows: the dissolving levosimendan adds other suitable adjuvants lack in the volume of ethanol as far as possible, and thin up divides the lyophilizing of packing into in the bottle, lyophilization to finite concentration after the aseptic filtration; Or first lyophilization, spray drying or vacuum drying, carry out the sterilized powder packing again.
But on the other hand, the invention provides the powder of pharmaceutically acceptable injection, particularly use preceding with water for injection dissolving carrying out intravenous injection.Sterile injection powder of the present invention contains: a) levosimendan or medicinal acceptable salt are as active component.B) can improve stable medicinal acceptable organic acid, its pKa value is about 2～4.Result of the test finds that adding pKa is 2～4 medicinal acceptable short chain (containing 6 following carbon) organic acid, has improved the stability of the sterile injection powder of preparation.Found freeze-dried powder can be successfully with the water for injection dissolving, obtain venous transfusion, and in the long time chemistry and physically stable.
Before the preparation freeze-dried powder, with the organic solvent dissolution of pharmaceutically acceptable acceptance, its consumption before lyophilizing 1～20% of the solution total amount, preferably 3～15%, optimally contains organic etoh solvent amount and accounts for 5～8% of solvent total amount usually.Be more suitable for ground, remaining solvent is a water for injection, after the solution of the ethanol-water mixed solvent of medicine prepares, carries out lyophilization immediately.
Medicinal acceptable organic acid preferred range is 0.005～2% of the preceding solution weight of lyophilizing, and more excellent is 0.01～1%.The preferably 2-hydroxyl alkanol acid of said medicinal acceptable organic acid, but such acid comprises citric acid, tartaric acid malic acid, most preferably citric acid.
Levosimendan consumption in the preparation of the present invention be for producing the amount of enough drug effects, and for example 0.01～10% of lyophilized formulations weight, preferably 0.1～5%, most preferred is 0.25～1%.Used for intravenous injection powder formulation of the present invention is to be grouped into by following one-tenth:
A) levosimendan or pharmaceutically useful salt account for 0.1～5% of total formulation weight amount;
B) the citric acid consumption is 0.01～5% of a total formulation weight amount;
C) the polyvidone consumption is 0.1～10% of a total formulation weight amount;
D) the mannitol consumption is 85～99% of a total formulation weight amount.
The preparation of lyophilized formulations: can first steady dissolution property improvement agent organic acid, levosimendan and appropriate solubilizing agent and other adjuvants that may use, under stirring condition, in sterile chamber, dissolve.The solution of gained filters with sterile filters.Making the aseptic best approach of preparation is aseptic filtration, because preparation process has used organic solvent ethanol, and the danger that certain density ethanol is easily blasted in the pressure sterilizing process.The solution of aseptic filtration can first lyophilization, carries out the freeze-dried powder packing again; Or divide the lyophilizing of packing into earlier with in the bottle, carrying out lyophilization, seal with rubber seal plug then.
The lyophilizing of earlier the solution branch being packed into only is described in detail in detail with bottle, carry out freeze dried preparation technology more here.The above-mentioned mixed solution that contains levosimendan and excipient is sub-packed in 10ml by every bottle of 5ml～30ml, in the lyophilizing bottle of 20ml or 50ml, do not seal and put into freeze drying box, freeze drying box is carried out sterilization treatment, and the temperature of its shelf reduced to-30 ℃～40 ℃, the metal dish that preparation will be housed is put into freeze drying box rapidly, kept 1～2 hour, then freeze drying box is carried out application of vacuum, making the vacuum in the case is 0.2～0.4Pa, again shelf is heated up, and be strict controlled in below the eutectic point-20 ℃ (promptly than low 20 degrees centigrade of eutectic point), kept 12～24 hours, be warming up to 25～40 ℃ at last, and the maintenance certain hour, formulation temperature is overlapped with shelf temperature, put into the gas of aseptic filtration, the water content of control preparation is sealed rapidly and is got final product 0.1～3%.
Selectable optimum physical condition is in the freezing dry process: at first shelf is cooled to-30 ℃, kept 2 hours, making the vacuum in the freeze drying box then is 0.2Pa, shelf is heated up and be strict controlled in below-20 ℃, kept 18 hours, with shelf be warming up to 30～40 ℃ put into aseptic gas after, control preparation water content be 1%.
The amount of solid of the injectable powder for preparing every bottle (25ml) is 0.5～1.0g, wherein contains levosimendan 4～8mg, contains citric acid 2.5～5mg, contains polyvidone 16～32mg, contains mannitol 0.478g～0.955g, accounts for 85～99% of amount of solid.
Freeze-dried powder dissolves with water for injection before venous transfusion.The clinical working concentration of levosimendan is generally 0.001～1.0mg/ml, is 0.005～0.5mg/ml more preferably, is more preferably 0.01～0.1mg/ml, and is relevant with Therapeutic Method and patient's situation.
The preparation of invention can be used following case description, but is not limited thereto;
Example 1: used for intravenous injection powder
A) citric acid 2.5mg polyvidone 16mg d mannitol 0.4775g c west, left side 4mg b in the Meng)))
Sterile injection powder is that citric acid, polyvidone PF12 and levosimendan under agitation are dissolved in the dehydrated alcohol, operates in the sterile chamber and carries out; Again mannitol is dissolved in the sterile water for injection, joins while stirring in the above levosimendan alcoholic solution, filter with sterile filters (0.22 μ m).Making product keep aseptic method is aseptic filtration.Can earlier above solution branch be installed to lyophilizing bottle, lyophilization.Also can first lyophilizing, carry out the sterilized powder packing again.
Product can be stored 2 years at 15～20 ℃.
Example 2:
The acid of structure rafter has been carried out the research of different storage temperatures to the influence of levosimendan used for intravenous injection power stability.Solution as described in Example 1.The results are shown in table 1 and 2." OR-R746 " is meant (4-ethyoxyl-6-imino group-5-{[4-(4-methyl-6-oxygen-1,4,5 in the table, 6-tetrahydrochysene-3-pyridazinyl)-and phenyl] hydrazono-}-5,6-dihydro-1 (H)-pyrimidine-2-subunit-[4-(4-methyl-6-oxygen-1,4,5,6-tetrahydrochysene-3-pyridazinyl)-phenylazo] acetonitrile.
The acid of table 1. structure rafter is to the influence of levosimendan chemical stability.All the components in the preparation comprises levosimendan 2mg, mannitol 0.4775, polyvidone 16mg.
| Citric acid mg/g | Period of storage/catabolite (OR-1746) | |
| 15～20℃ | 40℃ | |
| 0 | 5 week/0.36% | 5 week/2.9% |
| 0.5 | 13 week/0.32% | 13 week/1.7% |
| 1.0 | 13 week/0.28% | 13 week/1.3% |
| 1.5 | 13 week/0.19% | 13 week/1.0% |
| 2.0 | 13 week/0.15% | 13 week/0.8% |
| 2.5 | 13 week/0.15% | 13 week/0.7% |
| 3.0 | 13 week/0.15% | 13 week/0.7% |
Example 2. transfusions, pH4.5
A) levosimendan 0.025mg/ml
B) polyvidone PF12 0.10mg/ml
C) citric acid 0.0156mg/ml
D) mannitol 2.986mg/ml
E) water 1ml
Above aqueous solution is the used for intravenous injection powder of example 1 to be diluted to etc. with water for injection ooze, and obtains the levosimendan solution of 0.025mg/ml.Solution clarification after the dilution does not have precipitation.
The levosimendan solution of research example 2 is in the chemical stability of room temperature storage 24h, and 2～8 ℃ of stability of storing a week.The results are shown in Table 2, OR-1420 is meant (E)-2-cyano group-2-[[4-(1,4,5,6-tetrahydrochysene-4-methyl-6-oxygen-3-pyridazinyl) phenyl] hydrazono-] acetamide.
Table 2. levosimendan solution in example 2 is stored the 24h (25 ℃ of room temperatures) and the stability in a week (2～8 ℃)
| 0 | 24h | One week | |
| The related substance summation | ＜ | ＜ | 0.1％ |
| PH value | 4.5 | 4.5 | 4.5 |
＜refer at detectability below 0.1%
Be the stability of contrast injectable powder and solution, studied the levosimendan alcoholic solution, result of the test is listed in the table 3 15～20 ℃ and 40 ℃ of chemical stabilities of storing 5 weeks, 13 weeks.
Reference solution:
A) levosimendan 0.01～0.25mg/ml
B) polyvidone PF12 0.04～1mg/ml
C) citric acid 0.008～0.2mg/ml
D) ethanol is to 1ml
15～20 ℃ and 40 ℃ stability of storing 5 weeks, 13 weeks of table 3. levosimendan injection solution stability
| Citric acid mg/g | Period of storage/catabolite (OR-1746) | |
| 15～20℃ | 40℃ | |
| 0 | 5 week/3.3% | 5 week/10.9% |
| 0.5 | 13 week/2.8% | 13 week/6.2% |
| 1.0 | 13 week/2.2% | 13 week/4.4% |
| 1.5 | 13 week/1.70% | 13 week/3.5% |
| 2.0 | 13 week/1.3% | 13 week/3.0% |
| 2.5 | 13 week/0.9% | 13 week/2.2% |
| 3.2 | 13 week/0.8% | 13 week/1.7% |
The result shows: the stability of levosimendan sterile injection powder is far superior to reference levosimendan solution.
Claims (11)
1. one kind contains levosimendan and/or its officinal salt as the freeze drying powder preparations of active component, it is characterized in that this powder formulation contains at least a medicinal acid, solubilizing agent and lyophilizing filler.
2. according to the freeze drying powder preparations of claim 1, it is characterized in that described organic acid pKa value is 2～4, can be selected from citric acid, lactic acid, tartaric acid or malic acid, optimum is the acid of structure rafter.
3. according to the freeze drying powder preparations of claim 2, the consumption that it is characterized in that citric acid is 0.01～5% of a total formulation weight amount, and optimum is 0.1～1%.
4. according to the freeze drying powder preparations of claim 3, it is characterized in that the pH optimum with the solution that obtains behind the water dissolution is 3～4.5.
5. according to the freeze drying powder preparations of claim 1, it is characterized in that also containing the total formulation weight amount 0.1～20% be selected from polyvidone, Polyethylene Glycol or poloxamer as solubilizing agent.
6. according to the freeze drying powder preparations of claim 5, the preferred polyvidone of solubilizing agent, the specification preferred molecular weight is less than 2500 Kollidone PF12 (BASF AG's product).
7. according to the freeze drying powder preparations of claim 6, the polyvidone consumption is preferably 0.01～10% 0.001～20% of the total formulation weight amount, most preferably is 0.1～5%.
8. according to the freeze drying powder preparations of claim 1, its filler is selected from lactose, mannitol, glycine.
9. according to the freeze drying powder preparations of claim 8, it is characterized in that filler is a mannitol, consumption is 85～99% of a total formulation weight amount.
10. preparation is by the method for the freeze drying powder preparations of claim 1, it is characterized in that described powder formulation soluble in waterly, and the freeze-dried powder packing is carried out in directly lyophilizing after the optional filtration sterilization afterwards.Or solution is sub-packed in the lyophilizing usefulness bottle of 5ml, 10ml, 20ml or 50ml; Do not seal and put into and freeze drying box size corresponding metal dish, freeze drying box is carried out sterilization treatment, and its shelf temperature is reduced to-30 ℃～-40 ℃ kept 1～2 hour, then freeze drying box is carried out application of vacuum, make the interior vacuum of case at 0.2～0.1Pa, again shelf is heated up, and its 5 degree below fusing point of strict control, kept 12～24 hours, and be warming up to 25～30 ℃ at last, keep certain hour, formulation temperature is overlapped with shelf temperature, put into aseptic filtering gas, the water content of control preparation is sealed rapidly and is got final product 0.1～3%.
11., it is characterized in that in the freezing dry process at first the shelf cooling and be strict controlled in below-2 ℃ according to the method for claim 10, kept 12 hours, with shelf be warming up to 25 ℃～35 ℃ put into aseptic gas after, the water content of controlling preparation is 1～2%.
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Cited By (2)
| 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 |
| CN116473930A (en) * | 2023-05-17 | 2023-07-25 | 山东泰合医药科技有限公司 | Levosimendan for injection and preparation method thereof |
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2003
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Cited By (5)
| 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 |
| CN116473930A (en) * | 2023-05-17 | 2023-07-25 | 山东泰合医药科技有限公司 | Levosimendan for injection and preparation method thereof |
| CN116473930B (en) * | 2023-05-17 | 2023-12-15 | 山东泰合医药科技有限公司 | Levosimendan for injection and preparation method thereof |
| WO2024183828A1 (en) * | 2023-05-17 | 2024-09-12 | 山东泰合医药科技有限公司 | Levosimendan for injection and preparation method therefor |
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