CN1839842A - Pharmaceutical composition containing levosimendan or its pharmaceutically acceptable salt as active ingredient - Google Patents
Pharmaceutical composition containing levosimendan or its pharmaceutically acceptable salt as active ingredient Download PDFInfo
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- CN1839842A CN1839842A CN 200610000963 CN200610000963A CN1839842A CN 1839842 A CN1839842 A CN 1839842A CN 200610000963 CN200610000963 CN 200610000963 CN 200610000963 A CN200610000963 A CN 200610000963A CN 1839842 A CN1839842 A CN 1839842A
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- levosimendan
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Abstract
The invention relates to a pharmaceutical composition, wherein each unit dosage comprises: (1) 5-50mg of Levosimendan or its pharmaceutically acceptable salt, (2) 10-200mg of Solutol HS 15, (3) 0.1-1000ml of medicinal solvent.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation, a kind of pharmaceutical solutions of particularly anti-heart failure medicine levosimendan.The safety of intravenous administration and the problem of stability have been solved.
Background technology
Levosimendan, chemical name [(-)-[4-(1,4,5,6-tetrahydrochysene-4-methyl-6-oxo-3-pyridazinyl) phenyl] hydrazono-] Cyanoacetyl-Cyacetazid, be a kind of be effective medicine in the treatment of congestive heart failure.Levosimendan is effectively in the treatment of heart failure, and Ca-dependent significant and that troponin interrelates is arranged. levosimendan is expressed from the next:
Levosimendan is a kind of medicine that is insoluble in water, Sundberg, 5. etc., and at Am.J.Cardiol., 1995; Put down in writing the hematodinamics effect of levosimendan among the 75:1061-1066 to human body.Sandell, E-P. etc., at J.cardiovasc.Pharmacol., 26 (suppl.1) have put down in writing the pharmacokinetics of levosimendan behind human vein and the oral administration in 557-562,1995.WO93/21921 has put down in writing the purposes of levosimendan aspect the treatment myocardial ischaemia.WO98/01111 has put down in writing the transdermal composition of levosimendan.Clinical research confirmation the beneficial effect of levosimendan to the heart failure patient.Drug solution by the levosimendan of Orion-Yhtyma OY research and development in 2000, and apply for a patent in China, but its used solubilizing agent polyethylene pyrrole Lip river alkane ketone or other surfactant prove that clinically tool all has the blood coagulation side effect, brings the treatment risk to the patient.
The levosimendan pharmaceutical solutions adopts ethanol as solvent in addition in the prior art, or adds other organic solvents, or the levosimendan enclose is made methods such as dissolving, and above method does not all solve the dissolubility of preparation and the problem of stability fully.
Solutol
HS15 is a kind of solubilizing agents for drugs that is provided by BASF AG, is incorporated in the Deutscher Arzneibucs.Solutol
HS15 is a kind of Polyethylene Glycol (PEG) 12-hydroxy stearic acid ester, and structure is as follows:
Solutol
Outward appearance is light yellowish-white paste under the HS15 room temperature.It and used in the past solubilizing agent such as CremophorEL, Cremophor RH40, Cremophor 60 or Tweens, as Tween 80, Tween 65, Tween 20 or wheat pool class, as Myrj 52 or Labrafil M 1944 CS (Oleoyl Macrogo1-6 glycerides), LabrafilM 2125 CS (Linoleoyl macrogol-6 glycerides), Labrasol (Caprylocaproylmacrogol-8 glycerides), Lauroglycol 90 (Propylene glycol monolaurate), Plurololeique CC 497 (Polyflyceryl-6 dioleate) solubilization-aid effect is similar.
With Solutol
HS15 is used to prepare the levosimendan pharmaceutical solutions, and report is not arranged at present.
In order to improve the bioavailability of levosimendan, dissolubility, improve the medicine stability of preparation, the present invention is carrying out the levosimendan medicine on the basis of solubilization studies, combination to many kinds of surfactants, surface activity auxiliary agent, solubilizing agent, oily components is studied, and finds to use Solutol
HS15 can make medicine more stable in solution, and dissolubility is better, the appearance of catabolite in the restriction storage life, the haemolysis that is produced when reducing intravenous injection or the harm of other some side effect.
Summary of the invention:
The invention provides a kind of levosimendan pharmaceutical solutions prescription,
The present invention selects ethanol for use, propylene glycol, and glycerol, and other pharmaceutically acceptable organic solvent is as the levosimendan solvent, with Solutol
HS15 is solubilizing agent, Solutol
The HLB value of HS15 is 14 to 16, is a kind of hydrophilic surfactant active.
In the compositions of the present invention, select Solutol for use
The HS15HLB value is 14 to 16 the medicinal hydrophilic surfactant active solubilizing agent for fat-soluble medicine, to promote that hydrophilic and oleophilic moiety reaches balance in the compositions, forms stable drug solution.This class HLB value is that 14 to 16 surfactant is Solutol
HS15, than castor oil derivatives, as Cremophor EL, Cremophor RH40, Cremophor 60 or Tweens, as Tween 80, Tween 65, Tween 20 or wheat pool class, better as Myrj 52 lyotropy, more can avoid the precipitation of active component, other medicinal surfactant of injection stage that the haemolysis side effect is lower.
Levosimendan pharmaceutical solutions of the present invention wherein contains
(a) as the levosimendan of active component, every dose contains 5-50mg, preferably 10-25mg
(b) solubilizing agent Solutol
HS15, every dose contains 10-200mg, preferably 20-100mg
(c) medicinal solvent, every dose contains 0.1-1000ml, preferably 0.2-10ml
Levosimendan pharmaceutical solutions of the present invention can be prepared into different dosage forms as required, as dosage forms such as injection, frozen powder for injection, soft capsule, ointment, eye drop, oral liquids.
The above every dose unit form that is meant above dosage form, as each injection, each soft capsule.
Can be according to the different requirements of each dosage form, can not add entry or add suitable water or other solvent or add suitable pharmaceutical excipient,
Wherein said medicinal solvent is selected from ethanol, propylene glycol, glycerol, and other pharmaceutically acceptable organic solvent.Preferably: ethanol, propylene glycol.
Wherein said suitable pharmaceutical excipient comprises the pH value regulator, as pharmaceutically acceptable pH value regulator, is routine or known substance, and its Pka is in the 2-5 scope.As citric acid or phosphate, citrate, lactate, acetate etc., its consumption is determined as required, regulates PH between 4-9, and consumption is generally in 1.1%, preferably: in 1.0%.
Levosimendan of the present invention also comprises the pharmaceutically acceptable salt of levosimendan.
The most preferred prescription composition of the present invention is listed in the embodiment of the invention.
Prescription of the present invention is selected Solutol for use in forming
HS15 makes the present invention more stable than prior art as surfactant, and toxicity is lower, and patient's medication is safer, more is applicable to injecting drug use.
Another unique distinction of the present invention is, different use according to compositions can add water, also can add a certain proportion of water, as in levosimendan compositions liquid, adding a certain proportion of water, can reduce compositions and solidify or form the temperature of floccule, make it under relatively low temperature, still can keep haze-free.These characteristics also can be used for the preparation of hydrophilic ointment and eye drop.Simultaneously according to clinically different demands, the compositions that contains levosimendan or its pharmaceutically acceptable salt of the present invention can be prepared into gelatin and be encapsulated as soft capsule, also can be made into dosage forms such as ointment, oral liquid, injection, injection freeze-dried powder and liniment.
The preparation method of different dosage form of the present invention can require according to the galenic pharmacy routine techniques of said preparation to carry out.As the preparation of injection is levosimendan or pharmaceutically acceptable salt with recipe quantity, and Solutol
HS15, and medicinal solvent and pharmaceutical excipient mix, and make dissolving, and packing promptly.
Following data declaration beneficial effect of the present invention by experiment:
The drug solution (abbreviation Comparative formulation) of the contrast levosimendan that injection water injection that levosimendan compositions of the present invention and embodiment 1 are made and CN1203855C patent prescription make and the stability that the injection that makes is put illumination (4500lx), high temperature (60 ℃), high temperature (40 ℃) and low temperature (4 ℃) under thereof are investigated investigation data such as following table 1.
Table 1: the stability contrast of levosimendan compositions of the present invention and Comparative formulation
PROJECT TIME (my god) | Character | Clarity | Related substance % | Content % | |||||
The present composition | Comparative formulation | The present composition | Comparative formulation | The present composition | Comparative formulation | The present composition | Comparative formulation | ||
Illumination 4500LX | 0 | Yellow clear liquid | Yellow clear liquid | Qualified | Qualified | 0.22 | 0.24 | 99.78 | 99.76 |
5 | Yellow clear liquid | Yellow clear liquid | Qualified | Qualified | 0.53 | 0.55 | 99.47 | 99.45 | |
10 | Yellow clear liquid | Yellow clear liquid | Qualified | Qualified | 1.58 | 1.63 | 98.42 | 98.37 | |
60 ℃ of high temperature | 0 | Yellow clear liquid | Yellow clear liquid | Qualified | Qualified | 0.22 | 0.24 | 99.78 | 99.76 |
5 | Yellow clear liquid | Yellow clear liquid | Qualified | Qualified | 6.27 | 6.39 | 93.72 | 93.61 | |
10 | Yellow clear liquid | Yellow clear liquid | Qualified | Qualified | 7.69 | 7.90 | 92.31 | 92.10 | |
40 ℃ of high temperature | 0 | Yellow clear liquid | Yellow clear liquid | Qualified | Qualified | 0.22 | 0.24 | 99.78 | 99.76 |
5 | Yellow clear liquid | Yellow clear liquid | Qualified | Qualified | 0.61 | 0.63 | 99.39 | 99.37 | |
10 | Yellow clear liquid | Yellow clear liquid | Qualified | Qualified | 1.30 | 1.41 | 98.70 | 98.59 | |
4 ℃ of low temperature | 0 | Yellow clear liquid | Yellow clear liquid | Qualified | Qualified | 0.22 | 0.24 | 99.78 | 99.76 |
5 | Yellow clear liquid | Yellow clear liquid | Qualified | Qualified | 0.22 | 0.23 | 99.78 | 99.77 |
10 | Yellow clear liquid | Yellow clear liquid | Qualified | Qualified | 0.24 | 0.25 | 99.76 | 99.75 |
By table as seen, compositions of the present invention, under illumination (4500lx), high temperature (60 ℃), high temperature (40 ℃) condition, the drug solution of the contrast levosimendan that makes with CN1203855C patent prescription is compared better, and related substance and content are more or less the same, and illustrate that levosimendan compositions of the present invention is equally stable than the drug solution of the levosimendan of CN1203855C patent.Each 5ml of drug solution of the injection composition that example 1 is made and the levosimendan of CN1203855C patent respectively with 100ml5% glucose injection and 0.9% sodium chloride injection in compatibility, detect 8 hours in the mass change situation, the results are shown in Table 2.
Table 2: compatibility experimental result in the drug solution of the levosimendan of ejection preparation that pharmaceutical composition of the present invention makes and CN1203855C patent and glucose injection and 0.9% sodium chloride injection
Time h | Character | PH value | Clarity | Related substance (%) | ||||
5% glucose injection | 0.9% sodium chloride injection | 5% glucose injection | 0.9% sodium chloride injection | 5% glucose injection | 0.9% sodium chloride injection | 5% glucose injection | 0.9% sodium chloride injection | |
Ejection preparation of the present invention | ||||||||
0 | Faint yellow clear liquid | Faint yellow clear liquid | 3.89 | 3.45 | Qualified | Qualified | 0.23 | 0.24 |
2 | Faint yellow clear liquid | Faint yellow clear liquid | 3.89 | 3.45 | Qualified | Qualified | 0.23 | 0.25 |
4 | Faint yellow clear liquid | Faint yellow clear liquid | 3.90 | 3.44 | Qualified | Qualified | 0.26 | 0.27 |
6 | Faint yellow clear liquid | Faint yellow clear liquid | 3.91 | 3.46 | Qualified | Qualified | 0.34. | 0.37 |
8 | Faint yellow clear liquid | Faint yellow clear liquid | 3.89 | 3.45 | Qualified | Qualified | 0.51 | 0.59 |
Comparative formulation | ||||||||
0 | Faint yellow clear liquid | Faint yellow clear liquid | 3.88 | 3.43 | Qualified | Qualified | 0.24 | 0.23 |
2 | Faint yellow clear liquid | Faint yellow clear liquid | 3.88 | 3.45 | Qualified | Qualified | 0.24 | 0.23 |
4 | Faint yellow clear liquid | Faint yellow clear liquid | 3.89 | 3.41 | Qualified | Qualified | 0.25 | 0.26 |
6 | Faint yellow clear liquid | Faint yellow clear liquid | 3.87 | 3.42 | Qualified | Qualified | 0.26 | 0.26 |
8 | Faint yellow clear liquid | Faint yellow clear liquid | 3.90 | 3.43 | Qualified | Qualified | 0.35 | 0.36 |
0 | Faint yellow clear liquid | Faint yellow clear liquid | 3.88 | 3.43 | Qualified | Qualified | 0.51 | 0.60 |
The result shows: compatibility in injection that levosimendan compositions of the present invention is made and 5% glucose injection and 0.9% sodium chloride injection, and stable equally with the drug solution of the levosimendan of CN1203855C patent in the 8h.
The drug solution (being called for short Comparative formulation x) of the contrast levosimendan that frozen powder for injection injection that levosimendan compositions of the present invention and embodiment 3 are made and CN1203855C patent prescription make and the stability that the injection that makes is put under illumination (4500lx), high temperature (60 ℃), high temperature (40 ℃) and the low temperature (4 ℃) thereof are investigated
Investigate data such as following table.
Table 3: the stability contrast of levosimendan freeze-dried powder of the present invention and Comparative formulation
PROJECT TIME (my god) | Character | Clarity | Related substance % | Content % | |||||
Freeze-dried powder of the present invention | Comparative formulation | Freeze-dried powder of the present invention | Comparative formulation | Freeze-dried powder of the present invention | Comparative formulation | Freeze-dried powder of the present invention | Comparative formulation | ||
Illumination 4500LX | 0 | Yellow lyophilizing block | Yellow clear liquid | Qualified | Qualified | 0.26 | 0.24 | 99.74 | 99.76 |
5 | Yellow lyophilizing block | Yellow clear liquid | Qualified | Qualified | 0.41 | 0.55 | 99.59 | 99.45 | |
10 | Yellow lyophilizing block | Yellow clear liquid | Qualified | Qualified | 1.18 | 1.63 | 98.82 | 98.37 | |
60 ℃ of high temperature | 0 | Yellow lyophilizing block | Yellow clear liquid | Qualified | Qualified | 0.26 | 0.24 | 99.74 | 99.76 |
5 | Yellow lyophilizing block | Yellow clear liquid | Qualified | Qualified | 5.07 | 6.39 | 94.93 | 93.61 |
10 | Yellow lyophilizing block | Yellow clear liquid | Qualified | Qualified | 6.52 | 7.90 | 93.48 | 92.10 | |
40 ℃ of high temperature | 0 | Yellow lyophilizing block | Yellow clear liquid | Qualified | Qualified | 0.26 | 0.24 | 99.74 | 99.76 |
5 | Yellow lyophilizing block | Yellow clear liquid | Qualified | Qualified | 0.50 | 0.63 | 99.50 | 99.37 | |
10 | Yellow lyophilizing block | Yellow clear liquid | Qualified | Qualified | 0.81 | 1.41 | 99.19 | 98.59 | |
4 ℃ of low temperature | 0 | Yellow lyophilizing block | Yellow clear liquid | Qualified | Qualified | 0.26 | 0.24 | 99.74 | 99.76 |
5 | Yellow lyophilizing block | Yellow clear liquid | Qualified | Qualified | 0.26 | 0.23 | 99.74 | 99.77 | |
10 | Yellow lyophilizing block | Yellow clear liquid | Qualified | Qualified | 0.27 | 0.25 | 99.73 | 99.75 |
By table as seen, composite freeze-dried powder of the present invention, under illumination (4500lx), high temperature (60 ℃), high temperature (40 ℃) condition, the drug solution of the contrast levosimendan that makes with CN1203855C patent prescription is compared better, related substance and content are more or less the same, and illustrate that levosimendan compositions of the present invention is equally stable than the drug solution of the levosimendan of CN1203855C patent.Each 5ml of drug solution of one of the freeze-dried powder that example 3 is made and the levosimendan of CN1203855C patent respectively with 100ml5% glucose injection and 0.9% sodium chloride injection in compatibility, detect 8 hours in the mass change situation, the results are shown in Table 4.
Table 4: compatibility experimental result in the drug solution of the levosimendan of frozen powder for injection pin of the present invention and CN1203855C patent and glucose injection and 0.9% sodium chloride injection
Time h | Character | PH value | Clarity | Related substance (%) | ||||
5% glucose injection | 0.9% sodium chloride injection | 5% glucose injection | 0.9% sodium chloride injection | 5% glucose injection | 0.9% sodium chloride injection | 5% glucose injection | 0.9% sodium chloride injection | |
Ejection preparation of the present invention | ||||||||
0 | Faint yellow clear liquid | Faint yellow clear liquid | 7.52 | 7.40 | Qualified | Qualified | 0.28 | 0.29 |
2 | Faint yellow clear | Faint yellow clear and bright | 7.57 | 7.39 | Qualified | Qualified | 0.29 | 0.31 |
Prescribed liquid | Liquid | |||||||
4 | Faint yellow clear liquid | Faint yellow clear liquid | 7.58 | 7.40 | Qualified | Qualified | 0.30 | 0.33 |
6 | Faint yellow clear liquid | Faint yellow clear liquid | 7.59 | 7.43 | Qualified | Qualified | 0.31. | 0.35 |
8 | Faint yellow clear liquid | Faint yellow clear liquid | 7.60 | 7.42 | Qualified | Qualified | 0.49 | 0.52 |
Comparative formulation | ||||||||
0 | Faint yellow clear liquid | Faint yellow clear liquid | 3.88 | 3.43 | Qualified | Qualified | 0.24 | 0.23 |
2 | Faint yellow clear liquid | Faint yellow clear liquid | 3.88 | 3.45 | Qualified | Qualified | 0.24 | 0.23 |
4 | Faint yellow clear liquid | Faint yellow clear liquid | 3.89 | 3.41 | Qualified | Qualified | 0.25 | 0.26 |
6 | Faint yellow clear liquid | Faint yellow clear liquid | 3.87 | 3.42 | Qualified | Qualified | 0.26 | 0.26 |
8 | Faint yellow clear liquid | Faint yellow clear liquid | 3.90 | 3.43 | Qualified | Qualified | 0.35 | 0.36 |
0 | Faint yellow clear liquid | Faint yellow clear liquid | 3.88 | 3.43 | Qualified | Qualified | 0.51 | 0.60 |
The result shows: compatibility in levosimendan freeze-dried powder of the present invention and 5% glucose injection and 0.9% sodium chloride injection, and more stable with the drug solution of the levosimendan of CN1203855C patent in the 8h, satisfy the clinical application requirement.
Advantage of the present invention also shows:
(1) need not to use hydryllin and corticoid before low histamine release-art;
(2) low haemolysis;
(3) higher physiological tolerance; The used vapour sterilization need not expensive aseptic manufacturing process;
(4) low viscosity, high solubilising power-make the injection of low capacity high dose become possibility, even low viscosity when high concentration, 30% resolution solution also can painless administration; Stimulation and the some other serious problems that cause owing to used adjuvant high viscosity before solving to vascular system.
The present invention improves levosimendan dissolubility and water stability thereof, further makes its stability that has better chemistry and physics in the storage life that prolongs, and reduces the hemolytic of clinical injection medication, makes it be more suitable for intravenously administrable.Pharmaceutical composition of the present invention has stronger stability, and safe and effective especially as transfusion or injection solution or infusion concentrated solution.
The specific embodiment
The following examples will be made a more detailed description to the present invention.But, should be understood that, these embodiment be not be used for limiting of the present invention.
Embodiment 1 levosimendan injection
Amounts of components (g)
Levosimendan 2.5g
SolutolHS15 10g
Anhydrous citric acid 2g
Dehydrated alcohol adds to 1000ml
In aseptic preparation container, citric acid, Solutol HS15 and levosimendan are dissolved in the dehydrated alcohol with the preparation concentrated solution.(0.22 μ m) filters the gained tank solution by sterile filters.The sterilizing methods of this product is aseptic filtration, can not adopt autoclaving because alcoholic solution has the danger of blast.Solution sterile filling in bulk after the aseptic filtration in the injection bottle, and is covered transfusion with the sealing of dacron membrane rubber stopper with adding.
Embodiment 2 levosimendan oral liquids
Amounts of components
Levosimendan 12.5mg
SolutolHS15 30mg
Dehydrated alcohol 2.5ml
Semen Maydis oil " 10ml
Make 12ml
The levosimendan compositions is mixed with Semen Maydis oil, under stirring condition, stir evenly, make clarifying oily liquids, can be as oral liquid, or make soft capsule as soft capsule content.
Embodiment 3
Amounts of components
Levosimendan 12.5mg
Mannitol 280mg
SolutolHS15 50mg
0.2mol/L sodium hydrogen phosphate 1.46ml
0.2mol/L sodium dihydrogen phosphate 0.14ml
Water for injection adds to 3ml
Get levosimendan, Solutol HS15, mannitol adds sodium hydrogen phosphate and sodium dihydrogen phosphate, stirring makes dissolving (PH is 7.8) fully, adds active carbon 3mg, continues to stir 30min, take off charcoal, add the injection water and be settled to 3ml, the degerming of 0.22um microporous filter membrane fine straining.Under aseptic condition, gained solution is put in the aseptic cillin bottle, put and carry out lyophilization in the freezer dryer, seal.Promptly get xanchromatic levosimendan freeze-dried powder preparation of the present invention.
Claims (10)
- A levosimendan or its pharmaceutically acceptable salt it is characterized in that as the pharmaceutical preparation of active component, comprise following ingredients:(a) levosimendan or its acceptable salt pharmaceutically, every dose contains 5-50mg,(b) Solutol HS 15, every dose contains 10-200mg(c) medicinal solvent, every dose contains 0.1-1000ml.
- 2, the pharmaceutical preparation of claim 1 is characterized in that, also comprises pharmaceutical excipient, is selected from pH value regulator, antioxidant, flavoring agent, penetration enhancer, antiseptic.
- 3, the pharmaceutical preparation of claim 2 is characterized in that, wherein said have the pH value regulator to be selected from pharmaceutically acceptable organic acid or salt.
- 4, the pharmaceutical preparation of claim 3 is characterized in that, wherein said organic acid is selected from citric acid, lactic acid, and wherein said salt is selected from phosphate, citrate, lactate, acetate.
- 5, the pharmaceutical preparation of claim 1 is characterized in that, described medicinal solvent is selected from water, ethanol, propylene glycol, glycerol, buffer solution.
- 6, the pharmaceutical preparation of claim 1 is characterized in that, comprises following ingredients:(a) levosimendan or its acceptable salt pharmaceutically, every dose contains 10-25mg(b) Solutol HS 15, every dose contains 20-100mg(c) medicinal solvent, every dose contains 0.2-10ml(d) organic acid, percentage by weight are 0.02-1.0%.
- 7, the pharmaceutical preparation of claim 1 is characterized in that, described preparation is selected from injection, soft capsule, ointment, oral liquid and liniment.
- 8, the pharmaceutical preparation of claim 1 is characterized in that, described preparation is an injection.
- 9, the pharmaceutical preparation of claim 1 is characterized in that, is made up of following prescription:Levosimendan 2.5gSolutol HS 15 10gAnhydrous citric acid 2gDehydrated alcohol adds to 1000ml.
- 10, the pharmaceutical preparation of claim 1 is characterized in that, is made up of following prescription:Levosimendan 12.5mgSolutol HS 15 30mgDehydrated alcohol 2.5mlSemen Maydis oil 10ml.
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Cited By (3)
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CN101366696B (en) * | 2008-10-16 | 2012-04-11 | 姚定全 | Medicament composition for water-soluble injection of paclitaxel, preparation method and uses thereof |
WO2017077032A1 (en) * | 2015-11-06 | 2017-05-11 | Carinopharm Gmbh | Improved formulations of levosimendan for intravenous administration as infusion or injection and of infusion concentrate |
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 |
-
2006
- 2006-01-16 CN CN 200610000963 patent/CN1839842A/en active Pending
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101366696B (en) * | 2008-10-16 | 2012-04-11 | 姚定全 | Medicament composition for water-soluble injection of paclitaxel, preparation method and uses thereof |
WO2017077032A1 (en) * | 2015-11-06 | 2017-05-11 | Carinopharm Gmbh | Improved formulations of levosimendan for intravenous administration as infusion or injection and of infusion concentrate |
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 |
US10507179B2 (en) | 2015-11-06 | 2019-12-17 | Carinopharm Gmbh | Formulations of levosimendan for intravenous administration as infusion or injection and of infusion concentrate |
EA034565B1 (en) * | 2015-11-06 | 2020-02-20 | Каринофарм Гмбх | Compositions of levosimendan for intravenous administration as infusion or injection and of infusion 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 |
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 |
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