CN111514147B - Levosimendan sodium medicinal composition for acute decompensated heart failure symptoms and preparation method thereof - Google Patents
Levosimendan sodium medicinal composition for acute decompensated heart failure symptoms and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a levosimendan sodium pharmaceutical composition for acute decompensated heart failure symptoms and a preparation method thereof, the preparation of the invention can be injection or dry powder, the dry powder forms original solution after reconstruction, the invention is mainly used for injection administration, the pharmaceutical composition of the invention comprises: levosimendan sodium as an active ingredient, and excipients. The invention solves the problems of insolubility of levosimendan free base in water and instability of hydrolysis degradation impurities during the period of market sale and storage, and enables levosimendan sodium to be prepared into a stable injection taking water as a solvent.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a levosimendan sodium pharmaceutical composition and a preparation method thereof.
Background
Levosimendan is the first marketed variety in the new generation of cardiotonic drugs, calcium sensitizers, and is mainly used for treating various acute heart failure diseases clinically. The drug was developed by the company Freon (Orion) in Finland and first marketed in Sweden in l0 month 2000. Levosimendan is currently marketed in several dozen countries, both europe and america.
Levosimendan is insoluble in water but soluble in ethanol, and levosimendan compounds are poorly stable, especially upon prolonged storage (over 24 hours), the water content of ethanol tends to cause hydrolysis of the levosimendan side chains to form the hydrolysis products OR-1855, OR-1896, OR-1420 and OR-1746, and therefore anhydrous ethanol must be used to prepare commercial formulations to keep the hydrolyzed impurities stable over a period of time. Therefore, the pharmaceutical formulation of Eurein (Orion) on the market uses absolute ethyl alcohol, povidone K12 and citric acid to combine into a preparation. It should be noted that the products resulting from hydrolytic degradation during storage [ e.g., OR-1420 (mono-hydrolytic degradation products) ] are different from the products of metabolism. OR-1746 is the product formed by oxidation of levosimendan in ethanol solution.
OR-1420 structural formula is:
OR-1746 has the structural formula:
OR-1896 has the structural formula:
OR-1855 has the following structural formula:
however, absolute ethyl alcohol is a non-aqueous solvent used for assisting dissolution of levosimendan, and although an isotonic solution such as a 5% glucose injection is diluted for use in clinical application, in the dilution process, levosimendan is easily separated out due to the fact that the concentration of absolute ethyl alcohol is diluted, particulate matters in liquid medicine exceed the standard, and the safety of clinical medication is affected.
Patents CN108261398A and CN1082898832A disclose that levosimendan is included in sulfobutyl ether betacyclodextrin to obtain clear solution, and then the solution is made into freeze-dried powder, and the inclusion solubilization mechanism is the process of inserting levosimendan into the cavity of cyclodextrin molecule. However, the inclusion process of cyclodextrin and guest molecules and the stability of the inclusion compound are influenced by many factors, which can be mainly divided into two types, i.e., chemical factors and geometric factors. The geometrical factors mainly include the matching of host and guest sizes and the geometrical shapes of guest molecules, and the chemical factors include the polarity and charge of guest molecules, the formation of a dielectric cyclodextrin inclusion compound and the formation of intermolecular hydrogen bonds. Among the chemical and geometric factors, the geometric factor plays a decisive role in the formation of the inclusion compound, but the chemical factor influences the stability of the inclusion compound. Therefore, in the specific implementation examples of patents CN108261398A and CN1082898832A, in order to achieve the stability of levosimendan inclusion compound, levosimendan is prevented from being separated out after being reconstituted into a solution, which may result in increase of insoluble particles and particles, and affect the safety of clinical medication, the amount of sulfobutyl ether-beta-cyclodextrin is very large, and although sulfobutyl ether-beta-cyclodextrin has excellent characteristics of low hemolysis and low renal toxicity, excessive use of sulfobutyl ether-beta-cyclodextrin may bring certain safety risk to renal metabolism. Patents CN108261398A and CN1082898832A use cyclodextrin inclusion process, such as sulfobutyl ether betacyclodextrin sodium, hydroxypropyl betacyclodextrin, etc., to maintain the stability of the drug, not only the dosage is very large, but also such excipients are high molecular compounds, which bring particles into themselves and seriously affect the production and clinical administration of the drug if not strictly controlled, and when levosimendan is included by sulfobutyl ether betacyclodextrin or hydroxypropyl betacyclodextrin, if the inclusion process parameters and the ratio thereof are not reasonable, even if the levosimendan inclusion compound is unstable, the precipitation of levosimendan after re-dissolution of clinical administration causes the increase of particles and affects the clinical administration. The particulate matters show a plurality of potential safety hazards in clinic, such as drug anaphylaxis, phlebitis, granuloma generation, local tissue embolism and necrosis, tumor formation and tumor-like reaction and the like, and the great clinical adverse reactions cause that the cyclodextrin inclusion process is not an optimal scheme.
Disclosure of Invention
The invention takes the hidden troubles that levosimendan is unfavorable for clinical use into consideration, and the technical problems of levosimendan are solved by adopting levosimendan sodium.
The inventors have not retrieved any published report of levosimendan sodium nor have found any relevant research and clinical use of levosimendan sodium that is commercially useful, in particular levosimendan sodium and its thermostable crystalline forms of levosimendan sodium are reported in the published literature and are useful in the treatment of congestive heart failure or acute decompensated heart failure symptoms (ADHF).
Levosimendan sodium, chemical name (R) - [ [4- (1,4,5, 6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenyl ] hydrazono ] malononitrile sodium, structural formula as follows:
levosimendan sodium has a solubility in water of about 1g/20ml after dissolution. In the invention, levosimendan sodium can be used in the composition in the form of a thermally stable crystal form A, and the diffraction peak 2 theta angle of the specific crystal form is as follows: 12.1 degree plus or minus 0.2 degree, 15.1 degree plus or minus 0.2 degree, 18.3 degree plus or minus 0.2 degree, 19.4 degree plus or minus 0.2 degree, 22.9 degree plus or minus 0.2 degree, 24.3 degree plus or minus 0.2 degree, 27.4 degree plus or minus 0.2 degree, 29.4 degree plus or minus 0.2 degree, 32.3 degree plus or minus 0.2 degree, 33.9 degree plus or minus 0.2 degree. The production of the thermally stable crystalline form of the sodium salt of the chemically active ingredient levosimendan sodium is an inventive aspect of the present invention that needs to be addressed.
It has further been found by the inventors that levosimendan sodium, which also faces the same chemical sensitivity as levosimendan, is highly susceptible to hydrolytic degradation in aqueous solutions over a long period of time to yield the impurities OR-1746 and OR-1420, particularly the impurity OR-1420, which is the major hydrolytic degradation impurity, and affects the safety of pharmaceutical preparations for clinical use, and therefore, it is desirable to prepare dry powders for easy storage. In the process of preparing the dry powder, the fact that an excipient is needed to enable the product to have attractive appearance is found, and the difference between an aqueous solution reconstructed by the adopted excipient and a dry pre-drug solution is avoided, and through research, the fact that the product dried by the sulfobutyl ether betacyclodextrin sodium is full, loose and attractive in appearance is found, and the appearance is better than that of the product dried by mannitol, lactose, glucose and the like. In order to maintain the stability of levosimendan sodium in the production process, a pH value buffer pair is formed by anhydrous disodium hydrogen phosphate and phosphoric acid, so that the levosimendan sodium is not influenced by the pH value of an aqueous solution in a very short production time, and the initial level of hydrolysis impurities of OR-1420 in the levosimendan sodium is maintained.
The inventor further finds that after levosimendan is prepared into a medicinal sodium salt, the levosimendan and selected excipients are prepared into dry powder, after the solution is reconstructed, levosimendan sodium is dissolved in water in a molecular form to form a true solution, no particulate matter is increased, the safety of clinical medication is solved, and the preferable excipient sulfobutyl ether betacyclodextrin is used in a very low dosage and is only used as a freeze-drying propping agent to achieve the advantages of attractive appearance of a freeze-dried substance and redissolution of the freeze-dried substance within 30 seconds.
The inventor further found that: levosimendan sodium has other advantages which levosimendan does not have, such as thermal stability, and pharmaceutically acceptable levosimendan sodium has a plurality of crystal forms, and one of the thermally stable crystal forms is currently used in the present invention, and the stability of the active ingredient compound is not changed after being prepared into dry powder; the preparation has excellent water solubility, can solve the problem that special production equipment (such as explosion-proof production equipment) is not needed in the production process of the preparation, and improves the safety of the production equipment; due to the excellent water solubility, the quality control of active ingredients, such as the clarity of solution, bacterial endotoxin and other quality indexes, can be completed by a conventional detection means without using special solvents.
The inventor further found that: the use of levosimendan sodium eliminates the need for high risk solubilizers such as ethanol to maintain levosimendan chemical stability, and the use of sulfobutyl ether betacyclodextrin sodium as an excipient allows for superior product appearance and rapid reconstitution of a homogeneous solution in 30 seconds, which is superior to mannitol, lactose, glucose as a freeze-dried proppant or excipient. Intravenous infusion after dilution in an isotonic solution, such as 0.9% sodium chloride injection, addresses the risk of levosimendan precipitation. Furthermore, the solution can be advantageously used at physiological pH values and the solution can be diluted with different isotonic infusion solutions.
The invention provides a pharmaceutical composition for injection containing stable levosimendan sodium, which uses a thermal stable crystal form and aims to solve the problems of insolubility of levosimendan free base in water and instability of hydrolysis degradation impurities during the period of sale and storage on the market, so that the levosimendan sodium can be prepared into a stable injection taking water as a solvent.
The invention provides a pharmaceutical composition comprising: levosimendan sodium as an active ingredient, and excipients.
The sterile dry powder preparation can be used for clinical safe medication, can be filled with sterile dry powder, can also be prepared by adopting a freeze-drying process, and is a clear particle-free water injection preparation which needs to be re-dissolved by sterile water for injection.
Further, the ratio of levosimendan sodium: the weight ratio of sulfobutyl ether betacyclodextrin sodium is 1: 1-50, preferably 1: 10-30, most preferably 1: 12-15; the levosimendan sodium: the weight ratio of the anhydrous disodium hydrogen phosphate is 1: 0.1-0.45, preferably 1: 0.3-0.4, and most preferably 1: 0.35-0.39.
Further, the excipient is selected from cyclodextrin, cyclodextrin sodium salt, lactose, mannitol, glucose, disodium hydrogen phosphate, sodium acetate, sodium citrate, phosphoric acid, acetic acid, citric acid or a mixture thereof.
Further, the cyclodextrin is sulfobutyl ether betacyclodextrin.
Further, the cyclodextrin sodium salt is sulfobutyl ether betacyclodextrin sodium salt.
Further, the disodium hydrogen phosphate is anhydrous disodium hydrogen phosphate.
Further, the pharmaceutical composition limits the use of ethanol, propylene glycol, polyethylene glycols, polyvinylpyrrolidone as a solubilizer.
Further, the pharmaceutical composition limits the use of poloxamers, castor oil polyoxyl esters as surfactants.
Further, the pharmaceutical composition also contains a pH value regulator, and the pH value regulator is preferably sodium hydroxide or/and phosphoric acid.
Further, the pharmaceutical composition is in the form of a solution.
Further, the solution form is an aqueous solution form.
Further, the pH value of the aqueous solution form is 6.0-9.0.
Further, the pH value of the aqueous solution form is 7.5-8.5.
Further, the aqueous solution form has a pH of 8.0.
Further, the aqueous solution is a solution suitable for intravenous administration.
Further, the aqueous solution contains 1.06mg to 13.24mg of levosimendan sodium per ml of liquid, and preferably contains 2.65mg of levosimendan sodium per ml of liquid.
Further, the aqueous solution is used for the treatment of congestive heart failure or acute decompensated heart failure symptoms (ADHF).
Further, the pharmaceutical composition is made via dry powder.
Further, the dry powder is used as a clinical pharmaceutical preparation.
Further, the dry powder is used for treating congestive heart failure or acute decompensated heart failure symptoms (ADHF).
Further, for administration, the dry powder is reconstituted into a liquid medicine suitable for intravenous administration.
Further, the dry powder is reconstituted with a solvent to form a liquid medicine.
Further, the solvent is an aqueous solution.
Further, the aqueous solution is water or isotonic buffer with the pH value of 5.0-8.0.
Furthermore, the preparation or the liquid medicine contains 1.06mg-13.24mg of levosimendan sodium per milliliter of liquid, and preferably contains 2.65mg-13.24mg of levosimendan sodium per milliliter of liquid.
Furthermore, each milliliter of the preparation or the liquid medicine contains 1.06mg to 13.24mg of levosimendan sodium, and the pH value of the preparation or the liquid medicine is 6.0 to 9.0.
Further, the liquid contains 2.65mg-13.24mg of levosimendan sodium per ml of liquid.
Compared with the marketed levosimendan injection, the levosimendan injection takes water as a solvent and does not contain absolute ethyl alcohol; after the levosimendan sodium dry powder is re-dissolved by water, the stability is superior to that of levosimendan injection; furthermore, the dry powder formulation of the present invention is very stable and does not require special storage conditions.
The dry powder of the invention is a hydro-acupuncture product, can be prepared by aseptic dry powder filling or freeze-drying process.
The dry powder of the present invention is preferably prepared using a lyophilization process.
When the invention is prepared by adopting a freeze-drying process, the sterile production process can be adopted for tissue production, and the sterile indexes of clinical medicines meet the requirements.
In another aspect, the invention provides a method for preparing the pharmaceutical preparation. Provides a stable dry powder production process of levosimendan sodium, which can be organized without using special production conditions such as explosion-proof measures.
A method of preparing a dry powder comprising the steps of:
step (1): dissolving levosimendan sodium in water;
step (2): weighing an excipient, dissolving the excipient in the step (1), adding water to a constant volume to reach the total volume, and sterilizing and filtering by using a membrane;
and (3): filling each solution in the step (2) into a plurality of penicillin bottles, freezing and drying, and filling nitrogen to seal the bottles.
Further, in step (1), levosimendan sodium is dissolved in water, and the pH is adjusted with a pH adjuster.
Further, the pH value regulator is sodium hydroxide or/and acetic acid or/and phosphoric acid or/and hydrochloric acid.
Further, the pH value before freeze-drying is 6.0-9.0.
Further, the pH value before freeze-drying is 7.5-8.5.
Further, the pH value before freeze-drying is 7.8-8.2.
In order to solve the safety and effectiveness problems of clinical medication of levosimendan, the invention adopts a crystal form with high solubility and thermal stability of levosimendan sodium, and is matched with excipients required by a drying process, such as sulfobutyl ether betacyclodextrin sodium and anhydrous disodium hydrogen phosphate, so that a cosolvent and a surfactant which are very stable, high in solubility in water and free of ethanol and the like can be obtained, and another brand new clinical medication safe preparation formula of active ingredients is provided for levosimendan.
The active ingredient levosimendan sodium of the present invention is present in the form of a true solution in pharmaceutical compositions and the use of such formulations in the field of clinical medicine. The preparation of the invention can be injection or dry powder, and the dry powder forms original solution after reconstruction, and is mainly used for injection administration.
The invention adopts the thermally stable crystal form of levosimendan sodium to be directly dissolved in water, and does not need to adopt an absolute ethanol cosolvent (with administration vascular irritation, intolerance to ethanol of part of patients and the like), a cyclodextrin inclusion technology (with incomplete inclusion, levosimendan is separated out in the storage and clinical use processes to cause the increase of solution particles, serious clinical potential safety hazards and the like appear after administration), a surfactant solubilizer (with administration irritation, particularly serious hemolysis and the like) and the like.
The invention adopts the optimized anhydrous disodium hydrogen phosphate and sulfobutyl ether sodium betacyclodextrin as freeze-drying excipient, can obtain freeze-dried powder with excellent and stable long-term storage, and the dry powder can be quickly redissolved within 30 seconds and is a clear solution without particles.
The levosimendan sodium in the thermally stable crystal form is simple in production process (dissolving → sterilizing filtration → split charging/drying → capping/packaging) of a water injection without using inclusion technology or other preparation technical means, and particularly in the dissolving step, the levosimendan sodium is directly dissolved in water, so that the production process time and the production industrial cost are reduced, a plurality of potential safety hazards of clinical medication caused by levosimendan and an inclusion compound thereof are solved, and the levosimendan sodium is the fundamental direction needed to be solved by a preparation inventor.
Explanation and glossary of terms
% -% in the present invention means% by mass unless otherwise specified.
OR-1746-refers to 2- { 4-ethoxy-6-imino-5 { [4- (1,4,5, 6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenyl ] azo } -5, 6-dihydro-1H-pyrimidin-2-yl } -2- [4- (1,4,5, 6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) phenylhydrazono ] acetonitrile.
OR-1420-refers to 2-cyano-2- (2- (4- (4-methyl-6-oxo-1, 4,5, 6-tetrahydro-3-pyridazinyl) phenyl) hydrazono) acetamide.
Detailed Description
The present invention will be further explained below.
EXAMPLE 1 preparation of levosimendan sodium
To a 250ml flask were added 2.9g of sodium hydroxide and 120ml of purified water, and dissolved with stirring. Levosimendan (20 g) was added and stirred to dissolve levosimendan. Stirring at 5-10 deg.C for crystallizing for 2 hr. Filtration and washing of the filter cake with 30ml ethanol. Decompression drying at 60 deg.c to obtain stable crystal form A levosimendan sodium 17.8g in 89.0 wt%.
The thermally stable crystalline form of levosimendan sodium has diffraction peak angle 2 theta: 12.1 degree plus or minus 0.2 degree, 15.1 degree plus or minus 0.2 degree, 18.3 degree plus or minus 0.2 degree, 19.4 degree plus or minus 0.2 degree, 22.9 degree plus or minus 0.2 degree, 24.3 degree plus or minus 0.2 degree, 27.4 degree plus or minus 0.2 degree, 29.4 degree plus or minus 0.2 degree, 32.3 degree plus or minus 0.2 degree, 33.9 degree plus or minus 0.2 degree.
Levosimendan sodium prepared in this example 1 was used in examples 2-10.
Example 2
The method comprises the steps of taking 270mg of levosimendan sodium, stirring and dissolving the levosimendan sodium in water for injection, adding 2.0g of mannitol, stirring and dissolving, adding the water for injection, and adjusting the pH value to 7.8-8.2 by using sodium hydroxide or hydrochloric acid to form a solution A;
filtering the solution A with a 0.22-micron polyethersulfone filter membrane for sterilization, filling into bottles (each penicillin bottle is filled with 5ml of the solution A), and drying by adopting a conventional freeze-drying production process after bottling, wherein the water content is controlled to be below 2%;
and filling nitrogen into each penicillin bottle, and sealing the penicillin bottles by a gland to obtain sterile freeze-dried powder.
In this example, the total amount of water for injection was 100 ml.
The sterile lyophilized powder of this example was subjected to the respective tests for appearance, reconstitution time, solution granulation, pH and OR-1420 impurities, and the results are shown in table one below.
Example 3
The preparation method comprises the steps of taking 270mg of levosimendan sodium, stirring and dissolving the levosimendan sodium in water for injection, adding 3.0g of lactose and 100mg of anhydrous sodium acetate, stirring and dissolving, adding water for injection, and adjusting the pH value to 7.8-8.2 by using acetic acid to form a solution B;
filtering the solution B by using a 0.22-micron polyethersulfone filter membrane for sterilization, filling bottles (the bottles are penicillin bottles, and each penicillin bottle is filled with 5ml of the solution B), and drying by adopting a conventional freeze-drying production process after bottling, wherein the water content is controlled to be below 2%;
and filling nitrogen into each penicillin bottle, and sealing the penicillin bottles by a gland to obtain sterile freeze-dried powder.
In this example, the total amount of water for injection was 100 ml.
The sterile lyophilized powder of this example was subjected to the respective tests for appearance, reconstitution time, solution granulation, pH and OR-1420 impurities, and the results are shown in table one below.
Example 4
The preparation method comprises the steps of taking 270mg of levosimendan sodium, stirring and dissolving the levosimendan sodium in water for injection, adding 4.5g of glucose and 200mg of anhydrous sodium acetate, stirring and dissolving, adding water for injection, and adjusting the pH value to 7.8-8.2 by using acetic acid to form a solution C;
filtering the solution C with a 0.22-micron polyethersulfone filter membrane for sterilization, filling into bottles (each penicillin bottle is filled with 5ml of the solution C), and drying by adopting a conventional freeze-drying production process after bottling, wherein the water content is controlled to be below 2%;
and filling nitrogen into each penicillin bottle, and sealing the penicillin bottles by a gland to obtain sterile freeze-dried powder.
In this example, the total amount of water for injection was 100 ml.
The sterile lyophilized powder of this example was subjected to the respective tests for appearance, reconstitution time, solution granulation, pH and OR-1420 impurities, and the results are shown in table one below.
Example 5
The preparation method comprises the steps of taking 270mg of levosimendan sodium, stirring and dissolving the levosimendan sodium in water for injection, adding 3.5g of hydroxypropyl betadex and 200mg of anhydrous sodium acetate, stirring and dissolving the levosimendan sodium and the anhydrous sodium acetate, adding the water for injection, and adjusting the pH value to 7.8-8.2 by using 1% sodium hydroxide to form a solution D;
filtering the solution D with a 0.22-micron polyethersulfone filter membrane for sterilization, filling into bottles (each penicillin bottle is filled with 5ml of the solution D), and drying by adopting a conventional freeze-drying production process after bottling, wherein the water content is controlled to be below 2%;
and filling nitrogen into each penicillin bottle, and sealing the penicillin bottles by a gland to obtain sterile freeze-dried powder.
In this example, the total amount of water for injection was 100 ml.
The sterile lyophilized powder of this example was subjected to the respective tests for appearance, reconstitution time, solution granulation, pH and OR-1420 impurities, and the results are shown in table one below.
Example 6
The method comprises the steps of taking 270mg of levosimendan sodium, stirring and dissolving the levosimendan sodium in water for injection, adding 270mg of sulfobutyl ether betacyclodextrin sodium, stirring and dissolving the sulfobutyl ether betacyclodextrin sodium, adding the water for injection, and adjusting the pH value to 7.8-8.2 by using 1% of sodium hydroxide to form a solution E;
filtering the solution E by using a 0.22-micron polyethersulfone filter membrane for sterilization, filling into bottles (the bottles are penicillin bottles, and each penicillin bottle is filled with 5ml of the solution E), and drying by adopting a conventional freeze-drying production process after bottling, wherein the water content is controlled to be below 2%;
and filling nitrogen into each penicillin bottle, and sealing the penicillin bottles by a gland to obtain sterile freeze-dried powder.
In this example, the total amount of water for injection was 100 ml.
The sterile lyophilized powder of this example was subjected to the respective tests for appearance, reconstitution time, solution granulation, pH and OR-1420 impurities, and the results are shown in table one below.
Example 7
The preparation method comprises the steps of taking 270mg of levosimendan sodium, stirring and dissolving the levosimendan sodium in water for injection, adding 2.5g of sulfobutyl ether sodium betacyclodextrin and 27mg of anhydrous disodium hydrogen phosphate, stirring and dissolving the mixture, adding water for injection, and adjusting the pH value to 7.8-8.2 by using phosphoric acid to form a solution F;
filtering the solution F by using a 0.22-micron polyethersulfone filter membrane for sterilization, filling into bottles (the bottles are penicillin bottles, and each penicillin bottle is filled with 5ml of the solution F), and drying by adopting a conventional freeze-drying production process after bottling, wherein the water content is controlled to be below 2%;
and filling nitrogen into each penicillin bottle, and sealing the penicillin bottles by a gland to obtain sterile freeze-dried powder.
In this example, the total amount of water for injection was 100 ml.
The sterile lyophilized powder of this example was subjected to the respective tests for appearance, reconstitution time, solution granulation, pH and OR-1420 impurities, and the results are shown in table one below.
Example 8
The preparation method comprises the steps of taking 270mg of levosimendan sodium, stirring and dissolving the levosimendan sodium in water for injection, adding 3.51G of sulfobutyl ether sodium betacyclodextrin and 56mg of anhydrous disodium hydrogen phosphate, stirring and dissolving the mixture, adding water for injection, and adjusting the pH value to 7.8-8.2 by using phosphoric acid to form a solution G;
filtering the solution G by using a 0.22-micron polyethersulfone filter membrane for sterilization, filling bottles (the bottles are penicillin bottles, and each penicillin bottle is filled with 2ml of the solution G), and drying by adopting a conventional freeze-drying production process after bottling, wherein the water content is controlled to be below 2%;
and filling nitrogen into each penicillin bottle, and sealing the penicillin bottles by a gland to obtain sterile freeze-dried powder.
In this example, the total amount of water for injection was 40 ml.
The sterile lyophilized powder of this example was subjected to the respective tests for appearance, reconstitution time, solution granulation, pH and OR-1420 impurities, and the results are shown in table one below.
After the sterile freeze-dried powder of the embodiment is redissolved, the pH value is adjusted by phosphoric acid and sodium hydroxide (the pH value is adjusted to be within the range of 6.0-9.0), the liquid medicine is placed for 24 hours at room temperature, and the properties and the content of OR-1420 are detected, and the results are shown in the following table II.
After the sterile lyophilized powder of this example was redissolved, the sterile lyophilized powder was diluted with sterile water for injection, 0.9% sodium chloride injection, and sodium lactate ringer injection, respectively, and then left at room temperature for 24 hours, and the results were shown in table three below.
After the sterile lyophilized powder of this example was reconstituted, the lyophilized powder was diluted with 0.9% sodium chloride injection and left for 24 hours for key quality index testing, and the results are shown in table four below.
Example 9
The preparation method comprises the steps of taking 270mg of levosimendan sodium, stirring and dissolving the levosimendan sodium in water for injection, adding 13.5g of sulfobutyl ether sodium betacyclodextrin and 121.6mg of anhydrous disodium hydrogen phosphate, stirring and dissolving the levosimendan sodium and the anhydrous disodium hydrogen phosphate, adding water for injection, and adjusting the pH value to 7.8-8.2 by using phosphoric acid to form a solution H;
filtering the solution H with a 0.22-micron polyethersulfone filter membrane for sterilization, filling bottles (penicillin bottles are filled with 2ml of solution H), and drying by adopting a conventional freeze-drying production process after bottling, wherein the water content is controlled to be below 2%;
and filling nitrogen into each penicillin bottle, and sealing the penicillin bottles by a gland to obtain sterile freeze-dried powder.
In this example, the total amount of water for injection was 40 ml.
The sterile lyophilized powder of this example was subjected to the respective tests for appearance, reconstitution time, solution granulation, pH and OR-1420 impurities, and the results are shown in table one below.
Example 10
The preparation method comprises the steps of taking 270mg of levosimendan sodium, stirring and dissolving the levosimendan sodium in water for injection, adding 2.0g of sulfobutyl ether betacyclodextrin sodium and 40mg of anhydrous sodium citrate, stirring and dissolving the mixture, adding the water for injection, and adjusting the pH value to 7.8-8.2 by using citric acid to form a solution I;
filtering the solution I by using a 0.22-micron polyethersulfone filter membrane for sterilization, filling bottles (the bottles are penicillin bottles, and each penicillin bottle is filled with 2ml of the solution I), and drying by adopting a conventional freeze-drying production process after bottling, wherein the water content is controlled to be below 2%;
and filling nitrogen into each penicillin bottle, and sealing the penicillin bottles by a gland to obtain sterile freeze-dried powder.
In this example, the total amount of water for injection was 40 ml.
The sterile lyophilized powder of this example was subjected to the respective tests for appearance, reconstitution time, solution granulation, pH and OR-1420 impurities, and the results are shown in table one below.
Comparative example 1
Dissolving 17.5g of sulfobutyl ether betacyclodextrin sodium into water for injection, adding 250mg of levosimendan while stirring, and adjusting the pH value to 7.4 by using acetic acid or sodium hydroxide to form a solution J;
filtering the solution J with a polyethersulfone filter membrane of 0.22 mu m for sterilization, filling into bottles (the bottles are penicillin bottles, and each penicillin bottle is filled with 5ml of the solution J), and drying by adopting a conventional freeze-drying production process after bottling, wherein the water content is controlled to be below 2%;
and filling nitrogen into each penicillin bottle, and sealing the penicillin bottles by a gland to obtain sterile freeze-dried powder.
In this example, the total amount of water for injection was 100 ml.
The sterile lyophilized powder of this example was subjected to the respective tests for appearance, reconstitution time, solution granulation, pH and OR-1420 impurities, and the results are shown in table one below.
After the sterile lyophilized powder of this example was reconstituted, the key quality index was determined by diluting with 0.9% sodium chloride injection and standing for 24 hours, the results are shown in table four below.
Watch 1
As can be seen from the table I, the redissolved particles in comparative example 1 are several times more than those in examples 2-9, which brings potential safety hazard to clinical medication, and the hydrolyzed impurity OR-1420 is higher than 0.5%. Examples 3 and 4 use glucose and lactose as excipients and key hydrolysis impurity OR-1420 higher than 0.5%, the effect is worse than examples 2, 5-10;
watch two
As can be seen from the table II, the content of OR-1420 is far lower than 0.5% after 24h at the pH value of 6.0-9.0, the content of OR-1420 is not more than 0.112% after 24h at the pH value of 7.5-8.5, and the content of OR-1420 is only 0.089% after 24h at the pH value of 8.0.
Watch III
From the third table, the pH value of the solution diluted by sterile water for injection, 0.9% sodium chloride injection and sodium lactate ringer injection is 5.0-8.0, and the stability of each item is good.
Watch four
As can be seen from table four, example 8 (levosimendan sodium) is more stable than comparative example 1 (levosimendan cyclodextrin inclusion product) using an isotonic solution of 0.9% sodium chloride injection.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (33)
1. A pharmaceutical composition comprising: levosimendan sodium as an active ingredient, and excipients; the levosimendan sodium is a compound with thermal stability in a crystal form A, and the diffraction peak angle 2 theta of the crystal form is as follows: 12.1 ° ± 0.2 °, 15.1 ° ± 0.2 °, 18.3 ° ± 0.2 °, 19.4 ° ± 0.2 °, 22.9 ° ± 0.2 °, 24.3 ° ± 0.2 °, 27.4 ° ± 0.2 °, 29.4 ° ± 0.2 °, 32.3 ° ± 0.2 °, 33.9 ° ± 0.2 °, wherein the excipient is selected from cyclodextrin, cyclodextrin sodium salt, lactose, mannitol, glucose, disodium hydrogen phosphate, sodium acetate, sodium citrate, phosphoric acid, acetic acid, citric acid, or a mixture thereof.
2. The pharmaceutical composition of claim 1, wherein the cyclodextrin is sulfobutyl ether betacyclodextrin.
3. The pharmaceutical composition of claim 1, wherein the cyclodextrin sodium salt is sulfobutyl ether betacyclodextrin sodium salt.
4. A pharmaceutical composition according to claim 3 wherein the ratio of levosimendan sodium: the weight ratio of sulfobutyl ether betacyclodextrin sodium is 1: 1-50.
5. The pharmaceutical composition of claim 4, wherein the ratio of levosimendan sodium: the weight ratio of sulfobutyl ether betacyclodextrin sodium is 1: 10-30.
6. The pharmaceutical composition of claim 5, wherein the ratio of levosimendan sodium: the weight ratio of sulfobutyl ether betacyclodextrin sodium is 1: 12 to 15.
7. The pharmaceutical composition of claim 1, wherein the disodium phosphate is anhydrous disodium phosphate.
8. The pharmaceutical composition of claim 7, wherein the ratio of levosimendan sodium: the weight ratio of the anhydrous disodium hydrogen phosphate is 1: 0.1-0.45.
9. The pharmaceutical composition of claim 8, wherein the ratio of levosimendan sodium: the weight ratio of the anhydrous disodium hydrogen phosphate is 1: 0.3-0.4.
10. The pharmaceutical composition of claim 9, wherein the ratio of levosimendan sodium: the weight ratio of the anhydrous disodium hydrogen phosphate is 1: 0.35-0.39.
11. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is limited to the use of ethanol, propylene glycol, polyethylene glycols, polyvinylpyrrolidone as solubilizing agent.
12. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is limited to the use of poloxamers, castor oil polyoxyl esters as surfactants.
13. The pharmaceutical composition according to any one of claims 1 to 12, further comprising a pH adjusting agent.
14. The pharmaceutical composition of claim 13, wherein the pH adjusting agent is sodium hydroxide or/and phosphoric acid.
15. The pharmaceutical composition of claim 13, wherein: the pharmaceutical composition is in the form of a solution.
16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is in the form of an aqueous solution.
17. The pharmaceutical composition of claim 16, wherein: the pH value of the aqueous solution is 6.0-9.0.
18. The pharmaceutical composition of claim 17, wherein: the pH value of the aqueous solution form is 7.5-8.5.
19. The pharmaceutical composition of claim 18, wherein: the pH value of the aqueous solution form is 8.0.
20. The pharmaceutical composition of claim 16, wherein the aqueous solution is a solution suitable for intravenous administration.
21. The pharmaceutical composition of claim 16 wherein said aqueous solution contains from 1.06mg to 13.24mg of levosimendan sodium per ml of liquid.
22. The pharmaceutical composition of claim 21 wherein said aqueous solution contains 2.65mg of levosimendan sodium per ml of liquid.
23. The pharmaceutical composition of claim 22, wherein the aqueous solution is used to treat symptoms of congestive heart failure or acute decompensated heart failure.
24. The pharmaceutical composition of claim 13, wherein: the pharmaceutical composition is prepared by drying the levosimendan sodium, the excipient and the pH value regulator to remove water.
25. The pharmaceutical composition of claim 24, wherein: the drying is freeze drying.
26. The pharmaceutical composition of claim 24, wherein the dry powder is used as a clinical pharmaceutical formulation; or the dry powder is used to treat symptoms of congestive heart failure or acute decompensated heart failure; or for administration, the dry powder is reconstituted into a liquid medicament suitable for intravenous administration; or the dry powder is reconstituted by a solvent to prepare a liquid medicine, wherein the solvent is an aqueous solution.
27. The pharmaceutical composition of claim 26, wherein the aqueous solution is water or an isotonic buffer having a pH of 5.0-8.0.
28. The pharmaceutical composition of claim 27, wherein the isotonic buffer is an isotonic buffer having a pH of 7.0-8.0.
29. The pharmaceutical composition of claim 26, wherein said formulation or liquid medicine contains levosimendan sodium in an amount of 1.06mg to 13.24mg per ml of liquid.
30. The pharmaceutical composition of claim 29 wherein the formulation or solution contains 2.65mg to 13.24mg of levosimendan sodium per ml of liquid.
31. The pharmaceutical composition of claim 26 wherein said formulation or pharmaceutical solution contains levosimendan sodium in an amount of 1.06mg to 13.24mg per ml of liquid and said formulation or pharmaceutical solution has a pH of 6.0 to 9.0.
32. The pharmaceutical composition of claim 31 comprising 2.65mg to 13.24mg levosimendan sodium per ml liquid.
33. A process for preparing a pharmaceutical composition according to any one of claims 1 to 32, wherein: the method comprises the following steps:
step (1): dissolving levosimendan sodium in water;
step (2): weighing an excipient, dissolving the excipient in the step (1), adding water to a constant volume to reach the total volume, and sterilizing and filtering by using a membrane;
and (3): filling each solution in the step (2) into a plurality of penicillin bottles, freezing and drying the penicillin bottles, filling nitrogen, and sealing the bottles by pricking covers;
the preparation method of the levosimendan sodium comprises the following steps:
adding 2.9g of sodium hydroxide and 120ml of purified water into a 250ml flask, stirring for dissolving, adding 20g of levosimendan, stirring for dissolving the levosimendan, stirring for crystallizing at 5-10 ℃ for 2 hours, filtering, washing a filter cake by using 30ml of ethanol, and drying under reduced pressure at 60 ℃ to obtain 17.8g of thermally stable crystal form A levosimendan sodium with the weight yield of 89.0%, wherein the thermally stable crystal form A levosimendan sodium has a diffraction peak 2 theta angle: 12.1 degree plus or minus 0.2 degree, 15.1 degree plus or minus 0.2 degree, 18.3 degree plus or minus 0.2 degree, 19.4 degree plus or minus 0.2 degree, 22.9 degree plus or minus 0.2 degree, 24.3 degree plus or minus 0.2 degree, 27.4 degree plus or minus 0.2 degree, 29.4 degree plus or minus 0.2 degree, 32.3 degree plus or minus 0.2 degree, 33.9 degree plus or minus 0.2 degree.
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