CN116999433A - Brivaracetam pharmaceutical composition and preparation method thereof - Google Patents
Brivaracetam pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN116999433A CN116999433A CN202311210489.0A CN202311210489A CN116999433A CN 116999433 A CN116999433 A CN 116999433A CN 202311210489 A CN202311210489 A CN 202311210489A CN 116999433 A CN116999433 A CN 116999433A
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- brivaracetam
- liquid medicine
- pharmaceutical composition
- sodium
- stirring
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- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 title claims abstract description 79
- 229960002161 brivaracetam Drugs 0.000 title claims abstract description 78
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000007788 liquid Substances 0.000 claims abstract description 61
- 239000003814 drug Substances 0.000 claims abstract description 55
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 44
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 44
- 239000000243 solution Substances 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000008215 water for injection Substances 0.000 claims abstract description 34
- 238000003756 stirring Methods 0.000 claims abstract description 28
- 230000001954 sterilising effect Effects 0.000 claims abstract description 26
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 22
- 229960000583 acetic acid Drugs 0.000 claims abstract description 22
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 22
- 239000001632 sodium acetate Substances 0.000 claims abstract description 22
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 22
- 239000011780 sodium chloride Substances 0.000 claims abstract description 22
- 238000001914 filtration Methods 0.000 claims abstract description 18
- 239000003381 stabilizer Substances 0.000 claims abstract description 14
- 230000001105 regulatory effect Effects 0.000 claims abstract description 13
- 238000011049 filling Methods 0.000 claims abstract description 12
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 10
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 10
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 239000004695 Polyether sulfone Substances 0.000 claims description 8
- 239000003708 ampul Substances 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 8
- 229920006393 polyether sulfone Polymers 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 4
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 claims description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 6
- 229960004249 sodium acetate Drugs 0.000 abstract description 2
- 230000007721 medicinal effect Effects 0.000 abstract 1
- 229960002668 sodium chloride Drugs 0.000 abstract 1
- 238000004140 cleaning Methods 0.000 description 14
- 238000009472 formulation Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000009471 action Effects 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000003186 pharmaceutical solution Substances 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 150000003140 primary amides Chemical class 0.000 description 2
- -1 (4R) -2-oxo-4-propyl-pyrrolidin-1-yl Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 101710084141 Synaptic vesicle glycoprotein 2A Proteins 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940054133 brivaracetam injection Drugs 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- WPUMTJGUQUYPIV-JIZZDEOASA-L disodium (S)-malate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)CC([O-])=O WPUMTJGUQUYPIV-JIZZDEOASA-L 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical class CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 235000019265 sodium DL-malate Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001394 sodium malate Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010408 sweeping Methods 0.000 description 1
- 230000003977 synaptic function Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a brivaracetam pharmaceutical composition and a preparation method thereof, belonging to the technical field of medicines. The brivaracetam pharmaceutical composition comprises brivaracetam, sodium acetate, glacial acetic acid, sodium chloride and a solution stabilizer, wherein the dosage percentage of the solution stabilizer is 0.01-0.02%. The preparation method comprises the following steps: sequentially adding sodium chloride, sodium acetate and solution stabilizer into water for injection, stirring for dissolving, and regulating pH value of the liquid medicine to 6.5-7.5 with glacial acetic acid solution; adding brivaracetam, stirring to dissolve, transferring the liquid medicine into a volumetric flask, regulating the pH value of the liquid medicine to 6.5-7.5 by glacial acetic acid, and fixing the volume by water for injection; filtering, filling and sterilizing. According to the invention, the solution stabilizer is added, so that the pH tolerance range of the brivaracetam medicament is widened, the subsequent stability of the product is facilitated, and the medicinal effect of the brivaracetam medicament composition is effectively ensured.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a brivaracetam medicinal composition and a preparation method thereof.
Background
Brivaracetam (Brivaracetam), also known as Brivaracetam, is a derivative of levetiracetam. Brivaracetam can be combined with central synaptic vesicle protein 2A (SV 2A) in a strong selectivity and reversibility manner, and plays an antiepileptic role by influencing synaptic function; and inhibiting voltage-dependent sodium ion channels, reducing the duration and frequency of epileptic discharges, thereby reducing seizures. Brivaracetam has the chemical name (2S) -2- [ (4R) -2-oxo-4-propyl-pyrrolidin-1-yl) ] butanamide, and has the structural formula:
brivaracetam is an active substance, a non-hygroscopic crystalline solid with a white to off-white appearance, which is very soluble in aqueous media in the physiological ph range, and also in polar organic solvents, and has high permeability, and is therefore labeled as a BCS class i drug. The structure of the brivaracetam contains an amide bond and is easy to hydrolyze, so that the stability of a medicine solution is required to be further improved in theory.
Patent document CN113908120a discloses a brivaracetam pharmaceutical solution containing brivaracetam, a buffer pair and water, the buffer pair being malic acid and sodium malate, or sodium acetate and glacial acetic acid. The color of the solution is kept unchanged for a long time under the condition that degradation products in the brivaracetam solution are stable by controlling the weight ratio of brivaracetam to the buffer pair. The method further screens the types of the buffer of the solution, but the pH value of the drug solution system is not further limited, and the pH value has a great influence on the stability of the drug solution. Patent document CN115364048A discloses a preparation method of brivaracetam injection, which comprises the steps of 1) cooling water for injection, and continuously introducing nitrogen into the solution; 2) Dissolving and stirring sodium dihydrogen phosphate and sodium chloride; 3) Adding brivaracetam and stirring for dissolution; 4) Adjusting the pH to 5.0-6.0 with phosphoric acid or sodium hydroxide; 5) Adding water for injection, filtering and filling, and sweeping with nitrogen curtain before and after filling; 6) Sterilizing under damp heat. The method utilizes nitrogen charging to reduce oxygen content in the solution so as to inhibit the oxidation of brivaracetam, and phosphoric acid or sodium hydroxide ensures that the liquid medicine has stability at pH of 5.0-6.0; however, the use of nitrogen is prone to potential safety hazards and amide bonds are known to hydrolyze to amines in the presence of strong bases, resulting in reduced effectiveness and stability of the drug solution, and therefore, there is a need to develop a safe and complete formulation and preparation method to ensure good stability and pharmacodynamics of the brivaracetam composition.
Disclosure of Invention
The invention aims to provide a brivaracetam pharmaceutical composition and a preparation method thereof, which can reduce the hydrolysis rate of primary amide by adding a specific solution stabilizer into a solution so as to solve the problems of unsafe preparation method and unstable pharmaceutical solution.
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
a brivaracetam pharmaceutical composition, comprising brivaracetam, sodium acetate, sodium chloride, solution stabilizer and water for injection; wherein the solution stabilizer is one of sodium pyrosulfate, sodium metabisulfite and sodium thiosulfate, and the dosage mass percentages of the brivaracetam, the sodium acetate, the sodium chloride and the solution stabilizer are respectively 1%, 0.164%, 0.9% and 0.01% -0.02%.
The preparation method of the brivaracetam pharmaceutical composition provided by the invention comprises the following steps:
s1, preparing liquid: adding water for injection into a beaker under stirring at room temperature (25-30 ℃), sequentially adding sodium chloride, sodium acetate and a solution stabilizer, stirring for dissolution, and regulating the pH value of the liquid medicine by using glacial acetic acid solution; adding brivaracetam, stirring and dissolving, transferring the liquid medicine into a volumetric flask, and regulating the pH value of the liquid medicine by glacial acetic acid; repeatedly cleaning the beaker with water for injection for three times, transferring the cleaning liquid into a volumetric flask, fixing the volume of the water for injection to a scale, and shaking uniformly for later use;
s2, filtering: filtering the liquid medicine by using a 0.22 mu m polyether sulfone filter membrane;
s3, filling: the liquid medicine is filled into ampoule bottles.
S4, sterilizing: placing the filled sample in a sterilizing cabinet, and setting sterilizing parameters (F) at 121deg.C for 15min 0 ＞12)。
Further, the concentration of the glacial acetic acid solution in the step S1 is 1 mol/L.
Further, in the step S1, the pH value of the liquid medicine is regulated to 6.5-7.5.
The invention has the beneficial effects that:
1. according to the invention, the solution stabilizer is added into the brivaracetam pharmaceutical composition, so that the hydrolysis rate of primary amide in the brivaracetam structure is reduced, the pH tolerance range of the brivaracetam pharmaceutical composition is widened to 6.5-7.5, the stability of brivaracetam is effectively controlled, and the high pharmacodynamics of the pharmaceutical composition is fully exerted.
2. The preparation method is simple and safe, has fewer impurities, and effectively shortens the preparation time, thereby reducing the production cost.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described in the following in conjunction with the embodiments of the present invention, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The present example provides a brivaracetam pharmaceutical composition, each 1000mL brivaracetam pharmaceutical composition formulation:
brivaracetam: 10g
Sodium acetate: 1.64g
Sodium chloride: 9g
Sodium metabisulfite 0.15g
Water for injection: to 1000mL
The preparation method of the brivaracetam pharmaceutical composition of the embodiment comprises the following steps:
s1, preparing liquid: under the condition of stirring at room temperature, adding 800mL of water for injection into a beaker, sequentially adding 9g of sodium chloride, 1.64g of sodium acetate and 0.15g of sodium metabisulfite, stirring for dissolution, and adjusting the pH value of the liquid medicine to 7.0 by using 1 mol/L of glacial acetic acid solution; adding 10g of brivaracetam, stirring and dissolving, transferring the liquid medicine into a 1000mL volumetric flask, and regulating the pH value of the liquid medicine to 7.0 by glacial acetic acid; repeatedly cleaning the beaker with water for injection for three times, transferring the cleaning liquid into a volumetric flask, fixing the volume of the water for injection to 1000mL, and shaking uniformly for later use;
s2, filtering: filtering the liquid medicine by using a 0.22 mu m polyether sulfone filter membrane;
s3, filling: the liquid medicine is filled into ampoule bottles.
S4, sterilizing: placing the filled sample in a sterilizing cabinet, and setting sterilizing parameters (F) at 121deg.C for 15min 0 ＞12)。
Example 2
The present example provides a brivaracetam pharmaceutical composition, each 1000mL brivaracetam pharmaceutical composition formulation:
brivaracetam: 10g
Sodium acetate: 1.64g
Sodium chloride: 9g
Sodium metabisulfite 0.10g
Water for injection: to 1000mL
The preparation method of the brivaracetam pharmaceutical composition of this example is the same as that of example 1.
Example 3
The present example provides a brivaracetam pharmaceutical composition, each 1000mL brivaracetam pharmaceutical composition formulation:
brivaracetam: 10g
Sodium acetate: 1.64g
Sodium chloride: 9g
Sodium metabisulfite 0.20g
Water for injection: to 1000mL
The preparation method of the brivaracetam pharmaceutical composition of this example is the same as that of example 1.
Example 4
The present example provides a brivaracetam pharmaceutical composition, each 1000mL brivaracetam pharmaceutical composition formulation:
brivaracetam: 10g
Sodium acetate: 1.64g
Sodium chloride: 9g
Sodium pyrosulfate 0.15g
Water for injection: to 1000mL
The preparation method of the brivaracetam pharmaceutical composition of the embodiment comprises the following steps:
s1, preparing liquid: under the condition of stirring at room temperature, adding 800mL of water for injection into a beaker, sequentially adding 9g of sodium chloride, 1.64g of sodium acetate and 0.15g of sodium pyrosulfate, stirring for dissolution, and adjusting the pH value of the liquid medicine to 7.0 by using 1 mol/L glacial acetic acid solution; adding 10g of brivaracetam, stirring and dissolving, transferring the liquid medicine into a 1000mL volumetric flask, and regulating the pH value of the liquid medicine to 7.0 by glacial acetic acid; repeatedly cleaning the beaker with water for injection for three times, transferring the cleaning liquid into a volumetric flask, fixing the volume of the water for injection to 1000mL, and shaking uniformly for later use;
s2, filtering: filtering the liquid medicine by using a 0.22 mu m polyether sulfone filter membrane;
s3, filling: the liquid medicine is filled into ampoule bottles.
S4, sterilizing: placing the filled sample in a sterilizing cabinet, and setting sterilizing parameters (F) at 121deg.C for 15min 0 ＞12)。
Example 5
The present example provides a brivaracetam pharmaceutical composition, each 1000mL brivaracetam pharmaceutical composition formulation:
brivaracetam: 10g
Sodium acetate: 1.64g
Sodium chloride: 9g
Sodium thiosulfate 0.15g
Water for injection: to 1000mL
The preparation method of the brivaracetam pharmaceutical composition of the embodiment comprises the following steps:
s1, preparing liquid: under the condition of stirring at room temperature, adding 800mL of water for injection into a beaker, sequentially adding 9g of sodium chloride, 1.64g of sodium acetate and 0.15g of sodium thiosulfate, stirring for dissolution, and adjusting the pH value of the liquid medicine to 7.0 by using 1 mol/L glacial acetic acid solution; adding 10g of brivaracetam, stirring and dissolving, transferring the liquid medicine into a 1000mL volumetric flask, and regulating the pH value of the liquid medicine to 7.0 by glacial acetic acid; repeatedly cleaning the beaker with water for injection for three times, transferring the cleaning liquid into a volumetric flask, fixing the volume of the water for injection to 1000mL, and shaking uniformly for later use;
s2, filtering: filtering the liquid medicine by using a 0.22 mu m polyether sulfone filter membrane;
s3, filling: the liquid medicine is filled into ampoule bottles.
S4, sterilizing: placing the filled sample into a sterilizing cabinetSetting sterilization parameters (F) at 121deg.C for 15min 0 ＞12)。
Example 6
The present example provides a brivaracetam pharmaceutical composition, each 1000mL brivaracetam pharmaceutical composition formulation:
brivaracetam: 10g
Sodium acetate: 1.64g
Sodium chloride: 9g
Sodium metabisulfite 0.15g
Water for injection: to 1000mL
The preparation method of the brivaracetam pharmaceutical composition of the embodiment comprises the following steps:
s1, preparing liquid: under the condition of stirring at room temperature, adding 800mL of water for injection into a beaker, sequentially adding 9g of sodium chloride, 1.64g of sodium acetate and 0.15g of sodium metabisulfite, stirring for dissolution, and adjusting the pH value of the liquid medicine to 6.5 by using 1 mol/L of glacial acetic acid solution; adding 10g of brivaracetam, stirring and dissolving, transferring the liquid medicine into a 1000mL volumetric flask, and regulating the pH value of the liquid medicine to 6.5 by glacial acetic acid; repeatedly cleaning the beaker with water for injection for three times, transferring the cleaning liquid into a volumetric flask, fixing the volume of the water for injection to 1000mL, and shaking uniformly for later use;
s2, filtering: filtering the liquid medicine by using a 0.22 mu m polyether sulfone filter membrane;
s3, filling: the liquid medicine is filled into ampoule bottles.
S4, sterilizing: placing the filled sample in a sterilizing cabinet, and setting sterilizing parameters (F) at 121deg.C for 15min 0 ＞12)。
Example 7
The present example provides a brivaracetam pharmaceutical composition, each 1000mL brivaracetam pharmaceutical composition formulation:
brivaracetam: 10g
Sodium acetate: 1.64g
Sodium chloride: 9g
Sodium metabisulfite 0.15g
Water for injection: to 1000mL
The preparation method of the brivaracetam pharmaceutical composition of the embodiment comprises the following steps:
s1, preparing liquid: under the condition of stirring at room temperature, adding 800mL of water for injection into a beaker, sequentially adding 9g of sodium chloride, 1.64g of sodium acetate and 0.15g of sodium metabisulfite, stirring for dissolution, and adjusting the pH value of the liquid medicine to 7.5 by using 1 mol/L of glacial acetic acid solution; adding 10g of brivaracetam, stirring and dissolving, transferring the liquid medicine into a 1000mL volumetric flask, and regulating the pH value of the liquid medicine to 7.5 by glacial acetic acid; repeatedly cleaning the beaker with water for injection for three times, transferring the cleaning liquid into a volumetric flask, fixing the volume of the water for injection to 1000mL, and shaking uniformly for later use;
s2, filtering: filtering the liquid medicine by using a 0.22 mu m polyether sulfone filter membrane;
s3, filling: the liquid medicine is filled into ampoule bottles.
S4, sterilizing: placing the filled sample in a sterilizing cabinet, and setting sterilizing parameters (F) at 121deg.C for 15min 0 ＞12)。
Comparative example 1:
this comparative example provides a brivaracetam pharmaceutical composition, each 1000mL brivaracetam pharmaceutical composition formulation:
brivaracetam: 10g
Sodium acetate: 1.64g
Sodium chloride: 9g
Water for injection: to 1000mL
The preparation method of the brivaracetam pharmaceutical composition of the comparative example comprises the following steps:
s1, preparing liquid: adding 800mL of water for injection into a beaker under the condition of stirring at room temperature, sequentially adding 9g of sodium chloride and 1.64g of sodium acetate, stirring for dissolution, and adjusting the pH value of the liquid medicine to 5.5 by using 1 mol/L glacial acetic acid solution; adding 10g of brivaracetam, stirring and dissolving, transferring the liquid medicine into a 1000mL volumetric flask, and regulating the pH value of the liquid medicine to 5.5 by glacial acetic acid; repeatedly cleaning the beaker with water for injection for three times, transferring the cleaning liquid into a volumetric flask, fixing the volume of the water for injection to 1000mL, and shaking uniformly for later use;
s2, filtering: filtering the liquid medicine by using a 0.22 mu m polyether sulfone filter membrane;
s3, filling: the liquid medicine is filled into ampoule bottles.
S4, sterilizing: placing the filled sample in a sterilizing cabinet, and setting sterilizing parameters (F) at 121deg.C for 15min 0 ＞12)。
The samples of examples 1-7 and comparative example 1 were each tested for stability under accelerated conditions (40 ℃.+ -. 2 ℃ C./75%.+ -. 5% RH) and the results are shown in tables 1 and 2:
TABLE 1
TABLE 2
The single impurity is other unknown structural impurities except the impurities A-E, and the impurity D is not detected all the time. Impurity ABCDE structures and CAS numbers are shown in table 3:
TABLE 3 Table 3
As can be seen from table 1 and table 2, the samples of examples 1 to 7 have good stability at pH of 6.5 to 7.5, and the increase of total impurity content in the pharmaceutical composition is significantly lower than that of comparative example 1 within 3 months of acceleration, which indicates that the stability of the prepared sample by the solution stabilizer adopted in the sample of the present invention is superior to that of the sample of comparative example, and the sample is suitable for long-term storage of the brivaracetam pharmaceutical composition.
It is noted that relational terms such as first and second, and the like are used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (5)
1. The brivaracetam pharmaceutical composition is characterized by comprising the following raw materials: the brivaracetam, sodium acetate, sodium chloride and solution stabilizer are respectively 1 percent, 0.164 percent, 0.9 percent and 0.01 to 0.02 percent in terms of mass percent.
2. A brivaracetam pharmaceutical composition according to claim 1, characterized in that said solution stabilizer is one of sodium pyrosulfate, sodium metabisulfite and sodium thiosulfate.
3. A process for the preparation of a brivaracetam pharmaceutical composition according to claim 1, comprising the steps of:
s1, preparing liquid: under the condition of stirring at room temperature, sequentially adding sodium chloride, sodium acetate and a solution stabilizer into the water for injection, stirring and dissolving, and regulating the pH value of the liquid medicine by using glacial acetic acid solution; adding brivaracetam, stirring and dissolving, transferring the liquid medicine into a volumetric flask, regulating the pH value of the liquid medicine by glacial acetic acid, and fixing the volume;
s2, filtering: filtering the liquid medicine by using a 0.22 mu m polyether sulfone filter membrane;
s3, filling: filling the liquid medicine into an ampoule bottle;
s4, sterilizing: placing the filled sample in a sterilizing cabinet, sterilizing with damp heat at 121deg.C for 15min, F 0 ＞12。
4. A process for the preparation of a brivaracetam pharmaceutical composition according to claim 3, characterized in that the concentration of glacial acetic acid solution in S1 is 1 mol/L.
5. The method for preparing a brivaracetam pharmaceutical composition according to claim 3, wherein the pH value of the liquid medicine is adjusted to 6.5-7.5 in S1.
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