CN107115293A - A kind of injection containing levetiracetam medicinal composition and preparation method thereof - Google Patents
A kind of injection containing levetiracetam medicinal composition and preparation method thereof Download PDFInfo
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- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 238000002347 injection Methods 0.000 title claims abstract description 18
- 239000007924 injection Substances 0.000 title claims abstract description 18
- 239000000203 mixture Substances 0.000 title claims abstract description 13
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title claims abstract 11
- 239000000243 solution Substances 0.000 claims description 139
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
- 239000008215 water for injection Substances 0.000 claims description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 241001602688 Pama Species 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 17
- 239000011347 resin Substances 0.000 claims description 17
- 229920005989 resin Polymers 0.000 claims description 17
- AHLWZBVXSWOPPL-RGYGYFBISA-N 20-deoxy-20-oxophorbol 12-myristate 13-acetate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(C=O)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C AHLWZBVXSWOPPL-RGYGYFBISA-N 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 15
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 14
- 229920002401 polyacrylamide Polymers 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 239000003513 alkali Chemical class 0.000 claims description 11
- 239000000706 filtrate Substances 0.000 claims description 11
- 230000001954 sterilising effect Effects 0.000 claims description 11
- 238000005303 weighing Methods 0.000 claims description 11
- 230000003204 osmotic effect Effects 0.000 claims description 10
- -1 polypropylene Polymers 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 9
- 238000000108 ultra-filtration Methods 0.000 claims description 9
- 239000003182 parenteral nutrition solution Substances 0.000 claims description 8
- 239000003002 pH adjusting agent Substances 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 239000001632 sodium acetate Substances 0.000 claims description 6
- 235000017281 sodium acetate Nutrition 0.000 claims description 6
- 239000001509 sodium citrate Substances 0.000 claims description 6
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 3
- 238000005261 decarburization Methods 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 238000001179 sorption measurement Methods 0.000 claims description 3
- 239000004743 Polypropylene Substances 0.000 claims description 2
- 125000000129 anionic group Chemical group 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 229920001155 polypropylene Polymers 0.000 claims description 2
- 235000005979 Citrus limon Nutrition 0.000 claims 2
- 244000248349 Citrus limon Species 0.000 claims 1
- 244000131522 Citrus pyriformis Species 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
- 229940090044 injection Drugs 0.000 abstract description 12
- 229940037125 levetiracetam injection Drugs 0.000 abstract description 11
- 206010015037 epilepsy Diseases 0.000 abstract description 9
- 239000000463 material Substances 0.000 abstract 1
- 230000006641 stabilisation Effects 0.000 abstract 1
- 238000011105 stabilization Methods 0.000 abstract 1
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 32
- 229960000583 acetic acid Drugs 0.000 description 11
- 238000005516 engineering process Methods 0.000 description 11
- 239000012362 glacial acetic acid Substances 0.000 description 9
- 238000012545 processing Methods 0.000 description 9
- 238000003763 carbonization Methods 0.000 description 8
- 239000001961 anticonvulsive agent Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 230000003556 anti-epileptic effect Effects 0.000 description 5
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- 230000001037 epileptic effect Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000005374 membrane filtration Methods 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 3
- 229940058401 polytetrafluoroethylene Drugs 0.000 description 3
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 3
- 239000004810 polytetrafluoroethylene Substances 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 230000009471 action Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101000584505 Homo sapiens Synaptic vesicle glycoprotein 2A Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 102100030701 Synaptic vesicle glycoprotein 2A Human genes 0.000 description 1
- 102000004874 Synaptophysin Human genes 0.000 description 1
- 108090001076 Synaptophysin Proteins 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000064 cholinergic agonist Substances 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 201000009028 early myoclonic encephalopathy Diseases 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229940062717 keppra Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002151 myoclonic effect Effects 0.000 description 1
- 208000028492 myoclonic seizure Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 229940053180 other antiepileptics in atc Drugs 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000013441 quality evaluation Methods 0.000 description 1
- 208000005809 status epilepticus Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- 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
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
This application discloses injection containing levetiracetam medicinal composition of a kind of stabilization and preparation method thereof.Said preparation contains Levetiracetam and other pharmaceutically acceptable auxiliary materials, using special preparation method, can effectively improve the stability of Levetiracetam injection, the treatment for epilepsy.
Description
Technical field
The application belongs to technical field of medicine, and in particular to a kind of injection containing levetiracetam medicinal composition
Agent and preparation method thereof.
Background technology
Global annual about 2,000,000 epilepsies of kainogenesis.The incidence of disease of epilepsy is about annual every ten wherein in developed country
Wan Renzhong has 50 people.Equally, the incidence of disease of epilepsy also significantly increases in developing country, is to have 100 people in every 100,000 people.
China there are about 9,000,000 epileptics, wherein 6,000,000 patients still have breaking-out every year, and 400,000 neopathies can all occurs every year
Example.The mortality prediction of epileptic is about two to four times of general population（Death may and underlying diseases, commit suiside, accident
Or Status Epilepticus is relevant）.According to international anti-epileptic alliance（ILAE）Investigation, the death rate of the young man with epilepsy is just
4 times of normal young man.
Levetiracetam（Levetiracetam）Chemical entitled (-)-(S)-[α]-ethyl -2- oxo -1- pyrroles
Alkyl acetamide is coughed up, is a kind of new combination SV2A（Synaptophysin 2A）Isotype cholinergic agonist anti-epileptic
Medicine, different from the structure of other antiepileptics, its definite anti-epileptic mechanism is still failed to understand, but is acted on Antiepileptic drugs
It is different in ion channel or excitability, inhibitory neurotransmitter system.Levetiracetam almost possesses preferable antiepileptic
All pharmaco-kinetic properties of thing：Bioavilability height, linearity curve, low protein binding rate, without liver enzyme inducing action.Many animals
Model shows that Levetiracetam has anti-epileptic characteristic.
A kind of new antiepileptic drugs that Levetiracetam is researched and developed by Belgian UCB. S.A. (BE) Bruxelles Belgium, trade name KEPPRA®, in
Levetiracetam tablet in 1999 obtains FDA approvals, and listing formulation includes injection, tablet, oral administration solution, sustained release tablets.In U.S.
State, the product is represented as complementary oral medication, the part breaking-out of adult and children for treating 1 monthly age and greater age
Property epilepsy, wherein with epilepsy, myoclonic seizure and age in adult are teenager's myoclonic of 12 years old and the above
Epilepsy（JME）Broken out with the primary generalized tonic-clonic of 6 years old and above adult and Childhood idiopathic systemic epilepsy.
（R）- 2-（2- OXo-1-pyrrolidines）Butyramide is the optical isomer of Levetiracetam, for suppressing
Epileptic attack only has slight or unconspicuous drug action.Control of Impurities is the important component of drug quality, thus,
When preparing parenteral solution, the impurity is removed to greatest extent, is conducive to improving the product quality and safety of Levetiracetam injection
Property, it is of great importance to improving patient clinical drug safety.
The content of the invention
The purpose of the application is to provide that a kind of technique is simple, cost is low, the preferable Levetiracetam injection of stability
And preparation method.（R）- 2-（2- OXo-1-pyrrolidines）Butyramide is the optical isomer of Levetiracetam, for suppression
Epileptic attack processed only has slight or unconspicuous drug action.Therefore the application uses special preparation technology, that is, is preparing
PAMA is added in journey, due to（R）- 2-（2- OXo-1-pyrrolidines）Butyramide is in the solution in sun
Electrically, the strong suction-operated using PAMA to cation, can effectively remove the bulk drug in injection
Bring into（R）- 2-（2- OXo-1-pyrrolidines）Butyramide；It is several in the Levetiracetam injection finally given to be free of
Have（R）- 2-（2- OXo-1-pyrrolidines）Butyramide.
Injection containing levetiracetam medicinal composition provided herein, including by Levetiracetam, acidity
Compound, alkali compounds, the levetiracetam medicinal composition and water for injection of osmotic pressure regulator composition.Levetiracetam
The concentration of Levetiracetam is 90 ~ 110mg/mL in parenteral solution；Acid compound is one kind in acetic acid, citric acid, phosphate
Or it is several；Alkali compounds is the one or more in sodium acetate, sodium hydroxide, potassium hydroxide, sodium citrate, phosphate；Its
PH adjusting agent is acid compound solution, or alkaline compound solution, such as acetum, citric acid solution, phosphate solution, vinegar
Acid sodium solution, sodium hydroxide solution, potassium hydroxide solution, sodium citrate solution；Osmotic pressure regulator be sodium chloride, glucose,
One or more in mannitol.
Injection containing levetiracetam medicinal composition provided herein, wherein including：Levetiracetam 90 ~
110mg/mL, 0.5 ~ 6mg/mL of acid compound, 0.5 ~ 6mg/mL of alkali compounds, 5 ~ 150mg/mL of osmotic pressure regulator and note
Penetrate and use water；The pH values of the parenteral solution are 4.5 ~ 6.5.
Injection containing levetiracetam medicinal composition provided herein, wherein including：Levetiracetam 95 ~
105mg/mL, 1 ~ 3mg/mL of acid compound, 1 ~ 3mg/mL of alkali compounds, 9 ~ 50mg/mL of osmotic pressure regulator and injection
Water；The pH value of the parenteral solution is 5.0 ~ 6.0.
The preparation method of levetiracetam injection provided herein is as follows：
（1）Weigh 60% note that recipe quantity acid compound, alkali compounds and osmotic pressure regulator add about recipe quantity
Penetrate with water, stirring dissolves it, and/or, the pH scopes that solution system is controlled with pH adjusting agent are 4.5 ~ 6.5, obtain solution I；
（2）The Levetiracetam for weighing recipe quantity is added in solution I, obtains solution II；
（3）0.5 ~ 3.0mg/mL activated carbons are added into solution II, 10 ~ 30min is stirred, 10-30min is stood, carried out at decarburization
Reason, obtains solution III；
（4a）Solution III is adsorbed using polyacrylamide resin, solution IV is obtained；
（5）Solution IV is mended and added to the full amount of water for injection, and/or, the pH values of solution are adjusted with pH adjusting agent to 4.5 ~ 6.5；
Then aseptic filtration is carried out to solution with ultrafiltration apparatus, filtrate is filled into vial, sealed, pressure sterilizing is produced.
The preparation method of levetiracetam injection provided herein, in addition to：
（4b）Polyacrylamide resin is added in solution III, stirring and/or shaking table vibrate 10 ~ 30min；And/or by polypropylene
Amide resin is packed into post, adds solution III and carries out adsorption treatment, obtains solution IV；
Preparation method according to claim 8-9, its polyacrylamide resin be PAMA resin, sun from
Sub- polyacrylamide resin, amphiprotic polyacrylamide resin, preferred anionic polyacrylamide resin.
Levetiracetam injection preparation method described herein, the filter plant aperture of its pre-filtering processing is 0.22
~0.45μm；Ultrafiltration apparatus aperture is 0.001 ~ 0.02 μm.
In levetiracetam injection preparation method described herein, by adding PAMA, utilize
Its to presented in water it is electropositive（R）- 2-（2- OXo-1-pyrrolidines）The suction-operated of butyramide, removes left second
In La Xitan injections（R）- 2-（2- OXo-1-pyrrolidines）Butyramide.
The application provide levetiracetam injection, it is several do not contain（R）- 2-（2- OXo-1-pyrrolidines）Fourth
Acid amides.
Embodiment
Following examples further describe beneficial effects of the present invention, and embodiment is only used for the purpose of illustration, and this is not limited
The scope of invention, while obvious change and modification that those of ordinary skill in the art are made according to the present invention are also contained in
Within the scope of the invention.
（One）The preparation of Levetiracetam injection
Embodiment 1
。
Note：PH adjusting agent is the acid compound and/or alkaline compound solution used in the present embodiment, specific consumption
Adjusted according to pH, therefore consumption is appropriate, the following examples are ibid.
Preparation technology
（1）Weigh 60% water for injection that recipe quantity potassium dihydrogen phosphate, dipotassium hydrogen phosphate and sodium chloride add about recipe quantity
In, stirring dissolves it, with 1mol/L dipotassium hydrogen phosphate solution adjust solution pH value to 6.5 solution I；
（2）The Levetiracetam for weighing recipe quantity is added in solution I, obtains solution II；
（3）2.5mg/mL activated carbons are added into solution II, 30min is stirred, 30min is stood, carbonization treatment is carried out, obtains solution
Ⅲ；
（4）0.05% PAMA is added, 10min is stirred, pre-filtering processing is carried out, obtains solution IV；
（5）Solution IV is mended and added to the full amount of water for injection, the pH values of solution are adjusted with 1mol/L dipotassium hydrogen phosphate to 6.5,
Then aseptic filtration is carried out to solution with ultrafiltration apparatus, filtrate is filled into vial, sealed, pressure sterilizing is produced.
Embodiment 2
。
Preparation technology
（1）Weigh recipe quantity glacial acetic acid, potassium hydroxide and sodium chloride to add in about 60% water for injection of recipe quantity, stirring
Dissolve it, with 1mol/L glacial acetic acid adjust solution pH value to 4.5 solution I；
（2）The Levetiracetam for weighing recipe quantity is added in solution I, obtains solution II；
（3）0.5mg/mL activated carbons are added into solution II, 10min is stirred, 20min is stood, carbonization treatment is carried out, obtains solution
Ⅲ；
（4）0.3% PAMA is added, 10min is stirred, pre-filtering processing is carried out, obtains solution IV；
（5）Solution IV is mended and added to the full amount of water for injection, the pH values of solution are adjusted with 1mol/L glacial acetic acid to 4.5, then
Aseptic filtration is carried out to solution with ultrafiltration apparatus, filtrate is filled into vial, sealed, pressure sterilizing is produced.
Embodiment 3
。
Preparation technology
（1）Weigh recipe quantity citric acid, sodium citrate and glucose to add in about 60% water for injection of recipe quantity, stirring
Dissolve it, with 1mol/L citric acid solution adjust solution pH value to 5.6 solution I；
（2）The Levetiracetam for weighing recipe quantity is added in solution I, obtains solution II；
（3）3.0mg/mL activated carbons are added into solution II, 20min is stirred, 30min is stood, carbonization treatment is carried out, obtains solution
Ⅲ；
（4）0.25% PAMA is added, shaking table vibration 20min carries out pre-filtering processing, obtains solution IV；
（5）Solution IV is mended and added to the full amount of water for injection, the pH values of solution are adjusted with 1mol/L citric acid solution to 5.0,
Then aseptic filtration is carried out to solution with ultrafiltration apparatus, filtrate is filled into vial, sealed, pressure sterilizing is produced.
Embodiment 4
。
Preparation technology
（1）Weigh 60% water for injection that recipe quantity dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium chloride add about recipe quantity
In, stirring dissolves it, with 1mol/L dipotassium hydrogen phosphate solution adjust solution pH value to 5.8 solution I；
（2）The Levetiracetam for weighing recipe quantity is added in solution I, obtains solution II；
（3）2.0mg/mL activated carbons are added into solution II, 15min is stirred, 20min is stood, decarburization is carried out, obtains solution III；
（4）0.1% PAMA is added, shaking table vibration 15min carries out pre-filtering processing, obtains solution IV；
（5）Solution IV is mended and added to the full amount of water for injection, adjusted with 1mol/L potassium dihydrogen phosphate the pH values of solution to
5.5, aseptic filtration then is carried out to solution with ultrafiltration apparatus, filtrate is filled into vial, sealed, pressure sterilizing is produced.
Embodiment 5
。
Preparation technology
（1）Weigh recipe quantity glacial acetic acid, sodium acetate and mannitol to add in about 60% water for injection of recipe quantity, stirring makes
It dissolves, with 1mol/L sodium acetate adjust solution pH value to 5.6 solution I；
（2）The Levetiracetam for weighing recipe quantity is added in solution I, obtains solution II；
（3）1.0mg/mL activated carbons are added into solution II, 30min is stirred, 10min is stood, carbonization treatment is carried out, obtains solution
Ⅲ；
（4）0.2% PAMA is added, 1min is stirred, polyacrylamide resin is then packed into post, is added molten
Liquid III carries out adsorption treatment, carries out pre-filtering processing, obtains solution IV；
（5）Solution IV is mended and added to the full amount of water for injection, the pH values of solution are adjusted with 1mol/L sodium acetate solution to 5.8,
Then aseptic filtration is carried out to solution with ultrafiltration apparatus, filtrate is filled into vial, sealed, pressure sterilizing is produced.
Embodiment 6
。
Preparation technology
（1）Weigh recipe quantity glacial acetic acid, sodium hydroxide and sodium chloride to add in about 60% water for injection of recipe quantity, stirring
Dissolve it, with 1mol/L glacial acetic acid solution adjust solution pH value to 5.7 solution I；
（2）The Levetiracetam for weighing recipe quantity is added in solution I, obtains solution II；
（3）1.5mg/mL activated carbons are added into solution II, 15min is stirred, 30min is stood, carbonization treatment is carried out, obtains solution
Ⅲ；
（4）0.15% PAMA is added, 20min is stirred, pre-filtering processing is carried out, obtains solution IV；
（5）Solution IV is mended and added to the full amount of water for injection, the pH values of solution are adjusted with 1mol/L acetum to 5.5, so
Aseptic filtration is carried out to solution with ultrafiltration apparatus afterwards, filtrate is filled into vial, sealed, pressure sterilizing is produced.
Comparative example 1
。
Preparation technology
（1）Weigh recipe quantity glacial acetic acid, sodium hydroxide and sodium chloride to add in about 60% water for injection of recipe quantity, stirring
Dissolve it, with 1mol/L citric acid solution adjust solution pH value to 5.7 solution I；
（2）The Levetiracetam for weighing recipe quantity is added in solution I, obtains solution II；
（3）2.0mg/mL activated carbons are added into solution II, 30min is stirred, 30min is stood, carbonization treatment is carried out, obtains solution
Ⅲ；
（4）Solution III is mended and added to the full amount of water for injection, the pH values of solution are adjusted with 1mol/L sodium hydroxide solutions to 6.5,
Then with 0.22 μm of poly tetrafluoroethylene membrane filtration, filtrate is filled into vial, and sealing, pressure sterilizing is produced.
Comparative example 2
。
Preparation technology
（1）Weigh recipe quantity citric acid, sodium citrate and sodium chloride to add in about 60% water for injection of recipe quantity, stirring
Dissolve it, with 1mol/L citric acid solution adjust solution pH value to 5.7 solution I；
（2）The Levetiracetam for weighing recipe quantity is added in solution I, obtains solution II；
（3）2.0mg/mL activated carbons are added into solution II, 30min is stirred, 30min is stood, carbonization treatment is carried out；Add
0.01% PAMA, stirs 10min, carries out pre-filtering processing, obtains solution III；
（4）Solution III is mended and added to the full amount of water for injection, the pH values of solution are adjusted with 1mol/L glacial acetic acid to 7.0, Ran Houyong
0.22 μm of poly tetrafluoroethylene membrane filtration, filtrate is filled into vial, and sealing, pressure sterilizing is produced.
Comparative example 3
。
Preparation technology
（1）Weigh recipe quantity citric acid, sodium citrate and sodium chloride to add in about 60% water for injection of recipe quantity, stirring
Dissolve it, with 1mol/L citric acid solution adjust solution pH value to 5.7 solution I；
（2）The Levetiracetam for weighing recipe quantity is added in solution I, obtains solution II；
（3）2.0mg/mL activated carbons are added into solution II, 30min is stirred, 30min is stood, carbonization treatment is carried out；Add
0.4 % PAMAs, stir 20min, carry out pre-filtering processing, obtain solution III；
（4）Solution III is mended and added to the full amount of water for injection, the pH values of solution are adjusted with 1mol/L glacial acetic acid to 7.0, Ran Houyong
0.22 μm of poly tetrafluoroethylene membrane filtration, filtrate is filled into vial, and sealing, pressure sterilizing is produced.
（Two）Criteria of quality evaluation
In the parenteral solution prepared using USP standard test various embodiments above drug content and（R）- 2-（2- oxygen
Generation -1- pyrrolidines）The content of butyramide.
。
。
By the Levetiracetam content of comparative example 1-3 and embodiment 1 ~ 6 and（R）- 2-（2- oxos -1-
Pyrrolidines）Butyramide content results are understood, the PAMA of 0.05 ~ 0.3% consumption is added in preparation process, can
With effectively remove in injection（R）- 2-（2- OXo-1-pyrrolidines）Butyramide, while not influenceing left second to draw west
Smooth content；If the addition of PAMA be less than 0.05%, can not reach completely remove injection in
（R）- 2-（2- OXo-1-pyrrolidines）Butyramide；If the addition of PAMA is higher than 0.3%, although can
With remove in injection（R）- 2-（2- OXo-1-pyrrolidines）Butyramide, but the content of Levetiracetam is produced
Significant impact.To sum up, it is several in the levetiracetam injection obtained using preparation method described herein do not contain
（R）- 2-（2- OXo-1-pyrrolidines）Butyramide.
Embodiment described above is only the preferred embodiment to absolutely prove the present invention and being lifted, protection model of the invention
Enclose not limited to this.Equivalent substitute or conversion that those skilled in the art are made on the basis of the present invention, in the present invention
Protection domain within.Protection scope of the present invention is defined by claims.
Claims (9)
1. the injection containing levetiracetam medicinal composition, it includes levetiracetam medicinal composition and water for injection,
But its is several not to contain（R）- 2-（2- OXo-1-pyrrolidines）Butyramide, wherein the levetiracetam medicinal composition
Including Levetiracetam, acid compound, alkali compounds, osmotic pressure regulator.
2. with according to the injection described in claim 1, wherein the concentration of the Levetiracetam is 90 ~ 110mg/mL；The acid
One or more of the property compound in acetic acid, citric acid, phosphate；The alkali compounds is selected from sodium acetate, hydroxide
One or more in sodium, potassium hydroxide, sodium citrate, phosphate；The osmotic pressure regulator be selected from sodium chloride, glucose,
One or more in mannitol.
3. the parenteral solution according to claim 1-2 any claims, wherein 90 ~ 110mg/mL of Levetiracetam, acidity
0.5 ~ 6mg/mL of compound, 0.5 ~ 6mg/mL of alkali compounds, 5 ~ 150mg/mL of osmotic pressure regulator and water for injection；The injection
The pH value of liquid is 4.5 ~ 6.5.
4. the parenteral solution according to claim 1-3 any claims, wherein 95 ~ 105mg/mL of Levetiracetam, acidity
1 ~ 3mg/mL of compound, 1 ~ 3mg/mL of alkali compounds, 9 ~ 50mg/mL of osmotic pressure regulator and water for injection；The parenteral solution
PH value is 5.0 ~ 6.0.
5. the preparation method of the injection described in claim 1, it includes：
（1）Weigh 60% note that recipe quantity acid compound, alkali compounds and osmotic pressure regulator add about recipe quantity
Penetrate with water, stirring dissolves it, and/or, the pH scopes that solution system is controlled with pH adjusting agent are 4.5 ~ 6.5, obtain solution I；
（2）The Levetiracetam for weighing recipe quantity is added in solution I, obtains solution II；
（3）0.5 ~ 3.0mg/mL activated carbons are added into solution II, 10 ~ 30min is stirred, 10-30min is stood, carried out at decarburization
Reason, obtains solution III；
（4a）Solution III is adsorbed using polyacrylamide resin, solution IV is obtained；
（5）Solution IV is mended and added to the full amount of water for injection, and/or, the pH values of solution are adjusted with pH adjusting agent to 4.5 ~ 6.5；
Then aseptic filtration is carried out to solution with ultrafiltration apparatus, filtrate is filled into vial, sealed, pressure sterilizing produces the note
Penetrate agent.
6. preparation method according to claim 5, in addition to：
（4b）Polyacrylamide resin is added in solution III, stirring and/or shaking table vibrate 10 ~ 30min；And/or by polypropylene
Amide resin is packed into post, adds solution III and carries out adsorption treatment, obtains solution IV；
Preparation method according to claim 5-6, wherein polyacrylamide resin be selected from PAMA resin,
PAMC resin, amphiprotic polyacrylamide resin, preferred anionic polyacrylamide resin.
7. the preparation method according to claim 5-7, wherein the consumption of the PAMA be 0.05 ~
0.3%, preferably 0.1 ~ 0.2%.
8. the preparation method according to claim 5-8, wherein pH adjusting agent are acid compound solution, or alkali compounds
Solution, such as acetum, citric acid solution, phosphate solution, sodium acetate solution, sodium hydroxide solution, potassium hydroxide solution, lemon
Lemon acid sodium solution.
9. the preparation method according to claim 5-8, it is several do not contain（R）- 2-（2- OXo-1-pyrrolidines）Butyryl
Amine.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110836930A (en) * | 2018-08-17 | 2020-02-25 | 万特制药(海南)有限公司 | Method for measuring content of dichlorobutane in levetiracetam by gas chromatography-mass spectrometry |
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