CN107913247A - A kind of Levetiracetam injection preparation and preparation method thereof - Google Patents
A kind of Levetiracetam injection preparation and preparation method thereof Download PDFInfo
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- CN107913247A CN107913247A CN201610883888.7A CN201610883888A CN107913247A CN 107913247 A CN107913247 A CN 107913247A CN 201610883888 A CN201610883888 A CN 201610883888A CN 107913247 A CN107913247 A CN 107913247A
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- 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
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- 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
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- 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
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- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- 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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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0023—Heat
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
- A61L2202/20—Targets to be treated
- A61L2202/21—Pharmaceuticals, e.g. medicaments, artificial body parts
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Abstract
A kind of Levetiracetam injection preparation and preparation method thereof.It is using Levetiracetam as medicinal active ingredient, with pharmaceutically acceptable auxiliary material made of can injection composition.When preparing the injection of this active ingredient, only when the pH of levetiracetam pharmaceutical solution is between 5.4 to 5.6, between preferably 5.4 to 5.6, it can produce to obtain high-purity levetiracetam drug solution, and cause most product that there are acceptable long-time stability.In addition, when producing parenteral solution, it is necessary to using autoclaving steam sterilization under pressure method, terminal hot pressing steam sterilizes 15 minutes at a temperature of 121 DEG C, can produce to obtain high-purity levetiracetam parenteral solution, and have acceptable long-time stability.
Description
Technical field
The present invention relates to a kind of injection preparation using Levetiracetam as active ingredient, including powder-injection, large capacity to note
Penetrate liquid (more than 50ml), injection with small volume (below 20ml).Belong to pharmaceutical technology field.
Background technology
Levetiracetam is a kind of pyrrolidinone derivatives, its chemical constitution and existing antiepileptic non-correlation.
The mechanism of action of Levetiracetam anti-epileptic is still imprecise.It has evaluated the anti-insane of Levetiracetam in a variety of animal epileptic models
Epilepsy acts on.Levetiracetam acts on electric current or a variety of simple epileptic attack unrestraints for causing frightened agent maximal stimulation induction, and
Weak activity is only shown in sub- maximal stimulation and Test of threshold.But to the focal attack that pilocarpinum and kainic acid induce
Secondary generalized seizures observes protective effect, both chemical convulsivants can imitate some and be sent out with Secondary cases whole body
The characteristic of the complex partial seizures of work.
Levetiracetam injection by UCB drugmakers of the U.S. (UCB Pharma, Inc.) develop, in June, 2006 by
FDA approval listings, auxiliary treatment when break out for epileptic patient epilepsy part and sick with juvenile myoclonic epilepsy
The auxiliary treatment of the myoclonic seizures of people.The pharmacodynamic activity of Levetiracetam preparation of the present invention is excellent, stable quality,
It is controllable, safely and effectively.
Levetiracetam molecular formula is with molecular weight：
Molecular formula：C8H14N2O2Molecular weight：170.209
Structural formula：
Chemical name：(S)-alpha-ethyl-2-oxo -1- pyrrolidine acetamides
Inventor has found under study for action, in the prescription of Levetiracetam injection preparation and the key parameter of production technology,
The pH value of solution is to influence the key process parameter of preparation stability.
Pass through experimental study, it has been found that when preparing the injection of this active ingredient, only work as levetiracetam pharmaceutical
The pH of solution can produce to obtain high-purity levetiracetam drug solution when between 5.4 to 5.6, when production parenteral solution, need
To use autoclaving steam sterilization under pressure method, terminal sterilization 15 minutes at a temperature of 121 DEG C, can produce to obtain high-purity levetiracetam note
Liquid is penetrated, and there are acceptable long-time stability.
The content of the invention
The present invention provides a kind of using Levetiracetam as active ingredient, the injection preparation of stabilization.It is with Zuo Yila
It is western it is smooth be medicinal active ingredient, with pharmaceutically acceptable auxiliary material made of can injection composition.
The pH of levetiracetam pharmaceutical solution is one and the whether increased key factor of impurity.West is drawn preparing left second
During smooth parenteral solution, the pH value for preparing solution need to be controlled strictly, between preferably 5.4 to 5.6, then according to technological parameter, system
For into injection, it can ensure to obtain to have and stablize levetiracetam pharmaceutical preparation, and maintain its stability during storing.
Research also found：Levetiracetam is in addition to the pH of above-mentioned control drug solution, it is also necessary to and steamed using hot pressing
Gas sterilization, terminal rotating sterilizing is preferably 15 minutes at a temperature of 121 DEG C.By controlling above-mentioned technological parameter, can be made stablize,
The stronger Levetiracetam injection of pharmacological activity.
In heretofore described all injections containing active ingredient Levetiracetam, pharmaceutic adjuvant includes at least pH
One or more in conditioning agent, intercalating agent.Wherein, the pH adjusting agent is water-soluble conditioning agent, can be hydrochloric acid, phosphoric acid,
Hydrobromic acid, acetic acid, potassium acetate, sodium acetate, boric acid, citric acid, sodium carbonate, sodium acid carbonate, saleratus, sodium hydroxide, hydrogen-oxygen
Change the one or more in potassium, phosphate, dihydric phosphate, hydrophosphate, tartaric acid, biatrate, amino acid and its salt,
Acid regulator is preferably hydrochloric acid, and alkaline conditioner is preferably sodium hydroxide.For the metal-chelating used in ejection preparation
Agent, preferably using sodium ethylene diamine tetracetate calcium.
It is ripe using other medicines formulation arts personnel institute by controlling above-mentioned drug solution pH and sterilization method
The means and technology known, can produce to obtain stable levetiracetam injection.
Embodiment
The present invention is further described in detail by following instance, including but not limited to following instance.
1 levetiracetam pharmaceutical pH value of solution roughing of embodiment
280ml waters for injection are taken, sequentially add the Levetiracetam of recipe quantity, stirring is complete to dissolving, and adds recipe quantity
Sodium chloride, stirring is complete to dissolving, and adds recipe quantity sodium acetate, and stirring is complete to dissolving；Above-mentioned solution is divided into 5 parts；
Be separately added into dilute glacial acetic acid solution (1ml → 100ml) and adjust pH value, pH value is followed successively by 6.50,6.00,5.50,5.00,
4.50, record the dosage of dilute glacial acetic acid solution and measured pH value；70ml is settled to respectively with water for injection；It is micro- with 0.22 μm
Hole filter membrane refined filtration, filling, inflated with nitrogen, seals, leak detection, lamp inspection.At the beginning, high temperature (60 DEG C), illumination (4500Lx ± 500Lx)
Under the conditions of 10 days, it is and separately sampled in 0,5,10 day, investigate the color appearance of levetiracetam injection, content, related respectively
Material.Acquired results are as follows：
Levetiracetam injection pH value screening test influence factor result of the test
Strong illumination (4500Lx ± 500Lx) result of the test
60 DEG C of result of the tests of high temperature
2 levetiracetam pharmaceutical pH value of solution of embodiment is selected
280ml waters for injection are taken, sequentially add the Levetiracetam of recipe quantity, stirring is complete to dissolving, and adds recipe quantity
Sodium chloride, stirring is complete to dissolving, and adds recipe quantity sodium acetate, and stirring is complete to dissolving；Above-mentioned solution is divided into 5 parts；
Be separately added into dilute glacial acetic acid solution (1ml → 100ml) and adjust pH value, pH value is followed successively by 5.70,5.60,5.50,5.40,
5.30, record the dosage of dilute glacial acetic acid solution and measured pH value；70ml is settled to respectively with water for injection；It is micro- with 0.22 μm
Hole filter membrane refined filtration, filling, inflated with nitrogen, seals, leak detection, lamp inspection.At the beginning, high temperature (60 DEG C), illumination (4500Lx ± 500Lx)
Under the conditions of 10 days, it is and separately sampled in 0,5,10 day, investigate the color appearance of levetiracetam injection, content, related respectively
Material, content are in terms of initial results relative amount.Acquired results are as follows：
The selected experiment influence factor result of the test of levetiracetam injection pH value
Strong illumination (4500Lx ± 500Lx) result of the test
60 DEG C of result of the tests of high temperature
The above results show that：In pH value screening test, under conditions of illumination 10 days, single miscellaneous nothing substantially becomes each pH value sample
Change；Under the conditions of 60 DEG C, 10 days whens each pH value sample related material increased, but the related material of sample of difference pH contains
Amount is variant.Each sample character, content have no significant change, and prompt levetiracetam injection sensitive to pH, need to be controlled
System.
Influence of 3 heat exposure of embodiment to Levetiracetam stability
240ml waters for injection are taken, add recipe quantity Levetiracetam, stirring is complete to dissolving；Recipe quantity sodium chloride is added,
Stirring is complete to dissolving；Recipe quantity sodium acetate is added, stirring is complete to dissolving；Add dilute glacial acetic acid solution (1ml → 100ml) tune
PH value is saved to 5.50, records the dosage of dilute glacial acetic acid solution；Add 0.1% activated carbon through overactivation, 60 DEG C of constant temperature stirrings 20
Minute, the filtering of decarburization while hot, records constant temperature mixing time；Treat that solution is cooled to room temperature, 300ml is settled to water for injection, use
0.22 μm of miillpore filter refined filtration；Filling in low boron ampoule, the inflated with nitrogen by gained filtrate, seals, leak detection；By above-mentioned sample point
Into 4 groups, sterilize respectively in the following conditions：1. unsterilised, 2. 115 DEG C × 31min, 3. 115 DEG C × 49min, 4. 121 DEG C ×
15min；Sterilize and treated that sample is cooled to room temperature, carried out lamp inspection.
The result shows that：In sterilising conditions screening test, three kinds of distinct methods sterilize sample compared with the sample that do not sterilize, various kinds
Character, pH value, the content of product have no significant change, and total impurities is increased slightly.From above-mentioned experimental result, sample is through 121 DEG C
Sterilize after 15min, liquid is clear and bright, no visible foreign matters, the F of this condition0Value ＞ 12, belongs to the common terminal sterilization condition of big production, side
Method is convenient and reliable, thus select sterilising conditions for 121 DEG C sterilize 15min as this product sterilizing methods.Meanwhile with low boron ampoule
During the investigation of packaging material, do not find that it has an impact liquid medicine stability, thus it is packaging material to be determined as low borosilicate ampoule.It is real
Apply example 4：Levetiracetam injection
Prescription
Preparation method
Water for injection 40ml is taken, adds recipe quantity Levetiracetam, stirring is complete to dissolving；Recipe quantity sodium chloride is added,
Stirring is complete to dissolving；Measure and record pH value；Recipe quantity sodium acetate is added, stirring is complete to dissolving, and measures and records pH value；
Dilute glacial acetic acid solution (1ml → 100ml) is added into above-mentioned solution and adjusts pH value to 5.50, records pH value and dilute glacial acetic acid solution
Dosage；50ml is settled to water for injection；With 0.22 μm of miillpore filter refined filtration, filling, inflated with nitrogen, seals, leak detection.Hot pressing is steamed
Vapour sterilizes (121 DEG C, 15 minutes), you can.
Embodiment 5：Levetiracetam injection
Prescription
Preparation method
Water for injection 40ml is taken, recipe quantity sodium acetate, sodium chloride is added, stirs respectively to being completely dissolved, measure and record
PH value；Dilute glacial acetic acid solution (1ml → 100ml) with one equivalent of technique is added into above-mentioned solution, is stirred evenly, is measured and remember
Record pH value；Recipe quantity Levetiracetam is added into above-mentioned solution, stirring is complete to dissolving, and measures and records pH value；With injection
50ml is settled to water；With 0.22 μm of miillpore filter refined filtration, filling, inflated with nitrogen, seals, leak detection.Hot pressing steam sterilizing (121
DEG C, 15 minutes), you can.
Claims (4)
1. a kind of injection preparation using Levetiracetam as active ingredient, it is characterized in that containing active ingredient Levetiracetam or
Pharmaceutically acceptable pharmaceutic adjuvant, need to be molten by levetiracetam pharmaceutical when preparing the injection preparation of this active ingredient
The pH of liquid is adjusted between to 5.4 to 5.6.
2. injection preparation according to claim 1, it is characterised in that injected including freeze drying powder injection, more than 50ml large capacities
Liquid, below 20ml injection with small volume.
3. injection preparation according to claim 2, it is characterised in that need to adjust the pH of drug solution to particular range
Between 4.5~7.0, preferably 5.4~5.6, ensure and maintain its stability during storing.
4. any injection preparation according to claims 1 to 3, it is characterised in that：Using autoclaving steam sterilization under pressure method, 121 DEG C
At a temperature of terminal hot pressing steam sterilize 15 minutes.
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| CN201610883888.7A CN107913247A (en) | 2016-10-10 | 2016-10-10 | A kind of Levetiracetam injection preparation and preparation method thereof |
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| CN201610883888.7A CN107913247A (en) | 2016-10-10 | 2016-10-10 | A kind of Levetiracetam injection preparation and preparation method thereof |
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| CN101919811A (en) * | 2009-06-09 | 2010-12-22 | 北京博时安泰液体制剂科技有限公司 | Levetiracetam injection and preparation method thereof |
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