CN105853473A - Oxiracetam pharmaceutical composition and preparation method thereof - Google Patents
Oxiracetam pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN105853473A CN105853473A CN201610196278.XA CN201610196278A CN105853473A CN 105853473 A CN105853473 A CN 105853473A CN 201610196278 A CN201610196278 A CN 201610196278A CN 105853473 A CN105853473 A CN 105853473A
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
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- 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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Abstract
The invention belongs to the technical field of medicines, and particularly relates to an oxiracetam pharmaceutical composition, wherein the pharmaceutical composition is an injection for injection, and comprises the following components: 200mg/mL of oxiracetam, 1.0-3.0 mg/mL of water-soluble ginkgo leaf extract, 0.5-2.0 mg/mL of citric acid, an osmotic pressure regulator (such as sodium chloride and glucose) and a pH regulator, wherein the pH value of the pharmaceutical composition is 4.5-5.0. The invention also provides a preparation method of the oxiracetam pharmaceutical composition injection, which comprises the steps of dissolving the raw material medicines, decoloring by using active carbon, adjusting the pH value, sterilizing and the like. The oxiracetam and the water-soluble ginkgo leaf extract in the pharmaceutical composition obtained according to the formula and the preparation method have a synergistic effect, so that the capability of oxiracetam in repairing cerebral nerve cells is enhanced, the effects of improving the memory and the thinking ability of patients are improved, and the oxiracetam and the water-soluble ginkgo leaf extract have good stability.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, specifically, relate to a kind of oxiracetam pharmaceutical composition and
Preparation method.
Background technology
Oxiracetam (Oxiracetam) is a kind of ketopyrrolidine analog derivative, chemical entitled 4-hydroxyl-2-oxo pyrrole
Coughing up alkane-N-acetamide, molecule is for C6H10N2O3, structural formula is as follows:
Researched and developed successfully and in listing in 1987 in 1974 than Qie Mu company by Italy SmithKline.This medicine is in market
On have multiple dosage form, wherein injection administering mode is for being dissolved in normal saline or other diluent iv drip,
4g, once a day, can increase and decrease consumption as one sees fit every time.Treatment usual course for the treatment of to neurological deficit is 2 weeks,
Treatment usual course for the treatment of to memory with disturbance of intelligence is 3 weeks.
Oxiracetam is the derivant of piracetam, and its Main Function mechanism includes the following aspects: 1. promote
Phosphatidylcholine and phosphatidyl ethanolamine synthesis, improve the ratio of ATP/ADP in brain, make albumen in brain
The synthesis of matter and nucleic acid increases；2. strengthen the Changes of Plasticity of brain, the mouldability of strengthening synapse, improve old age silly
Slow-witted disease, the memory of memory disorder patient and learning functionality；3. reduce cerebral vascular resistance, suppress platelet aggregation,
Improve microcirculation and increase cerebral tissue blood flow；4. promote the neurotoxicity of damaged nerve cell excitatory amino acid
Effect.It is applicable to brain injury and the neurological deficit caused, memory and the treatment of disturbance of intelligence, the most applicable
In senile dementia, it may also be used for the convalescence treatment etc. of the brain diseases such as neurosis, encephalitis.
There is hydroxyl in the molecular conformation of oxiracetam and carbonyl is positioned at pyrrole ring homonymy and two kinds of situations of heteropleural, and shows
Have in technology and the oxiracetam disease that both space conformations are different can not be separated, therefore when oxiracetam
When hydroxyl and carbonyl are positioned at the homonymy of pyrrole ring simultaneously, easily forming intramolecular hydrogen bond, this will result in Aura
The western smooth reduction of dissolubility in water for injection, is affected by period of storage and ambient temperature especially, it may appear that from
Injection separates out the situation of the crystal powder of white.
It addition, in actual production process, oxiracetam needs contacting metal container and is heated to 40-60 DEG C
It is by dissolving, and it also requires experience high temperature carries out sterilizing, trace therefore can be detected in finished product injection
Metal ion, due to these metal ions itself have oxidation hydroxyl effect, having in injection can be caused
Related substance content increases with depositing for a long time, and especially when thermal extremes weather is stored, this oxidation is to product
The impact that product stability causes be can not ignore.
The Chinese invention patent of Application No. 201410135403.7 discloses a kind of containing 4-hydroxyl-2-oxo-1-
The pharmaceutical composition of pyrrolidine acetamide, this pharmaceutical composition includes oxiracetam and borneol component, at treatment blood
When the dull-witted neuromotor dysfunction caused with alzheimer disease of pipe and impaired memory dysfunction, there is association
Same-action.But owing to Borneolum Syntheticum is cold in nature, and the Borneolum Syntheticum and the 2-baras camphor that itself contain have certain zest, may
Gerontal patient can be made after making injection to produce the untoward reaction such as allergy.
The Chinese invention patent of Application No. 201210176595.7 discloses a kind of stable S-oxiracetam note
Penetrate with preparation and preparation side thereof, with S-oxiracetam or its salt as medicinal active ingredient, with pharmaceutically acceptable
Adjuvant make can the compositions of injection.This pharmaceutical composition employs calcium disodium chelate and makees
Remove metal ion that may be present in injection for chelating agent, but calcium disodium chelate cannot chelate calcium
Ion, still can produce impact to medicine stability.
The Chinese invention patent of Application No. 200910131292.1 discloses a kind of with levo-oxiracetam as work
The injection injection of property composition, this invention is with levo-oxiracetam or its salt or its purified hydrate as medical active
Composition, with pharmaceutically acceptable adjuvant make can the compositions of injection.This pharmaceutical composition uses
Antioxidant be sodium sulfite, sulphite can be produced after himself is oxidized human body is worked the mischief.
In view of this, the special proposition present invention.
Summary of the invention
It is an object of the invention to overcome existing technological deficiency, it is provided that a kind of stability is more preferable, and drug effect is more excellent
Oxiracetam pharmaceutical composition.
For realizing the purpose of the present invention, the present invention adopts the following technical scheme that
A kind of pharmaceutical composition of oxiracetam, wherein, described pharmaceutical composition is water for injection injection, its
Composition includes:
Oxiracetam 200mg/mL
Water-soluble gingko extract 1.0～3.0mg/mL
Citric acid 0.5～2.0mg/mL
Preferably, the composition of described water for injection injection includes:
Oxiracetam 200mg/mL
Water-soluble gingko extract 1.5～3.0mg/mL
Citric acid 1.0～2.0mg/mL
Folium Ginkgo extract (EGb761) has antioxidant activity, cardiac vascular activity, anti-inflammatory activity and antineoplastic
Active function, is the conventional Chinese medicine treating cardio-cerebralvascular diseases at present, and effective ingredient is mainly Ginkgolides
With Semen Ginkgo two terpene lactone compounds, wherein ginkgetin methods of glycosides mainly includes Quercetin, kaempferol, different
Rhamnetin.Semen Ginkgo two terpene lactone constituents mainly includes Ginkgolide A. B. C, J, M and bilobalide.
It is an unexpected discovery of the invention that after adding a certain amount of water soluble ginkgo leaf extract and citric acid in prescription,
The two creates synergism in non-oxidizability, and due to the citric acid self sequestering power to metal ion,
Can remove because technological problems is retained in the trace metal element in oxiracetam medicine composition injection.Simultaneously
Finding the research of this pharmaceutical composition through zoopery, water soluble ginkgo leaf extract enhances oxiracetam
Treatment dysmnesia and the effect improving learning capacity.
Pharmaceutical composition of the present invention, it is characterised in that described pharmaceutical composition also includes that osmotic pressure is adjusted
Joint agent, described osmotic pressure regulator is the one in sodium chloride, glucose.
Pharmaceutical composition of the present invention, it is characterised in that described pharmaceutical composition also includes that osmotic pressure is adjusted
One in joint agent, preferably sodium chloride, glucose.
Pharmaceutical composition of the present invention, it is characterised in that described osmotic pressure regulator is dense when being sodium chloride
Degree is 5～20mg/mL, preferably 5～10mg/mL；When described osmotic pressure regulator is glucose, concentration is
40～60mg/mL.
Ginkgo total flavones glycoside >=24% in water-soluble gingko extract of the present invention, the total terpene lactone of Semen Ginkgo >=
6%.
Pharmaceutical composition of the present invention also includes pH adjusting agent, and wherein, described pH adjusting agent is citron
Acid sodium, by add appropriate pH adjusting agent control the pH value of described water for injection injection 4.5～5.0 it
Between, preferable ph scope is 4.5～4.8.Pass having considered phosphate buffer, sodium hydroxide, hydrochloric acid etc.
System buffer reagent on the impact of oxiracetam long-time stability after, selected with citric acid can be formed buffer to
Sodium citrate, selected buffer agent can make citric acid preferably play the effect of metal ion chelation agent.
In pharmaceutical composition of the present invention, the concentration of metal ion is less than 1ppm, due in technical process
Trace metal ion can produce Oxidation to oxiracetam, therefore strictly to control its trace concentration.
The invention allows for the preparation method of the pharmaceutical composition of a kind of oxiracetam, this preparation method include as
Lower step:
(1) under nitrogen protective condition, water for injection being heated to 40 DEG C～60 DEG C, in liquid, remaining oxygen is less than
2ppm；
(2) under nitrogen protective condition, water-soluble Semen Ginkgo extrac and citric acid, inject with water the most molten
Solve；
(3) under nitrogen protective condition, the aqueous solution for injection described in step (1) is slowly added into step (2)
Described water soluble ginkgo leaf extract and the aqueous solution for injection of citric acid, be simultaneously introduced oxiracetam crude drug,
It is stirred well to all dissolve；
(4) solution after being completely dissolved described in step (3) adds the pin activity that weight ratio is 0.1～0.3%
Charcoal stirs, and uses filtering with microporous membrane carbon removal after standing decolouring in 20 minutes；
(5) solution temperature after step (4) described filtration is down to 25 DEG C, with sodium citrate regulation pH value extremely
4.5～5.0, add water for injection to full dose；
(6) with microporous filter membrane, the solution of step (5) is filtered；
(7) nitrogen charging embedding is after ampoule bottle, carries out pressure sterilizing.
In above-mentioned preparation method, the water for injection described in step (1) is also added into osmotic pressure regulator before heating,
Described osmotic pressure regulator is the one in sodium chloride or glucose.
PH value described in step (5) is 4.5～4.8.
Pressure sterilizing temperature described in step (7) is 121 DEG C, sterilization time 15～30 minutes, preferably 15 points
Clock, for preventing the high temperature impact on pharmaceutical composition stability, sterilization time in the case of ensureing sterilization effect
Unsuitable long.
Compared with prior art, the oxiracetam medicine composition injection of the present invention have more preferable stability and
Preferably drug effect.
Detailed description of the invention
Being below the detailed description of the invention of the present invention, described embodiment is to further describe the present invention, and
It not to limit the present invention.
First the oxiracetam pharmaceutical composition to the present invention carries out prescription screening experiment, selects Austria of same amount
La Xitan (200mg/mL), osmotic pressure regulator (sodium chloride) and the water soluble ginkgo leaf extract of variable concentrations
(EGb761), citric acid composition prescription and the identical composite medicine of component carry out molten under condition of different pH
The mensuration of liquid outward appearance, visible foreign matters, related substances or metal ion content determines the preferred scope of composition, presses
Carrying out according to the preparation method in summary of the invention, test result is shown in Table 1～table 3:
Table 1 prescription screening water soluble ginkgo leaf extract (EGb761) concentration experiment result
| EGb761(mg/mL) | Citric acid (mg/mL) | Solution appearance | Related substances (%) |
| 0.2 | 1.0 | Clear, colorless is transparent | 0.057 |
| 0.4 | 1.0 | Clear, colorless is transparent | 0.049 |
| 0.6 | 1.0 | Clear, colorless is transparent | 0.036 |
| 0.8 | 1.0 | Clear, colorless is transparent | 0.031 |
| 1.0 | 1.0 | Clear, colorless is transparent | 0.020 |
| 1.4 | 1.0 | Clear, colorless is transparent | 0.020 |
| 1.8 | 1.0 | Clear, colorless is transparent | 0.019 |
| 2.2 | 1.0 | Clear, colorless is transparent | 0.019 |
| 2.6 | 1.0 | Clear, colorless is transparent | 0.018 |
| 3.0 | 1.0 | Clear, colorless is transparent | 0.018 |
| 3.2 | 1.0 | Clear, colorless is transparent | 0.020 |
| 3.4 | 1.0 | Clear, light brown | 0.022 |
| 3.6 | 1.0 | Clear, light brown | 0.022 |
| 3.8 | 1.0 | Clear, rufous | 0.024 |
| 4.0 | 1.0 | Clear, rufous | 0.025 |
As shown in Table 1, water soluble ginkgo leaf extract concentration related substances inspection when 0.2～0.8mg/mL scope
Surveying content higher, do not meet the requirement of quality standard, water soluble ginkgo leaf extract concentration is 1.0～3.0mg/mL
During scope related substances begin to decline degree inconspicuous after close to 3.2mg/mL time promoted, and solution face
Color is transferred to light brown red by colourless, does not meets the requirement of quality standard, and therefore selecting 1.0～3.0mg/mL is water
The preferred concentration range of soluble ginkgo leaf extract.
Table 2 prescription screening citric acid concentration experiment result
| EGb761(mg/mL) | Citric acid (mg/mL) | Visible foreign matters | Metal ion (ppm) |
| 1.5 | 0.1 | Without visible foreign matters | 1.32 |
| 1.5 | 0.2 | Without visible foreign matters | 1.19 |
| 1.5 | 0.4 | Without visible foreign matters | 1.02 |
| 1.5 | 0.5 | Without visible foreign matters | 0.91 |
| 1.5 | 0.8 | Without visible foreign matters | 0.82 |
| 1.5 | 1.0 | Without visible foreign matters | 0.74 |
| 1.5 | 1.2 | Without visible foreign matters | 0.68 |
| 1.5 | 1.5 | Without visible foreign matters | 0.62 |
| 1.5 | 1.8 | Without visible foreign matters | 0.56 |
| 1.5 | 2.0 | Without visible foreign matters | 0.51 |
| 1.5 | 2.2 | There is insoluble granule | 0.45 |
| 1.5 | 2.5 | There is insoluble granule | 0.41 |
| 1.5 | 3.0 | There is insoluble granule | 0.37 |
As shown in Table 2, citric acid concentration related substances detection level when 0.1～0.4mg/mL scope is higher,
Not meeting the requirement of quality standard, citric acid concentration related substances when 2.2～3.0mg/mL scope still declines,
But solution occurs a small amount of insoluble granule, does not meets the requirement of quality standard, therefore select 0.5～2.0mg/mL
Preferred concentration range for citric acid.
(wherein water soluble ginkgo leaf extract concentration is 1.5mg/mL, Chinese holly to table 3 prescription screening pH value experimental result
Rafter acid concentration is 1.0mg/mL)
As shown in Table 3, pH value related substances detection level when 3.5～4.5 scope is higher but on a declining curve,
PH value related substances content when 5.2～5.9 scope is relatively low but in rising trend, and pH rises to solution when 5.9
Insoluble granule occurs, does not meets the requirement of quality standard, therefore select related substances content minimum and trend
PH scope 4.5～5.0 is preferred concentration range smoothly.
In sum, the concentration range of the water soluble ginkgo leaf extract that embodiment selects is 1.0～3.0mg/mL,
The concentration range of the citric acid selected is 0.5～2.0mg/mL, and the pH value range of selection is 4.5～5.0.
Embodiment 1
Prescription:
Preparation technology:
(1) under nitrogen protective condition, the sodium chloride taking recipe quantity is dissolved in the injection of 70%～80% recipe quantity
With in water, being heated to 40 DEG C～60 DEG C, in liquid, remaining oxygen is less than 2ppm；
(2) under nitrogen protective condition, separately take water-soluble gingko extract and the citric acid of recipe quantity, inject
Fully dissolve with water；
(3) under nitrogen protective condition, it is slowly added in the mixed solution described in step (1) described in step (2)
Mixed solution, is simultaneously introduced oxiracetam crude drug, is stirred well to all dissolve；
(4) in the mixed solution described in step (3), add the needle-use activated carbon that weight ratio is 0.1% to stir,
Filtering with microporous membrane carbon removal is used after standing decolouring in 20 minutes；
(5) solution temperature after the filtration described in step (4) is down to 25 DEG C, with sodium citrate regulation pH value extremely
4.5, add water for injection to full dose；
(6) with 0.22 μm microporous filter membrane, the solution of step (5) is filtered；
(7) nitrogen charging embedding is after ampoule bottle, and design temperature 121 DEG C carries out pressure sterilizing 30min and obtains finished product.
Embodiment 2
Prescription:
Preparation technology:
(1) under nitrogen protective condition, the sodium chloride taking recipe quantity is dissolved in the injection of 70%～80% recipe quantity
With in water, being heated to 60 DEG C, in liquid, remaining oxygen is less than 2ppm；
(2) under nitrogen protective condition, separately take water-soluble gingko extract and the citric acid of recipe quantity, inject
Fully dissolve with water；
(3) under nitrogen protective condition, it is slowly added in the mixed solution described in step (1) described in step (2)
Mixed solution, is simultaneously introduced oxiracetam crude drug, is stirred well to all dissolve；
(4) in the mixed solution described in step (3), add the needle-use activated carbon that weight ratio is 0.3% to stir,
Filtering with microporous membrane carbon removal is used after standing decolouring in 20 minutes；
(5) solution temperature after the filtration described in step (4) is down to 25 DEG C, with sodium citrate regulation pH value extremely
5.0, add water for injection to full dose；
(6) with 0.22 μm microporous filter membrane, the solution of step (5) is filtered；
(7) nitrogen charging embedding is after ampoule bottle, and design temperature 121 DEG C carries out pressure sterilizing 20min and obtains finished product.
Embodiment 3
Prescription:
Preparation technology:
(1) under nitrogen protective condition, the sodium chloride taking recipe quantity is dissolved in the injection of 70%～80% recipe quantity
With in water, being heated to 50 DEG C, in liquid, remaining oxygen is less than 2ppm；
(2) under nitrogen protective condition, separately take water-soluble gingko extract and the citric acid of recipe quantity, inject
Fully dissolve with water；
(3) under nitrogen protective condition, it is slowly added in the mixed solution described in step (1) described in step (2)
Mixed solution, is simultaneously introduced oxiracetam crude drug, is stirred well to all dissolve；
(4) in the mixed solution described in step (3), add the needle-use activated carbon that weight ratio is 0.2% to stir,
Filtering with microporous membrane carbon removal is used after standing decolouring in 20 minutes；
(5) solution temperature after the filtration described in step (4) is down to 25 DEG C, with sodium citrate regulation pH value extremely
4.8, add water for injection to full dose；
(6) with 0.22 μm microporous filter membrane, the solution of step (5) is filtered；
(7) nitrogen charging embedding is after ampoule bottle, and design temperature 121 DEG C carries out pressure sterilizing 15min and obtains finished product.
Embodiment 4
Prescription:
Preparation technology:
(1) under nitrogen protective condition, the glucose taking recipe quantity is dissolved in the injection of 70%～80% recipe quantity
With in water, being heated to 40 DEG C, in liquid, remaining oxygen is less than 2ppm；
(2) under nitrogen protective condition, separately take water-soluble gingko extract and the citric acid of recipe quantity, inject
Fully dissolve with water；
(3) under nitrogen protective condition, it is slowly added in the mixed solution described in step (1) described in step (2)
Mixed solution, is simultaneously introduced oxiracetam crude drug, is stirred well to all dissolve；
(4) in the mixed solution described in step (3), add the needle-use activated carbon that weight ratio is 0.2% to stir,
Filtering with microporous membrane carbon removal is used after standing decolouring in 20 minutes；
(5) solution temperature after the filtration described in step (4) is down to 25 DEG C, with sodium citrate regulation pH value extremely
4.8, add water for injection to full dose；
(6) with 0.22 μm microporous filter membrane, the solution of step (5) is filtered；
(7) nitrogen charging embedding is after ampoule bottle, and design temperature 121 DEG C carries out pressure sterilizing 20min and obtains finished product.
Embodiment 5
Prescription:
Preparation technology:
(1) under nitrogen protective condition, the glucose taking recipe quantity is dissolved in the injection of 70%～80% recipe quantity
With in water, being heated to 50 DEG C, in liquid, remaining oxygen is less than 2ppm；
(2) under nitrogen protective condition, separately take water-soluble gingko extract and the citric acid of recipe quantity, inject
Fully dissolve with water；
(3) under nitrogen protective condition, it is slowly added in the mixed solution described in step (1) described in step (2)
Mixed solution, is simultaneously introduced oxiracetam crude drug, is stirred well to all dissolve；
(4) in the mixed solution described in step (3), add the needle-use activated carbon that weight ratio is 0.1% to stir,
Filtering with microporous membrane carbon removal is used after standing decolouring in 20 minutes；
(5) solution temperature after the filtration described in step (4) is down to 25 DEG C, with sodium citrate regulation pH value extremely
4.5, add water for injection to full dose；
(6) with 0.22 μm microporous filter membrane, the solution of step (5) is filtered；
(7) nitrogen charging embedding is after ampoule bottle, and design temperature 121 DEG C carries out pressure sterilizing 15min and obtains finished product.
Embodiment 6
Prescription:
Preparation technology:
(1) under nitrogen protective condition, the glucose taking recipe quantity is dissolved in the injection of 70%～80% recipe quantity
With in water, being heated to 60 DEG C, in liquid, remaining oxygen is less than 2ppm；
(2) under nitrogen protective condition, separately take water-soluble gingko extract and the citric acid of recipe quantity, inject
Fully dissolve with water；
(3) under nitrogen protective condition, it is slowly added in the mixed solution described in step (1) described in step (2)
Mixed solution, is simultaneously introduced oxiracetam crude drug, is stirred well to all dissolve；
(4) in the mixed solution described in step (3), add the needle-use activated carbon that weight ratio is 0.3% to stir,
Filtering with microporous membrane carbon removal is used after standing decolouring in 20 minutes；
(5) solution temperature after the filtration described in step (4) is down to 25 DEG C, with sodium citrate regulation pH value extremely
5.0, add water for injection to full dose；
(6) with 0.22 μm microporous filter membrane, the solution of step (5) is filtered；
(7) nitrogen charging embedding is after ampoule bottle, and design temperature 121 DEG C carries out pressure sterilizing 30min and obtains finished product
Comparative example 1
Prescription:
Preparation technology:
(1) under nitrogen protective condition, the sodium chloride taking recipe quantity is dissolved in the injection of 70%～80% recipe quantity
With in water, being heated to 50 DEG C, in liquid, remaining oxygen is less than 2ppm；
(2) under nitrogen protective condition, separately take the water-soluble gingko extract of recipe quantity, inject with water abundant
Dissolve；
(3) under nitrogen protective condition, it is slowly added in the mixed solution described in step (1) described in step (2)
Mixed solution, is simultaneously introduced oxiracetam crude drug, is stirred well to all dissolve；
(4) in the mixed solution described in step (3), add the needle-use activated carbon that weight ratio is 0.2% to stir,
Filtering with microporous membrane carbon removal is used after standing decolouring in 20 minutes；
(5) solution temperature after the filtration described in step (4) is down to 25 DEG C, with sodium citrate regulation pH value extremely
4.8, add water for injection to full dose；
(6) with 0.22 μm microporous filter membrane, the solution of step (5) is filtered；
(7) nitrogen charging embedding is after ampoule bottle, and design temperature 121 DEG C carries out pressure sterilizing 15min and obtains finished product.
Comparative example 2
Prescription:
Preparation technology:
(1) under nitrogen protective condition, the sodium chloride taking recipe quantity is dissolved in the injection of 70%～80% recipe quantity
With in water, being heated to 50 DEG C, in liquid, remaining oxygen is less than 2ppm；
(2) under nitrogen protective condition, separately take the citric acid of recipe quantity, inject and fully dissolve with water；
(3) under nitrogen protective condition, it is slowly added in the mixed solution described in step (1) described in step (2)
Mixed solution, is simultaneously introduced oxiracetam crude drug, is stirred well to all dissolve；
(4) in the mixed solution described in step (3), add the needle-use activated carbon that weight ratio is 0.2% to stir,
Filtering with microporous membrane carbon removal is used after standing decolouring in 20 minutes；
(5) solution temperature after the filtration described in step (4) is down to 25 DEG C, with sodium citrate regulation pH value extremely
4.8, add water for injection to full dose；
(6) with 0.22 μm microporous filter membrane, the solution of step (5) is filtered；
(7) nitrogen charging embedding is after ampoule bottle, and design temperature 121 DEG C carries out pressure sterilizing 15min and obtains finished product.
Comparative example 3
Selected from commercially available product oxiracetam injection (manufacturer: Medisan Pharmaceutical Co., Ltd. Harbin, business
The name of an article: Ou Lantong, dosage form is 1g:5mL).
Test example 1 high temperature illumination effect factorial experiments
The oxiracetam pharmaceutical composition injection that the embodiment of the present invention 1,2,4,5 and comparative example 1～3 are prepared
Liquid carries out high temperature (60 DEG C ± 2 DEG C) and illumination (4500Lx ± 500Lx) the influence factor examination of continuous 10 days respectively
Test and in the 5th, 10 days sampling detection related substanceses and oxiracetam content, obtained experimental result is shown in Table 4.
Table 4 high temperature and illumination effect factorial experiments result
From table 4, comparative example 1 lacks citric acid component, comparative example 2 and embodiment phase compared with embodiment
Ratio lacks water soluble ginkgo leaf extract composition, and comparative example 3 is commercially available product, analyzes above-mentioned comparative example and embodiment
Relevant content of material finds individually add water soluble ginkgo leaf extract in contrast commercially available product prescription or individually add
Citric acid can act as reducing the effect of related substances content, but add water-soluble silver the most simultaneously
Under the prescription effect of Folium Pruni extract and citric acid, related substances content is lower.The most as shown in Table 4, city is compared
In prescription, individually add water soluble ginkgo leaf extract for selling product or the independent citric acid that adds can be stablized
Oxiracetam content, but the prescription the most simultaneously adding water soluble ginkgo leaf extract and citric acid is made
With lower oxiracetam stable content and higher than the comparative example individually added.Summary content, the embodiment of the present invention
High temperature resistant light durability is superior to comparative example, illustrates that water soluble ginkgo leaf extract and citric acid are collaborative and enhances
The heatproof light fastness stability of oxiracetam pharmaceutical composition.
Test example 2 accelerated test
The oxiracetam medicine composition injection embodiment of the present invention 3,6 and comparative example 1～3 prepared is respectively
Being accelerated test, under the conditions of 40 DEG C ± 2 DEG C, the constant temperature and humidity state of relative humidity 75% ± 5% stores 6
Individual month, in 0,1,3, June respectively samples detection, and obtained experimental result is shown in Table 5.
Table 5 accelerated test result
As shown in Table 5, embodiment 3 and embodiment 6 prescription are after the accelerated test of 6 months, outside solution
Seeing and visible foreign matters project all meets standards of pharmacopoeia, related substances has risen, but can accept model at quality standard
Enclosing, oxiracetam content decrease speed is slow；And individually add the comparative example 1 of water soluble ginkgo leaf extract
Comparative example 2 prescription of prescription and individually interpolation citric acid is after the accelerated test of half a year, although effect is better than
Accelerate 3 months solution appearance and comparative example 3 that visible foreign matters i.e. changes, but compared to embodiment 3,6,
Comparative example 1,2 visible foreign matters project did not met pharmacopoeial requirements when 6 months, and related substances content rises more,
The oxiracetam range of decrease is bigger.In sum, illustrate that water soluble ginkgo leaf extract and citric acid are collaborative and enhance Austria
The accelerated stability of La Xitan pharmaceutical composition, its effect is better than being used alone water soluble ginkgo leaf extract or Chinese holly
The prescription of rafter acid, and it is much better than commercially available similar drug.
Test example 3 causes the memory of dementia mice, the impact of learning capacity to Anisodine
1 experiment material
1.1 test medicine: the oxiracetam medicine that embodiment 1,3,5 and comparative example 1～3 obtain.
1.2 animal materials: SPF level mice, 80 male and female half and half, body weight is 18～22g.
1.3 devices: channel-type water maze (4 cecum), darkness avoidance test light and shade case.
2 experimental technique steps
2.1 packets and administration
Mice 80, is divided into 8 groups according to random distribution principle, respectively blank group, model group, reality
Execute example 1 group, embodiment 3 groups, embodiment 5 groups, comparative example 1 group, comparative example 2 groups, comparative example 3 groups,
Often group 10.Blank group group and model group give normal saline every day, medicine group give embodiment 2,4,
6 and the oxiracetam pharmaceutical composition that obtains of the method for comparative example 1～3, every day 1 time, continuous 14 days.
2.2 training and modelings
From the beginning of being administered the 1st, above-mentioned each group of mice is carried out channel-type water maze training and darkness avoidance test electric shock examination
Testing, the most continuous 7 days, trained leave the labyrinth time less than 20 seconds, route selection mistake does not surpasses
Crossing is for 2 times that training is qualified, is administered the 8th, 10,12, and in addition to blank group, remaining is respectively organized mice and all exists
Be administered latter 1 hour lumbar injection Anisodine (5.0mg/kg) carry out dysmnesia modeling, inject beginning in latter 30 minutes
Carry out channel-type water maze and keep away dark test, training result defective i.e. modeling success.After modeling on the 14th
Carry out aptitude tests.
2.3 memories, learning capacity test recording method
Darkness avoidance test: in light and shade case, darkroom passes to 36V alternating current, by mice face hole dorsad, puts into bright room,
Start timer simultaneously.Animal is shocked by electricity through entrance darkroom, hole, and timing stops, and takes out mice.Record
The number of times shocked by electricity in entering the incubation period and 5 minutes in darkroom, i.e. errors number.
Channel-type water maze: mice head is put in water maze towards wall, starts record.Record its trip completely
Time (incubation period) of journey and swim the number of times (errors number) into cecum, as beyond 2 minutes by 2 minutes notes.
3 data analysiss and conclusion
3.1 darkness avoidance test experimental result and analyses
The number of times that record mice is shocked by electricity in entering the incubation period and 5 minutes in darkroom, result is as shown in table 6:
Table 6 darkness avoidance test experimental result ()
| Group | Incubation period (s) | Errors number (/ 5min) |
| Blank group | 269.7±12.4 | 1.2±0.9 |
| Model group | 69.2±15.6* | 7.3±2.6* |
| Embodiment 1 group | 131.5±38.3** | 3.2±1.8** |
| Embodiment 3 groups | 152.2±52.3** | 2.4±0.8** |
| Embodiment 5 groups | 136.4±41.5** | 3.4±1.2** |
| Comparative example 1 group | 105.9±29.4*** | 3.9±1.4*** |
| Comparative example 2 groups | 93.7±24.8*** | 5.8±1.9*** |
| Comparative example 3 groups | 85.1±28.6*** | 6.3±2.8*** |
Comparing with blank, * is P ＜ 0.01；Comparing with model group: * * is P ＜ 0.01, * * * is P ＜ 0.05.
From table 6, compared with model group, embodiment 1,3,5 groups (P ＜ 0.01) and comparative example 1～3 groups
(P ＜ 0.05) all can extend Anisodine and cause Model of Dementia mice and in incubation period of bright room and reduce it and go to darkroom to meet with
The number of times shocked by electricity.The comparative example 3 groups wherein not containing water soluble ginkgo leaf extract and citric acid can be improved
The mnemonic learning ability of modeling mice, but effect is not as good as the contrast that with the addition of water soluble ginkgo leaf extract composition
Example 1 group, and with the addition of the comparative example 2 groups of citric acid component, and add simultaneously water soluble ginkgo leaf extract and
The embodiment of citric acid component 1,3,5 groups is compared comparative example 1,2 groups and is served significantly more improvement result.
It can thus be appreciated that water soluble ginkgo leaf extract, citric acid, the compositions of oxiracetam three can produce collaborative effect
Really, its effect is much larger than separate constituent.
3.2 channel-type water maze laboratory result and analyses
Record the time (incubation period) of mice covering the race and swim the number of times (errors number) into cecum, result
As shown in table 7:
Table 7 channel-type water maze laboratory result ()
| Group | Latent time (s) | Errors number |
| Blank group | 18.2±1.5 | 1.1±0.6 |
| Model group | 2min* | 6.2±2.7* |
| Embodiment 1 group | 31.7±6.3** | 2.4±1.8** |
| Embodiment 3 groups | 28.6±5.7** | 2.1±1.5** |
| Embodiment 5 groups | 33.9±5.9** | 2.8±1.4** |
| Comparative example 1 group | 59.0±11.6*** | 4.6±2.1*** |
| Comparative example 2 groups | 64.4±15.4*** | 4.2±1.6*** |
| Comparative example 3 groups | 72.1±13.0*** | 5.3±2.2*** |
Comparing with blank, * is P ＜ 0.01；Comparing with model group: * * is P ＜ 0.01, * * * is P ＜ 0.05.
From table 7, compared with model group, embodiment 1,3,5 groups (P ＜ 0.01) and comparative example 1～3 groups
(P ＜ 0.05) all can reduce Anisodine and cause Model of Dementia mice latent time in water maze and reduce its entrance
The number of times of cecum.The comparative example 3 groups wherein not containing water soluble ginkgo leaf extract and citric acid can improve note
Recall the cognitive learning ability of obstacle mice, but effect is not as good as with the addition of the right of water soluble ginkgo leaf extract composition
Ratio 1 group, and with the addition of the comparative example 2 groups of citric acid component, and add water soluble ginkgo leaf extract simultaneously
Compare comparative example 1,2 groups with the embodiment 1,3,5 groups of citric acid component and serve significantly more effect.
It can thus be appreciated that water soluble ginkgo leaf extract, citric acid, the compositions of oxiracetam three can produce collaborative effect
Really, its effect is much larger than separate constituent.
Oxiracetam pharmaceutical composition prepared by other embodiments of the present invention has been also carried out above-mentioned test, and it obtains
The result obtained is similar.
Above the present invention is described in detail, its object is to make those of ordinary skill in the art's energy much of that
Solve present disclosure and be carried out, can not limit the scope of the invention with this, all according to the present invention
The equivalence change done of spirit or modify, all should contain within the scope of the present invention.
Claims (10)
1. the pharmaceutical composition of an oxiracetam, it is characterised in that described pharmaceutical composition is injection liquid drugs injection
Agent, its composition includes:
Oxiracetam 200mg/mL
Water-soluble gingko extract 1.0～3.0mg/mL
Citric acid 0.5～2.0mg/mL
Preferably:
Oxiracetam 200mg/mL
Water-soluble gingko extract 1.5～3.0mg/mL
Citric acid 0.5～1.0mg/mL.
Pharmaceutical composition the most according to claim 1, it is characterised in that described pharmaceutical composition also includes
One in osmotic pressure regulator, preferably sodium chloride or glucose.
Pharmaceutical composition the most according to claim 2, it is characterised in that described osmotic pressure regulator is chlorine
When changing sodium, concentration is 5～20mg/mL, preferably 5～10mg/mL；Described osmotic pressure regulator is glucose
Time concentration be 40～60mg/mL.
4. according to the pharmaceutical composition described in claims 1 to 3 any one, it is characterised in that described water solublity
Ginkgo total flavones glycoside >=24% in Semen Ginkgo extrac, total terpene lactone >=6% of Semen Ginkgo.
Pharmaceutical composition the most according to claim 4, it is characterised in that also wrap in described pharmaceutical composition
Including pH adjusting agent, described pH adjusting agent is sodium citrate, controls by adding appropriate pH adjusting agent
The pH value of described water for injection injection is 4.5～5.0, preferably 4.5～4.8.
Pharmaceutical composition the most according to claim 5, it is characterised in that in described pharmaceutical composition metal from
The concentration of son is less than 1ppm.
7. the preparation method of the pharmaceutical composition described in a claim 1, it is characterised in that described preparation method
Comprise the steps:
(1) under nitrogen protective condition, water for injection being heated to 40 DEG C～60 DEG C, in liquid, remaining oxygen is less than
2ppm；
(2) under nitrogen protective condition, water-soluble Semen Ginkgo extrac and citric acid, inject with water the most molten
Solve；
(3) under nitrogen protective condition, in the aqueous solution for injection described in step (1), step (2) it is slowly added into
Described water soluble ginkgo leaf extract and the aqueous solution for injection of citric acid, be simultaneously introduced oxiracetam crude drug,
It is stirred well to be completely dissolved；
(4) solution after being completely dissolved described in step (3) adds the pin activity that weight ratio is 0.1～0.3%
Charcoal stirs, and uses filtering with microporous membrane carbon removal after standing decolouring in 20 minutes；
(5) solution temperature after step (4) described filtration is down to 25 DEG C, with sodium citrate regulation pH value extremely
4.5～5.0, add water for injection to full dose；
(6) with microporous filter membrane, the solution of step (5) is filtered；
(7) nitrogen charging embedding is after ampoule bottle, carries out pressure sterilizing.
Preparation method the most according to claim 7, it is characterised in that the water for injection described in step (1) exists
Being also added into osmotic pressure regulator before heating, described osmotic pressure regulator is the one in sodium chloride or glucose.
Preparation method the most according to claim 7, it is characterised in that the pH value described in step (5) be 4.5～
4.8。
Preparation method the most according to claim 7, it is characterised in that the pressure sterilizing temperature described in step (7)
Degree is 121 DEG C, sterilization time 15～30 minutes, preferably 15 minutes.
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