CN102266329B - Pharmaceutical composition comprising vinpocetine compound and preparation method thereof - Google Patents
Pharmaceutical composition comprising vinpocetine compound and preparation method thereof Download PDFInfo
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- CN102266329B CN102266329B CN2011101630368A CN201110163036A CN102266329B CN 102266329 B CN102266329 B CN 102266329B CN 2011101630368 A CN2011101630368 A CN 2011101630368A CN 201110163036 A CN201110163036 A CN 201110163036A CN 102266329 B CN102266329 B CN 102266329B
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- Prior art keywords
- vinpocetine
- pharmaceutical composition
- injection
- mannitol
- sorbic acid
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 24
- -1 vinpocetine compound Chemical class 0.000 title claims abstract description 10
- DDNCQMVWWZOMLN-IRLDBZIGSA-N Vinpocetine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OCC)N5C2=C1 DDNCQMVWWZOMLN-IRLDBZIGSA-N 0.000 claims abstract description 73
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- Medicinal Preparation (AREA)
Abstract
The invention discloses a pharmaceutical composition comprising a vinpocetine compound and a preparation method thereof, and the pharmaceutical composition comprises the following components vinpocetine, sorbic acid and mannitol in a weight ratio of (10-30):(5-30):(50-200). The pharmaceutical composition disclosed by the invention has the advantages of easy formation, good redissolution, stable properties and high safety, and all indicators meet the provisions on medicine use.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of pharmaceutical composition that contains the vinpocetine chemical compound and preparation method thereof.
Background technology
Vinpocetine (Vinpocetine) molecular formula C
22H
26N
2O
2, be a kind of natural drug that extracts from the Apocynaceae periwinkle, belong to indoles alkaloid.Claim vinpocetine again, carvinton see vinpocetine, Vinpocetine, white crystalline powder, odorless, 147～153 ℃ of fusing points are dissolved in chloroform and ethanol, and are water-soluble hardly.
Vinpocetine is widely used in the prevention and the treatment of ischemic cerebrovascular; Be usually used in cerebral arteriosclerosis, cerebral ischemia and disturbance of cerebral circulation property diseases such as hemorrhagic apoplexy sequela, transient ischemic attack; Be used to treat the symptom that circulatory disturbance is brought out, as aphasia, utilization can not, poor memory, cognitive dysfunction, dizzy and other brain vestibule problems and headache or the like.In addition, vinpocetine also is used to treat the acute and chronic ophthalmic diseases that multiple reason causes, treatment sensory nerve property hearing impairment.
But vinpocetine is water insoluble, and the bioavailability of oral administration is lower again, thereby is more suitable in intravenous injection; Because vinpocetine is poorly soluble; The injection of clinical use is prone to change in storage process, and the room temperature long-time stability are investigated and found that related substance obviously increases in the vinpocetine injection; Therefore, consider that vinpocetine is prepared into lyophilized formulations increases this stability of drug.
Patent CN200410046419.7 (abbreviating patent in 2004 as) discloses the freeze-dried powder of being made up of vinpocetine, mannitol, sorbic acid.
Patent CN200810089085.X discloses the freeze-dried powder of being made up of vinpocetine, frozen-dried supporting agent mannitol and cosolvent hydrochloric acid; This patent has also been enumerated the solute effect of the cosolvent in the patent in 2004 in stable contrast test simultaneously; Wherein the hydrochloric acid effect is best; And sorbic acid is in penultimate, and dissolubility is merely 0.158.This patent also disclosed 2004 patent accelerated tests after 6 months simultaneously, and sample appearance, pH value, expression content and related substance significant change explain that the freeze-dried powder effect that patent in 2004 provides is relatively poor.
Patent CN201010113013.1 has carried out prescription screening on the basis of patent in 2004, adopt weak acid class such as citric acid, tartaric acid, acetic acid, lactic acid, sorbic acid, ascorbic acid need assist common its stability that improves of adding antioxidant as cosolvent, is not adding obviously decline of preparation stability under the antioxidant situation; And above-mentioned acids such as citric acid, lactic acid, sorbic acid, ascorbic acid itself all be biological active substanceies, like citric acid blood coagulation resisting function arranged, and lactic acid may cause lactic acidosis etc.; This can influence the quality of preparation to a certain extent; And hydrochloric acid belongs to strong acid, though solubilizing effect is good, it is low excessively to control the bad solution pH value that will cause a little; If at this time regulating pH value more than 3.0 with alkali; Then vinpocetine can be separated out crystallization from solution, and this inventor finds to adopt the phosphoric acid solution of certain concentration can well overcome above-mentioned defective as cosolvent through a large amount of screenings, therefore provides by following component and has processed freeze-dried powder: vinpocetine 10-30g; Mannitol 70g; Sorbitol 20g, 10-20% phosphoric acid 50-100ml, water for injection adds to 2000ml.
The above-mentioned freeze-dried powder that provides; Though also can reach the requirement that increases stability, in use the incidence rate of erythra increases, in order to obtain the vinpocetine freeze dried powder of stable in properties, safety; The inventor has carried out lot of test, has finally confirmed the present invention.
Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical composition that contains the vinpocetine chemical compound and preparation method thereof.
The pharmaceutical composition that contains the vinpocetine chemical compound provided by the invention, be 10～30: 5～30 by vinpocetine, sorbic acid and mannitol according to weight ratio: 50～200 form, and preferred weight ratio is 10～30: 10～20: 70～150.
This pharmaceutical composition is an injection, preferred lyophilized injectable powder.
The specification of this pharmaceutical composition is: every bottle or contain the vinpocetine of 10mg, 20mg or 30mg.
The present invention also provides a kind of preparation to contain the method for the pharmaceutical composition of vinpocetine chemical compound, comprises the steps:
1) vinpocetine is dissolved with water for injection, add mannitol and sorbic acid then, stirring is dissolved it fully;
2) with the solution of step 1) preparation with 1mol/L sodium hydroxide adjust pH to 3.0, add water for injection to capacity, add 0.05% activated carbon adsorption, take off charcoal, with the microporous filter membrane fine straining of 0.22 μ m;
3) inspection of semifinished product, half plug is pressed in fill, and lid is rolled in lyophilization, check.
Take off the routine operation that steps such as charcoal, filtering with microporous membrane, lyophilizing all belong to those skilled in the art in the said method, here repeat no more.
Lyophilized injectable powder of the present invention contains vinpocetine (C
22H
26N
2O
2) be 90.0%～110.0% of labelled amount; Be white loose block or powder.
Differentiate that item down: the bismuth potassium iodide experiment should generate orange deposition, and the retention time of main peak of the present invention is consistent with the retention time at reference substance peak;
Under the inspection item: pH value is 3.0～4.0; The aqueous solution of lyophilized powder of the present invention should be clarified colourless; Uniformity of dosage units meets the " regulation of Chinese pharmacopoeia; Related substance is not more than the peak area 1.5% of contrast solution, and the weight loss that subtracts of loss on drying is no more than 5.0%, contains the endotoxin amount among every 1mg less than 10EU;
Assay: measure according to HPLC (" 2005 editions appendix of Chinese pharmacopoeia), number of theoretical plate calculates by the vinpocetine peak and is not less than 2000.
Clinical method for using of the present invention is: the said pharmaceutical composition that contains the vinpocetine chemical compound is dissolved in gives patient's intravenous drip in 5% glucose solution or 0.9% sodium chloride solution.This lyophilized injectable powder can be used for treating the chronic cerebral dysfunction of blood vessel clinically, the chronic insufficient cerebral blood supply that causes like a variety of causes such as cerebral arteriosclerosis, apoplexy, cerebral traumas, dementia polysclerotica etc.; The acute cerebrovascular dysfunction, completed stroke that causes like transient ischemic attack, reversibility ischemic mental disorder and the match of brain bolt, cerebral hemorrhage, hypertensive encephalopathy, subarachnoid hemorrhage etc. etc.; Various mental symptoms such as anxiety, depression, the hypomnesis that blood supply insufficiency of brain causes, have a headache, lose sense, pace of learning and ability drop, aprosexia etc.; The Vasculocardiology Deparment disease is like hyperlipidemia, coronary heart disease, angina pectoris etc.; Ophthalmic diseases, otological disease, the rehabilitation of neurocranial surgery surgery recovery phase brain-capacity.
The pharmaceutical composition that contains the vinpocetine chemical compound provided by the invention has following advantage:
1, in the pharmaceutical composition provided by the invention, form identical with the embodiment 3,7 of CN200410046419.7 (abbreviating patent in 2004 as) patent, but the consumption of mannitol and sorbic acid is more in this patent; During clinical use; The red and swollen probability in erythra or injection site occurring increases, and the inventor reduces the consumption of mannitol and sorbic acid, the unexpected discovery; The freeze-dried powder of preparation still keeps good stability, and safety increases;
2, the present invention contains the freeze dried powder of vinpocetine, through adding the proportioning of sorbic acid and mannitol, has increased the dissolving of vinpocetine; Make that preparation is shaped good behind the lyophilized powder; Solubility is good, stable in properties, and safety is good, and each item index all meets the drug use regulation;
3, Vinpocetine medicine composition provided by the invention has overcome the shortcoming that oxidation takes place vinpocetine in solution, has guaranteed product quality, is convenient to simultaneously store and transportation.
The specific embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
Below method for preparing in, activated carbon adsorption, take off the routine operation that steps such as charcoal, filtering with microporous membrane, lyophilizing belong to those skilled in the art, here repeat no more.
Embodiment 1: Vinpocetine freeze-dried powder for injection
1, form (in 10mg/ bottle vinpocetine, 1000 bottles):
| Form | Proportioning (weight: g) |
| Vinpocetine | ?10 |
| Sorbic acid | ?15 |
| Mannitol | ?70 |
2, method for preparing:
1) vinpocetine is dissolved with 200ml water for injection, add mannitol and sorbic acid then, stirring is dissolved it fully;
2) with the solution of step 1) preparation with 1mol/L sodium hydroxide adjust pH to 3.7, add water for injection to 2000ml, add 0.05% activated carbon adsorption, take off charcoal, with the microporous filter membrane fine straining of 0.22 μ m;
3) inspection of semifinished product, half plug is pressed in fill, and lid is rolled in lyophilization, check.
Embodiment 2: Vinpocetine freeze-dried powder for injection
1, form (in 10mg/ bottle vinpocetine, 1000 bottles):
| Form | Proportioning (weight: g) |
| Vinpocetine | ?10 |
| Sorbic acid | ?15 |
| Mannitol | ?100 |
2, method for preparing:
1) vinpocetine is dissolved with 200ml water for injection, add mannitol and sorbic acid then, stirring is dissolved it fully;
2) with the solution of step 1) preparation with 1mol/L sodium hydroxide adjust pH to 4.0, add water for injection to 2000ml, add 0.05% activated carbon adsorption, take off charcoal, with the microporous filter membrane fine straining of 0.22 μ m;
3) inspection of semifinished product, half plug is pressed in fill, and lid is rolled in lyophilization, check.
Embodiment 3: Vinpocetine freeze-dried powder for injection
1, form (in 10mg/ bottle vinpocetine, 1000 bottles):
| Form | Proportioning (weight: g) |
| Vinpocetine | ?20 |
| Sorbic acid | ?30 |
| Mannitol | ?150 |
2, method for preparing:
1) vinpocetine is dissolved with 300ml water for injection, add mannitol and sorbic acid then, stirring is dissolved it fully;
2) with the solution of step 1) preparation with 1mol/L sodium hydroxide adjust pH to 3.0, add water for injection to 2000ml, add 0.05% activated carbon adsorption, take off charcoal, with the microporous filter membrane fine straining of 0.22 μ m;
3) inspection of semifinished product, half plug is pressed in fill, and lid is rolled in lyophilization, check.
Embodiment 4: Vinpocetine freeze-dried powder for injection
1, form (in 10mg/ bottle vinpocetine, 1000 bottles):
| Form | Proportioning (weight: g) |
| Vinpocetine | ?20 |
| Sorbic acid | ?10 |
| Mannitol | ?150 |
2, method for preparing:
1) vinpocetine is dissolved with 300ml water for injection, add mannitol and sorbic acid then, stirring is dissolved it fully;
2) with the solution of step 1) preparation with 1mol/L sodium hydroxide adjust pH to 3.7, add water for injection to 2000ml, add 0.05% activated carbon adsorption, take off charcoal, with the microporous filter membrane fine straining of 0.22 μ m;
3) inspection of semifinished product, half plug is pressed in fill, and lid is rolled in lyophilization, check.
Embodiment 5: Vinpocetine freeze-dried powder for injection
1, form (in 10mg/ bottle vinpocetine, 1000 bottles):
| Form | Proportioning (weight: g) |
| Vinpocetine | ?30 |
| Sorbic acid | ?20 |
| Mannitol | ?150 |
2, method for preparing:
1) vinpocetine is dissolved with 350ml water for injection, add mannitol and sorbic acid then, stirring is dissolved it fully;
2) with the solution of step 1) preparation with 1mol/L sodium hydroxide adjust pH to 3.7, add water for injection to 2000ml, add 0.05% activated carbon adsorption, take off charcoal, with the microporous filter membrane fine straining of 0.22 μ m;
3) inspection of semifinished product, half plug is pressed in fill, and lid is rolled in lyophilization, check.
Embodiment 6: Vinpocetine freeze-dried powder for injection
1, form (in 10mg/ bottle vinpocetine, 1000 bottles):
| Form | Proportioning (weight: g) |
| Vinpocetine | ?30 |
| Sorbic acid | ?20 |
| Mannitol | ?200 |
2, method for preparing:
1) vinpocetine is dissolved with 350ml water for injection, add mannitol and sorbic acid then, stirring is dissolved it fully;
2) with the solution of step 1) preparation with 1mol/L sodium hydroxide adjust pH to 3.0, add water for injection to 2000ml, add 0.05% activated carbon adsorption, take off charcoal, with the microporous filter membrane fine straining of 0.22 μ m;
3) inspection of semifinished product, half plug is pressed in fill, and lid is rolled in lyophilization, check.
Comparative Examples 1: with reference to 200410046419.7 (promptly 2004 patents) patent
The embodiment 3 of composition and method for preparing reference 200410046419.7.
Experimental example 1: the screening of invention proppant mannitol consumption
Take by weighing vinpocetine 10g, sorbic acid 15g; Frozen-dried supporting agent mannitol is respectively 50,70,100,150,200,250g; Add an amount of water for injection stirring and make its dissolving, regulate pH to prescribed limit, respectively preparating liquid 200ml; According to prepared lyophilized powder of the present invention, the outward appearance of the dried frozen aquatic products of paired observation different content frozen-dried supporting agent and changes of contents situation thereof (HPLC method mensuration).
Table 1: the injection vinpocetine lyophilized powder characteristic of different amounts mannitol relatively
| Mannitol consumption (g) | The lyophilizing sample appearance | Rehydration | Labelled amount (%) |
| 50 | Slightly atrophy, frangible | -- | -- |
| 70 | Plastic, it is frangible to vibrate | Good | 99.9 |
| 100 | Forming, fine and closely woven non-friable | Good | 100.81 |
| 150 | Forming, fine and closely woven non-friable | Good | 99.52 |
| 200 | Forming, fine and closely woven non-friable | Good | 99.46 |
| 250 | Forming, fine and closely woven non-friable | Solution is saturated, slightly insoluble matter | 99.62 |
The result: the sample molding that add in this vinpocetine solution that mannitol is respectively 70,100,150, obtains during 200g through lyophilizing is better, and outward appearance is finer and closely woven, and rehydration is preferably arranged.
Experimental example 2: the screening of cosolvent sorbic acid consumption of the present invention
Take by weighing vinpocetine 10g, mannitol 150g; The cosolvent sorbic acid is 1,5,10,15,20,25,30 respectively, 35g; Add an amount of water for injection stirring and make its dissolving, regulate pH to prescribed limit, respectively preparating liquid 200ml; According to prepared lyophilized powder of the present invention, the outward appearance of the dried frozen aquatic products of paired observation different content cosolvent sorbic acid and changes of contents situation thereof (HPLC method mensuration).
The result adds in this vinpocetine solution that sorbic acid is 5,10,15,20,25 respectively, its dissolubility is better during 30g, and better through the sample molding that lyophilizing obtains, outward appearance is finer and closely woven, and rehydration is preferably arranged.
Experimental example 3: stability test
The vinpocetine freeze-dried powder of embodiment of the invention 1-6 and Comparative Examples 1 preparation is carried out stability relatively, serves as to investigate index with character color and luster, content, carries out 12 months by a definite date observation and mensuration, and the result sees the following form:
Table 1: the study on the stability of the vinpocetine freeze-dried powder of embodiment 1-3 preparation
Table 2: the study on the stability of the vinpocetine freeze-dried powder of embodiment 4-5 and Comparative Examples 1 preparation
Table 3: the study on the stability of the vinpocetine lyophilized powder of Comparative Examples 2,3 preparations
Table 1-3 result show:
The freeze-dried powder of Comparative Examples 1 preparation redissolved weak effect in the time of 12 months.Supposition possibly be that the mannitol amount is excessive, deposit long-time after, other compositions reactions with in the lyophilized powder form crystallization;
The freeze-dried powder of embodiment of the invention 1-6 preparation is prepared into freeze-dried powder, redissolves and imitates, and stable content is easier to clinical use.
Experimental example 4: safety
Vinpocetine freeze-dried powder for injection to embodiment 1-6 and Comparative Examples 1 preparation carries out the safety testing investigation, and test method and result are following:
One, blood vessel irritation experiment
Get body weight and be 48 of the healthy rabbits of 2.0-2.5kg, be divided into blank group, experiment 1-7 group at random, 6 every group, adopt rabbit ear edge vein slowly to inject, injection volume is 10ml/kg.Wherein the blank group adopts sodium chloride injection, and experiment 1-6 group adopts embodiment 1-6 to prepare Vinpocetine freeze-dried powder for injection respectively, tests 7 groups of vinpocetine freeze-dried powders that adopt Comparative Examples 1 preparation respectively, and freeze-dried powder adds injection water dissolving back injection.
Once a day; Successive administration 7 days; Cut short the rabbit ear in last administration after 24 hours; Place 10% formalin fixed preparation, send pathology to carry out histological examination (5 places at rabbit ear edge venous different parts draw materials, and promptly begin entad to hold every separated 1cm to do a section from injecting initial position) then.
Through rabbit ear edge vein pathological examination, the blank group is complete with the auricular vein tube wall of test 1-6 group, and the endotheliocyte structure is clear, does not have obvious pathological changes, the slight dilatation and congestion of blood vessel, no cell infiltration.Test 7 groups and the slight dilatation and congestion of part blood vessel occurs, each experimental group blood vessel of the present invention is normal, does not see obvious stimulation such as slightly expansion of blood vessel, vascular degeneration, necrosis are arranged reaction.
Two, hemolytic experiment
Laboratory observation sodium chloride blank group, experiment 1-7 group external haemolysis to tame Sanguis Leporis seu oryctolagi; Wherein the blank group adopts sodium chloride injection; Test 1-6 group adopts embodiment 1-6 to prepare the vinpocetine freeze-dried powder respectively; Test 7 groups of vinpocetine freeze-dried powders that adopt Comparative Examples 1 preparation respectively, wherein freeze-dried powder adds injection water dissolving back injection.
The result shows 37 ℃, 3 hours, test 7 groups and the erythrocyte aggregation phenomenon occurred, and all the other blank groups and test 1-6 group does not all have haemolysis, and show cell aggregation phenomenon does not occur.
Three, allergic experiment
Observe the anaphylaxis of Cavia porcellus intravenous injection sodium chloride blank group, experiment 1-7 group; Wherein the blank group adopts sodium chloride injection; Experiment 1-6 group adopts embodiment 1-6 to prepare the vinpocetine freeze-dried powder respectively; Test 7 groups of vinpocetine freeze-dried powders that adopt Comparative Examples 1 preparation respectively, freeze-dried powder adds injection water dissolving back injection.
Concrete grammar is: laboratory animal every other day gives the vinpocetine injection sensitization of lumbar injection Comparative Examples 1 preparation; Continuous three times, then laboratory animal is divided into blank group, experiment 1-7 group, totally 8 groups; And the 14th day and 21 days of beginning in sensitization attack administration respectively, observed immediately 1 hour.
The result shows, tests 7 groups and phenomenons such as perpendicular hair, dyspnea, sneeze, retch, cough or rale, tic, collapse, death occurred, and above-mentioned phenomenon does not appear in all the other each groups.
The experiment brief summary: the Vinpocetine freeze-dried powder for injection of embodiments of the invention 1-6 preparation is safe.
Conclusion: the vinpocetine freeze-dried powder of embodiments of the invention 1-6 preparation is prone to be shaped, good, the good stability, safe of solubility.
Though, the present invention has been done detailed description in the preceding text with general explanation and specific embodiment, on basis of the present invention, can to some modifications of do or improvement, this will be apparent to those skilled in the art.Therefore, these modifications or the improvement on the basis of not departing from spirit of the present invention, made all belong to the scope that requirement of the present invention is protected.
Claims (5)
1. a pharmaceutical composition that contains the vinpocetine chemical compound is characterized in that, this pharmaceutical composition is 10～30: 5～30 by vinpocetine, sorbic acid and mannitol according to weight ratio: 50～200 form.
2. pharmaceutical composition according to claim 1 is characterised in that, this pharmaceutical composition is 10～30: 10～20 by vinpocetine, sorbic acid and mannitol according to weight ratio: 70～150.
3. pharmaceutical composition according to claim 1 and 2 is characterised in that, this pharmaceutical composition is an injection.
4. pharmaceutical composition according to claim 3 is characterised in that, this pharmaceutical composition is a lyophilized injectable powder.
5. the method for a pharmaceutical compositions is characterized in that, said pharmaceutical composition is 10～30: 5～30 by vinpocetine, sorbic acid and mannitol according to weight ratio: 50～200 form;
Said method comprises the steps:
1) vinpocetine is dissolved with water for injection, add mannitol and sorbic acid then, stirring is dissolved it fully;
2) with the solution of step 1) preparation with 1mol/L sodium hydroxide adjust pH to 3.0, add water for injection to capacity, add 0.05% activated carbon adsorption, take off charcoal, with the microporous filter membrane fine straining of 0.22 μ m;
3) inspection of semifinished product, half plug is pressed in fill, and lid is rolled in lyophilization, check.
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