CN1480140A - Injection medication combination of nimodipine and its preparing method - Google Patents
Injection medication combination of nimodipine and its preparing method Download PDFInfo
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- CN1480140A CN1480140A CNA031531709A CN03153170A CN1480140A CN 1480140 A CN1480140 A CN 1480140A CN A031531709 A CNA031531709 A CN A031531709A CN 03153170 A CN03153170 A CN 03153170A CN 1480140 A CN1480140 A CN 1480140A
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- nimodipine
- injection
- pharmaceutical composition
- propylene glycol
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Abstract
A composite injection of nimodipine in the form of liquid injection or freeze dried powder is prepared from nimodipine and propanediol and tween kind of surfactant. Its advantage is high solubility. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to injection medicine preparation of nimodipine and preparation method thereof.
Background technology
Nimodipine is the second filial generation 1,4-dihydropyridine calcium channel blocker, chemistry (±) isopropyl by name-2-methoxyethyl-1,4 dihydro-2,6-dimethyl-4 (3-nitrobenzophenone)-3,5-pyrrole piperazine dicarboxylic ester.Molecular formula is C
21H
26N
2O
2, molecular weight is 418.45.It has vasoconstriction and ischemia resisting effect to brain, nimodipine is external to prevent or eliminate various vaso-active substances (as 5-hydroxy tryptamine, prostaglandin and histamine) or the vasoconstriction that causes of blood and catabolite thereof, nimodipine also has neural and psychopharmacology character.To studies show that of acute brain blood supply disorder patient, nimodipine can expansion of cerebral vascular and is improved cerebral blood supply, usually greater than normal position, nimodipine can obviously reduce subarachnoid hemorrhage patient's ischemic potassium through damage and mortality rate to the perfusion increase at cerebral lesion and hypoperfusion position.
Nimodipine is difficult to water-soluble, has greatly limited its application clinically.When nimodipine was prepared into the liquid preparation that vein uses, for avoiding producing the adverse consequences in the medication process, needing to seek suitable method increase its dissolubility.The existing nimotop vial trade name of China market has nimotop, Ni Lisu etc., contains 96% ethanol in the injection, excipient such as PEG400, owing to contain a large amount of ethanol, in use zest and side effect are bigger.Publication number is that the Chinese patent application of CN02155645.8 discloses a kind of technical scheme that addresses the above problem, and promptly adding phospholipid, cyclodextrin etc. increases its dissolubility, but technology is comparatively complicated, the difficult quality control of final products.
Propylene glycol is main as cosolvent in medicament, and tween is main as solubilizing agent in medicament, and the two all can improve the water solublity of medicine.Although the two all has certain solubilization to nimodipine, use all can not reach satisfied solubilizing effect separately.
Summary of the invention
The present inventor is surprised to find that, adds a certain amount of propylene glycol and tween simultaneously and can improve the dissolubility of nimodipine in water significantly in preparation, reaches the requirement of injection preparation, has finished the present invention thus.
The invention provides a kind of medicinal composition for injections of nimodipine, comprise nimodipine and the propylene glycol and the Tweens surfactant for the treatment of effective dose.
In pharmaceutical composition of the present invention, the Tweens surfactant is selected from tween 20, and one or more in Tween-40, Tween-60 and the tween 80 are preferably tween 80.
In pharmaceutical composition of the present invention, the weight ratio of nimodipine and propylene glycol and Tweens surfactant is 1: 75-750: 5-150 is preferably 1: 150-300: 12-30.
Pharmaceutical composition of the present invention is the dosage form of injection or injection freeze-dried powder.In injection of the present invention or in the solution before the freeze-dried powder lyophilization, the concentration of propylene glycol is 50mg～500mg/ml, is preferably 100mg～200mg/ml, and the Tweens surfactant concentrations is 5mg～100mg/ml, is preferably 8mg～20mg/ml.
Pharmaceutical composition of the present invention can also comprise the adjuvant of any routine that is used for injection or injection freeze-dried powder.Include but not limited to diluent, lyophilization excipient, antiseptic, stabilizing agent, pH regulator agent, isotonic agent.Preferably, pharmaceutical composition of the present invention further comprises the lyophilization excipient that is selected from mannitol or glucose.
In pharmaceutical composition of the present invention, the consumption of nimodipine has no particular limits, and can be normally used any dosage in injection." treatment effective dose " is meant that the nimodipine ejection preparation reaches the common consumption of therapeutic effect, and the doctor can make suitable adjustment according to patient's the state of an illness and otherwise situation.Usually, the content of nimodipine is 0.5-2mg/ml in the injection of the present invention.
The invention further relates to the preparation method of aforementioned pharmaceutical compositions, comprise nimodipine is dissolved in propylene glycol, Tweens surfactant and the water, form the step of injection, wherein the concentration of propylene glycol is 50mg～500mg/ml in described injection, and the Tweens surfactant concentrations is 5mg～100mg/ml.This method further comprises the step of above-mentioned injection lyophilization being made freeze-dried powder.
Nimodipine and propylene glycol and Tweens surfactant can make the injectable aqueous solution of clear and bright nimodipine, and can further be processed into the dosage form of injection freeze-dried powder.Can the direct dissolved freeze-dried powder pin of water, obtain clear and bright injection.
Nimotop vial of the present invention or injection freeze-dried powder have following characteristics:
1. this injectable powder does not contain ethanol, and nonaqueous phase content is few, reduces the zest of clinical application.
2. this injectable powder is the drying solid powder, can prevent the influence of nimodipine in solution factor such as oxidation, hydrolysis in injection, increases the stability in the goods storage process.
3. because of this injectable powder exists with solid state, be convenient to transportation.
4. this injectable powder and publication number are that technical scheme in the Chinese patent of CN02155645.8 is compared, and preparation technology is simple, constant product quality, and convenient quality control is convenient to suitability for industrialized production.
5. the lowest total of the melting point of content is low among the present invention, and pre-freeze gets final product under-40 ℃ temperature, and outward appearance is better.
6. this injectable powder contained humidity can reach below 1%, generally is controlled at 5% and gets final product with interior.
7. goods pH value of solution value stabilization need not to add the pH regulator agent again between 6.0-8.0.
Particularly, pharmaceutical composition of the present invention can make by the following method:
1. take by weighing nimodipine, propylene glycol, stir and make the nimodipine dissolving, take by weighing tween, stir, add water again, promptly get settled solution.
2. solution adds 0.1% active carbon stirring 20 minutes.
3. after solution takes off charcoal through 0.8 μ m filter membrane coarse filtration, reuse 0.22 μ m filter membrane degerming.
4. above-mentioned solution branch is filled in the brown cillin bottle.
5. with the lyophilizing to the freezer dryer of above-mentioned solution.
6. whole process is carried out under aseptic condition.
According to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, will place nessler colorimetric tube according to the solution of method for preparing, inspection under the daylight lamp is relatively answered clear with water, is not deeper than No. 1 than turbid liquid.
Nimotop vial of the present invention or injection freeze-dried powder are suitable for intramuscular injection, intravenous injection.
The specific embodiment
Embodiment 1
Nimodipine 2mg
Propylene glycol 350mg
Tween 80 50mg
Mannitol 200mg
Water for injection is to 3ml
According to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, place nessler colorimetric tube, inspection under the daylight lamp compares clear with water, is not deeper than No. 1 than turbid liquid.
Embodiment 2
Nimodipine 2mg
Propylene glycol 350mg
Tween 80 30mg
Mannitol 250mg
Water for injection is to 3ml
According to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, place nessler colorimetric tube, inspection under the daylight lamp compares clear with water, is not deeper than No. 1 than turbid liquid.
Embodiment 3:
Nimodipine 2mg
Propylene glycol 400mg
Tween 80 50mg
Mannitol 300mg
Water for injection is to 2.5ml
According to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, place nessler colorimetric tube, inspection under the daylight lamp compares clear with water, is not deeper than No. 1 than turbid liquid.
Embodiment 4
Nimodipine 2mg
Propylene glycol 300mg
Tween 80 60mg
Mannitol 300mg
Water for injection is to 2.5ml
According to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, place nessler colorimetric tube, inspection under the daylight lamp compares clear with water, is not deeper than No. 1 than turbid liquid.
Embodiment 5
Nimodipine 2mg
Propylene glycol 450mg
Tween 80 30mg
Mannitol 200mg
Water for injection is to 3ml
According to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, place nessler colorimetric tube, inspection under the daylight lamp compares clear with water, is not deeper than No. 1 than turbid liquid.
Embodiment 6
Nimodipine 2mg
Propylene glycol 300mg
Tween 80 100mg
Mannitol 250mg
Water for injection is to 2ml
According to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, place nessler colorimetric tube, inspection under the daylight lamp compares clear with water, is not deeper than No. 1 than turbid liquid.
Embodiment 7
Nimodipine 2mg
Propylene glycol 150mg
Tween 80 240mg
Mannitol 200mg
Water for injection is to 2ml
According to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, place nessler colorimetric tube, inspection under the daylight lamp compares clear with water, is not deeper than No. 1 than turbid liquid.
Embodiment 8
Nimodipine 2mg
Propylene glycol 1200mg
Tween 80 15mg
Mannitol 200mg
Water for injection is to 2ml
According to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, place nessler colorimetric tube, inspection under the daylight lamp compares clear with water, is not deeper than No. 1 than turbid liquid.
Embodiment 9
Nimodipine 2mg
Propylene glycol 350mg
Tween 20 50mg
Mannitol 200mg
Water for injection is to 3ml
According to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, place nessler colorimetric tube, inspection under the daylight lamp compares clear with water, is not deeper than No. 1 than turbid liquid.
Embodiment 10
Nimodipine 2mg
Propylene glycol 350mg
Tween-40 50mg
Mannitol 200mg
Water for injection is to 3ml
According to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, place nessler colorimetric tube, inspection under the daylight lamp compares clear with water, is not deeper than No. 1 than turbid liquid.
Embodiment 11
Nimodipine 2mg
Propylene glycol 350mg
Tween-60 50mg
Mannitol 200mg
Water for injection is to 3ml
According to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, place nessler colorimetric tube, inspection under the daylight lamp compares clear with water, is not deeper than No. 1 than turbid liquid.
After the solution lyophilization that above-mentioned 11 prescriptions are made, add the dissolving of 2～10ml water for injection again, according to " Chinese Pharmacopoeia version (two ones) in 2000 " appendix IX A method, place nessler colorimetric tube, inspection under the daylight lamp compares all clears of each solution with water, is not deeper than No. 1 than turbid liquid.Reference examples 1
The prescription that only adds propylene glycol:
Nimodipine 2mg
Propylene glycol 350mg
Water for injection is to 3ml
Nimodipine can not be dissolved in propylene glycol and the water for injection, can't form clear and bright solution before freezing, adds 10ml water for injection after the lyophilization, muddiness.Reference examples 2 only adds the prescription of tween:
Nimodipine 2mg
Tween 80 100mg
Water for injection is to 3ml
Nimodipine can not be dissolved in tween 80 and the water for injection, can't form clear and bright solution before freezing, adds 10ml water for injection after the lyophilization, muddiness.
This shows, add the combination of propylene glycol and tween and can obviously improve the clarity of nimodipine solution, and singly add propylene glycol or tween all can not obviously increase the dissolubility of nimodipine in water.
Stability experiment under embodiment 12 acceleration environments
In addition, the lyophilized products that makes according to the method for embodiment 1-6 has the required characteristic of freeze-dried composition of the present invention.Each sample was deposited 6 months under the accelerated tests condition, measured the variation of indexs such as content, related substance, the results are shown in Table 1.
Table 1 accelerated tests result
| Embodiment | Outward appearance | Content (%) | Catabolite (%) | PH value |
| ?1 | The white cake | 98.6 | ?0.82 | ?6.5 |
| ?2 | The white cake | 97.9 | ?0.31 | ?6.9 |
| ?3 | The white cake | 100.8 | ?0.65 | ?6.2 |
| ?4 | The white cake | 98.2 | ?0.49 | ?7.1 |
| ?5 | The white cake | 96.7 | ?0.71 | ?6.5 |
| ?6 | The white cake | 101.0 | ?0.28 | ?6.3 |
6 months measurement results of accelerated test show that the obtained freeze-drying goods are stable, and effect duration is measurable to 2 years.
Claims (10)
1. the medicinal composition for injections of a nimodipine comprises nimodipine and the propylene glycol and the Tweens surfactant for the treatment of effective dose.
2. according to the pharmaceutical composition of claim 1, wherein said Tweens surfactant is selected from tween 20, and one or more in Tween-40, Tween-60 and the tween 80 are preferably tween 80.
3. according to the pharmaceutical composition of claim 1, wherein the weight ratio of nimodipine and propylene glycol and Tweens surfactant is 1 in described pharmaceutical composition: 75-750: 7.5-150.
4. according to the pharmaceutical composition of claim 3, wherein the weight ratio of nimodipine and propylene glycol and Tweens surfactant is 1 in described pharmaceutical composition: 150-300: 12-30.
5. according to any one pharmaceutical composition among the claim 1-4, the dosage form of wherein said pharmaceutical composition is injection or injection freeze-dried powder.
6. according to the pharmaceutical composition of claim 5, wherein in described injection or in the solution before the freeze-dried powder lyophilization, the concentration of described propylene glycol is 50mg～500mg/ml, is preferably 100mg～200mg/ml.
7. according to the pharmaceutical composition of claim 5, wherein in described injection or in the solution before the freeze-dried powder lyophilization, described Tweens surfactant concentrations is 5mg～100mg/ml, is preferably 8mg～20mg/ml.
8. according to the pharmaceutical composition of claim 1, wherein said pharmaceutical composition further comprises the lyophilization excipient that is selected from mannitol or glucose.
9. according to the preparation of drug combination method of claim 1-8, comprise nimodipine is dissolved in propylene glycol, Tweens surfactant and the water, form the step of injection, wherein the concentration of propylene glycol is 50mg～500mg/ml in described injection, and the Tweens surfactant concentrations is 5mg～100mg/ml.
10. according to the method for claim 9, further comprise the step of described injection lyophilization being made freeze-dried powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03153170 CN1183908C (en) | 2003-08-08 | 2003-08-08 | Injection medication combination of nimodipine and its preparing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03153170 CN1183908C (en) | 2003-08-08 | 2003-08-08 | Injection medication combination of nimodipine and its preparing method |
Publications (2)
| Publication Number | Publication Date |
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| CN1480140A true CN1480140A (en) | 2004-03-10 |
| CN1183908C CN1183908C (en) | 2005-01-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 03153170 Expired - Lifetime CN1183908C (en) | 2003-08-08 | 2003-08-08 | Injection medication combination of nimodipine and its preparing method |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105796490A (en) * | 2016-04-01 | 2016-07-27 | 广东药学院 | Nimodipine injection composition containing amino acid and preparation method of nimodipine injection composition |
| WO2017180718A1 (en) | 2016-04-13 | 2017-10-19 | Grace Therapeutics Llc | Stable nimopidine parenteral formulation |
| US20180325882A1 (en) * | 2016-04-13 | 2018-11-15 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| CN114557960A (en) * | 2022-03-16 | 2022-05-31 | 陕西省人民医院 | Medicine for treating subarachnoid hemorrhage and application thereof |
| CN115990262A (en) * | 2022-06-27 | 2023-04-21 | 北京德立福瑞医药科技有限公司 | Damp heat sterilized nimodipine composition without ethanol and phosphatide and its preparing method |
-
2003
- 2003-08-08 CN CN 03153170 patent/CN1183908C/en not_active Expired - Lifetime
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105796490A (en) * | 2016-04-01 | 2016-07-27 | 广东药学院 | Nimodipine injection composition containing amino acid and preparation method of nimodipine injection composition |
| US10765671B2 (en) | 2016-04-13 | 2020-09-08 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| US20180325882A1 (en) * | 2016-04-13 | 2018-11-15 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| US20180325886A1 (en) * | 2016-04-13 | 2018-11-15 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| CN109069651A (en) * | 2016-04-13 | 2018-12-21 | 诺迪克控股公司 | Stable Nimodipine parenteral administration |
| EP3442586A4 (en) * | 2016-04-13 | 2019-11-20 | Nortic Holdings Inc. | Stable nimopidine parenteral formulation |
| WO2017180718A1 (en) | 2016-04-13 | 2017-10-19 | Grace Therapeutics Llc | Stable nimopidine parenteral formulation |
| US10799486B2 (en) | 2016-04-13 | 2020-10-13 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| AU2020201863B2 (en) * | 2016-04-13 | 2022-04-28 | Acasti Pharma U.S., Inc. | Stable Nimopidine Parenteral Formulation |
| EP4032527A1 (en) * | 2016-04-13 | 2022-07-27 | Grace Therapeutics Inc. | Stable nimodipine parenteral formulation |
| US11433062B2 (en) * | 2016-04-13 | 2022-09-06 | Acasti Pharma U.S., Inc. | Stable nimodipine parenteral formulation |
| CN114557960A (en) * | 2022-03-16 | 2022-05-31 | 陕西省人民医院 | Medicine for treating subarachnoid hemorrhage and application thereof |
| CN115990262A (en) * | 2022-06-27 | 2023-04-21 | 北京德立福瑞医药科技有限公司 | Damp heat sterilized nimodipine composition without ethanol and phosphatide and its preparing method |
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| Publication number | Publication date |
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| CN1183908C (en) | 2005-01-12 |
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Address after: 102629 No. 5, Xiangrui street, biomedical base, Daxing District, Beijing Patentee after: Beijing Sihuan Kebao Pharmaceutical Co.,Ltd. Address before: 100070 Beijing science and Technology Park of Fengtai Haiying Road No. 11 Patentee before: BEIJING SIHUAN KEBAO PHARMACEUTICAL Co.,Ltd. |
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Granted publication date: 20050112 |