CN1732936A - Nimodipine emulsion injection liquid and method for preparing the same - Google Patents
Nimodipine emulsion injection liquid and method for preparing the same Download PDFInfo
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- CN1732936A CN1732936A CN 200510081668 CN200510081668A CN1732936A CN 1732936 A CN1732936 A CN 1732936A CN 200510081668 CN200510081668 CN 200510081668 CN 200510081668 A CN200510081668 A CN 200510081668A CN 1732936 A CN1732936 A CN 1732936A
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Abstract
The invention provides a high concentration nimodipine emulsion injection for intravenous injection, which is prepared from active component of nimodipine and auxiliary materials including oil for injection, emulsifying agent, auxiliary solvent, isotonic conditioning agent and water for injection.
Description
Technical field
The present invention relates to Nimodipine emulsion injection liquid that injection for intravenous uses and preparation method thereof.
Background technology
Nimodipine (Nimodipine) is a second filial generation calcium ion antagonist, this medicine acts preferentially on small artery, selectively acting is in cerebrovascular, can obviously alleviate the recovery of cerebral hemorrhage damage and promotion function of nervous system, be used for treatment of diseases such as cerebral hemorrhage and hypertension under ischemic cerebrovascular, migraine, sudden deafness, the arachnoidea clinically, obtained excellent curative.
Nimodipine is a kind ofly to be dissolved in organic solvents such as ethanol, ether and water-fast insoluble drug.At present the nimotop vial of selling is on the market all made non-water-soluble matchmaker's injection, includes a large amount of ethanol (20～25%) and Polyethylene Glycol (17～20%) is made solvent.Said preparation is when clinical practice, mainly there is concentration low (0.2mg/ml), easily separate out crystallization during dilution and non-water-soluble matchmaker produces phlebitic problem to vascular stimulation, in addition when clinical use, when with after the 5% glucose injection dilution 2～3 hours, needle-like or the crystallization of column nimodipine promptly occur, content descends rapidly directly influences drug safety and effectiveness.For the crystallization after preventing to dilute is separated out, external product adopts after the transfusion three-way valve on-line mixing infusion immediately, and its drip velocity and dosage are wayward.Domestic some product employing is added polyvinylpyrrolidone (PVP) prolongation crystallization and is separated out the time, and its effect is general, and meeting hinders blood coagulation in the body because PVP enters, and is placed restrictions on use by state food and Drug Administration (SFDA).
The inventor has invented a kind of new Nimodipine emulsion injection liquid.
Summary of the invention
The object of the present invention is to provide a kind of Nimodipine emulsion injection liquid.The active component nimodipine is added adjuvant oil for injection, emulsifying agent, cosolvent, isoosmotic adjusting agent and water for injection make Nimodipine emulsion injection liquid.Thereby, we have improved dissolubility and the preparation stability of nimodipine in Emulsion because having added suitable cosolvent in preparation, make our concentration of nimodipine Emulsion higher relatively, for example under high concentration such as every ml emulsion injection contain the situation of 1mg nimodipine, still keep stable.This Emulsion can directly use with glucose injection dilution back, does not see content decline in the use and separates out crystallization.And every ml injection contains the emulsion injection of 1mg nimodipine, and when using a certain amount of active substance, the liquid of injection significantly reduces with respect to prior art, has reduced patient's metabolism burden.Nimodipine emulsion injection liquid of the present invention does not use ethanol, Polyethylene Glycol etc. as solvent, has alleviated the stimulation to blood vessel, has guaranteed clinical drug safety, and has improved the compliance of patient's medication.
Another object of the present invention is to provide a kind of method for preparing Nimodipine emulsion injection liquid.
Nimodipine emulsion injection liquid of the present invention adds adjuvant oil for injection, emulsifying agent, cosolvent, isoosmotic adjusting agent and water for injection by the active component nimodipine and forms, and its prescription is as follows:
Nimodipine 0.1～3g
Oil for injection 50～300g
Emulsifying agent 5～30g
Cosolvent 0.5～50g
Isoosmotic adjusting agent 10～50g
Water for injection adds to 1000ml
Wherein nimodipine is the 0.1-3 gram in the 1000ml emulsion injection, is preferably the 0.2-3 gram, is preferably the 0.5-2 gram again, most preferably is the 1-2 gram; Oil for injection is the 50-300 gram, is preferably the 100-300 gram, is preferably the 100-150 gram again; Emulsifying agent is the 5-30 gram, is preferably the 10-20 gram, is preferably the 12-20 gram again; Cosolvent is the 0.5-50 gram, is preferably the 1-15 gram, is preferably the 2.5-10 gram again; Isoosmotic adjusting agent is the 10-50 gram, is preferably 20-50, is preferably 20-30 again.
Oil for injection is optional from soybean oil, Oleum Gossypii semen, safflower oil, fish oil, Oleum sesami, Fructus Canarii albi wet goods, or, be preferably soybean oil, safflower oil with the mixture of the aforementioned multiple oil for injection of any mixed, fish oil, or with the mixture of the aforementioned multiple oil for injection of any mixed; Soybean oil more preferably.
Emulsifying agent can be selected from Ovum Gallus domesticus Flavus lecithin or soybean phospholipid etc., or with the Ovum Gallus domesticus Flavus lecithin of any mixed and the mixture of soybean phospholipid, is preferably Ovum Gallus domesticus Flavus lecithin.
Cosolvent can be selected from ethanol, 1,2-propylene glycol, Polyethylene Glycol, benzyl alcohol, ethyl lactate, ethyl oleate or benzyl benzoate, or, be preferably benzyl alcohol or Polyethylene Glycol, more preferably benzyl alcohol with the mixture of the aforementioned multiple cosolvent of any mixed.
Isoosmotic adjusting agent can be selected from glycerol, mannitol, xylitol, sorbitol or glucose etc., or with the mixture of the aforementioned multiple isoosmotic adjusting agent of any mixed, is preferably glycerol, mannitol, xylitol or glucose, more preferably glycerol.
The prescription of the Nimodipine emulsion injection liquid that can enumerate is:
Nimodipine 0.2～2g
Soybean oil 100～300g
Lecithin 10～15g
Benzyl alcohol 1～15g
Glycerol 20～30g
Water for injection adds to 1000ml
The Nimodipine emulsion injection liquid optimization formula is as follows:
Nimodipine 0.5-2g
Injection soybean oil 100-150g
Injection Ovum Gallus domesticus Flavus lecithin 12-20g
Benzyl alcohol 5-10g
Glycerol 20-30g
Water for injection adds to 1000ml
The preparation method of Nimodipine emulsion injection liquid of the present invention is as follows:
Under inert gas shielding, emulsifying agent, nimodipine and cosolvent are added in the oil for injection, high-speed stirred is evenly as oil phase; In addition isoosmotic adjusting agent is added in the proper amount of water for injection, behind the mixing as water; Then with the oil phase colostrum of making mixed with water, and regulate pH to 5.0～9.0, add to the full amount of water for injection, become the breast grain through homogenizing, its breast grain mean diameter is about 0.5 μ m, and the above particle of 1 μ m must not surpass 3%, and must not detect greater than the breast of 5 μ m.Obtain Nimodipine emulsion injection liquid after filtering, encapsulate, sterilizing.Noble gas is a nitrogen in preferred version, and oil for injection is a soybean oil, and emulsifying agent is that Ovum Gallus domesticus Flavus lecithin, cosolvent are benzyl alcohol.
Detailed embodiment is, under inert gas shielding, takes by weighing oil for injection, and heating adds emulsifying agent, nimodipine and cosolvent in the oil for injection under high-speed stirred, stirs as oil phase.In addition isoosmotic adjusting agent is added in the proper amount of water for injection, the mixing after-filtration is as water.Under high-speed stirred, oil phase is mixed with water and continue high-speed stirred to making colostrum, and adjusting pH to 5.0～9.0, add to the full amount of water for injection, mixing is after the high pressure homogenizer homogenize is qualified to the breast grain, promptly breast grain mean diameter is about 0.5 μ m, and the above particle of 1 μ m must not surpass 3%, and must not detect the breast grain greater than 5 μ m.After the filtration, fill, logical nitrogen, sealing by fusing are put in the rotary steam steriliser and are sterilized, and promptly get Nimodipine emulsion injection liquid after the cooling.
Preferred manufacturing procedure is as follows:
Under nitrogen protection, take by weighing the injection soybean oil, heating adds Ovum Gallus domesticus Flavus lecithin, nimodipine and benzyl alcohol in the oil for injection under high-speed stirred, stirs as oil phase.In addition glycerol is added in the proper amount of water for injection mixing after-filtration as water.Under high-speed stirred, oil phase continuation high-speed stirred mixed with water is made colostrum, and adjusting pH to 5.0～9.0, add to the full amount of water for injection, mixing is after the high pressure homogenizer homogenize is qualified to the breast grain, promptly breast grain mean diameter is about 0.5 μ m, and the above particle of 1 μ m must not surpass 3%, and must not detect the breast grain greater than 5 μ m.After the filtration, fill, logical nitrogen, sealing by fusing are put in the rotary steam steriliser and are sterilized, and promptly get Nimodipine emulsion injection liquid after the cooling.
Advantage of the present invention:
1. high concentration is still stable., make our concentration of nimodipine Emulsion higher relatively because thereby we have added dissolubility and stability of formulation that suitable cosolvent has improved nimodipine in preparation.The nimotop vial of selling on the market (the nimotop transfusion of import) contains nimodipine 10mg for 50ml solution now.Nimodipine emulsion injection liquid for example of the present invention is 10mg/10ml in nimodipine concentration, when promptly being equivalent to commercially available with the kind drug concentration 5 times, room temperature place 12 months still stable.Because Nimodipine emulsion injection liquid of the present invention can be made into high concentration, as makes the little pin of the 10ml that contains the 10mg nimodipine, makes production, transportation, storage and the use of product of the present invention make things convenient for manyly than existing product.
2. the preparation zest is little.Contain 23.7% ethanol and 17% PEG400 in the nimotop vial of selling on the market now, during intravenous drip patient is had certain zest, easily cause untoward reaction.And do not contain ethanol and Polyethylene Glycol in the Nimodipine emulsion injection liquid of the present invention, and soybean oil in its adjunct ingredient and lecithin etc. all are biocompatible components, and natural metabolism has no side effect to human body in vivo, and the zest to patient in the time of quiet is little.
3. can not produce crystallization when diluting and separate out phenomenon.Nimotop vial can only dilute quiet, commercially available nimotop vial and 5% glucose injection compatibility after 2～3 hours in the visible transfusion of naked eyes crystallization separate out, content sharply reduces thereupon.Place no crystallization in 24 hours behind Nimodipine emulsion injection liquid among the present invention and the 5% glucose injection compatibility under the room temperature and separate out, stable content guarantees drug safety and effectiveness.
4. during with the general infusion set infusion, not obvious to the medicine adsorption phenomena.Nimodipine in the commercially available nimotop vial can be absorbed by polrvinyl chloride (PVC) tube for transfusion, so only allow to use polyethylene (PE) tube for transfusion in the infusion.Nimodipine among the present invention contacts with tube wall and lacks, so can reduce the absorption of common transfusion pipe (PVC) to the principal agent nimodipine because be wrapped in the Emulsion oil phase.
5. more stable to light.Nimodipine is a photosensitizer, so commercially available nimotop vial is packed with brown bottle, is also noted that in the infusion and avoids the sunlight direct projection.The nimodipine that is wrapped in the Emulsion is relatively stable to light, can use the brown bottle packing, also can not use the brown bottle packing, does not also need the special measure protection during infusion.
6. the dissolubility of nimodipine significantly improves in above-mentioned Emulsion, so both can improve drug safety, also can avoid the trophism adjuvant patients with cerebrovascular disease Excessive Intake, unnecessary.Use above-mentioned reagent just to reach very high dissolubility, thereby saved the cost of injection.
7. report is arranged now, and the adding of excessive cosolvent can produce bigger negative effect to patient.Emulsion injection of the present invention has used an amount of cosolvent, and the dissolubility of nimodipine is improved and has controlled the use amount of cosolvent.
Stability test:
This test is carried out according to the regulation of medicine stability test guideline, observe illumination (to the influence of Nimodipine emulsion injection liquid stability, test method and result are as follows for 2001 type illuminance tester 4500Lux ± 500Lux), temperature (40 ℃ ± 2 ℃ acceleration) and long term test (25 ℃ ± 2 ℃):
1, sample source and lot number:
Nimodipine emulsion injection liquid is provided by Jiangsu Zhengda Tianqing Drug Industry Co., Ltd
Dosage form is the 20mg/20ml lot number: 20030626-1 20030626-2 20030626-3
Wherein the proportioning of emulsion injection is
Nimodipine 1.0g
Injection soybean oil 100.0g
Injection Ovum Gallus domesticus Flavus lecithin 12.0g
Benzyl alcohol 10.0g
Glycerol 22.5g
Water for injection adds to 1000ml
2, inspection item:
| Visual examination | The natural light visual inspection |
| PH value | 25 type acidometers |
| Breast grain size | TSM ultrafine dust analyzer |
| Free fatty | Chemical titration |
| Nimodipine content | High performance liquid chromatography |
| The nimodipine catabolite | High performance liquid chromatography |
3, accelerated test
Get three batches of above-mentioned Nimodipine emulsion injection liquids respectively, place constant incubator (40 ℃, RH75%) to make the low temperature accelerated test, regularly 0,1,2,3, June sampling and measuring, the results are shown in Table 1.
4, the test that keeps sample for a long time
Get three batches of above-mentioned Nimodipine emulsion injection liquids respectively, in 25 ± 2 ℃, RH 60 ± 10% places, and at 0,3,6,9,12,18,24 month difference sample analysis, the results are shown in Table 2.
5, conclusion:
5.1 the result showed this product accelerated test (40 ℃, RH 75%) in 6 months: Nimodipine emulsion injection liquid was placed six months through 40 ℃ of constant temperature, and pH has decline slightly, and free fatty and related substance increase to some extent, but all in acceptability limit.
The test 5.2 keep sample for a long time: room temperature was placed 24 months, and every quality index all in acceptability limit, illustrates that this product under existing proportioning and terms of packing, has good stability.
Table 1 Nimodipine emulsion injection liquid (20ml:20mg) accelerated test result (RH75%, 40 ℃)
| Lot number | Time | pH | Free fatty mmol/L | Content (%) | Related substance (%) | The breast grain | Outward appearance |
| 20030626-1 | Original | 7.32 | 3.98 | 105.30 | 0.89 | Qualified | The white emulsion liquid |
| January | 7.30 | 3.96 | 102.50 | 1.16 | Qualified | The white emulsion liquid | |
| February | 7.23 | 4.50 | 102.27 | 1.19 | Qualified | The white emulsion liquid | |
| March | 7.16 | 5.70 | 101.51 | 1.24 | Qualified | The white emulsion liquid | |
| June | 6.95 | 7.47 | 99.01 | 1.41 | Qualified | The white emulsion liquid | |
| 20030626-2 | Original | 7.45 | 4.40 | 105.34 | 0.88 | Qualified | The white emulsion liquid |
| January | 7.40 | 4.57 | 102.68 | 1.09 | Qualified | The white emulsion liquid | |
| February | 7.32 | 4.80 | 102.50 | 1.23 | Qualified | The white emulsion liquid | |
| March | 7.18 | 6.00 | 101.20 | 1.25 | Qualified | The white emulsion liquid | |
| June | 6.89 | 7.78 | 99.50 | 1.44 | Qualified | The white emulsion liquid | |
| 20030626-3 | Original | 7.30 | 4.20 | 105.49 | 0.86 | Qualified | The white emulsion liquid |
| January | 7.28 | 4.27 | 102.64 | 1.11 | Qualified | The white emulsion liquid | |
| February | 7.14 | 4.65 | 102.44 | 1.20 | Qualified | The white emulsion liquid | |
| March | 6.91 | 5.90 | 101.24 | 1.26 | Qualified | The white emulsion liquid | |
| June | 6.78 | 7.93 | 99.55 | 1.42 | Qualified | The white emulsion liquid |
Table 2 Nimodipine emulsion injection liquid (20ml:20mg) result of the test that keeps sample for a long time
(25±2℃；RH 60±10％)
| Lot number | Time | pH | Free fatty mmol/L | Content (%) | Related substance (%) | The breast grain | Outward appearance |
| 20030626-1 | Original | 7.32 | 3.98 | 105.30 | 0.89 | Qualified | The white emulsion liquid |
| March | 7.30 | 4.35 | 102.12 | 1.18 | Qualified | The white emulsion liquid | |
| June | 7.18 | 4.58 | 101.90 | 1.19 | Qualified | The white emulsion liquid | |
| JIUYUE | 7.08 | 4.50 | 101.61 | 1.29 | Qualified | The white emulsion liquid | |
| December | 6.87 | 4.94 | 100.84 | 1.45 | Qualified | The white emulsion liquid | |
| 18 months | 6.85 | 4.96 | 101.03 | 1.48 | Qualified | The white emulsion liquid | |
| 24 months | 6.83 | 4.98 | 100.52 | 1.54 | Qualified | The white emulsion liquid | |
| 20030626-2 | Original | 7.45 | 4.40 | 105.34 | 0.88 | Qualified | The white emulsion liquid |
| March | 7.45 | 4.50 | 102.11 | 1.18 | Qualified | The white emulsion liquid | |
| June | 7.22 | 4.73 | 102.24 | 1.20 | Qualified | The white emulsion liquid | |
| JIUYUE | 7.10 | 4.95 | 101.25 | 1.28 | Qualified | The white emulsion liquid | |
| December | 6.92 | 4.94 | 100.21 | 1.40 | Qualified | The white emulsion liquid | |
| 18 months | 6.95 | 4.96 | 100.84 | 1.42 | Qualified | The white emulsion liquid | |
| 24 months | 6.88 | 4.99 | 100.66 | 1.45 | Qualified | The white emulsion liquid | |
| 20030626-3 | Original | 7.30 | 4.20 | 105.49 | 0.86 | Qualified | The white emulsion liquid |
| March | 7.24 | 4.35 | 102.49 | 1.19 | Qualified | The white emulsion liquid | |
| June | 7.13 | 4.73 | 101.92 | 1.20 | Qualified | The white emulsion liquid | |
| JIUYUE | 6.95 | 4.95 | 101.12 | 1.26 | Qualified | The white emulsion liquid | |
| December | 6.82 | 5.10 | 100.23 | 1.44 | Qualified | The white emulsion liquid | |
| 18 months | 6.80 | 5.16 | 101.33 | 1.48 | Qualified | The white emulsion liquid | |
| 24 months | 6.75 | 5.20 | 101.56 | 1.56 | Qualified | The white emulsion liquid |
The specific embodiment:
Embodiment 1
Under nitrogen protection, take by weighing injection soybean oil 50g and be heated to 70 ℃, under high-speed stirred, add Ovum Gallus domesticus Flavus lecithin 5g, nimodipine 0.1g, benzyl alcohol 0.5g, stir as oil phase; Glycerol for injection 10g is added in the 600ml water for injection, behind the mixing with the membrane filtration of 0.45 μ m as water.Under high-speed stirred, oil phase is added aqueous phase and make colostrum.Surveying pH value is 6.0, adds the injection water to 1000ml, through high pressure homogenizer homogenizing repeatedly, checks breast grain size, and the particle diameter of all particles is all less than 1 μ m.Emulsion is filtered the logical nitrogen fill in back, is sealed, the rotary steam sterilization.Cooling promptly gets Nimodipine emulsion injection liquid after the passed examination.
Embodiment 2
Under nitrogen protection, take by weighing injection soybean oil 300g and be heated to 80 ℃, under high-speed stirred, add Ovum Gallus domesticus Flavus lecithin 30g, nimodipine 3g, benzyl alcohol 50g, stir as oil phase; Glycerol for injection 50g is added in the 500ml water for injection, behind the mixing with the membrane filtration of 0.45 μ m as water.Under high-speed stirred, oil phase is added aqueous phase and make colostrum.Surveying pH value is 8.0, adds the injection water to 1000ml, through high pressure homogenizer homogenizing repeatedly, checks breast grain size, and the particle diameter of all particles is all less than 1 μ m.Emulsion is filtered the logical nitrogen fill in back, is sealed, the rotary steam sterilization.Promptly get Nimodipine emulsion injection liquid after the cooling.
Embodiment 3
Under nitrogen protection, take by weighing injection soybean oil 100g and be heated to 75 ℃, under high-speed stirred, add Ovum Gallus domesticus Flavus lecithin 12g, nimodipine 1g, benzyl alcohol 10g, stir as oil phase; Glycerol for injection 22.5g is added in the 600ml water for injection, behind the mixing with the membrane filtration of 0.45 μ m as water.Under high-speed stirred, oil phase is added aqueous phase and make colostrum.Surveying pH value is 7.0, adds the injection water to 1000ml, through high pressure homogenizer homogenizing repeatedly, checks breast grain size, and the particle diameter of all particles is all less than 1 μ m.Emulsion is filtered the logical nitrogen fill in back, is sealed, the rotary steam sterilization.Promptly get Nimodipine emulsion injection liquid after the cooling.
Embodiment 4
Under nitrogen protection, take by weighing injection soybean oil 100g and be heated to 70 ℃, under high-speed stirred, add Ovum Gallus domesticus Flavus lecithin 12g, nimodipine 0.5g, benzyl alcohol 2.5g, stir as oil phase; Glycerol for injection 22.5g is added in the 600ml water for injection, behind the mixing with the membrane filtration of 0.45 μ m as water.Under high-speed stirred, oil phase is added aqueous phase and make colostrum.Regulate about pH value to 7.5, add the injection water to 1000ml, through high pressure homogenizer homogenizing repeatedly, check breast grain size, the particle diameter of all particles is all less than 1 μ m.Emulsion is filtered the logical nitrogen fill in back, is sealed, the rotary steam sterilization.Cooling promptly gets Nimodipine emulsion injection liquid after the passed examination.
Embodiment 5
Under nitrogen protection, take by weighing injection safflower oil 150g and be heated to 75 ℃, under high-speed stirred, add soybean phospholipid 12g, Ovum Gallus domesticus Flavus lecithin 3g, nimodipine 0.8g, benzyl alcohol 8g stir as oil phase; Glycerol for injection 22.5g is added in the 600ml water for injection, behind the mixing with the membrane filtration of 0.45 μ m as water.Under high-speed stirred, oil phase is added aqueous phase and make colostrum.Regulate pH value to 7.0, add the injection water to 1000ml, through high pressure homogenizer homogenizing repeatedly, check breast grain size, the particle diameter of all particles is all less than 1 μ m.Emulsion is filtered the logical nitrogen fill in back, is sealed, the rotary steam sterilization.Promptly get Nimodipine emulsion injection liquid after the cooling.
Embodiment 6
Under nitrogen protection, take by weighing Oleum Gossypii semen 50g, Oleum sesami 50g and be heated to 80 ℃, under high-speed stirred, add soybean phospholipid 20g, nimodipine 0.3g, Polyethylene Glycol 20g, stir as oil phase; Glucose 50g is added in the 600ml water for injection, behind the mixing with the membrane filtration of 0.45 μ m as water.Under high-speed stirred, oil phase is added aqueous phase and make colostrum.Regulate pH value to 6.0, add the injection water to 1000ml, through high pressure homogenizer homogenizing repeatedly, check breast grain size, the particle diameter of all particles is all less than 1 μ m.Emulsion is filtered the logical nitrogen fill in back, is sealed, the rotary steam sterilization.Promptly get Nimodipine emulsion injection liquid after the cooling.
Embodiment 7
Under nitrogen protection, take by weighing fish oil 150g and be heated to 70 ℃, under high-speed stirred, add Ovum Gallus domesticus Flavus lecithin 9g, nimodipine 0.2g, ethanol 10g, stir as oil phase; Mannitol 10g, xylitol 20g are added in the 600ml water for injection, behind the mixing with the membrane filtration of 0.45 μ m as water.Under high-speed stirred, oil phase is added aqueous phase and make colostrum.Regulate pH value to 8.0, add the injection water to 1000ml, through high pressure homogenizer homogenizing repeatedly, check breast grain size, the particle diameter of all particles is all less than 1 μ m.Emulsion is filtered the logical nitrogen fill in back, is sealed, the rotary steam sterilization.Promptly get Nimodipine emulsion injection liquid after the cooling.
Embodiment 8
Under nitrogen protection, take by weighing injection soybean oil 100g and be heated to 75 ℃, under high-speed stirred, add Ovum Gallus domesticus Flavus lecithin 12g, nimodipine 1g, benzyl alcohol 5g, stir as oil phase; Glycerol for injection 22.5g is added in the 600ml water for injection, behind the mixing with the membrane filtration of 0.45 μ m as water.Under high-speed stirred, oil phase is added aqueous phase and make colostrum.Surveying pH value is 7.0, adds the injection water to 1000ml, through high pressure homogenizer homogenizing repeatedly, checks breast grain size, and the particle diameter of all particles is all less than 1 μ m.Emulsion is filtered the logical nitrogen fill in back, is sealed, the rotary steam sterilization.Promptly get Nimodipine emulsion injection liquid after the cooling.
Embodiment 9
Under nitrogen protection, take by weighing soybean oil 100g and be heated to 70 ℃, under high-speed stirred, add soybean phospholipid 10g, nimodipine 2g, ethyl oleate 5g, stir as oil phase; Glycerol 22.5g is added in the 600ml water for injection, behind the mixing with the membrane filtration of 0.45 μ m as water.Under high-speed stirred, oil phase is added aqueous phase and make colostrum.Regulate pH value to 6.5, add the injection water to 1000ml, through high pressure homogenizer homogenizing repeatedly, check breast grain size, the particle diameter of all particles is all less than 1 μ m.Emulsion is filtered the logical nitrogen fill in back, is sealed, the rotary steam sterilization.Promptly get Nimodipine emulsion injection liquid after the cooling.
Embodiment 10
Under nitrogen protection, take by weighing olive oil 50g and be heated to 80 ℃, under high-speed stirred, add Ovum Gallus domesticus Flavus lecithin 10g, nimodipine 1.5g, benzyl alcohol 2g, ethyl lactate 1g, stir as oil phase; Glucose 25g, xylitol 25g are added in the 600ml water for injection, behind the mixing with the membrane filtration of 0.45 μ m as water.Under high-speed stirred, oil phase is added aqueous phase and make colostrum.Regulate pH value to 6.0, add the injection water to 1000ml, through high pressure homogenizer homogenizing repeatedly, check breast grain size, the particle diameter of all particles is all less than 1 μ m.Emulsion is filtered the logical nitrogen fill in back, is sealed, the rotary steam sterilization.Promptly get Nimodipine emulsion injection liquid after the cooling.
Claims (19)
1, a kind of Nimodipine emulsion injection liquid, this injection composed as follows:
Nimodipine 0.1～3g
Oil for injection 50～300g
Emulsifying agent 5～30g
Cosolvent 0.5～50g
Isoosmotic adjusting agent 10～50g
Water for injection adds to 1000ml
2, the described Nimodipine emulsion injection liquid of claim 1, wherein the content of nimodipine is the 0.2-2 grams per liter.
3, the described Nimodipine emulsion injection liquid of claim 2, wherein the content of nimodipine is the 0.5-2 grams per liter.
4, the described Nimodipine emulsion injection liquid of claim 1, wherein the content of emulsifying agent is the 10-20 grams per liter.
5, the described Nimodipine emulsion injection liquid of claim 4, wherein the content of emulsifying agent is the 12-20 grams per liter.
6, the described Nimodipine emulsion injection liquid of claim 1, wherein cosolvent content be the 1-15 grams per liter.
7, the described Nimodipine emulsion injection liquid of claim 6, wherein cosolvent content be the 5-10 grams per liter.
8, the Nimodipine emulsion injection liquid of claim 2, wherein composed as follows:
Nimodipine 0.2～2g
Soybean oil 100～300g
Lecithin 10～15g
Benzyl alcohol 1～15g
Glycerol 20～30g
Water for injection adds to 1000ml
9, the Nimodipine emulsion injection liquid of claim 3, this injection composed as follows:
Nimodipine 0.5-2g
Injection soybean oil 100-150g
Injection Ovum Gallus domesticus Flavus lecithin 12-20g
Benzyl alcohol 5-10g
Glycerol 20-30g
Water for injection adds to 1000ml
10, each described Nimodipine emulsion injection liquid of claim 1-7, wherein oil for injection is selected from soybean oil, Oleum Gossypii semen, safflower oil, fish oil, Oleum sesami, olive oil, or with the mixture of the aforementioned multiple oil for injection of any mixed.
11, each described Nimodipine emulsion injection liquid of claim 1-7, wherein emulsifying agent is selected from Ovum Gallus domesticus Flavus lecithin or soybean phospholipid, or with the Ovum Gallus domesticus Flavus lecithin of any mixed and the mixture of soybean phospholipid.
12, each described Nimodipine emulsion injection liquid of claim 1-7, wherein cosolvent is selected from ethanol, 1,2-propylene glycol, Polyethylene Glycol, benzyl alcohol, ethyl lactate, ethyl oleate or benzyl benzoate, or with the mixture of the aforementioned multiple cosolvent of any mixed.
13, each described Nimodipine emulsion injection liquid of claim 1-7, wherein isoosmotic adjusting agent can be selected from glycerol, mannitol, xylitol, sorbitol or glucose, or with the mixture of the aforementioned multiple isoosmotic adjusting agent of any mixed.
14, the described Nimodipine emulsion injection liquid of claim 10, oil for injection is a soybean oil.
15, the described Nimodipine emulsion injection liquid of claim 11, emulsifying agent is an Ovum Gallus domesticus Flavus lecithin.
16, the described Nimodipine emulsion injection liquid of claim 12, cosolvent is a benzyl alcohol.
17, the described Nimodipine emulsion injection liquid of claim 13, isoosmotic adjusting agent is a glycerol.
18, a kind of preparation method of Nimodipine emulsion injection liquid as claimed in claim 1 is included under the inert gas shielding, and emulsifying agent, nimodipine and cosolvent are added in the oil for injection, and the heating high-speed stirred is evenly as oil phase; In addition isoosmotic adjusting agent is added in the proper amount of water for injection, behind the mixing as water; Then with the oil phase colostrum of making mixed with water, and regulate pH to 5.0～9.0, add to the full amount of water for injection, become the breast grain through high pressure homogenize, wherein a breast grain mean diameter is about 0.5 μ m, and the above particle of 1 μ m must not cross 3%, and must not detect greater than the breast of 5 μ m.Obtain Nimodipine emulsion injection liquid after filtration, fill, the sterilization.
19, the preparation method of Nimodipine emulsion injection liquid according to claim 12, wherein noble gas is a nitrogen, and oil for injection is a soybean oil, and emulsifying agent is an Ovum Gallus domesticus Flavus lecithin, and cosolvent is a benzyl alcohol, isoosmotic adjusting agent is a glycerol.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010139278A1 (en) | 2009-06-04 | 2010-12-09 | 江苏恒瑞医药股份有限公司 | Preparation method of drug loaded emulsion |
| 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 |
| CN105796494A (en) * | 2016-04-01 | 2016-07-27 | 广东药学院 | Nimodipine microemulsion injection containing amino acid and preparation method of nimodipine microemulsion injection |
| US20210338649A1 (en) * | 2018-09-08 | 2021-11-04 | Jiangsu Jiuxu Haitian Pharmaceutical Co., Ltd. | Nimodipine injection composition and preparation method therefor |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100486577C (en) * | 2002-12-13 | 2009-05-13 | 沈阳药科大学 | Nimodipine lipid nano particle compositions, and its preparation method |
| CN1562010A (en) * | 2004-03-30 | 2005-01-12 | 四川科伦药业股份有限公司 | Nimodipine injection emulsion and its preparing method |
-
2005
- 2005-07-06 CN CNB2005100816684A patent/CN100386078C/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010139278A1 (en) | 2009-06-04 | 2010-12-09 | 江苏恒瑞医药股份有限公司 | Preparation method of drug loaded emulsion |
| 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 |
| CN105796494A (en) * | 2016-04-01 | 2016-07-27 | 广东药学院 | Nimodipine microemulsion injection containing amino acid and preparation method of nimodipine microemulsion injection |
| CN105796494B (en) * | 2016-04-01 | 2019-10-11 | 广东药科大学 | A kind of Nimodipine sub micro-emulsion injection and preparation method thereof containing amino acid |
| US20210338649A1 (en) * | 2018-09-08 | 2021-11-04 | Jiangsu Jiuxu Haitian Pharmaceutical Co., Ltd. | Nimodipine injection composition and preparation method therefor |
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