CN105796494B - A kind of Nimodipine sub micro-emulsion injection and preparation method thereof containing amino acid - Google Patents
A kind of Nimodipine sub micro-emulsion injection and preparation method thereof containing amino acid Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K9/10—Dispersions; Emulsions
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Abstract
The invention discloses a kind of Nimodipine sub micro-emulsion injection and preparation method thereof containing amino acid, it includes Nimodipine, oil for injection, injection phosphotide, coemulsifier, amino acid, glycerol and water for injection that it, which is formed, and wherein the content of amino acid is 0.01-3%.Protective agent present invention adds amino acid as Nimodipine; pass through the dihydropyridine ring in protection drug molecule; avoid dehydrogenation reaction; reduce the generation of Nimodipine catabolite; reduce Light absorbing impurty; the chemical stability for carrying medicine sub-micellar emulsion is improved, is effectively prevented due to impurity content height and existing genotoxic potential risk.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, it is related to a kind of Nimodipine sub micro-emulsion injection and preparation method thereof, more
Body says that the present invention relates to a kind of Nimodipine sub micro-emulsion injection containing amino acid or amino acid composition and its preparation sides
Method.
Background technique
A kind of clinically widely applied Isosorbide-5-Nitrae-dihydrogen pyridine derivative of Nimodipine (Nimodipine, NMP) system is
Second generation calcium-ion channel antagonists after nifedipine, verapamil.Nimodipine has height to select brain tissue receptor
Blood-brain barrier is readily penetrated through, by preventing calcium ion from entering intracellular, inhibition smooth muscle contraction, stablizing its function and promoting brain blood
Perfusion improves brain blood supply situation.The blood circulation that Nimodipine is clinically mainly used for acute cerebrovascular disease convalescence improves, spider
The posthemorrhagic cerebral angiospasm of nethike embrane cavity of resorption and its caused ischemic neurologic deficits hypertension, migraine etc., at the same also by with
Make the treatment of ischaemic neuronal protection and vascular dementia.
Nimodipine venous injection is Bayer A.G's imported product (Nimotop), since Nimodipine belongs to indissoluble
Property drug, therefore joined in the injection 23.7% ethyl alcohol and 17% PEG-400 improve drug solubility reach
Medication specification.The drug using when must mix with physiological saline administration using special Three-way transfusion system and pole is needed to drip at a slow speed
It infuses, usual administration time needs 5 hours or more, moreover, Nimodipine is easily precipitated during the administration to be caused in administration blood vessel portion
The deposition of position causes the pain of patient and phlebitis occurs, and compliance is poor.
Nimodipine belongs to fat-soluble medicine, can be using sub-micellar emulsion as pharmaceutical carrier, in raising drugloading rate and surely
While qualitative, the compliance of patient when significantly improving administration.Patent 200510081668.4 discloses a kind of Nimodipine
Emulsion injection and preparation method thereof, this method using benzyl alcohol as solubilizer, by Nimodipine be dissolved in benzyl alcohol and with
Oil for injection mixing prepares Nimodipine drug loaded emulsion injection as emulsifier using phosphatide, although this method as oily phase
The crucial cosolvent benzyl alcohol that Nimodipine emulsion injection liquid can be prepared, but used is in injection in use, having potential safety
Hidden danger, State Food and Drug Administration in 2012, which once sent the documents and (eats medicine prison and does peace letter [2012] 323), highlights benzyl alcohol
The risk that intramuscular injection uses, and the emulsion is intravenous injection, administration safety issue can not be ignored.Patent
200910021091.6 also disclosing a kind of lipid microsphere injection and preparation method thereof containing Nimodipine, in the patent simultaneously
Cosolvent composition is not used, but injection soybean oil is mixed with medium chain triglyceride as oily phase, while using and spitting
Temperature -80 and enuatrol increase the stability for carrying medicine lipid microspheres.
Nimodipine belongs to dihydrogen pyridine derivatives, and United States Pharmacopeia, European Pharmacopoeia and Chinese Pharmacopoeia are to it in relation to substance
Content is required, and is shown according to European Pharmacopoeia, and the main degradation products of Nimodipine are impurity A, impurity B and impurity C,
Middle impurity A is main impurity (impurity I in corresponding Chinese Pharmacopoeia), which has potential liver renal toxicity, and too high levels can deposit
It is main Quality Control impurity in security risk, and Chinese Pharmacopoeia has also carried out bound requirements to it.In the related substance of Nimodipine
Impurity A is 2,6- dimethyl -4- (3- nitrobenzophenone) -3,5- pyridinedicarboxylic acid -2- methoxy ethyl ester isopropyl ester (following formula), the impurity
It is that Nimodipine dihydropyridine ring dehydrogenation generates, a variety of conditions can promote Nimodipine to generate this impurity, including strong acid, strong
Alkali, high temperature, oxidation, illumination etc..For Nimodipine raw material, in the case where protectant situation is not added, using conventional Asia
Micro emulsion preparation process, which prepares Nimodipine drug loaded emulsion, can lead to impurity A generation and content raising.
There is provided that a kind of impurity content is low, the strong nimotop vial of stability, become problem urgently to be resolved at present it
One.
Summary of the invention
The purpose of the present invention is to provide a kind of Nimodipine sub micro-emulsion injection and preparation method thereof containing amino acid.
The technical solution used in the present invention is:
Amino acid is preparing the application in Nimodipine sub micro-emulsion injection.
A kind of Nimodipine sub micro-emulsion injection, composition in contain amino acid.
Preferably, the composition of the Nimodipine sub micro-emulsion injection includes Nimodipine, oil for injection, injection
Phosphatide, coemulsifier, amino acid, glycerol and water for injection.
Preferably, containing amino acid 0.01-3g in the every 100ml of Nimodipine sub micro-emulsion injection.
It is further preferred that containing amino acid 0.02-1.0g in the every 100ml of Nimodipine sub micro-emulsion injection.
It is further preferred that containing amino acid 0.02-0.3g in the every 100ml of Nimodipine sub micro-emulsion injection.
It is further preferred that the composition of the every 100ml of Nimodipine sub micro-emulsion injection includes:
| Nimodipine | 0.01-1g |
| Oil for injection | 2-30ml |
| Injection phosphotide | 0.4-5g |
| Coemulsifier | 0.01-10g |
| Amino acid | 0.01-3g |
| Glycerol | 2-4g |
| Water for injection | Add to 100ml |
It is further preferred that the composition of the every 100ml of Nimodipine sub micro-emulsion injection includes:
Preferably, the amino acid is at least one of arginine, methionine, leucine, lysine.It is described
Amino acid can be D type, L-type or DL type amino acid.
Preferably, the oil for injection is selected from the medium-chain fatty glyceride of injection soybean oil, C8-C10
(MCT), at least one of olive oil, vitamin E, vitamin E esters.
Preferably, the injection phosphotide be selected from phosphatidylcholine content not less than 70% injection lecithin,
At least one of injection soybean lecithin, hydrolecithin, hydrogenated soya phosphatide.
Preferably, the coemulsifier is solid selected from Tween-80, Tween-85, PLURONICS F87, gallbladder
At least one of alcohol sulfuric ester sodium salt, enuatrol.
The preparation method of above-described Nimodipine sub micro-emulsion injection, includes the following steps:
1) oil for injection being heated to 50-80 DEG C, nimodipine medicament is added, stirring is allowed to be completely dissolved to form solution,
As oily phase；
2) water for injection is heated to 50-80 DEG C, sequentially adds injection phosphotide, glycerol, amino acid, co-emulsifier
Agent, stirring are allowed to dissolution or evenly dispersed as water phase；
3) oil-phase solution of above-mentioned preparation is added in water phase, in a heated condition (50-80 DEG C), with 8000-
15000rpm high-speed stirred, and repeat 2-3 times and load medicine colostrum is made；
4) above-mentioned colostrum is taken into NaOH or HCl that concentration is 0.1M and adjusts pH, be allowed to be 6.50~8.50, add injection
After water polishing to normal concentration, using high pressure homogenizer, homogeneous 5-10 times under the conditions of 600~1200bar, Nimodipine Asia is made
Microemulsion injection；
5) Nimodipine sub micro-emulsion injection of preparation is filling into brown ampoule bottle, 121 DEG C are used after nitrogen charging sealing
Pressure sterilizing condition makes F0The Nimodipine sub micro-emulsion injection containing amino acid is finally made in value > 12.
Inventor has found that amino acid can play a protective role to the dihydropyridine ring of Nimodipine in early-stage study,
The dehydrogenation of dihydropyridine ring is avoided, so that Nimodipine relative substance A is remarkably decreased, further study show that, amino acid is logical
What-NH the structure in overprotection dihydropyridine ring was realized.Simultaneously because the molecule buffer capacity of amino acid, it can be with maintenance system pH
Value is steady, will not lead to pH value significant changes due to high-pressure homogeneous process and sterilization process, avoid Nimodipine injection emulsion
The pH of preparation process is fluctuated, and helps to improve the stability of drug.
In consideration of it, pharmaceutical carrier of the present invention using sub-micellar emulsion as Nimodipine, using injection phosphotide as emulsification
Agent and the use for cooperating coemulsifier prepare the Nimodipine Injeetion that a kind of drugloading rate is high, stability is good, meanwhile, it utilizes
Protective effect of the amino acid to Nimodipine effectively controls limit of the Nimodipine in relation to substance, it is often more important that, the low note of drop
Impurity content in liquid is penetrated, the safety of clinical application is improved, effectively avoids genotoxic potential risk.
Compared with traditional nimotop vial, a kind of Nimodipine sub-micro containing amino acid provided by the present invention
Emulsion injection has the advantage that
1) it is wrapped up using the opposite Nimodipine of oil, improves the drugloading rate and solubility of Nimodipine, avoid
Devitrification problem when traditional intravenously administrable, administration compliance significantly improve.
2) compared with the emulsion containing nimodipine medicament, protective agent present invention adds amino acid as Nimodipine,
By the dihydropyridine ring in protection drug molecule, dehydrogenation reaction is avoided, the generation of Nimodipine catabolite is reduced, reduced
Light absorbing impurty improves the chemical stability for carrying medicine sub-micellar emulsion, effectively prevents existing latent since impurity content is high
In risk of toxicity.
3) compared with the emulsion containing nimodipine medicament, the amino acid that the present invention is added has excellent pH buffer capacity,
Without the pH as the common multiple regulation system of Nimodipine emulsion, after adjusting 1 time, sterilizing front and back pH is without significant change, system
PH stablizes.
4) preparation process simple possible of the present invention, favorable reproducibility is quality controllable, is easy to industrialized mass production.
Detailed description of the invention
Nimodipine sub micro-emulsion injection transmission electron microscope picture of the Fig. 1 containing amino acid；
Nimodipine sub micro-emulsion injection dilution stability figure of the Fig. 2 containing amino acid；
Nimodipine sub micro-emulsion injection rat Internal pharmacokinetics curve graph of the Fig. 3 containing amino acid；
Nimodipine sub micro-emulsion injection HPLC chromatogram of the Fig. 4 containing amino acid.
Specific embodiment
Below with reference to embodiment, the present invention is further illustrated, and however, it is not limited to this.
Embodiment 1
A kind of Nimodipine sub micro-emulsion injection comprising following component:
| Nimodipine | 0.02g |
| Injection soybean oil | 5ml |
| Injection lecithin | 0.6g |
| Tween-80 | 0.1g |
| Methionine | 0.02g |
| Glycerol | 2.5g |
| Water for injection | Add to 100ml |
Preparation method: under the conditions of nitrogen protection, 75 DEG C will be heated in injection soybean oil and the Buddhist nun of recipe quantity is added
Horizon is not allowed to dissolution as oily phase；By 2/3 amount water for injection be heated to 75 DEG C and be added recipe quantity injection lecithin,
Tween-80, methionine and glycerol are allowed to dissolution or evenly dispersed；Oil is added in water phase, at 75 DEG C,
10000rpm high-speed stirred 2-3 times, each 5min prepare colostrum；It is 7.5 that remaining recipe quantity water for injection, which is added, and adjusts pH value,
It recycles 6 times, is sub-packed in brown ampoule bottle under the conditions of high-pressure homogeneous 1000bar, inflated with nitrogen sealing.It is hot under the conditions of 121 DEG C
Pressure sterilizing, makes F0 > 12.
As a result: average grain diameter=187.4nm；PDI=0.031；Encapsulation rate=94.32%；Impurity A=0.11%；Impurity B
=0.00%；Impurity C=0.22%.
Embodiment 2
A kind of Nimodipine sub micro-emulsion injection comprising following component:
| Nimodipine | 0.04g |
| Injection soybean oil | 8ml |
| Injection soybean lecithin | 1.0g |
| Tween-80 | 0.1g |
| Arginine | 0.05g |
| Glycerol | 2.5g |
| Water for injection | Add to 100ml |
Preparation method: under the conditions of nitrogen protection, injection soybean oil is heated to 70 DEG C and the Buddhist nun of recipe quantity is added not
Horizon is allowed to dissolution as oily phase；2/3 amount water for injection is heated to 70 DEG C and the injection soybean lecithin of recipe quantity, essence is added
Propylhomoserin and glycerol are allowed to dissolution or evenly dispersed；Oil is added in water phase, at 70 DEG C, 12000rpm high-speed stirred 2-3
Secondary, each 5min prepares colostrum；It is 7.5 that remaining recipe quantity water for injection, which is added, and adjusts pH value, in high-pressure homogeneous 1000bar item
It recycles 6 times, is sub-packed in brown ampoule bottle under part, inflated with nitrogen sealing.Pressure sterilizing under the conditions of 121 DEG C, makes F0> 12.
As a result: average grain diameter=201.4nm；PDI=0.023；Encapsulation rate=95.44%；Impurity A=0.08%；Impurity B
=0.00%；Impurity C=0.14%.
Embodiment 3
A kind of Nimodipine sub micro-emulsion injection comprising following component:
| Nimodipine | 0.08g |
| Injection soybean oil | 10ml |
| Injection lecithin | 1.2g |
| Tween-80 | 0.2g |
| Leucine | 0.1g |
| Glycerol | 2.5g |
| Water for injection | Add to 100ml |
Preparation method: under the conditions of nitrogen protection, injection soybean oil is heated to 80 DEG C and the Buddhist nun of recipe quantity is added not
Horizon is allowed to dissolution as oily phase；2/3 amount water for injection is heated to 80 DEG C and the injection lecithin, poly- of recipe quantity is added
Sorb ester -80, leucine and glycerol are allowed to dissolution or evenly dispersed；Oil is added in water phase, at 80 DEG C, 10000rpm
High-speed stirred 2-3 times, each 5min prepare colostrum；It is 7.5 that remaining recipe quantity water for injection, which is added, and adjusts pH value, equal in high pressure
It recycles 6 times, is sub-packed in brown ampoule bottle under the conditions of matter 1000bar, inflated with nitrogen sealing.Pressure sterilizing under the conditions of 121 DEG C, makes
F0> 12.
As a result: average grain diameter=193.7nm；PDI=0.041；Encapsulation rate=94.75%；Impurity A=0.12%；Impurity B
=0.00%；Impurity C=0.19%.
Embodiment 4
A kind of Nimodipine sub micro-emulsion injection comprising following component:
| Nimodipine | 0.1g |
| Injection soybean oil | 10ml |
| Injection lecithin | 1.2g |
| Tween-80 | 0.1g |
| Lysine | 0.1g |
| Glycerol | 2.5g |
| Water for injection | Add to 100ml |
Preparation method: under the conditions of nitrogen protection, injection soybean oil is heated to 70 DEG C and the Buddhist nun of recipe quantity is added not
Horizon is allowed to dissolution as oily phase；2/3 amount water for injection is heated to 70 DEG C and the injection lecithin of recipe quantity, poly- mountain is added
Pear ester -80, lysine and glycerol are allowed to dissolution or evenly dispersed；Oil is added in water phase, at 70 DEG C, 10000rpm high
Speed stirring 2-3 times, each 5min prepares colostrum；It is 7.5 that remaining recipe quantity water for injection, which is added, and adjusts pH value, high-pressure homogeneous
It recycles 6 times, is sub-packed in brown ampoule bottle under the conditions of 1000bar, inflated with nitrogen sealing.Pressure sterilizing under the conditions of 121 DEG C, makes F0
> 12.
As a result: average grain diameter=213.5nm；PDI=0.101；Encapsulation rate=94.33%；Impurity A=0.19%；Impurity B
=0.00%；Impurity C=0.21%.
Embodiment 5
A kind of Nimodipine sub micro-emulsion injection comprising following component:
| Nimodipine | 0.1g |
| Injection soybean oil | 10ml |
| Injection lecithin | 1.5g |
| PLURONICS F87 | 0.6g |
| Arginine | 0.1g |
| Glycerol | 2.5g |
| Water for injection | Add to 100ml |
Preparation method: under the conditions of nitrogen protection, injection soybean oil is heated to 70 DEG C and the Buddhist nun of recipe quantity is added not
Horizon is allowed to dissolution as oily phase；2/3 amount water for injection is heated to 70 DEG C and the injection lecithin of recipe quantity, pool Lip river is added
Husky nurse 188, arginine and glycerol are allowed to dissolution or evenly dispersed；Oil is added in water phase, at 70 DEG C, 10000rpm high
Speed stirring 2-3 times, each 5min prepares colostrum；It is 7.5 that remaining recipe quantity water for injection, which is added, and adjusts pH value, equal in high pressure
It recycles 6 times, is sub-packed in brown ampoule bottle under the conditions of matter 1000bar, inflated with nitrogen sealing.Pressure sterilizing under the conditions of 121 DEG C, makes
F0> 12.
As a result: average grain diameter=231.9nm；PDI=0.201；Encapsulation rate=95.75%；Impurity A=0.06%；Impurity B
=0.00%；Impurity C=0.16%.
Embodiment 6
A kind of Nimodipine sub micro-emulsion injection comprising following component:
| Nimodipine | 0.1g |
| Injection soybean oil: MCT=8:2 | 10ml |
| Injection lecithin | 1.5g |
| Tween-80 (coemulsifier) | 0.2g |
| Enuatrol (coemulsifier) | 0.02g |
| Leucine | 0.1g |
| Glycerol | 2.5g |
| Water for injection | Add to 100ml |
Preparation method: it is prepared by the process in embodiment 1-5.
As a result: average grain diameter=212.4nm；PDI=0.221；Encapsulation rate=95.33%；Impurity A=0.11%；Impurity B
=0.00%；Impurity C=0.16%.
Embodiment 7
A kind of Nimodipine sub micro-emulsion injection comprising following component:
| Nimodipine | 0.1g |
| Injection soybean oil: MCT=8:2 | 10ml |
| Injection lecithin | 1.5g |
| Enuatrol (coemulsifier) | 0.02g |
| PLURONICS F87 (coemulsifier) | 0.5g |
| Methionine | 0.2g |
| Glycerol | 2.5g |
| Water for injection | Add to 100ml |
Preparation method: it is prepared by the process in embodiment 1-5.
As a result: average grain diameter=225.4nm；PDI=0.181；Encapsulation rate=93.83%；Impurity A=0.14%；Impurity B
=0.00%；Impurity C=0.20%.
Embodiment 8
A kind of Nimodipine sub micro-emulsion injection comprising following component:
Preparation method: it is prepared by the process in embodiment 1-5.
As a result: average grain diameter=204.4nm；PDI=0.231；Encapsulation rate=92.3%；Impurity A=0.15%；Impurity B
=0.00%；Impurity C=0.19%.
Embodiment 9
A kind of Nimodipine sub micro-emulsion injection comprising following component:
| Nimodipine | 0.1g |
| Injection soybean oil: MCT=7:3 | 10ml |
| Injection lecithin | 1.2g |
| PLURONICS F87 | 2g |
| Arginine: methionine=1:1 | 0.1g |
| Glycerol | 2.5g |
| Water for injection | Add to 100ml |
Preparation method: it is prepared by the process in embodiment 1-5.
As a result: average grain diameter=187.4nm；PDI=0.146；Encapsulation rate=91.8%；Impurity A=0.04%；Impurity B
=0.00%；Impurity C=0.19%.
Embodiment 10
A kind of Nimodipine sub micro-emulsion injection comprising following component:
| Nimodipine | 0.1g |
| Injection soybean oil: MCT=6:4 | 10ml |
| Injection lecithin | 1.2g |
| Tween-80 | 0.3g |
| Leucine: lysine=1:1 | 0.2g |
| Glycerol | 2.5g |
| Water for injection | Add to 100ml |
Preparation method: it is prepared by the process in embodiment 1-5.
As a result: average grain diameter=221.3nm；PDI=0.136；Encapsulation rate=92.9%；Impurity A=0.09%；Impurity B
=0.00%；Impurity C=0.21%.
Embodiment 11
A kind of Nimodipine sub micro-emulsion injection comprising following component:
Preparation method: it is prepared by the process in embodiment 1-5.
As a result: average grain diameter=231.3nm；PDI=0.144；Encapsulation rate=94.2%；Impurity A=0.10%；Impurity B
=0.00%；Impurity C=0.18%.
Embodiment 12
A kind of Nimodipine sub micro-emulsion injection comprising following component:
| Nimodipine | 0.1g |
| Injection soybean oil: MCT=5:5 | 10ml |
| Injection soybean lecithin | 1.2g |
| PLURONICS F87 (coemulsifier) | 2.5g |
| Enuatrol (coemulsifier) | 0.03g |
| Methionine: lysine: leucine=1:1:1 | 0.3g |
| Glycerol | 2.5g |
| Water for injection | Add to 100ml |
Preparation method: it is prepared by the process in embodiment 1-5.
As a result: average grain diameter=201.6nm；PDI=0.144；Encapsulation rate=94.2%；Impurity A=0.12%；Impurity B
=0.00%；Impurity C=0.20%.
Embodiment 13
A kind of Nimodipine sub micro-emulsion injection comprising following component:
| Nimodipine | 0.2g |
| Injection soybean oil: MCT=5:5 | 20ml |
| Injection soybean lecithin | 1.6g |
| Tween-80 (coemulsifier) | 1.0g |
| Enuatrol (coemulsifier) | 0.02g |
| Methionine | 1g |
| Glycerol | 2.5g |
| Water for injection | Add to 100ml |
Preparation method: it is prepared by the process in embodiment 1-5.
As a result: average grain diameter=211.1nm；PDI=0.203；Encapsulation rate=96.1%；Impurity A=0.21%；Impurity B
=0.00%；Impurity C=0.19%.
Embodiment 14
Take in embodiment 3 prepared Nimodipine sub micro-emulsion sample, after 500 times of dilution, using phosphotungstic acid dye into
Row transmission electron microscope observing, as a result as shown in Figure 1, showing the distribution of Submicron Emulsion particle diameter preferably, particle roundness is good, according to software
Scale partial size is about 200nm, almost the same with the result of laser scattering method.
Embodiment 15
Nimodipine sub micro-emulsion sample prepared in embodiment 3 is taken, 5% Glucose Liquid or 0.9% physiology salt are used
Water dilutes 100 times, and sampling sends out measurement particle diameter variation by laser light scattering in different time points, steady after observation sample dilution
It is qualitative, as a result as shown in Fig. 2, showing that sample dilution stability is good, slightly increase in interior particle diameter for 24 hours, but be respectively less than
300nm, clinical use safety are good.
Embodiment 16
SD rat 12, after fasting for 24 hours are taken, by the Nimodipine sub-micro in 2.5mg/kg tail vein injection embodiment 3
Emulsion injection carries out determination of plasma concentration according to document the method, and plasma drug level-time graph is as shown in Figure 3.As a result
Show after carrying the administration of medicine Submicron Emulsion, blood concentration declines rapidly, and drug is prompted to be distributed in tissue internal organs rapidly in vivo.
Claims (7)
1. a kind of Nimodipine sub micro-emulsion injection, which is characterized in that include: in every 100ml sub-microemulsion injection
Wherein, the amino acid is at least one of arginine, methionine, leucine, lysine.
2. Nimodipine sub micro-emulsion injection according to claim 1, which is characterized in that every 100ml sub-microemulsion injection
In include:
。
3. -2 described in any item Nimodipine sub micro-emulsion injections according to claim 1, which is characterized in that the amino acid can
To be D type, L-type or DL type amino acid.
4. Nimodipine sub micro-emulsion injection according to claim 1 or 2, which is characterized in that the oil for injection is selected from
Injection soybean oil, the medium-chain fatty glyceride (MCT) of C8-C10, olive oil, vitamin E, in vitamin E esters at least
It is a kind of.
5. Nimodipine sub micro-emulsion injection according to claim 1 or 2, which is characterized in that the injection phosphotide choosing
Injection lecithin, injection soybean lecithin, hydrolecithin, hydrogenated soybean phosphorus from phosphatidylcholine content not less than 70%
At least one of rouge.
6. Nimodipine sub micro-emulsion injection according to claim 1 or 2, which is characterized in that the coemulsifier choosing
From at least one of Tween-80, Tween-85, PLURONICS F87, Cholesterol sulfate ester sodium salt, enuatrol.
7. the preparation method of Nimodipine sub micro-emulsion injection described in any one of claims 1-6, includes the following steps:
1) oil for injection is heated, Nimodipine is added, stirring is allowed to be completely dissolved to form solution, as oily phase；
2) water for injection is heated, sequentially adds injection phosphotide, glycerol, amino acid, coemulsifier, stirring is allowed to dissolve
Or it is evenly dispersed as water phase；
3) oil-phase solution of above-mentioned preparation is added in water phase, in a heated condition, with 8000-15000rpm high-speed stirred,
It is made and carries medicine colostrum；
4) pH value of above-mentioned colostrum is adjusted to 6.50~8.50, after adding water for injection polishing to normal concentration, use is high-pressure homogeneous
Machine is finally made Nimodipine sub micro-emulsion injection to the operation of medicine colostrum homogeneous is carried.
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| CN1732936A (en) * | 2004-07-08 | 2006-02-15 | 上海医药工业研究院 | Nimodipine emulsion injection liquid and method for preparing the same |
| CN101416942A (en) * | 2008-12-02 | 2009-04-29 | 沈阳万爱普利德医药科技有限公司 | Nimodipine sub micro-emulsion injection and preparation method thereof |
| CN101416963A (en) * | 2008-12-02 | 2009-04-29 | 沈阳万爱普利德医药科技有限公司 | Nimodipine freeze-drying sub micellar emulsion for injection and preparation method thereof |
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| US7585978B2 (en) * | 2006-11-28 | 2009-09-08 | Navinta Llc | Processes of manufacturing substituted-1,4-dihydropyridines, improved aqueous solutions thereof, and processes of manufacturing the solutions |
| JP5917034B2 (en) * | 2011-07-15 | 2016-05-11 | ニプロ株式会社 | Solid pharmaceutical composition containing calcium blocker |
| US11737989B2 (en) * | 2014-05-19 | 2023-08-29 | Chiesi Farmaceutici S.P.A. | Clevidipine nanoparticles and pharmaceutical compositions thereof |
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| CN1732936A (en) * | 2004-07-08 | 2006-02-15 | 上海医药工业研究院 | Nimodipine emulsion injection liquid and method for preparing the same |
| CN101416942A (en) * | 2008-12-02 | 2009-04-29 | 沈阳万爱普利德医药科技有限公司 | Nimodipine sub micro-emulsion injection and preparation method thereof |
| CN101416963A (en) * | 2008-12-02 | 2009-04-29 | 沈阳万爱普利德医药科技有限公司 | Nimodipine freeze-drying sub micellar emulsion for injection and preparation method thereof |
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