CN104146958B - Clevidipine butyrate emulsion and preparation method thereof - Google Patents
Clevidipine butyrate emulsion and preparation method thereof Download PDFInfo
- Publication number
- CN104146958B CN104146958B CN201410425732.5A CN201410425732A CN104146958B CN 104146958 B CN104146958 B CN 104146958B CN 201410425732 A CN201410425732 A CN 201410425732A CN 104146958 B CN104146958 B CN 104146958B
- Authority
- CN
- China
- Prior art keywords
- oil
- emulsion
- acid
- butyrate clevidipine
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a clevidipine butyrate emulsion and a preparation method thereof. The clevidipine butyrate emulsion includes an oil phase and a water phase. The oil phase comprises clevidipine butyrate, long-chain oil and a stabilizer. The water phase comprises an emulsifier and water. A mass ratio of the oil phase and the water phase is 1:11-1:1. The clevidipine butyrate accounts for 0.05-0.5% of the total mass of the clevidipine butyrate emulsion; the long-chain oil accounts for 10-50% of the total mass of the clevidipine butyrate emulsion; the stabilizer accounts for 0.01-0.5% of the total mass of the clevidipine butyrate emulsion; and the emulsifier accounts for 0.5-5.0% of the total mass of the clevidipine butyrate emulsion. The water phase can also include a metal ion chelating agent and/or an isotonic agent. The emulsion can also include a pH adjusting agent. The clevidipine butyrate emulsion is safe and effective, is less in adverse reactions, is high in drug encapsulation efficiency, is good in storage stability, is controllable in preparation processes and is low in contents of impurities. The method is easy to industrially control.
Description
Technical field
The present invention relates to a kind of butyrate clevidipine Emulsion and preparation method thereof.
Background technology
Hypertensive emergency refers to that blood pressure steeply rises caused severe clinical signs." the Chinese high blood of revision in 2005
Pressure guideline of prevention and treatment " in point out that hypertensive emergency is that blood pressure seriously raises, more than 180/120mmhg, and the progressive target organ that occurs together
Insufficient performance.Perioperative Hypertension is also included in hypertensive emergency esc/esh Europe Hypertension Guideline within 2007.
Show according to U.S.'s epidemiologic data, because hypertensive crises are come in the patient that emergency treatment is gone to a doctor, 1/3 is hypertensive emergency.In China
In hyperpietic, about 5% can occur hypertensive emergency.According to documents and materials, the incidence rate of hypertensive emergency target organ damage: brain
Disease 16.3%, intracranial or subarachnoid hemorrhage 4.5%, cerebral infarction 24.5%, acute heart failure, pulmonary edema 36.8%, cardiac muscle stalk
Extremely/angina pectoriss 12%, eclamposia 4.5%, dissection of aorta 2%, seriously threaten the life of patient.
Therapeutic Principle for the patient of hypertensive emergency is should to enter ICW, continues to monitor blood pressure and as early as possible
Apply suitable antihypertensive drugs.Need to alleviate in a short time the state of an illness, the progressive injury of prevention target organ, reduce cardiovascular event
And mortality rate.With often needing intravenous infusion antihypertensive drugs, blood pressure can be made to be dropped rapidly to level of security, again can not be excessive or too fast
Blood pressure lowering, to avoid the occurrence of locally or systemically hypoperfusion (especially kidney, brain or coronary ischemia).Clinically it is used for controlling at present
In the medicine of critically ill patient blood pressure processed, one kind can not taken into account blood vessel and select rapid-onset in system, infusion process, rapid knot
The medicine of bundle and no intravenous injection toxicity requirements.Therefore, develop a kind of medicine that can reduce rapidly simultaneously precise control blood pressure
Thing preparation is significant.
Butyrate clevidipine (clevidipine butyrate), chemical entitled 4- (2,3- Dichlorobenzene base)-Isosorbide-5-Nitrae-dihydro-
2,6- dimethyl-3,5-dipicolinic acid methyl (1- oxobutoxy) methyl ester, its structural formula is as follows:
Butyrate clevidipine belongs to dihydrogen pyridine derivative, is a kind of calcium channel blocker used for intravenous injection of ultrashort effect,
There is the blood vessel of height and myocardium selectivity, rapid metabolization is inert matter in vivo.It is rapid-action, and effect eliminates also soon,
Can ascending-dose precise control blood pressure.It is different from current many antihypertensive drug through kidney and (or) hepatic metabolism for the intravenous injection,
Its metabolism in blood and tissue, thus do not accumulate in vivo.Butyrate clevidipine is almost insoluble in water, but has certain journey
That spends is fat-soluble.Therefore suitably it is prepared into the liquid emulsion for intravenous administration.Except insoluble drugs, Emulsion can be delivered
Decomposition susceptible to hydrolysis, can prevent medicine and plastic applicators used during intravenous injection tool adhesion, reduce office during transfusion
Portion's toxicity., in August in 2008 approval butyrate clevidipine Emulsion listing on the 1st, it is invalid to be administered orally for treatment or be administered orally for fda
Hypertension it can also be used to treatment surgical site infections acute blood pressure raise.
Because Emulsion is thermodynamic unstable system, and wherein important component oil phase and emulsifying agent have the oxidizable, Yishui River
The characteristic of solution.The butyrate clevidipine injectable emulsion of listing needs cold preservation under cryogenic, and the temperature in storage process becomes
Changing (as refrigeration-room temperature-cold preservation) easily causes the gathering of emulsion droplet to merge, and particle diameter increases, or even it is existing local breakdown of emulsion oil slick etc.
As.The stability of Emulsion has become the key factor of restriction drug loaded emulsion clinical practice.
Therefore, still in the urgent need to providing a kind of butyrate clevidipine that can solve the problem that above-mentioned technological deficiency to produce in prior art
Product are so as to can take into account quick acting, precise control blood pressure, reduce the needs such as untoward reaction simultaneously, and have higher storage
Deposit stability, or at least meet one in above-mentioned requirements.
Content of the invention
The technical problem to be solved is to overcome existing butyrate clevidipine injectable emulsion bin stability
A kind of defect of difference, there is provided butyrate clevidipine Emulsion and preparation method thereof.The butyrate clevidipine Emulsion of the present invention passes through
Add stabilizer in raw material prescription, add emulsifying agent in aqueous phase simultaneously, control oil phase to add the speed of aqueous phase, reached peace
Entirely effectively, entrapment efficiency, the purpose reducing untoward reaction and increasing preparation stored stability are improved.And the butanoic acid of the present invention
Clevidipine Emulsion preparation process is controlled, impurity content low it is easy to industrialization.
The invention provides a kind of butyrate clevidipine Emulsion, it includes oil phase and aqueous phase, and described oil phase includes butanoic acid chlorine
Dimension Horizon, long-chain oil and stabilizer, described aqueous phase includes emulsifying agent and water, and the mass ratio of described oil phase and described aqueous phase is 1:11
～1:1；The consumption of described butyrate clevidipine is 0.05～0.5%, and the consumption of described long-chain oil is 10～50%, described stable
The consumption of agent is 0.01～0.5%, and the consumption of described emulsifying agent is 0.5～5.0%；Described percentage ratio accounts for fourth for each constituent mass
The percentage ratio of sour clevidipine Emulsion gross mass.
In the present invention, described long-chain oil is injection long-chain oil commonly used in the art, meets Chinese Pharmacopoeia injection
The regulation of long-chain oil, described long-chain oil is preferably soybean oil, Oleum Arachidis hypogaeae semen, safflower oil, Oleum Ricini, Oleum Gossypii semen, olive oil, fiber crops
Oil, fish oil, ethyl oleate, acetylated monoglyceride, propylene glycol dibasic acid esters, glyceryl linoleate, Polyethylene Glycol and glycerol decanoate
One or more of, more preferably for one or more of soybean oil, fish oil, Oleum Ricini, safflower oil and olive oil, most preferably
For soybean oil.
In the present invention, described stabilizer be this area in conventional use of stabilizer, preferably Oleic acid, antiform oleic acid,
One or more of Semen Myristicae Oleic acid, palmitoleic acid, castor oil acid, erucic acid, cetoleic acid, more preferably for Oleic acid, vaccenic
One or more of acid and palmitoleic acid；
In the present invention, described emulsifying agent is emulsifying agent commonly used in the art, preferably lecithin, Semen sojae atricolor lecithin
Fat, hydrogenated soy phosphatidyl choline, Egg Yolk Lecithin (PC-98T), hydrogenated yolk lecithin, double Semen Myristicae phospholipid acid choline, double Semen Myristicae phosphatidyl
Glycerol, DOPC, DPPA, DPPC, PHOSPHATIDYL ETHANOLAMINE, peg derive
Change one or more of PHOSPHATIDYL ETHANOLAMINE and peg derivatization phospholipid acyl serine, more preferably for Egg Yolk Lecithin (PC-98T) and/or big
Bean lecithin, most preferably for Egg Yolk Lecithin (PC-98T).
In the present invention, described water is water for injection commonly used in the art, meets the regulation of Chinese Pharmacopoeia water for injection
?.
In the present invention, described aqueous phase preferably also includes metal ion chelation agent and/or isotonic agent；
Described metal ion chelation agent is the conventional metal ion chelation agent in this area, preferably amino carboxylic acid metalloid
Ion chelating agent, more preferably for ethylenediaminetetraacetic acid, one kind of aminotriacetic acid, diethylidene triamine pentaacetic acid and its esters or many
Kind, most preferably for ethylenediaminetetraacetic acid, the consumption of described metal ion chelation agent is 0.001～0.05%；
Described isotonic agent is the conventional isotonic agent in this area, preferably sodium chloride, Sorbitol, xylitol, glucose, sweet
One or more of dew alcohol, propylene glycol and glycerol, more preferably for one or more of sodium chloride, propylene glycol and glycerol,
It is glycerol, the consumption of described isotonic agent is 1.0～5.0% goodly.
In the present invention, described percentage ratio is the percentage ratio that each constituent mass accounts for butyrate clevidipine Emulsion gross mass.
In the present invention, described butyrate clevidipine Emulsion preferably also includes ph regulator, and described ph regulator is ability
Conventional use of ph regulator in domain, described ph regulator consumption is preferably the ph to 4.0 adjusting butyrate clevidipine Emulsion
～9.0, described ph regulator is preferably one or more of disodium hydrogen phosphate, citric acid, sodium hydroxide and hydrochloric acid.At this
In one better embodiment of invention, the concentration of described ph regulator is 1mol/l, the consumption of described ph regulator is 0.04～
0.1ml/100g butyrate clevidipine Emulsion.
In another better embodiment of the present invention, described butyrate clevidipine Emulsion is by described oil phase, described water
Mutually form with described ph regulator；Described oil phase is made up of described butyrate clevidipine, the oily and described stabilizer of described long-chain, institute
State aqueous phase to be made up of described emulsifying agent, described water, described metal ion chelation agent and described isotonic agent.
Present invention also offers a kind of preparation method of above-mentioned butyrate clevidipine Emulsion, described preparation method includes following
Step:
(1) in an inert atmosphere, described oil phase is added in described aqueous phase, control described oil phase to add the speed of described aqueous phase
Spend for 10～100g/min, in 40～90 DEG C of down cut emulsifyings, obtain oil-in-water emulsion；
(2) in an inert atmosphere, adjust the ph to 4.0～9.0 of described oil-in-water emulsion with described ph regulator, through height
Pressure homogenizing, sterilizing, obtain butyrate clevidipine Emulsion.
In step (1), described inert atmosphere is this area conventional inert atmosphere, preferably nitrogen and/or argon.
In step (1), preferably 50～70 DEG C of the temperature of described emulsification pretreatment, more preferably for 50～60 DEG C.
In step (1), other conditions of described emulsification pretreatment can be the conventional condition in this area；Described emulsification pretreatment point
Preferably 10～50 minutes scattered time, the speed of described emulsification pretreatment is preferably 4000～12000rpm.
In step (1), by common sense in the field, described oil phase is oily and described by described butyrate clevidipine, described long-chain
Stabilizer mixes, and described butyrate clevidipine and described stabilizer can dissolve and/or be scattered in described long-chain oil i.e.
Can.Preferably 50～70 DEG C of the temperature of described mixing, more preferably for 50～60 DEG C.
In step (1), by common sense in the field, described aqueous phase is to be mixed by each component in described aqueous phase, described water
Each component in phase can dissolve and/or be scattered in described water.Preferably 50～70 DEG C of the temperature of described mixing, more
It is 50～60 DEG C goodly.The mode of described mixing preferably using high speed shear, ultrasonic or grind by the way of, described high speed shear
Shear rate be generally 4000～12000rpm.
In step (2), described inert atmosphere is this area conventional inert atmosphere, preferably nitrogen and/or argon.
In step (2), the described ph adjusting described oil-in-water emulsion is preferably to 6.0～8.0.
In step (2), described high pressure homogenize is this area routine operation, and the pressure of described high pressure homogenize is preferably 500
～1500bar, more preferably for 700～1000bar；The number of times of described high pressure homogenize preferably 3～6 times.
In step (2), described sterilize as this area routine operation, generally filtration sterilization and/or high temperature sterilize.
On the basis of meeting common sense in the field, above-mentioned each optimum condition, can combination in any, obtain final product each preferable reality of the present invention
Example.
Agents useful for same of the present invention and raw material are all commercially available.
The positive effect of the present invention is:
1st, the butyrate clevidipine Emulsion of the present invention by conventional oil phase, water phase components composition breakthrough, by emulsifying agent
Add in aqueous phase, control oil phase to add the speed of aqueous phase it is ensured that emulsifying power, can make to make major part during water-oil phase mixing
Medicine can be distributed in the oil phase of fat milk or interfacial film it is ensured that its stability.
2nd, the butyrate clevidipine Emulsion of the present invention is safe and effective, untoward reaction is few, and entrapment efficiency is compared with commercially available prod
Height, bin stability is also superior to commercially available prod.
3rd, the butyrate clevidipine Emulsion preparation process of the present invention is controlled, and impurity content is low it is easy to industrialization controls.
Specific embodiment
Further illustrate the present invention below by the mode of embodiment, but therefore do not limit the present invention to described reality
Apply among a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product description selects.
In following embodiments:
Described butyrate clevidipine is provided by Nanjing Sen Beijia bio tech ltd；Described soybean oil is by Guangzhou Chinese prescription
Modern Chinese medicine development corporation, Ltd. provides；Described Egg Yolk Lecithin (PC-98T) and Oleic acid are provided by Shanghai Dong Shang bio tech ltd；
Described glycerol is provided by Hu'nan Erkang Pharmaceutical Co., Ltd.；Remaining raw material is commercially available.
Embodiment 1
A kind of butyrate clevidipine Emulsion, its component and content are as follows:
The preparation method of the butyrate clevidipine Emulsion of the present embodiment comprises the steps:
(1) under nitrogen atmosphere, butyrate clevidipine, soybean oil and Oleic acid are mixed at 60 DEG C all by above-mentioned formula
Even, obtain oil phase；Egg Yolk Lecithin (PC-98T), glycerol, ethylenediaminetetraacetic acid are mixed homogeneously with water for injection at 60 DEG C, obtains water
Phase；Oil phase is uniformly added in aqueous phase with the speed of 10～20g/min, in 60 DEG C of down cut emulsifyings, shear rate is
10000rpm, shear time 30 minutes, obtain oil-in-water emulsion；
(2) under nitrogen atmosphere, after described oil-in-water emulsion is cooled to below 25 DEG C, with sodium hydroxide adjust ph to
7.0, through high pressure homogenize, homogenization pressure 1000bar, homogenization cycles 4 times, below 40 DEG C, embedding sterilizes homogenizing temperature, obtains final product fourth
Sour clevidipine Emulsion.
Embodiment 2
A kind of butyrate clevidipine Emulsion, its component and content are as follows:
The preparation method of the butyrate clevidipine Emulsion of the present embodiment comprises the steps:
(1) under nitrogen atmosphere, by above-mentioned formula by butyrate clevidipine, fish oil and Oleic acid mix homogeneously at 40 DEG C,
Obtain oil phase；Soybean lecithin, sodium chloride, ethylenediaminetetraacetic acid are mixed homogeneously with water for injection at 40 DEG C, obtains aqueous phase；
Oil phase is uniformly added in aqueous phase with the speed of 40～60g/min, in 40 DEG C of down cut emulsifyings, shear rate is 4000rpm, cuts
Cut the time 50 minutes, obtain oil-in-water emulsion；
(2) under nitrogen atmosphere, after described oil-in-water emulsion is cooled to below 25 DEG C, with sodium hydroxide adjust ph to
9.0, through high pressure homogenize, homogenization pressure 1500bar, homogenization cycles 3 times, below 40 DEG C, embedding sterilizes homogenizing temperature, obtains final product fourth
Sour clevidipine Emulsion.
Embodiment 3
A kind of butyrate clevidipine Emulsion, its component and content are as follows:
The preparation method of the butyrate clevidipine Emulsion of the present embodiment comprises the steps:
(1) under nitrogen atmosphere, by above-mentioned formula, butyrate clevidipine, Oleum Ricini and antiform oleic acid are mixed at 90 DEG C
Uniformly, obtain oil phase；Egg Yolk Lecithin (PC-98T), glycerol, aminotriacetic acid are mixed homogeneously with water for injection at 90 DEG C, obtains water
Phase；Oil phase is uniformly added in aqueous phase with the speed of 90～100g/min, in 90 DEG C of down cut emulsifyings, shear rate is
12000rpm, shear time 10 minutes, obtain oil-in-water emulsion；
(2) under nitrogen atmosphere, after described oil-in-water emulsion is cooled to below 25 DEG C, adjust ph to 4.0 with hydrochloric acid,
Through high pressure homogenize, homogenization pressure 500bar, homogenization cycles 6 times, below 40 DEG C, embedding sterilizes homogenizing temperature, obtains final product butanoic acid chlorine
Dimension Horizon Emulsion.
Embodiment 4
A kind of butyrate clevidipine Emulsion, its component and content are as follows:
The preparation method of the butyrate clevidipine Emulsion of the present embodiment comprises the steps:
(1) under nitrogen atmosphere, butyrate clevidipine, safflower oil and Oleic acid are mixed at 70 DEG C all by above-mentioned formula
Even, obtain oil phase；Egg Yolk Lecithin (PC-98T), propylene glycol, diethylidene triamine pentaacetic acid are mixed homogeneously with water for injection at 70 DEG C, obtains
To aqueous phase；Oil phase is uniformly added in aqueous phase with the speed of 40～60g/min, in 60 DEG C of down cut emulsifyings, shear rate is
6000rpm, shear time 20 minutes, obtain oil-in-water emulsion；
(2) under nitrogen atmosphere, after described oil-in-water emulsion is cooled to below 25 DEG C, adjust ph with disodium hydrogen phosphate
To 6.5, through high pressure homogenize, homogenization pressure 800bar, homogenization cycles 5 times, below 40 DEG C, embedding sterilizes homogenizing temperature, obtains final product
Butyrate clevidipine Emulsion.
Embodiment 5
A kind of butyrate clevidipine Emulsion, its component and content are as follows:
The preparation method of the butyrate clevidipine Emulsion of the present embodiment comprises the steps:
(1) under nitrogen atmosphere, by above-mentioned formula, butyrate clevidipine, olive oil and palmitoleic acid are mixed at 80 DEG C
Uniformly, obtain oil phase；Egg Yolk Lecithin (PC-98T), glycerol, ethylenediaminetetraacetic acid are mixed homogeneously with water for injection at 70 DEG C, obtains water
Phase；Oil phase is uniformly added in aqueous phase with the speed of 70～100g/min, in 60 DEG C of down cut emulsifyings, shear rate is
10000rpm, shear time 20 minutes, obtain oil-in-water emulsion；
(2) under nitrogen atmosphere, after described oil-in-water emulsion is cooled to below 25 DEG C, with sodium hydroxide adjust ph to
7.5, through high pressure homogenize, homogenization pressure 1200bar, homogenization cycles 4 times, below 40 DEG C, embedding sterilizes homogenizing temperature, obtains final product fourth
Sour clevidipine Emulsion.
Comparative example 1
A kind of butyrate clevidipine Emulsion, its component and content are as follows:
The preparation method of the butyrate clevidipine Emulsion of this comparative example comprises the steps:
(1) under nitrogen atmosphere, by above-mentioned formula, butyrate clevidipine, soybean oil and Egg Yolk Lecithin (PC-98T) is mixed at 60 DEG C
Close uniformly, obtain oil phase；Glycerol, ethylenediaminetetraacetic acid are mixed homogeneously with water for injection at 60 DEG C, obtains aqueous phase；By oil phase
It is uniformly added in aqueous phase with the speed of 10～20g/min, in 60 DEG C of down cut emulsifyings, shear rate is 10000rpm, during shearing
Between 30 minutes, obtain oil-in-water emulsion；
(2) under nitrogen atmosphere, after described oil-in-water emulsion is cooled to below 25 DEG C, with sodium hydroxide adjust ph to
7.0, through high pressure homogenize, homogenization pressure 1000bar, homogenization cycles 4 times, below 40 DEG C, embedding sterilizes homogenizing temperature, obtains final product fourth
Sour clevidipine Emulsion.
Comparative example 2
A kind of butyrate clevidipine Emulsion, its component and content are as follows:
The preparation method of the butyrate clevidipine Emulsion of this comparative example comprises the steps:
(1) under nitrogen atmosphere, by above-mentioned formula, butyrate clevidipine is mixed homogeneously with soybean oil at 60 DEG C, obtain
Oil phase；Egg Yolk Lecithin (PC-98T), glycerol, ethylenediaminetetraacetic acid are mixed homogeneously with water for injection at 60 DEG C, obtains aqueous phase；By oil phase
It is uniformly added in aqueous phase with the speed of 10～20g/min, in 60 DEG C of down cut emulsifyings, shear rate is 10000rpm, during shearing
Between 30 minutes, obtain oil-in-water emulsion；
(2) under nitrogen atmosphere, after described oil-in-water emulsion is cooled to below 25 DEG C, with sodium hydroxide adjust ph to
7.0, through high pressure homogenize, homogenization pressure 1000bar, homogenization cycles 4 times, below 40 DEG C, embedding sterilizes homogenizing temperature, obtains final product fourth
Sour clevidipine Emulsion.
Comparative example 3
A kind of butyrate clevidipine Emulsion, its component and content are as follows:
The preparation method of the butyrate clevidipine Emulsion of this comparative example comprises the steps:
(1) under nitrogen atmosphere, by above-mentioned formula, butyrate clevidipine, soybean oil and Egg Yolk Lecithin (PC-98T) is mixed at 60 DEG C
Close uniformly, obtain oil phase；Oleic acid, glycerol, ethylenediaminetetraacetic acid are mixed homogeneously with water for injection at 60 DEG C, obtains aqueous phase；
Oil phase is uniformly added in aqueous phase with the speed of 10～20g/min, in 60 DEG C of down cut emulsifyings, shear rate is 10000rpm,
Shear time 30 minutes, obtains oil-in-water emulsion；
(2) under nitrogen atmosphere, after described oil-in-water emulsion is cooled to below 25 DEG C, with sodium hydroxide adjust ph to
7.0, through high pressure homogenize, homogenization pressure 1000bar, homogenization cycles 4 times, below 40 DEG C, embedding sterilizes homogenizing temperature, obtains final product fourth
Sour clevidipine Emulsion.
In following effect example:
Described commercially available butyrate clevidipine preparation is provided by American Medical company (the medicines company).
Effect example 1
The butyrate clevidipine Emulsion that be obtained the embodiment of the present invention 1～5, comparative example 1～3 and commercially available butyrate clevidipine
Preparation distilled water suitably dilutes, and carries out particle diameter and potential test.Described particle diameter and potential test adopt malvern nano
Zs-90 laser particle analyzer is measured, and test result is shown in Table 1.
Effect example 2
Butyrate clevidipine Emulsion and commercially available butanoic acid chlorine dimension ground that the mensure embodiment of the present invention 1～5, comparative example 1～3 are obtained
The envelop rate of flat preparation.Described entrapment efficiency determination method is as follows: take appropriate butyrate clevidipine Emulsion to load centrifuge tube,
100000 revs/min of centrifugation 1-2h, take off clear liquid according to content assaying method high effective liquid chromatography for measuring, with external standard method with
Calculated by peak area free drug content, bound drug total content computational envelope rate, test result is shown in Table 1.
The particle diameter of table 1 butyrate clevidipine Emulsion, current potential and envelop rate
| Sample | Particle diameter (nm) | Polydispersity coefficient | ζ-potential (mv) | Envelop rate (%) |
| Commercially available butyrate clevidipine preparation | 290.1±1.4 | 0.089±0.002 | -44.84±0.62 | 93.44±0.80 |
| Embodiment 1 | 290.4±0.9 | 0.060±0.002 | -47.55±0.88 | 98.80±0.28 |
| Embodiment 2 | 293.7±1.7 | 0.902±0.006 | -45.35±0.12 | 97.21±0.28 |
| Embodiment 3 | 297.4±4.9 | 0.805±0.006 | -44.27±0.47 | 96.80±0.56 |
| Embodiment 4 | 305.4±4.6 | 0.053±0.023 | -42.11±0.91 | 94.92±1.11 |
| Embodiment 5 | 308.4±4.9 | 0.075±0.083 | -41.11±0.18 | 94.75±1.27 |
| Comparative example 1 | 301.9±0.5 | 0.154±0.007 | -31.79±1.38 | 85.29±0.84 |
| Comparative example 2 | 295.2±0.5 | 0.115±0.006 | -34.29±0.82 | 90.82±0.29 |
| Comparative example 3 | 298.1±1.4 | 0.127±0.004 | -44.19±0.96 | 89.72±0.62 |
Can be seen that the present invention from above experimental result and add stabilizer prescription, simultaneously that emulsifying agent is dispersed
In aqueous phase, can make when oil phase is mixed with water conjunction most of drug distribution in the oil phase or interfacial film of fat milk so that
To butyrate clevidipine Emulsion emulsion droplet interface reach saturation absorption, be difficult assemble, envelop rate improve.Comparing embodiment and contrast
Example finds, is added without stabilizer, or emulsifying agent is dispersed in oil phase in prescription, prepared butyrate clevidipine Emulsion bag
Envelope rate is all low compared with commercial reagent.
Effect example 3
The butyrate clevidipine Emulsion that embodiment 1-5 is obtained is contrasted with commercially available butyrate clevidipine preparation, respectively
Measure stability.Described 4stability determination is as follows: the butyrate clevidipine Emulsion that be obtained embodiment 1-5 and commercially available fourth
Sour clevidipine preparation is placed in temperature for placing 6 months under conditions of 25 DEG C of ± 2 DEG C/rh60% ± 5%, respectively at the 0th, 3 and 6
The particle diameter of moon sampling detection sample, content and impurity, test result is shown in Table 2.
The stability of table 2 butyrate clevidipine Emulsion
From the above experimental results, the butyrate clevidipine Emulsion of the present invention during accelerated test (because of butanoic acid chlorine
Dimension Horizon is 2～8 DEG C of preservations of cold preservation, therefore the condition of 25 DEG C of ± 2 DEG C/rh60% ± 5% is accelerated stability test condition),
Particle diameter is not easy to assemble, and total impurities is less than commercial preparation, shows that the butyrate clevidipine Emulsion of the present invention is stable compared with commercially available product.
Claims (10)
1. a kind of butyrate clevidipine Emulsion it is characterised in that: described butyrate clevidipine Emulsion includes oil phase and aqueous phase, described
Oil phase includes butyrate clevidipine, long-chain oil and stabilizer, and described aqueous phase includes emulsifying agent and water, described oil phase and described aqueous phase
Mass ratio be 1:11～1:1；The consumption of described butyrate clevidipine is 0.05～0.5%, and the consumption of described long-chain oil is 10
～50%, the consumption of described stabilizer is 0.01～0.5%, and the consumption of described emulsifying agent is 0.5～5.0%；Described percentage ratio
Account for the percentage ratio of butyrate clevidipine Emulsion gross mass for each constituent mass.
2. butyrate clevidipine Emulsion as claimed in claim 1 it is characterised in that: described long-chain oil is soybean oil, Oleum Arachidis hypogaeae semen,
Safflower oil, Oleum Ricini, Oleum Gossypii semen, olive oil, Oleum Sesami, fish oil, ethyl oleate, acetylated monoglyceride, propylene glycol dibasic acid esters, sub- oil
One or more of acid glyceride and glycerol decanoate；
Described stabilizer is in Oleic acid, antiform oleic acid, Semen Myristicae Oleic acid, palmitoleic acid, castor oil acid, erucic acid and cetoleic acid
One or more；
Described emulsifying agent is lecithin, double Semen Myristicae phospholipid acid choline, double Semen Myristicae phosphatidyl glycerol, dioleoyl phospholipid acyl gallbladder
Alkali, DPPA, DPPC, PHOSPHATIDYL ETHANOLAMINE, peg derivatization phospholipid acyl ethanolamine and peg
One or more of derivatization phospholipid acyl serine；Described lecithin is soybean lecithin, hydrogenated soy phosphatidyl choline, egg yolk ovum
One or more of phospholipid and hydrogenated yolk lecithin.
3. butyrate clevidipine Emulsion as claimed in claim 2 it is characterised in that: described long-chain oil is soybean oil, fish oil, castor
One or more of Oleum Sesami, safflower oil and olive oil；
And/or, described stabilizer is one or more of Oleic acid, antiform oleic acid and palmitoleic acid；
And/or, described emulsifying agent is Egg Yolk Lecithin (PC-98T) and/or soybean lecithin.
4. butyrate clevidipine Emulsion as claimed in claim 3 it is characterised in that: described long-chain oil is soybean oil；
And/or, described emulsifying agent is Egg Yolk Lecithin (PC-98T).
5. the butyrate clevidipine Emulsion as described in any one of Claims 1 to 4 it is characterised in that: described aqueous phase also includes gold
Belong to ion chelating agent and/or isotonic agent；Described metal ion chelation agent is amino carboxylic acid metalloid ion chelating agent, described metal
The consumption of ion chelating agent is 0.001～0.05%；And/or, described isotonic agent is sodium chloride, Sorbitol, xylitol, Fructus Vitis viniferae
One or more of sugar, Mannitol, propylene glycol and glycerol, the consumption of described isotonic agent is 1.0～5.0%；Described percentage ratio
Account for the percentage ratio of butyrate clevidipine Emulsion gross mass for each constituent mass；
And/or, described butyrate clevidipine Emulsion also includes ph regulator, and described ph regulator consumption is to adjust butanoic acid chlorine dimension ground
The ph of flat Emulsion to 4.0～9.0, described ph regulator be one of disodium hydrogen phosphate, citric acid, sodium hydroxide and hydrochloric acid or
Multiple.
6. butyrate clevidipine Emulsion as claimed in claim 5 it is characterised in that: described metal ion chelation agent be ethylenediamine
One or more of tetraacethyl, aminotriacetic acid, diethylidene triamine pentaacetic acid and its esters；
And/or, described isotonic agent is one or more of sodium chloride, propylene glycol and glycerol；
And/or, the concentration of described ph regulator is 1mol/l, and the consumption of described ph regulator is 0.04～0.1ml/100g butanoic acid
Clevidipine Emulsion.
7. the preparation method of the butyrate clevidipine Emulsion as described in any one of claim 1～6 is it is characterised in that described system
Preparation Method comprises the steps:
(1) in an inert atmosphere, described oil phase is added in described aqueous phase, the speed of the control described oil phase described aqueous phase of addition is
10～100g/min, in 40～90 DEG C of down cut emulsifyings, obtains oil-in-water emulsion；
(2) in an inert atmosphere, with ph regulator adjust described oil-in-water emulsion ph to 4.0～9.0, through high pressure homogenize,
Sterilizing, obtains butyrate clevidipine Emulsion.
8. preparation method as claimed in claim 7 it is characterised in that: in step (1), described inert atmosphere be nitrogen and/or
Argon；
And/or, in step (1), the temperature of described emulsification pretreatment is 50～70 DEG C；
And/or, in step (1), the jitter time of described emulsification pretreatment is 10～50 minutes, and the speed of described emulsification pretreatment is
4000～12000rpm.
9. preparation method as claimed in claim 7 it is characterised in that: in step (2), described inert atmosphere be nitrogen and/or
Argon；
And/or, in step (2), the described ph to 6.0～8.0 adjusting described oil-in-water emulsion；
And/or, in step (2), the pressure of described high pressure homogenize is 500～1500bar, and the number of times of described high pressure homogenize is 3～6
Secondary.
10. preparation method as claimed in claim 8 or 9 it is characterised in that: in step (1), the temperature of described emulsification pretreatment is
50～60 DEG C；
And/or, in step (2), the pressure of described high pressure homogenize is 700～1000bar.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410425732.5A CN104146958B (en) | 2014-08-26 | 2014-08-26 | Clevidipine butyrate emulsion and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410425732.5A CN104146958B (en) | 2014-08-26 | 2014-08-26 | Clevidipine butyrate emulsion and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104146958A CN104146958A (en) | 2014-11-19 |
| CN104146958B true CN104146958B (en) | 2017-01-18 |
Family
ID=51872728
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410425732.5A Active CN104146958B (en) | 2014-08-26 | 2014-08-26 | Clevidipine butyrate emulsion and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104146958B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105878182A (en) * | 2014-12-30 | 2016-08-24 | 南京海纳医药科技有限公司 | Preparation method of clevidipine butyrate injection fat emulsion |
| CN105853353A (en) * | 2015-01-20 | 2016-08-17 | 江苏正大丰海制药有限公司 | Method for preparing clevidipine fat emulsion injection |
| CN105362224A (en) * | 2015-10-09 | 2016-03-02 | 北京万全德众医药生物技术有限公司 | Cleviprex containing emulsion for injection, freeze-dried emulsion and preparation method thereof |
| CN107661294B (en) * | 2016-07-27 | 2020-04-14 | 武汉科福新药有限责任公司 | Anti-hypertension drug fat emulsion injection and preparation method thereof |
| CN107982215B (en) * | 2017-12-04 | 2020-09-01 | 江苏九旭药业有限公司 | Clevidipine butyrate emulsion and preparation method and application thereof |
| CN113197853B (en) * | 2021-05-06 | 2023-05-12 | 上海上药第一生化药业有限公司 | Emulsion for clevidipine butyrate injection, and preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102228434A (en) * | 2011-07-01 | 2011-11-02 | 四川大学 | Clevidipine butyrate emulsion, preparation method thereof and purpose thereof |
| CN103126986A (en) * | 2013-03-19 | 2013-06-05 | 董慧芳 | Emulsion for clevidipine butyrate intravenous injection and preparation method thereof |
-
2014
- 2014-08-26 CN CN201410425732.5A patent/CN104146958B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN104146958A (en) | 2014-11-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104146958B (en) | Clevidipine butyrate emulsion and preparation method thereof | |
| JP6169110B2 (en) | Hormone-containing emulsion | |
| CN102946865B (en) | Comprise the pharmaceutical emulsion composition of the low oil of progestogen | |
| CN107970208B (en) | Butylphthalide injection and preparation method thereof | |
| RU2664700C2 (en) | Depot formulations of local anesthetic and methods for preparation thereof | |
| US20100189596A1 (en) | Composite emulsifier, an emulsion prepared from it and the preparation method thereof | |
| CN103110579B (en) | Alprostadil injection | |
| JP2003535884A (en) | Improved injectable dispersion of propofol | |
| EP0204987B1 (en) | Medicine containing vitamin e for improving the properties of blood | |
| JP2002502811A (en) | Propofol compositions containing sulfites | |
| WO2010127541A1 (en) | A nano-emulsion injection of vinca alkaloids and the preparation method thereof | |
| US20230398072A1 (en) | Concentrate containing poorly soluble drug and emulsion prepared therefrom | |
| JP2018515484A (en) | Cabazitaxel fat emulsion injection, preparation method thereof and use thereof | |
| CN101766568A (en) | Emulsion containing clevidipine and preparation process and application thereof | |
| US20100130619A1 (en) | Pharmaceutical composition for parenteral administration of idebenone | |
| EP0945136B1 (en) | Topical pharmaceutical preparation comprising ciclosporin | |
| CN101791311A (en) | Pharmaceutical composition with short pressure-reducing function | |
| CN103110580B (en) | Clevidipine butyrate injection | |
| JPH10510267A (en) | Emulsion suitable for administration of sphingolipid and use thereof | |
| JP2008512447A (en) | Stable emulsion composition for intravenous administration with antiseptic action | |
| KR20220152228A (en) | Sunflower phospholipid composition containing phosphatidylcholine | |
| CN106137963B (en) | Antiarrhythmic drug fat emulsion injection and preparation method thereof | |
| CN106109412A (en) | Flurbiprofen axetil lipid microsphere injection and preparation method thereof | |
| RU2141313C1 (en) | Pharmaceutical emulsion containing biologically active steroids and method of emulsion preparing | |
| WO2022090807A2 (en) | Cannabigerol and tetrahydrocannabivarin antidote formulations and methods of using the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 201206 No. 905 Jinqiao Road, Pudong New Area Free Trade Zone, Shanghai, China Patentee after: Shanghai Xinyi Pharmaceutical Co. Ltd.. Address before: 201206 Pudong New Area new Jinqiao Road, Shanghai, No. 905 Patentee before: Shanghai Sine Pharmaceutical Co., Ltd. |