CN104546707B - Injection butyrate clevidipine composition and preparation method thereof - Google Patents
Injection butyrate clevidipine composition and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of injection butyrate clevidipine composition, it is made up of the supplementary material of following weight proportion, 25 50 parts of butyrate clevidipine; 100 1000 parts of oil for injection, 6 180 parts of egg yolk lecithin, 0.3 9 parts of oleic acid; 0.05 5 parts of natrium adetate, 50~4000 parts of freeze drying protectant.Invention removes the big aqueous phase surfactant of excitant, and use oil phase coemulsifier oleic acid instead, not only ensure that emulsifying effectiveness, more improve security；Glycerine is eliminated, freeze-drying process is not easy to collapse, and adds the operability of freeze-drying prods, meanwhile, it is found surprisingly that, removes glycerine, improve the envelop rate of product, reduces the seepage of medicine.
Description
Technical field
The present invention relates to a kind of butyrate clevidipine composition and preparation method thereof, more particularly to a kind of injection butyric acid
Clevidipine emulsion and preparation method thereof.
Background technology
Clevidipine (Clevidipine) belongs to dihydrogen pyridine derivative, is that a kind of calcium used for intravenous injection of ultrashort effect leads to
Road blocking agent.Clevidipine has the blood vessel and cardiac muscle selectivity of height, and its is rapid-action, and effect elimination is also fast, can ascending-dose
Accurately control blood pressure.
The chemical name of butyrate clevidipine is (±) -4- (2 ', 3 '-dichlorophenyl) -2,6- dimethyl-Isosorbide-5-Nitrae-dihydro pyrroles
Pyridine -3,5- dicarboxyl acid methyl (butyryl acyloxy methyl) ester, its molecular formula are C21H23Cl2NO6, molecular weight 456.3, structural formula
For：
Butyrate clevidipine is not soluble in water, and the liquid emulsion for being adapted to intravenous injection need to be made.The butyric acid chlorine listed at present
The auxiliary material used in dimension Horizon parenteral solution (trade name Cleviprex) for refined soybean oil, refined lecithin, oleic acid, concentrated glycerin,
Natrium adetate, sodium hydroxide, water for injection.
Many impurity of butyrate clevidipine are described in patent CN102170786, it can pass through water by clevidipine
Solution, decarboxylation and condensation reaction produce.It is using the method for reducing temperature that it, which controls the approach of degradation impurity,.The butyric acid chlorine listed
Pointed out in dimension Horizon parenteral solution specification, said preparation must be stored in 2~8 DEG C of refrigerators, but can not be freezed, if room temperature (25
DEG C) can not then refrigerate again after rewarming, and place at ambient temperature, the storage period of said preparation may not exceed 2 months.Butyric acid chlorine
The packing specification for tieing up Horizon parenteral solution is 50 and 100ml (0.5mg/ml), so big specification, for transport and storage all
It is no small challenge.Nonetheless, referred to (Instructions Page 9) in patent CN102186351, butyric acid chlorine is tieed up under the conditions of 5 ± 3 DEG C
In Horizon emulsion the content of hydrolysis impurity be up to 0.5% and the content of decarboxylation impurity be up to 0.4%, illustrate that the product is very unstable
It is fixed.
Secondly, to be pointed out in the butyrate clevidipine parenteral solution specification listed, said preparation can not be further diluted, and
The dosage of said preparation because injection speed is excessively slow, clinically needs to lead to be per hour 2ml (1mg)~32ml (16mg)
The infusion device of fine adjustment dosage " special can " be crossed, with other Large Copacity liquid fit applications, this brings to Clinical practice
Very big inconvenience.Patent 201210033558.0 discloses a kind of delivery system, is made up of main preparation and auxiliary emulsion two parts,
Main preparation contains medicine organic solution, and auxiliary emulsion is the blank emulsion of not drug containing, is administered after mixing.Patent
201210054616.2 disclose a kind of Clevidipine butyrate injection, including medicine, oil, phosphatide and organic solvent, during use
Become emulsion after dilution.Above two mode all using add organic solvent mode, and organic solvent all have compare
Big excitant, therefore, safety risks still be present.
Patent 201210595653.X has been made into lyophilized breast, adds its stability, has been also convenient for clinical injection, its
It is prepared by the supplementary material of following weight proportion：0.01~1.2 part of butyrate clevidipine, glycerine 10-50 parts, acidity regulator
In right amount, stabilizer 0.01-1.2 parts, freeze drying protectant 30-100 parts, oil for injection 80-130 parts, aqueous phase surfactant 0.1-
15 parts, oil phase surfactant 0.1-15 parts, water for injection adds to 1000 parts.In its aqueous phase surfactant used, tween
All there is certain excitant with poloxamer, moreover, after adding glycerine in prescription, sample easily collapses in freeze-drying process,
The envelop rate of medicine declines after more seriously redissolving, and causes the seepage of medicine to increase.
Therefore, the prescription that we freeze breast to butyrate clevidipine has carried out bold improvement, the work of aqueous phase surface is eliminated
Property agent, and use oil phase coemulsifier instead, emulsifying effectiveness is not only ensure that, more improves security；Glycerine is eliminated, is added
The operability of freeze-drying prods, meanwhile, it is found surprisingly that, improves the envelop rate of product, reduces the seepage of medicine.
The content of the invention
The technical problems to be solved by the invention are to overcome the defect of prior art, there is provided a kind of injection butyric acid chlorine dimension ground
Flat breast and preparation method thereof.
Technical scheme is as follows：
A kind of injection butyrate clevidipine composition, is made up of, butyrate clevidipine the supplementary material of following weight proportion
25-50 parts, oil for injection 100-1000 parts, egg yolk lecithin 6-180 parts, oleic acid 0.3-9 parts, natrium adetate 0.05-5 parts,
50~4000 parts of freeze drying protectant.
Described oil for injection be selected from refined soybean oil, peanut oil, safflower oil, cottonseed oil, olive oil, coconut oil, sesame oil,
Fish oil, medium chain mono, medium chain triglyceride dibasic acid esters, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propane diols are double
In ester, glyceryl linoleate, polyethylene glycol glyceryl laurate ester or it is combined.Preferably exquisite soybean oil and medium chain triglyceride
Combination, both weight ratios be 1：1.
Described freeze drying protectant is selected from lactose, sucrose, trehalose, dextran or its combination.
The present invention provides a kind of preparation method of injection butyrate clevidipine composition, comprises the following steps：
(1) preparation of oil phase：Egg yolk lecithin, oleic acid and butyrate clevidipine are separately added into oil for injection, stirring makes
It dissolves, as oil phase；
(2) preparation of aqueous phase：Natrium adetate and freeze drying protectant are added to the water, stirring makes its dissolving, as aqueous phase；
(3) preparation of colostrum：Step (1) oil phase is added in step (2) aqueous phase, high speed shear is disperseed, and forms colostrum；
(4) it is high-pressure homogenising：It is high-pressure homogenising by step (3) colostrum, obtain smart breast；
(5) initial filter：By step (4) essence breast through 0.45 μm of filter membrane initial filter；
(6) sterile filling：Step (5) essence breast is degerming through 0.22 μm of filtering with microporous membrane, and sterile embedding is into cillin bottle；
(7) it is freeze-dried：By sample vacuum freeze drying in step (6) cillin bottle, produce；
(8) step (1) to (7) operates under nitrogen protection.
High speed shear jitter time described in step (3) is 10~60 minutes, and shear rate is 3000~10000rpm, temperature
55~75 DEG C of degree；High-pressure homogenising pressure described in step (4) is 600~2000bar, homogenizes number 2~6 times；Step (7) is described
Vacuum freeze drying be by sample snap frozen to temperature -50~-45 DEG C, to maintain 1~3 hour；Primary drying temperature -35
~-30 DEG C, 24~48 hours primary drying time；25~40 DEG C of redrying temperature, 2~6 hours redrying time.
Invention removes the big aqueous phase surfactant of excitant, and use oil phase coemulsifier oleic acid instead, not only protect
Emulsifying effectiveness has been demonstrate,proved, has more improved security；Glycerine is eliminated, freeze-drying process is not easy to collapse, and adds grasping for freeze-drying prods
The property made, meanwhile, it is found surprisingly that, removes glycerine, improve the envelop rate of product, reduces the seepage of medicine；Meanwhile relevant thing
Matter has also obtained significant control.
Specific embodiment
Comparative example 1：
Prescription：
Technical process：
(1) preparation of aqueous phase：Glycerine, sucrose and natrium adetate are added to the water dissolving, are heated to 65 DEG C, it is standby；
(2) preparation of oil phase：Medium chain triglyceride is heated to 65 DEG C, egg yolk lecithin is separately added into, oleic acid dissolving, adds
Enter butyrate clevidipine, stirring makes its dissolving；
(3) preparation of colostrum：Step (2) oil phase is added in step (1) aqueous phase, 65 DEG C of temperature, high speed shear is disperseed, and is cut
Cutting speed degree 10000rpm, 15 minutes time, form colostrum
(4) it is high-pressure homogenising：By step (3) high-pressure homogenising 2 times through Microfluidizer, 1000~1200bar of pressure；
(5) initial filter：By step (4) essence breast through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered：Emulsion degerming, sterile embedding through 0.22 μm of filtering with microporous membrane is made in step (5)
(7) it is freeze-dried：By sample vacuum freeze drying obtained by step (6), by sample snap frozen to temperature -50~-
45 DEG C, -35~-30 DEG C are warming up to, is maintained 1~3 hour；- 35~-30 DEG C of primary drying temperature, primary drying time 12~24
Hour；25~40 DEG C of redrying temperature, three times drying time 2~6 hours；
(8) step (1) to (7) operates under nitrogen protection.
Embodiment 1：
Prescription：
Technical process：
(1) preparation of aqueous phase：Sucrose and natrium adetate are added to the water dissolving, are heated to 65 DEG C, it is standby；
(2) preparation of oil phase：Medium chain triglyceride is heated to 65 DEG C, egg yolk lecithin is separately added into, oleic acid dissolving, adds
Enter butyrate clevidipine, stirring makes its dissolving；
(3) preparation of colostrum：Step (2) oil phase is added in step (1) aqueous phase, 65 DEG C of temperature, high speed shear is disperseed, and is cut
Cutting speed degree 10000rpm, 15 minutes time, form colostrum
(4) it is high-pressure homogenising：By step (3) high-pressure homogenising 2 times through Microfluidizer, 1000~1200bar of pressure；
(5) initial filter：By step (4) essence breast through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered：Emulsion degerming, sterile embedding through 0.22 μm of filtering with microporous membrane is made in step (5)
(7) it is freeze-dried：By sample vacuum freeze drying obtained by step (6), by sample snap frozen to temperature -50~-
45 DEG C, -35~-30 DEG C are warming up to, is maintained 1~3 hour；- 35~-30 DEG C of primary drying temperature, primary drying time 12~24
Hour；25~40 DEG C of redrying temperature, three times drying time 2~6 hours；
(8) step (1) to (7) operates under nitrogen protection.
Embodiment 2
The comparison of comparative example 1 and embodiment 1
(1) ocular estimate
To maintain original volume, do not collapse, not shrinkage, any surface finish, can monoblock come off but not fragmentary be preferred.Color and luster evaluation with
Uniform color, no piebald, quality exquisiteness person are preferred.
(2) redispersibility is evaluated
Each prescription dried frozen aquatic products is taken, adds water for injection 1mL, shaking is scattered.It can disperse to obtain quickly after shaking uniform molten
Liquid liquid person is preferred.Shaking number is fewer, and redispersibility is better.
(3) entrapment efficiency determination
Envelop rate is determined using ultrafiltration centrifugal determination
1. select 10K ultra-filtration centrifuge tube, 3000rpm centrifuge 5 minutes, determine the sticky part in upper strata particle diameter distribution and under
Whether particle appearance is had in clear liquid, if lower floor passes through without particulate after centrifugation and upper strata distribution is substantially unchanged, according to assay
Method under, determine the content of medicine in ultra-filtration centrifuge tube lower clear liquid.
2. the measure of total drug content
Determined according to the determination method under assay item, as a result the as total drug content of this product.
Chromatographic condition：Octadecylsilane chemically bonded silica is filler；0.05mol/L sodium dihydrogen phosphate (phosphoric acid,diluteds
PH value is adjusted to 4.0)-acetonitrile-methanol (40: 20：40) it is mobile phase；Flow velocity：1.0ml per minute；40 DEG C of column temperature；Detection wavelength
220nm。
3. the measure of envelop rate
The envelop rate of this product such as following formula, which calculates, to be produced.
It the results are shown in Table 1.
The comparison whether glycerine of table 1 adds
(4) hot test
The hot test result of table 2 (60 DEG C, RH60%)
Embodiment 3
Prescription：
Technical process：
(1) preparation of aqueous phase：Lactose and natrium adetate are added to the water dissolving, are heated to 55 DEG C, it is standby；
(2) preparation of oil phase：Medium chain triglyceride is heated to 55 DEG C, egg yolk lecithin is separately added into, oleic acid dissolving, adds
Enter butyrate clevidipine, stirring makes its dissolving；
(3) preparation of colostrum：Step (2) oil phase is added in step (1) aqueous phase, 55 DEG C of temperature, high speed shear is disperseed, and is cut
Cutting speed degree 8000rpm, 30 minutes time, form colostrum
(4) it is high-pressure homogenising：By step (3) high-pressure homogenising 3 times through Microfluidizer, 800~1000bar of pressure；
(5) initial filter：By step (4) essence breast through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered：Emulsion degerming, sterile embedding through 0.22 μm of filtering with microporous membrane is made in step (5)
(7) it is freeze-dried：By sample vacuum freeze drying obtained by step (6), by sample snap frozen to temperature -50~-
45 DEG C, -35~-30 DEG C are warming up to, is maintained 1~3 hour；- 35~-30 DEG C of primary drying temperature, primary drying time 12~24
Hour；25~40 DEG C of redrying temperature, three times drying time 2~6 hours；
(8) step (1) to (7) operates under nitrogen protection.
Embodiment 4
Prescription：
Technical process：
(1) preparation of aqueous phase：Trehalose and natrium adetate are added to the water dissolving, are heated to 75 DEG C, it is standby；
(2) preparation of oil phase：Medium chain triglyceride is heated to 75 DEG C, egg yolk lecithin is separately added into, oleic acid dissolving, adds
Enter butyrate clevidipine, stirring makes its dissolving；
(3) preparation of colostrum：Step (2) oil phase is added in step (1) aqueous phase, 75 DEG C of temperature, high speed shear is disperseed, and is cut
Cutting speed degree 8000rpm, 45 minutes time, form colostrum
(4) it is high-pressure homogenising：By step (3) high-pressure homogenising 3 times through Microfluidizer, 600~1200bar of pressure；
(5) initial filter：By step (4) essence breast through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered：Emulsion degerming, sterile embedding through 0.22 μm of filtering with microporous membrane is made in step (5)
(7) it is freeze-dried：By sample vacuum freeze drying obtained by step (6), by sample snap frozen to temperature -50~-
45 DEG C, -35~-30 DEG C are warming up to, is maintained 1~3 hour；- 35~-30 DEG C of primary drying temperature, primary drying time 12~24
Hour；25~40 DEG C of redrying temperature, three times drying time 2~6 hours；
(8) step (1) to (7) operates under nitrogen protection.
Embodiment 5
Prescription：
Technical process：
(1) preparation of aqueous phase：Trehalose and natrium adetate are added to the water dissolving, are heated to 65 DEG C, it is standby；
(2) preparation of oil phase：Medium chain triglyceride is heated to 65 DEG C, egg yolk lecithin is separately added into, oleic acid dissolving, adds
Enter butyrate clevidipine, stirring makes its dissolving；
(3) preparation of colostrum：Step (2) oil phase is added in step (1) aqueous phase, 65 DEG C of temperature, high speed shear is disperseed, and is cut
Cutting speed degree 8000rpm, 45 minutes time, form colostrum
(4) it is high-pressure homogenising：By step (3) high-pressure homogenising 3 times through Microfluidizer, 1000~1200bar of pressure；
(5) initial filter：By step (4) essence breast through 0.45 μm of filter membrane initial filter；
(6) it is sterile filtered：Emulsion degerming, sterile embedding through 0.22 μm of filtering with microporous membrane is made in step (5)
(7) it is freeze-dried：By sample vacuum freeze drying obtained by step (6), by sample snap frozen to temperature -50~-
45 DEG C, -35~-30 DEG C are warming up to, is maintained 1~3 hour；- 35~-30 DEG C of primary drying temperature, primary drying time 12~24
Hour；25~40 DEG C of redrying temperature, three times drying time 2~6 hours；
(8) step (1) to (7) operates under nitrogen protection.
Claims (9)
1. a kind of injection butyrate clevidipine composition, it is characterised in that without glycerine, by the supplementary material of following weight proportion
Composition, butyrate clevidipine 25-50 parts, oil for injection 100-1000 parts, egg yolk lecithin 6-180 parts, oleic acid 0.3-9 parts, according to
Ground acid disodium 0.05-5 parts, 50~4000 parts of freeze drying protectant.
2. injection butyrate clevidipine composition according to claim 1, it is characterised in that described injection grease separation
Autofining soybean oil, peanut oil, safflower oil, cottonseed oil, olive oil, coconut oil, sesame oil, fish oil, medium chain mono, middle chain are sweet
Oily dibasic acid esters, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propane diols dibasic acid esters, glyceryl linoleate, polyethylene glycol
In glyceryl laurate ester or it is combined.
3. injection butyrate clevidipine composition according to claim 2, it is characterised in that described oil for injection is
Refined soybean oil and medium chain triglyceride, both weight ratios are 1: 1.
4. according to claim 1 inject for sour clevidipine composition, it is characterised in that described egg yolk lecithin
The content of middle phosphatidyl choline is more than 80%.
5. injection butyrate clevidipine composition according to claim 1, it is characterised in that described freeze drying protectant
Selected from lactose, sucrose, trehalose, dextran or its combination.
6. a kind of preparation method of any described injection butyrate clevidipine composition of Claims 1 to 5, its feature exist
In comprising the following steps：
(1) preparation of oil phase：Egg yolk lecithin, oleic acid and butyrate clevidipine are separately added into oil for injection, stirring makes its molten
Solution, as oil phase；
(2) preparation of aqueous phase：Natrium adetate and freeze drying protectant are added to the water, stirring makes its dissolving, as aqueous phase；
(3) preparation of colostrum：Step (1) oil phase is added into the shearing of step (2) aqueous phase high speed to disperse, forms colostrum；
(4) it is high-pressure homogenising：It is high-pressure homogenising by step (3) colostrum, obtain smart breast；
(5) initial filter：By step (4) essence breast through 0.45 μm of filter membrane initial filter；
(6) sterile filling：Step (5) essence breast is degerming through 0.22 μm of filtering with microporous membrane, and sterile embedding is into cillin bottle；
(7) it is freeze-dried：By sample vacuum freeze drying in the woods bottle of step (6) two, produce；
(8) step (1) to (7) operates under nitrogen protection.
7. the preparation method of injection butyrate clevidipine composition according to claim 6, it is characterised in that step
(3) high speed shear jitter time described in is 10~60 minutes, and shear rate is 3000~10000rpm, 55~75 DEG C of temperature.
8. the preparation method of injection butyrate clevidipine composition according to claim 7, it is characterised in that step
(4) the high-pressure homogenising pressure described in is 600~2000bar, homogenizes number 2~6 times.
9. the preparation method of injection butyrate clevidipine composition according to claim 8, it is characterised in that step
(7) vacuum freeze drying described in is, by sample snap frozen to temperature -50~-45 DEG C, to maintain 1~3 hour；Primary drying
Temperature -35~-30 DEG C, 24~48 hours primary drying time；25~40 DEG C of redrying temperature, the redrying time 2~6 is small
When.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101780036A (en) * | 2010-03-30 | 2010-07-21 | 武汉武药科技有限公司 | Butyrate clevidipine lipid microsphere injection and preparation method thereof |
| CN103126986A (en) * | 2013-03-19 | 2013-06-05 | 董慧芳 | Emulsion for clevidipine butyrate intravenous injection and preparation method thereof |
| CN103169672A (en) * | 2012-12-26 | 2013-06-26 | 辰欣药业股份有限公司 | Clevidipine butyrate freeze-dried emulsion |
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2013
- 2013-10-25 CN CN201310506903.2A patent/CN104546707B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101780036A (en) * | 2010-03-30 | 2010-07-21 | 武汉武药科技有限公司 | Butyrate clevidipine lipid microsphere injection and preparation method thereof |
| CN103169672A (en) * | 2012-12-26 | 2013-06-26 | 辰欣药业股份有限公司 | Clevidipine butyrate freeze-dried emulsion |
| CN103126986A (en) * | 2013-03-19 | 2013-06-05 | 董慧芳 | Emulsion for clevidipine butyrate intravenous injection and preparation method thereof |
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