CN103520104B - Clevidipine butyrate fat emulsion injection and preparation method thereof - Google Patents

Abstract

A kind of Clevidipine butyrate fat emulsion injection, containing butyrate clevidipine, oil for injection, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, wherein, the weight portion of butyrate clevidipine is 1, the weight portion of oil for injection is 200 ~ 400, and phosphatidylcholine weight portion is 12 ~ 36, and the weight portion of PHOSPHATIDYL ETHANOLAMINE is 1.6 ~ 4.8.The weight portion of PHOSPHATIDYL ETHANOLAMINE is preferably 2.4 ~ 4.0, and more preferably 3.0 ~ 4.0.

Description

Clevidipine butyrate fat emulsion injection and preparation method thereof

Technical field

The present invention relates to a kind of butyrate clevidipine pharmaceutical preparation, particularly relate to a kind of more stable Clevidipine butyrate fat emulsion injection and preparation method thereof.

Background technology

Clevidipine (Clevidipine) belongs to dihydrogen pyridine derivative, is a kind of calcium channel blocker used for intravenous injection of ultrashort effect.Clevidipine has the blood vessel of height and myocardium selectivity, and it is rapid-action, and effect is eliminated also fast, accurately can control blood pressure by ascending-dose.

The chemical name of butyrate clevidipine is (±)-4-(2 ', 3 '-Dichlorobenzene base)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic acids methyl (butyryl acyloxy methyl) ester, and its molecular formula is C ₂₁h ₂₃cl ₂nO ₆, molecular weight is 456.3, and structural formula is such as formula shown in (I):

Butyrate clevidipine is water insoluble, need make applicable intravenous liquid emulsion.Patent documentation CN102170786A reports in butyrate clevidipine Emulsion that the adjuvant adopted is refined soybean oil, the egg yolk lecithin of purification, glycerol, water and for regulating the sodium hydroxide of pH.

It is reported, phospholipid is found from human brain in 1812 by Uauquelin the earliest, and Golbley separated from egg yolk in 1844, and in 1850 according to Greek Iekithos (egg yolk) called after Lecithin (lecithin).Its main component is phosphatidylcholine (PC), and in the egg yolk lecithin of purification, the content of phosphatidylcholine (PC) can reach more than 98%, purification egg yolk lecithin is called phosphatidylcholine (PC).What adopt in the alprostadil injection gone on the market is the egg yolk lecithin of purification, and the content of its phosphatidylcholine is more than 98%.

Also document is had to claim lecithin to be a kind of mixture, main component is phosphatidylcholine (PC), content accounts for about 80%, other compositions are LYSO-PHOSPHATIDYLCHOLINE LYSOPC (L-HPC), phosphatidylinositols (PI), Phosphatidylserine (PS), PHOSPHATIDYL ETHANOLAMINE (PE).PHOSPHATIDYL ETHANOLAMINE, also known as cephalin, can be made antioxidant and use in prior art.

Butyrate clevidipine is easily degraded, and its degradation pathway is as follows:

Butyrate clevidipine is easily hydrolyzed formation impurity A, and impurity A structural formula is such as formula shown in (II):

Impurity A decarboxylation can form impurity B further, and impurity B structure is such as formula shown in (III):

Data disclosed in prior art CN102186351A, the content of impurity A is 0.3 ~ 1.2%, and the content 0.3 ~ 0.6% of impurity B, therefore needs to prepare a kind of more stable Clevidipine butyrate fat emulsion injection, to overcome above-mentioned shortcoming.

Do not mention the content of PHOSPHATIDYL ETHANOLAMINE in prior art, also do not provide technology enlightenment, what impact is the quality of PHOSPHATIDYL ETHANOLAMINE on this product have.The shortcoming that the impurity that we exist for prior art is too high, further studies, and unexpected discovery, PHOSPHATIDYL ETHANOLAMINE and butyrate clevidipine weight ratio are lower than 1.6, and the content of sterilizing rear impurity B is more than 0.2%.PHOSPHATIDYL ETHANOLAMINE and butyrate clevidipine weight ratio, higher than 4.8, can cause Impurity A content to enlarge markedly.Owing to there is a hydrolysising balance between butyrate clevidipine and impurity A, also there is a chemical equilibrium between impurity A and impurity B, therefore, no matter the content of impurity A or impurity B changes, and the amount of another kind of impurity all can be caused to change.Compared with existing butyrate clevidipine and preparation thereof, the Clevidipine butyrate fat emulsion injection prepared by the present invention, reduces the content of impurity A and B, decreases safety risks.

Summary of the invention

Technical problem to be solved by this invention overcomes the above-mentioned defect existed in prior art, provides a kind of more stable Clevidipine butyrate fat emulsion injection and preparation method thereof.

Technical scheme of the present invention is as follows:

A kind of Clevidipine butyrate fat emulsion injection, containing butyrate clevidipine, oil for injection, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, wherein, the weight portion of butyrate clevidipine is 1, the weight portion of oil for injection is 200 ~ 400, and phosphatidylcholine weight portion is 12 ~ 36, and the weight portion of PHOSPHATIDYL ETHANOLAMINE is 1.6 ~ 4.8.The weight portion of PHOSPHATIDYL ETHANOLAMINE is preferably 2.4 ~ 4.0, and more preferably 3.0 ~ 4.0.

Above-mentioned Clevidipine butyrate fat emulsion injection contains oleic acid, and the weight portion of oleic acid is 0.6 ~ 4.8, and preferably 1.2 ~ 2.4.

Above-mentioned Clevidipine butyrate fat emulsion injection contains glycerol, and glycerin weight part is 40 ~ 50.

Above-mentioned Clevidipine butyrate fat emulsion injection contains disodium edetate, and disodium edetate weight portion is 0.1 ~ 0.2.

Described grease separation autofining soybean oil, Oleum Arachidis hypogaeae semen, safflower oil, Oleum Gossypii semen, olive oil, Oleum Cocois, Oleum Sesami, fish oil, medium chain mono, medium chain triglyceride dibasic acid esters, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propylene glycol dibasic acid esters, glyceryl linoleate, Polyethylene Glycol glyceryl laurate ester or its combination.Be preferably soybean oil and medium chain triglyceride compositions, both weight ratios are 1: 1, and the weight portion of oil is 200.

The preparation method of described Clevidipine butyrate fat emulsion injection, it comprises the following steps:

(1) preparation of oil phase: add butyrate clevidipine in oil, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, stirs and makes it dissolve, as oil phase;

(2) preparation of colostrum: step (1) oil phase is added to the water, high speed shear is disperseed, and forms colostrum;

(3) high-pressure homogenising: step (2) colostrum is high-pressure homogenising, obtains smart breast;

(4) embedding, sterilizing, to obtain final product.

The preparation method of described Emulsion, wherein, comprises the following steps:

(1) preparation of oil phase: add butyrate clevidipine respectively in oil, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, oleic acid, stirs and makes it dissolve, as oil phase;

(2) preparation of colostrum: added by step (1) oil phase in the water containing glycerol and disodium edetate, high speed shear is disperseed, and forms colostrum;

(3) high-pressure homogenising: step (2) colostrum is high-pressure homogenising, obtains smart breast;

(4) embedding, sterilizing, to obtain final product.

The mixture that phosphatidylcholine and PHOSPHATIDYL ETHANOLAMINE feed postition also can adopt certain proportion to form adds.

Specific embodiment

Embodiment 1

Prescription:

Prescription	1	2	3	4
					Butyrate clevidipine raw material	0.5g	0.5g	0.5g	0.5g
Phosphatidylcholine	10g	10g	10g	10g
					PHOSPHATIDYL ETHANOLAMINE	0.8g	1.6g	2.4g	3.2g
Soybean oil	200g	200g	200g	200g
					Oleic acid	0.3g	0.3g	0.3g	0.3g
Glycerol	22.5g	22.5g	22.5g	22.5g
					Water for injection adds to	1000ml	1000ml	1000ml	1000ml

Technique:

(1) preparation of aqueous phase: glycerol is added to the water dissolving, is heated to 75 DEG C, for subsequent use;

(2) preparation of oil phase: refined soybean oil is heated to 75 DEG C, adds butyrate clevidipine, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, oleic acid, stirs and makes it dissolve;

(3) preparation of colostrum: step (2) oil phase is added in step (1) aqueous phase, temperature 75 DEG C, high speed shear is disperseed, shear rate 10000rpm, 15 minutes time, forms colostrum;

(4) high-pressure homogenising: by step (3) colostrum through microjet instrument high-pressure homogenising 2 times, pressure 1000bar;

(5) filter: by obtained for step (4) Emulsion through 0.8 μm of filtering with microporous membrane, embedding, obtains butyrate clevidipine injection;

(6) 122 ± 1 DEG C of sterilizings 8 minutes.

Impurity determination:

Chromatographic condition: octadecylsilane chemically bonded silica is filler; 0.05mol/L sodium dihydrogen phosphate (phosphoric acid,diluted adjust ph to 4.0)-acetonitrile-methanol (40: 20: 40) is mobile phase; Flow velocity: 1.0ml per minute; Column temperature 40 DEG C; Determined wavelength 220nm.

Measurement result:

Prescription	1	2	3	4
					Impurity A content (%)	0.16	0.06	0.17	0.36
Impurity B content (%)	0.18	0.07	0.13	0.21

Data disclosed in CN102186351A, the content of impurity A 0.7%, the content 0.3% of impurity B.According to the requirement of ICH guideline and the maximum clinical use amount of this kind, the single contaminant limit of this kind should lower than 0.2%, and the weight ratio therefore selecting PHOSPHATIDYL ETHANOLAMINE and butyrate clevidipine is 1.6 ~ 4.8.

Embodiment 2

Prescription:

Prescription	5	6
			Butyrate clevidipine raw material	0.5g	0.5g
Phosphatidylcholine	10g	10g
			PHOSPHATIDYL ETHANOLAMINE	1.2g	2.0g
Exquisite soybean oil	50g	50g
			Medium chain triglyceride	50g	50g
Oleic acid	0.9g	0.9g
			Glycerol	25g	25g
Disodium edetate	0.05g	0.05g
			Water for injection adds to	1000ml	1000ml

Technique:

(1) preparation of aqueous phase: by disodium edetate, glycerol is added to the water dissolving, is heated to 65 DEG C, for subsequent use;

(2) preparation of oil phase: refined soybean oil and midchain oil are heated to 65 DEG C, add butyrate clevidipine, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, oleic acid, stirs and makes it dissolve;

(3) preparation of colostrum: step (2) oil phase is added in step (1) aqueous phase, temperature 65 DEG C, high speed shear is disperseed, shear rate 10000rpm, 15 minutes time, forms colostrum;

(4) high-pressure homogenising: by step (3) colostrum through microjet instrument high-pressure homogenising 3 times, pressure 700bar;

(5) filter: by obtained for step (4) Emulsion through 0.8 μm of filtering with microporous membrane, embedding, obtains butyrate clevidipine injection;

(6) 122 ± 1 DEG C of sterilizings 8 minutes.

Impurity determination:

Chromatographic condition: octadecylsilane chemically bonded silica is filler; 0.05mol/L sodium dihydrogen phosphate (phosphoric acid,diluted adjust ph to 4.0)-acetonitrile-methanol (40: 20: 40) is mobile phase; Flow velocity: 1.0ml per minute; Column temperature 40 DEG C; Determined wavelength 220nm.

Measurement result:

Prescription	5	6
			Impurity A content (%)	0.13	0.08
Impurity B content (%)	0.12	0.08

Claims (9)

1. a Clevidipine butyrate fat emulsion injection, containing butyrate clevidipine, oil for injection, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, is characterized in that, the weight portion of butyrate clevidipine is 1, the weight portion of oil for injection is 200 ~ 400, and phosphatidylcholine weight portion is 12 ~ 36, and the weight portion of PHOSPHATIDYL ETHANOLAMINE is 1.6 ~ 4.8.

2. Clevidipine butyrate fat emulsion injection according to claim 1, is characterized in that, the weight portion of PHOSPHATIDYL ETHANOLAMINE is 2.4 ~ 4.0.

3. Clevidipine butyrate fat emulsion injection according to claim 2, is characterized in that, the weight portion of PHOSPHATIDYL ETHANOLAMINE is 3.2 ~ 4.0.

4. Clevidipine butyrate fat emulsion injection according to claim 3, it is characterized in that, containing oleic acid, the weight portion of oleic acid is 0.6 ~ 4.8.

5. Clevidipine butyrate fat emulsion injection according to claim 4, it is characterized in that, the weight portion of oleic acid is 1.2 ~ 2.4.

6. Clevidipine butyrate fat emulsion injection according to claim 1; it is characterized in that, described oil for injection is selected from refined soybean oil, Oleum Arachidis hypogaeae semen, safflower oil, Oleum Gossypii semen, olive oil, Oleum Cocois, Oleum Sesami, fish oil, medium chain mono, medium chain triglyceride dibasic acid esters, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propylene glycol dibasic acid esters, glyceryl linoleate, Polyethylene Glycol glyceryl laurate ester or its combination.

7. Clevidipine butyrate fat emulsion injection according to claim 6, is characterized in that, described oil for injection weight portion is 200, is selected from refined soybean oil and medium chain triglyceride, and both weight ratios are 1: 1.

8. the arbitrary described Clevidipine butyrate fat emulsion injection preparation method of claims 1 to 3, it comprises the following steps:

(1) preparation of oil phase: add butyrate clevidipine in oil for injection, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, stirs and makes it dissolve, as oil phase;

(2) preparation of colostrum: step (1) oil phase is added to the water, high speed shear is disperseed, and forms colostrum;

(3) high-pressure homogenising: step (2) colostrum is high-pressure homogenising, obtains smart breast;

(4) embedding, sterilizing, to obtain final product.

9. the preparation method of Clevidipine butyrate fat emulsion injection according to claim 4, wherein, comprises the following steps:

(1) preparation of oil phase: add butyrate clevidipine respectively in oil for injection, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, oleic acid, stirs and makes it dissolve, as oil phase;

(2) preparation of colostrum: step (1) oil phase is added to the water, high speed shear is disperseed, and forms colostrum;

(3) high-pressure homogenising: step (2) colostrum is high-pressure homogenising, obtains smart breast;

(4) embedding, sterilizing, to obtain final product.