CN104706586A - Cleviprex fat emulsion concentrated solution, preparation method and application thereof - Google Patents
Cleviprex fat emulsion concentrated solution, preparation method and application thereof Download PDFInfo
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Abstract
A cleviprex fat emulsion concentrated solution, a preparation method and an application thereof belong to the field of pharmacology and pharmaceutics. According to the invention, the defect that a traditional fat emulsion preparation technology is complex and stability is poor is overcome. The preparation technology provided by the invention is simple; the general physical stirring process is only needed; and no homogenization technology is required. A product prepared in the invention can be sterilized through a 0.22-micron microfiltration membrane; in clinical use, the product can be spontaneously emulsified after diluted by the use of an aqueous solution such as normal saline or a glucose solution, etc. and slightly oscillated; and under optimized conditions, average particle size is about 0.2 micron, and injection fat emulsion characteristics are fully embodied. The product has good fluidity, will not be retained on the wall, is single-phase, transparent and clear in appearance, can undergo clarification detection and will not cause preparation stratification after multigelation. The product is used in blood pressure control during surgical operation and control of acute blood pressure elevation after operation, and also can be used in controlling blood pressure of hypertensives who are not suitable for oral administration or fail in oral administration.
Description
Technical field
The invention belongs to materia medica and pharmaceutical art, relate to a kind of butyrate clevidipine lipid fat breast concentrated solution, Preparation Method And The Use.
Background technology
Butyrate clevidipine (Clevidipine butyrate), it is the novel fugitive dihydropyridine calcium channel antagonist of the third generation developed by AstraZeneca company of Britain, in August, 2008 goes on the market in the U.S. first, trade name Cleviprex is first dihydropyridine calcium channel blocade used for intravenous injection.Cleviprex is injectable emulsion, rapid-action, and effect is eliminated also fast, accurately can control blood pressure by ascending-dose.Different through the antihypertensive of kidney and (or) hepatic metabolism from current many intravenous injections, its metabolism in blood and tissue, does not thus accumulate in vivo.Butyrate clevidipine is as a kind of intravenous injection antihypertensive, and represent the much progress in current hypertension management, it can control blood pressure quickly and accurately in critical care nursing.From the aggregate data display of emergency room, operating room and intensive care unit, the listing of butyrate clevidipine, provides new, important clinical means by when controlling patients' blood for doctor.
Cleviprex take fat milk as drug administration carrier (http://en.wikipedia.org/wiki/Clevidipine), butyrate clevidipine is dissolved in Semen sojae atricolor by system, and being wrapped in immobilized artificial membrane by phospholipid emulsification, to be encapsulated in mean diameter be in the milk-globule of 0.2 μm.Fat milk, also known as lipid microsphere, is a kind ofly be soft substrate with fatty oil and the microsome disperse system encapsulated by immobilized artificial membrane, thermodynamics and kinetics all belongs to Unstable Systems.
Fat milk contains the surfactants such as phospholipid, soybean oil, medium chain length fatty acid triglyceride (medium chain triglycerides, MCT) or Fructus Canarii albi wet goods fatty oil, glycerol, and a large amount of water, by preparing colostrum and after homogenizing, obtaining the lipid particles system of moderate in grain size.This is due to after the mixing of materials such as direct phospholipid, oil, water, oil-water separation phenomenon can be there is, only have these materials, through special homogenizer process, as high pressure homogenizer, emulsion (Hiroko Shibata, et al. (2009) the Int. J. Pharm. 378:167-176 of stable uniform could be formed; Dirk L. Teagarden, et al.(1996) Adv. Drug. Deliv. Rev. 20:155-164).In homogenizing process, material is subject to dither, hole, shearing, and the coordinative role such as impact, is finally broken up or be refined as the insoluble phase granule in liquid.Therefore, in fat milk preparation process, need strictly to control parameters such as the shear rate in colostrum, homogenization, temperature, homogenization pressure and cycle-indexes, take time and effort, considerably increase production cost.
The fat milks such as Cleviprex, Diprivan are rendered as opaque milkiness liquid (http://www.apsf.org/newsletters/html/2012/winter/14propofol.htm) in outward appearance, if because of preserve improper and there is the phenomenons such as flocculation, cohesion time can not get rid of in time.This type of preparation can not carry out clarity detection, and clarity detection is injection essential items for inspection, brings hidden danger thus to drug safety.Further, existing fat milk needs Special Equipment under high pressure sterilizing.
A desirable butyrate clevidipine ejection preparation is the characteristic that can keep lipid microsphere, has that preparation stability is high, appearance transparent is limpid, technique is simple, without the need to special installation, to lower preparation cost simultaneously.
Summary of the invention
The present inventor is through deep research and performing creative labour, obtain a kind of butyrate clevidipine lipid fat breast concentrated solution, the present inventor is surprised to find, butyrate clevidipine lipid fat breast concentrated solution of the present invention, after mixing with water, without homogenizing means, stable emulsion can be formed, can effectively overcome Oil-water separation phenomenon.And the preparation lamination that product of the present invention can effectively overcome the density contrast between different auxiliary material and bring, obtain single-phase, transparent, stable thus, meeting after water can the butyrate clevidipine lipid fat breast concentrated solution, particularly a kind of injection butyrate clevidipine lipid fat breast concentrated solution of spontaneous emulsification.Thus provide following invention:
One aspect of the present invention relates to a kind of butyrate clevidipine lipid fat breast concentrated solution, and it comprises the butyrate clevidipine as principal agent, and oil for injection, cosolvent, low hlb surfactant and high hlb surfactant.
Butyrate clevidipine lipid fat breast concentrated solution according to any one of the present invention, is characterized in that any one in the item of following (1)-(4) or multinomial:
(1) in described injection grease separation soybean oil, safflower oil, olive oil, fish oil and medium chain fatty acid ester any one or multiple; Preferably, described oil for injection is soybean oil and/or medium chain fatty acid ester; Particularly, described medium chain fatty acid ester is medium chain length fatty acid triglyceride and/or Medium chain fatty acid propylene glycol ester; Preferably, described medium chain fatty acid ester is medium chain length fatty acid triglyceride;
(2) described cosolvent be selected from propylene glycol, glycerol and PEG400 one or more; Preferably, described cosolvent comprises propylene glycol, alternatively, also comprise be selected from glycerol and PEG400 one or more; Particularly, described propylene glycol is 1,2-PD;
(3) described low hlb surfactant is the surfactant of 4≤HLB≤9; Particularly, it is selected from one or more in phospholipid, polyglycerol acrylate, span 20, sorbester p18, sorbester p17 and polyglycereol-6-dioleate; Preferably, described low hlb surfactant comprises phospholipid, alternatively, its also comprise be selected from polyglycerol acrylate and sorbester p17 one or more; Particularly, described phospholipid is soybean lecithin and/or Ovum Gallus domesticus Flavus lecithin; Preferably, be soybean lecithin;
(4) described high hlb surfactant is the non-ionic surface active agent of HLB >=12; Particularly, it is selected from one or more in polysorbas20, Tween 80, tocopherol polyethyleneglycol succinate, polyoxyethylene ether (35) Oleum Ricini, polyoxyethylene ether (40) castor oil hydrogenated, Gelucire 44/14, Polyethylene Glycol caprylic/capric glyceride, polyethyleneglycol-12-hydroxy stearin; Preferably, described high hlb surfactant comprises polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini, and alternatively, it also comprises Tween 80 and/or tocopherol polyethyleneglycol succinate.
The present invention relates to a kind of butyrate clevidipine lipid fat breast concentrated solution, it comprises:
Principal agent: butyrate clevidipine,
Oil for injection: soybean oil,
Cosolvent: 1,2-PD,
Low hlb surfactant: phospholipid, and
High hlb surfactant: polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini;
Alternatively, described oil also comprises medium chain length fatty acid triglyceride;
Alternatively, described low hlb surfactant also comprises polyglycerol acrylate;
Alternatively, described high hlb surfactant also comprises Tween 80.
Butyrate clevidipine lipid fat breast concentrated solution according to any one of the present invention, is characterized in that any one in the item of following (1)-(5) or multinomial:
(1) content of described butyrate clevidipine is 0.1-1%(w/w); Be preferably 0.15-0.5%(w/w);
(2) content of described oil for injection is 45-85%(w/w); Be preferably 45-70%(w/w);
(3) content of described cosolvent is 5-30%(w/w); Be preferably 7-21%(w/w);
(4) content of described low hlb surfactant is 7.5%-17%(w/w);
(5) content of described high hlb surfactant is 8%-25%(w/w).
Butyrate clevidipine lipid fat breast concentrated solution according to any one of the present invention, is characterized in that any one in the item of following (1)-(9) or multinomial:
(1) content of described butyrate clevidipine is 0.15-0.5%(w/w), be preferably 0.2-0.35%(w/w);
(2) content of described soybean oil is 5-60%, is preferably 5-50%;
(3) content of described medium chain length fatty acid triglyceride is 0%-80%, is preferably 0%-65%;
(4) content of described 1,2-PD is 5%-15%, is preferably 7%-10%;
(5) content of described phospholipid is 5%-15%, is preferably 7%-13%;
(6) content of described polyglycerol acrylate is 0-8%, is preferably 0-5%;
(7) content of described polyethyleneglycol-12-hydroxy stearin is 0-20%, is preferably 0-15%;
(8) content of described polyoxyethylene ether (35) Oleum Ricini is 0-20%;
(9) content of described Tween 80 is 0-20%, is preferably 0-15%.
Butyrate clevidipine lipid fat breast concentrated solution according to any one of the present invention, is characterized in that any one in the item of following (1)-(7) or multinomial:
(1) the not moisture or water content of described butyrate clevidipine lipid fat breast concentrated solution is lower than 1%;
(2) described butyrate clevidipine lipid fat breast concentrated solution is not containing saccharide;
(3) the unambiguous essence of described butyrate clevidipine lipid fat breast concentrated solution;
(4) described butyrate clevidipine lipid fat breast concentrated solution its preparation method does not comprise removing or falls low-moisture step (such as rotary evaporation, spraying dry or lyophilization);
(5) alternatively, described butyrate clevidipine lipid fat breast concentrated solution also comprises antioxidant; Particularly, described antioxidant be selected from oleic acid, enuatrol, vitamin E and vitamin A any one or multiple;
(6) described butyrate clevidipine lipid fat breast concentrated solution is transparent, single phase soln;
(7) described butyrate clevidipine lipid fat breast concentrated solution adopts 0.22 μm of microporous filter membrane mode degerming.
Butyrate clevidipine lipid fat breast concentrated solution according to any one of the present invention, its component and content are as below 1)-4) shown in group any one group:
1）
Butyrate clevidipine 0.2-0.35 gram
Soybean oil 5-30 grams
MCT Oil (Crodamol GTCC) 30-65 grams
1,2-PD 6-12 grams
Soybean lecithin (Epikuron 170, Degussa) 7-12 grams
Polyglycerol acrylate 0-5 gram
Tween 80 4-10 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 6-15 grams
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin A 0-3 gram
Vitamin E 0-3 gram;
2）
Butyrate clevidipine 0.2-0.35 gram
Soybean oil 20-45 grams
Miglyol 812 (Miglyol 812, SASOL) 20-45 grams
1,2-PD 6-14 grams
Soybean lecithin (Epikuron 170, Degussa) 7-13 grams
Polyglycerol acrylate 0-5 gram
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 5-15 grams
Tween 80 3-8 grams
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin A 0-3 gram
Vitamin E 0-3 gram;
3）
Butyrate clevidipine 0.2-0.35 gram
Soybean oil 35-50 grams
Miglyol 812 (Miglyol 812, SASOL) 0 – 15 grams
1,2-PD 6-14 grams
Soybean lecithin (Epikuron 170, Degussa) 7-13 grams
Polyglycerol acrylate 0-3 gram
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 5-15 grams
Tween 80 2-11 grams
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin A 0-3 gram
Vitamin E 0-3 gram;
4）
Butyrate clevidipine 0.2-0.35 gram
Soybean oil 25-45 gram
Miglyol 812 (Miglyol 812, SASOL) 5-45 grams
1,2-PD 6-14 grams
Soybean lecithin (Epikuron 170, Degussa) 7-13 gram
Refining polyoxyethylene ether (35) Oleum Ricini (Cremophor ELP, BASF) 10-20 gram
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin A 0-3 gram
Vitamin E 0-3 gram.
Butyrate clevidipine lipid fat breast concentrated solution according to any one of the present invention, its component and content are as shown in any a group in (1) below-(4) group:
（1）
Butyrate clevidipine 0.35 gram
Soybean oil 5 grams
MCT Oil (Crodamol GTCC) 65 grams
1,2-PD 8.5 grams
Soybean lecithin (Epikuron 170, Degussa) 8 grams
Tween 80 4.3 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 8.5 grams
Vitamin E 0.35 gram;
（2）
Butyrate clevidipine 0.25 gram
Soybean oil 30.5 grams
Miglyol 812 (Miglyol 812, SASOL) 30.5 grams
1,2-PD 7.3 grams
Soybean lecithin (Epikuron 170, Degussa) 11.5 grams
Polyglycerol acrylate 4 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 11.5 grams
Tween 80 4 grams
Vitamin E 0.3 gram
Oleic acid 0.15 gram;
（3）
Butyrate clevidipine 0.3 gram
Soybean oil 50 grams
1,2-PD 9.5 grams
Soybean lecithin (Epikuron 170, Degussa) 12.5 grams
Polyglycerol acrylate 3 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 13.5 grams
Tween 80 10.5 grams
Vitamin E 0.35 gram
Oleic acid 0.35 gram;
（4）
Butyrate clevidipine 0.2 gram
Soybean oil 31 grams
Miglyol 812 (Miglyol 812, SASOL) 31 grams
1,2-PD 9.5 grams
Soybean lecithin (Epikuron 170, Degussa) 12.5 grams
Refining polyoxyethylene ether (35) Oleum Ricini (Cremophor ELP, BASF) 15.5 grams
Vitamin E 0.15 gram
Enuatrol 0.15 gram.
It should be noted that; above-mentioned 1) unit of gram-4) in group or (1)-(4) group represents the ratio between each component, if be revised as other unit of weight, includes but not limited to; such as kilogram and milligram etc., also all within protection scope of the present invention.
Another aspect of the invention relates to a kind of injection butyrate clevidipine lipid fat breast, and its butyrate clevidipine lipid fat breast concentrated solution according to any one of the present invention adds water or aqueous solution self emulsifying obtains; Particularly, described injection butyrate clevidipine lipid fat breast mean diameter is 0.05-0.7 μm; Be preferably 0.1-0.4 μm; More preferably, be 0.17-0.23 μm.
After butyrate clevidipine lipid fat breast concentrated solution of the present invention meets water dilution, can spontaneous emulsification be the butyrate clevidipine lipid fat breast meeting injection requirement.
Another aspect of the invention relates to the preparation method of the butyrate clevidipine lipid fat breast concentrated solution according to any one of the present invention, comprises the steps:
1) at 20-45 DEG C, low hlb surfactant is added oil, under 2000-20000rpm condition, be stirred to and form transparent clear solution;
2) under 20-45 DEG C of condition, butyrate clevidipine is added step 1) product, and under 200-2000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 20-45 DEG C of condition, cosolvent, high hlb surfactant and optional antioxidant are added step 2) product, and under 200-800rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition butyrate clevidipine lipid fat breast concentrated solution.
About step 1) or step 2) or step 3) in the oil, low hlb surfactant, high hlb surfactant and the cosolvent that use, wherein moisture will lower than 1%, or do not have free water.
Product in step 3), without removing or low-moisture step (such as rotary evaporation, spraying dry or lyophilization) is fallen, water content is lower than 1%(by weight percentage).
Another aspect of the invention relate to according to any one of the present invention butyrate clevidipine lipid fat breast concentrated solution or injection butyrate clevidipine lipid fat of the present invention breast, when treating surgical operation, controlling of blood pressure and postoperative acute blood pressure raise, and also can be used for the clinical applications such as unsuitable oral or oral invalid hyperpietic's controlling of blood pressure.
The explanation of the part term that the present invention relates to:
Fat milk, refers to also known as lipid microsphere, and after emulsion or the emulsifying of fat milk concentrated solution, the one of formation is soft substrate with fatty oil and is encapsulated by immobilized artificial membrane, and mean diameter is the microparticulate system of about 0.2 μm.
In the present invention, for the percentage ratio of the content of each component, if not otherwise specified, the percentage by weight (w/w) accounting for pharmaceutical composition gross weight is all referred to.
The beneficial effect of the invention
Good product mobility of the present invention, not wall built-up, outward appearance is single-phase, transparent, limpid shape, can accept clarity and detect, after multigelation, preparation lamination can not occur; Product of the present invention is met water and is formed in butyrate clevidipine lipid fat breast plant process, without the need to homogenizing process, only need slight oscillatory can spontaneous emulsification, during Clinical practice after the dilution of the aqueous solution such as normal saline or glucose solution also slight oscillatory, can spontaneous emulsification be the fat milk system meeting injection requirement, under optimum condition, after emulsifying, mean diameter is at 0.2 μm, and particle size distribution is narrow and small fully demonstrates injection fat milk characteristic.
Preparation technology of the present invention is simple, only needs General Physics whipping process, does not need homogenization, do not need dewatering process, and butyrate clevidipine lipid fat breast concentrated solution prepared by the present invention, can be degerming by 0.22 μm of microporous filter membrane, and convenient drug administration, safety is high.The present invention has that preparation technology is simple, low production cost, is easy to the advantage of transporting, storing, has application prospect.
Detailed description of the invention
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturer suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
embodiment 1: the preparation of butyrate clevidipine lipid fat breast concentrated solution sample 1
Its constituent is as follows:
Butyrate clevidipine 0.35 gram
Soybean oil 5 grams
MCT Oil (Crodamol GTCC) 65 grams
1,2-PD 8.5 grams
Soybean lecithin (Epikuron 170, Degussa) 8 grams
Tween 80 4.3 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 8.5 grams
Vitamin E 0.35 gram
This butyrate clevidipine lipid fat breast concentrated solution preparation method is as follows:
1) under 45 DEG C of conditions, after the soybean lecithin of above-mentioned weight, soybean oil are mixed with MCT Oil, under 8000rpm condition, be stirred to and form transparent clear solution;
2), under 20 DEG C of conditions, above-mentioned weight butyrate clevidipine is added 1) product, and under 200rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 25 DEG C of conditions, by 1 of above-mentioned weight, 2-propylene glycol, Tween 80, polyethyleneglycol-12-hydroxy stearin, vitamin E add step 2) in product, and under 200rpm stirring condition Keep agitation, to forming homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition butyrate clevidipine lipid fat breast concentrated solution.
embodiment 2: the preparation of butyrate clevidipine lipid fat breast concentrated solution sample 2
Its constituent is as follows:
Butyrate clevidipine 0.25 gram
Soybean oil 30.5 grams
Miglyol 812 (Miglyol 812, SASOL) 30.5 grams
1,2-PD 7.3 grams
Soybean lecithin (Epikuron 170, Degussa) 11.5 grams
Polyglycerol acrylate 4 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 11.5 grams
Tween 80 4 grams
Vitamin E 0.3 gram
Oleic acid 0.15 gram
This butyrate clevidipine lipid fat breast concentrated solution preparation method is as follows:
1) under 20 DEG C of conditions, after the soybean lecithin of above-mentioned weight, polyglycerol acrylate are mixed with Miglyol 812 and soybean oil, under 20000rpm condition, be stirred to and form transparent clear solution;
2), under 45 DEG C of conditions, above-mentioned weight butyrate clevidipine is added 1) product, and under 1000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 45 DEG C of conditions, by 1 of above-mentioned weight, 2-propylene glycol, polyethyleneglycol-12-hydroxy stearin, Tween 80, vitamin E, oleic acid add step 2) in product, and under 800rpm stirring condition Keep agitation, to forming homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition butyrate clevidipine lipid fat breast concentrated solution.
embodiment 3: the preparation of butyrate clevidipine lipid fat breast concentrated solution sample 3
Its constituent is as follows:
Butyrate clevidipine 0.3 gram
Soybean oil 50 grams
1,2-PD 9.5 grams
Soybean lecithin (Epikuron 170, Degussa) 12.5 grams
Polyglycerol acrylate 3 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 13.5 grams
Tween 80 10.5 grams
Vitamin E 0.35 gram
Oleic acid 0.35 gram
This butyrate clevidipine lipid fat breast concentrated solution preparation method is as follows:
1) under 25 DEG C of conditions, after the Semen sojae atricolor ovum phosphorus of above-mentioned weight, polyglycerol acrylate are mixed with soybean oil, under 2000rpm condition, be stirred to and form transparent clear solution;
2), under 30 DEG C of conditions, above-mentioned weight butyrate clevidipine is added 1) product, and under 2000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 20 DEG C of conditions, by 1 of above-mentioned weight, 2-propylene glycol, polyethyleneglycol-12-hydroxy stearin, Tween 80, vitamin E add step 2) in product, and under 600rpm stirring condition Keep agitation, to forming homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition butyrate clevidipine lipid fat breast concentrated solution.
embodiment 4: the preparation of butyrate clevidipine lipid fat breast concentrated solution sample 4
Its constituent is as follows:
Butyrate clevidipine 0.2 gram
Soybean oil 31 grams
Miglyol 812 (Miglyol 812, SASOL) 31 grams
1,2-PD 9.5 grams
Soybean lecithin (Epikuron 170, Degussa) 12.5 grams
Refining polyoxyethylene ether (35) Oleum Ricini (Cremophor ELP, BASF) 15.5 grams
Vitamin E 0.15 gram
Enuatrol 0.15 gram
This butyrate clevidipine lipid fat breast concentrated solution preparation method is as follows:
1) under 25 DEG C of conditions, after the soybean lecithin of above-mentioned weight is mixed with Miglyol 812, soybean oil, under 12000rpm condition, be stirred to and form transparent clear solution;
2), under 25 DEG C of conditions, above-mentioned weight butyrate clevidipine is added 1) product, and under 1500rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 25 DEG C of conditions, by 1 of above-mentioned weight, 2-propylene glycol, PEG400, refining polyoxyethylene ether (35) Oleum Ricini, vitamin E, enuatrol add step 2) in product, and under 500rpm stirring condition Keep agitation, to forming homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition butyrate clevidipine lipid fat breast concentrated solution.
embodiment 5: spectrodensitometry is tested
With Hitachi U-2001 ultraviolet-uisible spectrophotometer, at ambient temperature, 600nm place measures optical density.Wherein butyrate clevidipine lipid fat breast concentrated solution is the sample 1-4 according to embodiment 1-4 preparation process gained, and select commercially available prod Cleviprex in contrast, result is as shown in table 1.
Table 1: the optical density value of different sample solution
| Sample | 1 | 2 | 3 | 4 | Cleviprex? |
| Optical density | 0.001 | 0.007 | -0.001 | -0.002 | 2.163 |
Optical density represents the permeability of light, and numerical value is lower, shows that sample is more clarified homogeneous, and from result, product appearance of the present invention is homogeneous, limpid, transparent.
embodiment 6: stability test
Sample 1-4 prepared by embodiment 1-4, reference substance is commercially available prod Cleviprex.
Experimental technique: by different sample after-20 DEG C of freeze overnight, is positioned over 20 DEG C and naturally thaws, and multigelation like this 6 times, observe sample appearance under environmental condition, result of the test is in table 2.
Table 2: different sample is after freeze thawing, and sample appearance changes
| Sample | Cosmetic variation |
| 1 | Outward appearance is clarified, not stratified, not wall built-up, good fluidity |
| 2 | Outward appearance is clarified, not stratified, not wall built-up, good fluidity |
| 3 | Outward appearance is clarified, not stratified, not wall built-up, good fluidity |
| 4 | Outward appearance is clarified, not stratified, not wall built-up, good fluidity |
| Cleviprex? | Oil-water stratification, wall built-up is serious |
From table 2, sample 1-4 all has fabulous stability, and through multigelation, outward appearance still can keep transparent homogeneous phase, not wall built-up, not stratified, has good mobility.
embodiment 7: particle size determination
Sample 1-4 prepared by embodiment of the present invention 1-4, adopt Mastersizer 2000 Particle Size Analyzer to detect particle diameter, sample adds the normal saline of 10 times of volumes, measures after slight oscillatory spontaneous emulsification.
Table 3: particle size distribution after different sample emulsifying
Note: d(0.1) represent that the cumulative particle sizes distribution number of sample is the particle diameter of 10% correspondence, d(0.5), d(0.9), d(1) the rest may be inferred.
Its particle size distribution is as shown in table 3, the particle size distribution of four embodiments between 0.1-0.5 μm, mean diameter about 0.2 μm, the d(0.9 of four embodiment products) be all less than 0.6 μm, meet injection fat milk Particle size requirements.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various amendment and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (10)
1. a butyrate clevidipine lipid fat breast concentrated solution, it comprises the butyrate clevidipine as principal agent, and oil for injection, cosolvent, low hlb surfactant and high hlb surfactant.
2. pharmaceutical composition according to claim 1, is characterized in that any one in the item of following (1)-(4) or multinomial:
(1) in described injection grease separation soybean oil, safflower oil, olive oil, fish oil and medium chain fatty acid ester any one or multiple; Preferably, described oil for injection is soybean oil and/or medium chain fatty acid ester; Particularly, described medium chain fatty acid ester is medium chain length fatty acid triglyceride and/or Medium chain fatty acid propylene glycol ester; Preferably, described medium chain fatty acid ester is medium chain length fatty acid triglyceride;
(2) described cosolvent be selected from propylene glycol, glycerol and PEG400 one or more; Preferably, described cosolvent comprises propylene glycol, alternatively, also comprise be selected from glycerol and PEG400 one or more; Particularly, described propylene glycol is 1,2-PD;
(3) described low hlb surfactant is the surfactant of 4≤HLB≤9; Particularly, it is selected from one or more in phospholipid, polyglycerol acrylate, span 20, sorbester p18, sorbester p17 and polyglycereol-6-dioleate; Preferably, described low hlb surfactant comprises phospholipid, alternatively, its also comprise be selected from polyglycerol acrylate and sorbester p17 one or more; Particularly, described phospholipid is soybean lecithin and/or Ovum Gallus domesticus Flavus lecithin; Preferably, be soybean lecithin;
(4) described high hlb surfactant is the non-ionic surface active agent of HLB >=12; Particularly, it is selected from one or more in polysorbas20, Tween 80, tocopherol polyethyleneglycol succinate, polyoxyethylene ether (35) Oleum Ricini, polyoxyethylene ether (40) castor oil hydrogenated, Gelucire 44/14, Polyethylene Glycol caprylic/capric glyceride, polyethyleneglycol-12-hydroxy stearin; Preferably, described high hlb surfactant comprises polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini, and alternatively, it also comprises Tween 80 and/or tocopherol polyethyleneglycol succinate.
3. a butyrate clevidipine lipid fat breast concentrated solution, it comprises:
Principal agent: butyrate clevidipine,
Oil for injection: soybean oil,
Cosolvent: 1,2-PD,
Low hlb surfactant: phospholipid, and
High hlb surfactant: polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini;
Alternatively, described oil also comprises medium chain length fatty acid triglyceride;
Alternatively, described low hlb surfactant also comprises polyglycerol acrylate;
Alternatively, described high hlb surfactant also comprises Tween 80.
4. pharmaceutical composition according to any one of claim 1 to 3, is characterized in that any one in the item of following (1)-(5) or multinomial:
(1) content of described butyrate clevidipine is 0.1-1%(w/w); Be preferably 0.15-0.5%(w/w);
(2) content of described oil for injection is 45-85%(w/w); Be preferably 45-70%(w/w);
(3) content of described cosolvent is 5-30%(w/w); Be preferably 7-21%(w/w);
(4) content of described low hlb surfactant is 7.5%-17%(w/w);
(5) content of described high hlb surfactant is 8%-25%(w/w).
5. the pharmaceutical composition according to claim 3 or 4, is characterized in that any one in the item of following (1)-(9) or multinomial:
(1) content of described butyrate clevidipine is 0.15-0.5%(w/w), be preferably 0.2-0.35%(w/w);
(2) content of described soybean oil is 5-60%, is preferably 5-50%;
(3) content of described medium chain length fatty acid triglyceride is 0%-80%, is preferably 0%-65%;
(4) content of described 1,2-PD is 5%-15%, is preferably 7%-10%;
(5) content of described phospholipid is 5%-15%, is preferably 7%-13%;
(6) content of described polyglycerol acrylate is 0-8%, is preferably 0-5%;
(7) content of described polyethyleneglycol-12-hydroxy stearin is 0-20%, is preferably 0-15%;
(8) content of described polyoxyethylene ether (35) Oleum Ricini is 0-20%;
(9) content of described Tween 80 is 0-20%, is preferably 0-15%.
6. pharmaceutical composition according to any one of claim 1 to 5, is characterized in that any one in the item of following (1)-(7) or multinomial:
(1) the not moisture or water content of described butyrate clevidipine lipid fat breast concentrated solution is lower than 1%;
(2) described butyrate clevidipine lipid fat breast concentrated solution is not containing saccharide;
(3) the unambiguous essence of described butyrate clevidipine lipid fat breast concentrated solution;
(4) described butyrate clevidipine lipid fat breast concentrated solution its preparation method does not comprise removing or falls low-moisture step (such as rotary evaporation, spraying dry or lyophilization);
(5) alternatively, described butyrate clevidipine lipid fat breast concentrated solution also comprises antioxidant; Particularly, described antioxidant be selected from oleic acid, enuatrol, vitamin E and vitamin A any one or multiple;
(6) described butyrate clevidipine lipid fat breast concentrated solution is transparent, single phase soln;
(7) described butyrate clevidipine lipid fat breast concentrated solution adopts 0.22 μm of microporous filter membrane mode degerming.
7. a butyrate clevidipine lipid fat breast concentrated solution, its component and content are as 1 below)-4) shown in group any one group:
1）
Butyrate clevidipine 0.2-0.35 gram
Soybean oil 5-30 grams
MCT Oil (Crodamol GTCC) 30-65 grams
1,2-PD 6-12 grams
Soybean lecithin (Epikuron 170, Degussa) 7-12 grams
Polyglycerol acrylate 0-5 gram
Tween 80 4-10 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 6-15 grams
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin A 0-3 gram
Vitamin E 0-3 gram;
2）
Butyrate clevidipine 0.2-0.35 gram
Soybean oil 20-45 grams
Miglyol 812 (Miglyol 812, SASOL) 20-45 grams
1,2-PD 6-14 grams
Soybean lecithin (Epikuron 170, Degussa) 7-13 grams
Polyglycerol acrylate 0-5 gram
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 5-15 grams
Tween 80 3-8 grams
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin A 0-3 gram
Vitamin E 0-3 gram;
3）
Butyrate clevidipine 0.2-0.35 gram
Soybean oil 35-50 grams
Miglyol 812 (Miglyol 812, SASOL) 0 – 15 grams
1,2-PD 6-14 grams
Soybean lecithin (Epikuron 170, Degussa) 7-13 grams
Polyglycerol acrylate 0-3 gram
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 5-15 grams
Tween 80 2-11 grams
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin A 0-3 gram
Vitamin E 0-3 gram;
4）
Butyrate clevidipine 0.2-0.35 gram
Soybean oil 25-45 gram
Miglyol 812 (Miglyol 812, SASOL) 5-45 grams
1,2-PD 6-14 grams
Soybean lecithin (Epikuron 170, Degussa) 7-13 gram
Refining polyoxyethylene ether (35) Oleum Ricini (Cremophor ELP, BASF) 10-20 gram
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin A 0-3 gram
Vitamin E 0-3 gram.
8. injection butyrate clevidipine lipid fat breast, its butyrate clevidipine lipid fat breast concentrated solution according to any one of claim 1 to 7 adds water or aqueous solution self emulsifying obtains; Particularly, described injection butyrate clevidipine lipid fat breast mean diameter is 0.05-0.7 μm; Be preferably 0.1-0.4 μm; More preferably, be 0.17-0.23 μm.
9. the preparation method of the butyrate clevidipine lipid fat breast concentrated solution according to any one of claim 1 to 7, comprises the steps:
1) at 20-45 DEG C, low hlb surfactant is added oil, under 2000-20000rpm condition, be stirred to and form transparent clear solution;
2) under 20-45 DEG C of condition, butyrate clevidipine is added step 1) product, and under 200-2000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 20-45 DEG C of condition, cosolvent, high hlb surfactant and optional antioxidant are added step 2) product, and under 200-800rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear.
10. the butyrate clevidipine lipid fat breast concentrated solution according to any one of claim 1 to 7 or injection butyrate clevidipine lipid fat according to claim 8 breast controlling of blood pressure and postoperative acute blood pressure when treating surgical operation raise, and also can be used for the clinical applications such as unsuitable oral or oral invalid hyperpietic's controlling of blood pressure.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020151444A1 (en) * | 2019-01-23 | 2020-07-30 | 广东嘉博制药有限公司 | Clevidipine butyrate fat emulsion injection and preparation process therefor |
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| WO2003000295A2 (en) * | 2001-06-21 | 2003-01-03 | Pfizer Products Inc. | Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors |
| 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 |
| CN102319212A (en) * | 2011-09-01 | 2012-01-18 | 辽宁中海康生物药业有限公司 | Clevidipine butyrate structured lipid emulsion and preparation method thereof |
| CN103110580A (en) * | 2013-02-20 | 2013-05-22 | 北京德立福瑞医药科技有限公司 | Clevidipine butyrate injection |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003000295A2 (en) * | 2001-06-21 | 2003-01-03 | Pfizer Products Inc. | Self-emulsifying formulations of cholesteryl ester transfer protein inhibitors |
| 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 |
| CN102319212A (en) * | 2011-09-01 | 2012-01-18 | 辽宁中海康生物药业有限公司 | Clevidipine butyrate structured lipid emulsion and preparation method thereof |
| CN103110580A (en) * | 2013-02-20 | 2013-05-22 | 北京德立福瑞医药科技有限公司 | Clevidipine butyrate injection |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2020151444A1 (en) * | 2019-01-23 | 2020-07-30 | 广东嘉博制药有限公司 | Clevidipine butyrate fat emulsion injection and preparation process therefor |
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