CN104288130A - A propofol composition used for injection, a preparing method thereof and uses of the propofol composition - Google Patents
A propofol composition used for injection, a preparing method thereof and uses of the propofol composition Download PDFInfo
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- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
The invention belongs to the field of pharmacology and pharmaceutics, and relates to a propofol composition used for injection, a preparing method thereof and uses of the propofol composition. A product of the propofol composition is good in fluidity and free of wall hanging, has a single-phase, transparent, clear and bright appearance, can be subjected to clarity detection, and is free of preparation layering phenomena after the product is repeatedly frozen and thawed. In a process of forming a propofol fat emulsion system when the product encounters water, homogenization treatment is not needed, and spontaneous emulsification can occur only by slight oscillation. During clinical using, the product can spontaneously emulsify to form a fat emulsion system meeting injection requirements after the product is diluted with normal saline or a glucose solution, and other aqueous solutions and is slightly oscillated. A preparation process is simple. Only a common physical stirring step is needed, and a homogenizing step or a water removing step is not needed. A prepared propofol fat emulsion concentrate liquid can be sterilized by passing through a microporous filtration membrane having a size of 0.22 [mu]m. After emulsification, the content of free propofol is low, and the phenomenon of pain during administration caused by existence of the free propofol is reduced. The propofol composition, the preparing method and uses have advantages of simple preparation process, low production cost, and easy transportation and storage, and have a good application prospect.
Description
Technical field
The invention belongs to materia medica and pharmaceutical art, relate to injection injection propofol, Preparation Method And The Use.
Background technology
The chemistry by name 2 of propofol, 6-diisopropyl phenol (Propofol, 2,6-disopropylphenol), belong to alkyl phenol, as a kind of intravenous anesthetic, rapid with its onset, action time is short, clear-headed fast, be easy to control and the feature such as untoward reaction is few, be widely used in general anesthesia induction by anesthetist, epidural anesthesia is auxiliary calm, painless abortion, the fields such as painless gastroscope.The advantages such as its postoperative nausea, vomiting rate are low, establish the status of the first-selected general anesthesia medicine of its outpatient operation further.AstraZeneca (Italy) company in 1981 as excipient with soybean oil, has developed the propofol injection of lipomul, within 1986, has gone on the market with trade name " Diprivan ".1989 years recommend Clinical practice by U.S. FDA.In December, 1993 goes on the market interiorly through Chinese SFDA approval.Since propofol is after China's listing, the performance excellent due to it and less side effect, be subject to the favor in market soon, application surface constantly expands, and application quantity continues to rise.Now, propofol Yi Shi China application medicine very widely.
Drug Loaded Intravenous Lipid Emulsions, is a kind ofly be soft substrate with fatty oil and the microsome disperse system encapsulated by immobilized artificial membrane, is dissolved in fatty oil, is wrapped in the milk-globule of immobilized artificial membrane encapsulating by phospholipid emulsification at this system Chinese medicine.Major part drug distribution, at oil phase or oil-water interfaces, is avoided directly contacting with water.For facile hydrolysis or the medicine to water sensitive, this isolation serves the effect increasing stability.Because outer aqueous phase Chinese medicine is less, effectively can reduce and cause phlebitic possibility by medicine, strengthen the compliance of patient; In addition, intravenous lipid emulsion has certain targeting, can reduce the concentration of non-target area medicine.Intravenous lipid emulsion is submicron microparticulate system, its mean diameter about 0.2 μm, blood capillary can not be blocked, as pharmaceutical carrier, there is obvious lymphsystem and monocytes/macrophages system (MPS) targeting, can assemble at the tissue (as tumor, inflammation district) with leaky blood vessel, namely strengthen through with retention effect (enhanced permeability and retention effect, thus there is natural passive target effect EPR).Electron Microscopy shows, fat milk drug delivery system enters active inflammatory cell (as huge phagocyte, neutrophilic granulocyte), vascular endothelial cell, tumor cell (as: MM46 cell, Kupffer ' s cell) by endocytosis; Flow Cytometry display fat milk drug delivery system also can be absorbed by Activated T-lymphocytes.Fat milk drug delivery system, due to its superior safety, stability and biocompatibility, is a kind of desirable pharmaceutical carrier.
Untoward reaction common when injection pain is the induction of application propofol.In 33 common Anesthesias of outpatient operation, its occurrence frequency comes in third.According to the literature, adult injection pain incidence rate is 28% ~ 90%.The injection pain of propofol is shown to be because in aqueous phase, free propofol causes through large quantity research, reduces the concentration of propofol in aqueous phase, can reduce the incidence rate of injection pain.Research shows in 1% propofol long-chain fat Ruzhong, free propofol concentration is 19.4mg/l, and in 1% propofol long-chain fat Ruzhong, free propofol concentration is 14mg/l, corresponding pain rate also reduces (Chen Tao greatly, Wang Rutao, waits (2011) international anesthesiology recovery magazine, 32:109-112).The key factor that free propofol exists is exactly large water gaging existence in fat milk, as
composition is the propofol of 1%, the soybean oil of 10%, the purification egg phosphatide of 1.2%, the glycerol of 2.25%, and the water of more than 95%.In this fat milk system, dynamic equilibrium relation is there is in propofol at oil, water, oil-water interface, because propofol water solublity is low, propofol in aqueous phase can progressively be separated out, free propofol is caused constantly to increase, therefore, in clinical, the filter of 0.22 μm can significantly reduce injection pain incidence rate and the order of severity.
In preparation aspect, fat milk all belongs to Unstable Systems on thermodynamics and kinetics, and preparation process has strict requirement to equipment, technological parameter, ratio of adjuvant etc.Fat milk contains the surfactants such as phospholipid, soybean oil, medium chain length fatty acid triglyceride (medium chain triglycerides, or Fructus Canarii albi wet goods fatty oil MCT), glycerol, and a large amount of water, by supercritical ultrasonics technology or two step emulsion processes etc., obtain the lipid particles system of moderate in grain size, wherein: the even method of ultrasound wave breast utilizes hyperacoustic cavitation, oil phase is dispersed in aqueous phase, but in the method, ultrasonic probe and medium contact, transient energy is larger, temperature is higher, the degraded of medicine may be caused, general the method is not used in mass industrialized production, two step emulsion processes refer at a certain temperature by the adjuvant such as medicine and emulsifying agent uniform dissolution or be scattered in aqueous phase or oil phase, then at a certain temperature water-oil phase is mixed, first through the thick breast of high speed shear preparation, then second emulsifying is carried out through high pressure homogenizer or microfluidizer, obtain whole breast, wherein high pressure homogenization technique and micro jetting technology are the keys of this kind of method, the method is applicable to produce (Zhao Mingming in enormous quantities, Su Min, Tang Xing, (2010) Shenyang Pharmaceutical University's journal, 12:1014-1022, Liu Zhihong, Song Hongtao, (2009) Bai Fang army Acta Pharmaceutica Sinica, 25:527-530), wherein especially universal with high pressure homogenization method.
As injection preparation, medicine prison system has high requirement to safety, extremely tight at the control overflow of the selection of adjuvant and particle diameter, as national Specification mean diameter must not cross 0.4 μm, 90% particle diameter aggregate-value must not be greater than 0.6 μm (1 μm equals 1000 nanometers).Therefore, in colostrum preparation, homogenization, need strictly to control parameters such as shear rate, temperature, homogenization pressure and cycle-indexes, take time and effort, considerably increase production cost.This is due to directly will suitable (Hiroko Shibata, et al. (2009) Int.J.Pharm.378:167-176 under composition condition; Dirk L.Teagarden, et al. (1996) Adv.Drug.Deliv.Rev.20:155-164) after the mixing of materials such as phospholipid, oil, water, oil-water separation phenomenon can be there is, only have these materials, through special homogenizer process, as high pressure homogenizer, could form the emulsion of stable uniform, in homogenizing process, material is subject to dither, hole, shearing, and the coordinative role such as impact, finally broken up or be refined as the insoluble phase granule in liquid.
In addition, those skilled in the art understand, and propofol fat emulsion etc. are rendered as opaque milkiness liquid 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 propofol fat ejection preparation is that preparation technology is simple, without the need to special installation, appearance transparent is limpid, and can be degerming by microporous filter membrane mode, to lower preparation cost.Meanwhile, the preparation after emulsifying, free propofol is low, can reduce the pain of patient.What is more important, adjuvant used can not bring potential safety hazard, centralized particle diameter after emulsifying, meets drug administration by injection requirement.
Summary of the invention
The present inventor is through deep research and performing creative labour, obtain a kind of injection propofol composition, the present inventor is surprised to find, injection propofol 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 can effectively overcome the density contrast between different auxiliary material and bring, obtain single-phase, transparent, stable thus, meeting after water can the propofol fat emulsion concentrated solution, particularly a kind of injection propofol concentrated solution of spontaneous emulsification.Thus provide following invention:
One aspect of the present invention relates to a kind of injection propofol composition, and it comprises as the propofol of principal agent, oil for injection, cosolvent, low surfactant and high surfactant.
Injection propofol composition 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 length fatty acid triglyceride is Miglyol 812;
(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 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 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 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 surfactant comprises polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini, and alternatively, it also comprises Tween 80.
The invention still further relates to a kind of injection propofol fat emulsion concentrated solution, it comprises:
Principal agent: propofol,
Oil: soybean oil,
Cosolvent: 1,2-PD,
Low surfactant: phospholipid, and
High surfactant: polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini;
Alternatively, described oil also comprises Miglyol 812;
Alternatively, described cosolvent also comprises PEG400;
Alternatively, described low surfactant also comprises polyglycerol acrylate and/or sorbester p17;
Alternatively, described high surfactant also comprises Tween 80.
Injection propofol composition 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 propofol is 1-20% (w/w); Be preferably 1-15% (w/w);
(2) content of described oil 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 surfactant is 4.5%-17% (w/w);
(5) content of described high surfactant is 8%-22% (w/w).
Injection propofol composition 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 propofol is 1-15% (w/w), is preferably 2-10% (w/w);
(2) content of described soybean oil is 5-60%, is preferably 5-50%;
(3) content of described Miglyol 812 is 0%-80%, is preferably 0%-65%;
(4) content of described 1,2-PD is 5%-15%, is preferably 6%-14%;
(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%, is preferably 0-15%;
(9) content of described Tween 80 is 0-15%, is preferably 0-10%.
Injection propofol composition according to any one of the present invention, is characterized in that any one in the item of following (1)-(9) or multinomial:
(1) described oil is oil for injection;
(2) the not moisture or water content of described injection propofol composition is lower than 1%;
(3) described injection propofol composition is not containing saccharide;
(4) the unambiguous essence of described injection propofol composition;
(5) described injection propofol composition its preparation method does not comprise removing or falls low-moisture step (such as rotary evaporation, spraying dry or lyophilization);
(6) alternatively, described injection propofol composition also comprises antioxidant; Particularly, described antioxidant be selected from oleic acid, enuatrol, vitamin E and vitamin A any one or multiple;
(7) described injection propofol composition is injection propofol fat emulsion concentrated solution;
(8) described injection propofol composition is transparent, single phase soln;
(9) described injection propofol composition adopts 0.22 μm of microporous filter membrane mode degerming.
Injection propofol composition according to any one of the present invention, its component and content are as below 1)-4) shown in group any one group:
1)
2)
3)
4)
Injection propofol composition 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)
(2)
(3)
(4)
It should be noted that; above-mentioned 1) unit of gram, milligram and microgram-4) in group or (1)-(4) group all represent the ratio between each component; if be revised as other unit of weight; include but not limited to; such as kilogram and gram etc., also all within protection scope of the present invention.
Another aspect of the invention relates to a kind of injection propofol fat emulsion, and its injection propofol composition according to any one of the present invention adds water or aqueous solution self emulsifying obtains; Particularly, described injection propofol fat emulsion mean diameter is 0.05-0.7 μm; Be preferably 0.1-0.4 μm.
After injection propofol composition of the present invention meets water dilution, can spontaneous emulsification be the propofol fat emulsion meeting injection requirement.
Another aspect of the invention relates to the preparation method of the injection propofol composition according to any one of the present invention, comprises the steps:
1) at 20-75 DEG C, low surfactant is added oil, under 1200-8000rpm condition, be stirred to and form transparent clear solution;
2) under 4-45 DEG C of condition, propofol is added step 1) product, and under 200-2000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 4-45 DEG C of condition, cosolvent, high 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.
About step 1) or step 2) or step 3) in the oil, low surfactant, high surfactant and the cosolvent that use, wherein moisture will lower than 1%, or do not have free water.
Step 3) in product, 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 relates to the clinical applications such as injection propofol composition according to any one of the present invention or the propofol fat emulsion injection of the present invention calmness when induction of anesthesia, anesthesia maintenance, ICU critical patient accept mechanical ventilation.
The explanation of the part term that the present invention relates to:
Fat milk refers to, after emulsion or the emulsifying of fat milk concentrated solution, a kind of of formation is soft substrate with fatty oil and the microparticulate system encapsulated by immobilized artificial membrane.
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 propofol fat emulsion system system 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 be at 0.1-0.4, particle size distribution is narrow and small fully demonstrates injection fat milk characteristic.
Preparation technology of the present invention is simple, only need General Physics whipping process, do not need homogenization, do not need dewatering process, injection propofol fat emulsion concentrated solution prepared by the present invention, can be degerming by 0.22 μm of microporous filter membrane, and after emulsifying, free propofol content is low, the existence due to free propofol can be reduced, and cause administration pain phenomenon.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 injection propofol composition sample 1
Its constituent is as follows:
(1)
This injection propofol composition preparation method is as follows:
1) under 75 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 propofol is added 1) product, and under 200rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 45 DEG C of conditions, the propylene glycol of above-mentioned weight, Tween 80, polyethyleneglycol-12-hydroxy stearin, vitamin E are added 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 injection-used fat emulsion concentrated solution.
embodiment 2: the preparation of injection propofol composition sample 2
Its constituent is as follows:
This injection propofol composition preparation method is as follows:
1) under 60 DEG C of conditions, after the soybean lecithin of above-mentioned weight, polyglycerol acrylate, soybean oil are mixed with Miglyol 812, under 6000rpm condition, be stirred to and form transparent clear solution;
2), under 45 DEG C of conditions, above-mentioned weight propofol is added 1) product, and under 1000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 35 DEG C of conditions, the propylene glycol of above-mentioned weight, Tween 80, polyethyleneglycol-12-hydroxy stearin, vitamin E are added 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 injection-used fat emulsion concentrated solution.
embodiment 3: the preparation of injection propofol composition sample 3
Its constituent is as follows:
This injection propofol composition 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 soybean oil, under 6000rpm condition, be stirred to and form transparent clear solution;
2), under 4 DEG C of conditions, above-mentioned weight propofol is added 1) product, and under 2000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 40 DEG C of conditions, the propylene glycol of above-mentioned weight, polyethyleneglycol-12-hydroxy stearin, Tween 80, vitamin E, oleic acid are added 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 injection-used fat emulsion concentrated solution.
embodiment 4: the preparation of injection propofol composition sample 4
Its constituent is as follows:
This injection propofol composition preparation method is as follows:
1) under 20 DEG C of conditions, after the soybean lecithin of above-mentioned weight, soybean oil are mixed with Miglyol 812, under 1200rpm condition, be stirred to and form transparent clear solution;
2), under 20 DEG C of conditions, above-mentioned weight propofol is added 1) product, and under 1500rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 4 DEG C of conditions, the propylene glycol of above-mentioned weight, refining polyoxyethylene ether (35) Oleum Ricini, vitamin E, enuatrol are added 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 injection-used fat emulsion concentrated solution.
embodiment 5: spectrodensitometry is tested
With Hitachi U-2001 ultraviolet-uisible spectrophotometer, at ambient temperature, 600nm place measures optical density.Wherein injection propofol composition is the sample 1-4 according to embodiment 1-4 preparation process gained, selects commercially available prod
in contrast.
Result is as shown in table 1.
Table 1: the optical density value of different sample solution
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
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
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 Mastersizer2000 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) represents that the cumulative particle sizes distribution number of sample is the particle diameter of 10% correspondence, and d (0.5), d (0.9), the rest may be inferred for d (1).
Its particle size distribution is as shown in table 3, and the particle size distribution of four embodiments is between 0.1-0.8 μm, and mean diameter is less than 0.4 μm, and the d (0.9) of four embodiment products is all less than 0.6 μm, meets injection fat milk Particle size requirements.
embodiment 8: free propofol measures
By dialysis, free propofol drug level after the emulsifying of mensuration different product.Concrete test procedure is as follows:
1. get sample 1-4 prepared by embodiment of the present invention 1-4, being diluted to propofol content in Emulsion is respectively 1% (w/w), separately gets 1% propofol
compare.The Emulsion of 1% propofol content is mixed (Emulsion: 5% glucose solution volume ratio is 1: 4) with 5% glucose solution after, be positioned over respectively in 5 different beakers.
2. getting five by molecular cut off is 10000 daltonian bag filters, after being respectively charged into 2ml5% glucose solution, is positioned over beaker, stirs dialysis 24 hours.
3. take out bag filter, after centrifugal, HPLC measures bag filter drug concentration.
Table 4: different sample free propofol content
From table 4, after sample 1-4 dilutes, the free propofol in emulsion system reduces greatly, greatly can reduce the existence due to free propofol thus in theory, and cause administration pain phenomenon.
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. an injection propofol composition, it comprises as the propofol of principal agent, oil for injection, cosolvent, low surfactant and high surfactant.
2. injection propofol 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 length fatty acid triglyceride is Miglyol 812;
(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 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 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 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 surfactant comprises polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini, and alternatively, it also comprises Tween 80.
3. an injection propofol composition, it comprises:
Principal agent: propofol,
Oil: soybean oil,
Cosolvent: 1,2-PD,
Low surfactant: phospholipid, and
High surfactant: polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini;
Alternatively, described oil also comprises Miglyol 812;
Alternatively, described cosolvent also comprises PEG400;
Alternatively, described low surfactant also comprises polyglycerol acrylate and/or sorbester p17;
Alternatively, described high surfactant also comprises Tween 80.
4. injection propofol 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 propofol is 1-20% (w/w); Be preferably 1-15% (w/w);
(2) content of described oil 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 surfactant is 4.5%-17% (w/w);
(5) content of described high surfactant is 8%-22% (w/w).
5. the injection propofol 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 propofol is 1-15% (w/w), is preferably 2-10% (w/w);
(2) content of described soybean oil is 5-60%, is preferably 5-50%;
(3) content of described Miglyol 812 is 0%-80%, is preferably 0%-65%;
(4) content of described 1,2-PD is 5%-15%, is preferably 6%-14%;
(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%, is preferably 0-15%;
(9) content of described Tween 80 is 0-15%, is preferably 0-10%.
6. injection propofol composition according to any one of claim 1 to 5, is characterized in that any one in the item of following (1)-(9) or multinomial:
(1) described oil is oil for injection;
(2) the not moisture or water content of described injection propofol composition is lower than 1%;
(3) described injection propofol composition is not containing saccharide;
(4) the unambiguous essence of described injection propofol composition;
(5) described injection propofol composition its preparation method does not comprise removing or falls low-moisture step (such as rotary evaporation, spraying dry or lyophilization);
(6) alternatively, described injection propofol composition also comprises antioxidant; Particularly, described antioxidant be selected from oleic acid, enuatrol, vitamin E and vitamin A any one or multiple;
(7) described injection propofol composition is injection propofol fat emulsion concentrated solution;
(8) described injection propofol composition is transparent, single phase soln;
(9) described injection propofol composition adopts 0.22 μm of microporous filter membrane mode degerming.
7. an injection propofol composition, its component and content are as below 1)-4) shown in group any one group:
1)
2)
3)
4)
8. an injection propofol fat emulsion, its injection propofol composition according to any one of claim 1 to 7 adds water or aqueous solution self emulsifying obtains; Particularly, described injection propofol fat emulsion mean diameter is 0.05-0.7 μm; Be preferably 0.1-0.4 μm.
9. the preparation method of the injection propofol composition according to any one of claim 1 to 7, comprises the steps:
1) at 20-75 DEG C, low surfactant is added oil, under 1200-8000rpm condition, be stirred to and form transparent clear solution;
2) under 4-45 DEG C of condition, propofol is added step 1) product, and under 200-2000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 4-45 DEG C of condition, cosolvent, high 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 clinical applications such as the injection propofol composition according to any one of claim 1 to 7 or the injection propofol fat emulsion according to claim 8 calmness when induction of anesthesia, anesthesia maintenance, ICU critical patient accept mechanical ventilation.
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Cited By (1)
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| CN107708669A (en) * | 2015-07-01 | 2018-02-16 | 费森尤斯卡比德国有限公司 | Propofol emulsion for parenteral |
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| CN101155580A (en) * | 2005-04-13 | 2008-04-02 | 株式会社大塚制药工场 | Propofol-containing fat emulsion |
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| CN107708669A (en) * | 2015-07-01 | 2018-02-16 | 费森尤斯卡比德国有限公司 | Propofol emulsion for parenteral |
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