CN104523591B - Without sensitization, painless propofol fat micro emulsion frozen preparation formula and preparation method - Google Patents
Without sensitization, painless propofol fat micro emulsion frozen preparation formula and preparation method Download PDFInfo
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- CN104523591B CN104523591B CN201410802238.6A CN201410802238A CN104523591B CN 104523591 B CN104523591 B CN 104523591B CN 201410802238 A CN201410802238 A CN 201410802238A CN 104523591 B CN104523591 B CN 104523591B
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Abstract
The invention discloses a kind of no sensitization, the propofol fat micro emulsion frozen preparation formula without injection pain and preparation methods.Said preparation uses artificial synthesized phosphatide and artificial synthesized fatty acid glycerine fat, avoid the presence of the sensitization sources such as trace of albumin in natural lecithin and soybean oil, it avoids using metal complex EDTA, with antioxidant sulphite, thiosulfate, eliminate the allergic reaction that metal chelating agent and sulfide may cause, and water phase free propofol is removed by multiple means on prescription and preparation process, injection pain is mitigated or eliminated, to improve the safety of preparation and the compliance of patient.
Description
Technical field
The invention belongs to medical drugs series, are related to formula and the preparation of a kind of lyophilized preparation of drug, more particularly to
Without sensitization, the formula of painless novel propofol fat micro emulsion frozen preparation and preparation.
Background technique
Propofol (also known as dipropofol, propofol, 2,6-Bis(1-methylethyl)phenol, structure are shown in Fig. 1) is a kind of hindered phenol, parent
Lipid is strong, is mostly induced and is maintained for clinical anesthesia with fat emulsion formulation dosage form[1].Propofol is as a kind of clinical common vein
Arcotic is rapid-action with its, it is short to hold time, revival is rapid, metabolism is fast, has obtained widely without accumulation, highly-safe feature
Using[2]。
Propofol injection clinically uses increasingly extensive with it, and the report of adverse reaction increases increasingly[3].Third
Phenol injection adverse reaction complicated clinical manifestation multiplicity is moored, the ratio that anaphylactic shock occurs is higher[4], seriously can lead to death.
The specification points for attention of propofol injection (Jing'an) are mentioned: this product contains soybean oil, and only a few patient is likely to occur serious
Allergic reaction.And adverse reaction also prompts: being likely to occur low blood pressure and of short duration respiration inhibition.Only a few case uses Propofol
After allergic reaction, including QuinckeShi oedema, bronchial spasm, erythema and low blood pressure occurs.It is each including U.S. FDA
Pharmaceutical control and administration department of state is all clearly indicated in the specification of the propofol injection of approval: prohibiting to the allergies person such as soybean, yolk
Only use.In addition, propofol Injection administration process can cause the injection pain of injection site incidence up to (30-70%), it is right
Life, body and the spirit of patient, which causes, to be seriously affected[5-7], to limit its clinical further popularization and application.Therefore
Without sensitization, painless novel propofol formulations have certain clinical use value for exploitation.
The clinical application dosage form of Propofol is fat emulsion at present, generallys use natural yolk lecithin and soybean oil conduct
Auxiliary material, they contain micro yolk protein and soybean protein, are easy to cause allergic reaction.These auxiliary materials or good natural training
Base is supported, supports the growth of microorganism.If improper use be easy to cause postoperative infection, lead to grave consequences[8].Propofol is in beauty
Between 1 year after state's listing, said preparation constantly has the report for leading to postoperative infection and fever[9-11].In 2010, U.S.'s food medicine
Product management board (FDA) indicates, since the problem of production aspect forces ladder watt and its third pool of Hospira Inc (HSP) pause production
Phenol sedative, and recall portioned product.The generation of postoperative infection in order to prevent joined EDTA and sulphite in regular dosage form
As antimicrobial component.
In addition, there are phenolic hydroxyl groups in Propofol structure, it is easily oxidized generation 2,6- diisopropyl-Isosorbide-5-Nitrae-benzoquinones.It can also send out
It gives birth to polymerization reaction and generates 3,3,5,5 '-tetra isopropyl xenols (chemical structure is shown in Fig. 2), the two impurity have biggish poison
Property[12]；Furthermore how unsaturated double bond compound in auxiliary material, unstable chemcial property are easy to happen lipid peroxidation in air
Reaction generates peroxide[2].Aoxidize in order to prevent, conventional formulation be usually added into sulphite perhaps thiosulfate or
EDTA is added and carrys out complexation of metal ions, prevents the oxidation of Propofol and auxiliary material, but EDTA and sulphite can cause allergy anti-
It answers[13], especially to essential asthma patient, using the Propofol containing EDTA or sulphite in age >=40, long-term suction
Cigarette patient can lead to total pulmonary resistance increase.
In order to achieve the effect that no sensitization, EDTA, sulphite or thiosulfate are not used in novel formulation of the invention,
Effectively prevent anaphylactoid generation.In addition to still guaranteeing the stabilization of preparation under no situation that the above auxiliary material is added
Property, we have been made into fatty micro emulsion frozen preparation, and use brown cillin bottle as inner packing.Exist in Propofol structure
Phenolic hydroxyl group is easily oxidized.The generation that illumination can be reacted with accelerated oxidation.In addition it is mostly unsaturated double-bond compound in auxiliary material, changes
It is also unstable to learn property.Brown cillin bottle can accomplish hypersorption in 200nm~400nm, and absorption curve enters visible light
Range[14-15].It is possible to prevente effectively from illumination increases preparation stability to Propofol and auxiliary material prooxidant effect.Test proves, makes
For at after micro emulsion frozen preparation and using brown cillin bottle, the stability of sample increases and effectively prevents the microorganisms such as bacterium
Infection, the light degradation reaction for being also prevented from preparation occur, and are specifically shown in embodiment.
Propofol Injection pain has been anesthetized boundary and medicine administrative organ is classified as the most important side effect of Propofol.For
Alleviate, inhibit propofol Injection pain, people have conducted extensive research propofol Injection Theory of Pain Mechanism, comprehensive injection at present
The result of study of Pain mechanisms, injection pain inducement can be summarized as three hypothesis: 1, free propofol directly stimulates vacation
If[16-18]；2, free propofol excites indirectly generates bradykinin hypothesis[19-21]；3, it is false to cause prostaglandin release for free propofol
If[22].Propofol vein injection causes injection pain to be a complicated process, no matter analyzes from current most results of study
That is a kind of to cause injection pain mechanism all and in water phase and Propofol that emulsion droplet outer surface is sticked has direct relation.Accommodating is not doubted,
The Propofol that free propofol and emulsion droplet outer surface are sticked in pharmaceutical preparation water phase is the arch-criminal for causing pain.
The adverse reactions such as allergic reaction and injection pain for conventional formulation, we have done following improvement.1, using people
Work synthetic phospholipid and artificial synthesized fatty acid glycerine fat fundamentally eliminate natural phosphatidyl choline and soybean oil in conventional formulation
In the sensitization sources such as micro presence.2, do not use metal complex EDTA, also without using as antioxidant sulphite or
Thiosulfate eliminates the allergic reaction that metal chelating agent and sulfide may cause.3, using fatty micro emulsion frozen preparation
Form, keep preparation more stable.Solve the problems, such as easily to be oxidized under no anti-oxidant protective agent, effectively prevent Propofol and
The oxidative degradation of auxiliary material；The growth of preparation bacterium during preservation is also effectively prevented simultaneously.4, made using brown cillin bottle
For interior packaging material, the degradation of Propofol caused by avoiding because of illumination and light-catalysed phospholipid oxidation[2].5, using advanced work
Skill effectively reduces and is not wrapped in the Propofol to dissociate in fatty micro emulsion emulsion droplet or the Propofol in the absorption of emulsion droplet outer surface,
And encapsulation rate does not reduce after redissolving, and free propofol aqueous phase content≤10 μ g/ml, partial size meets the requirements less than 180nm, reduces
Stimulation of the free propofol to blood vessel, to reach no injection pain.
The present invention is by avoiding using possible sensitization source in prescription, and using lyophilized preparation, brown bottle has ensured product
Stability during preservation, and use the independent of a variety of methods and be used in combination and reach reduction or basic removing micro emulsion jelly
The purpose for the Propofol that free propofol and emulsion droplet outer surface are sticked in water phase after dry preparation redissolves.Due to fundamentally eliminating
Anaphylactogen and avoid the induced pain root for causing pain, prepared propofol fat micro emulsion frozen preparation reached without sensitization,
Painless or substantially painless ideal effect becomes the better preparation of safety.
Three, summary of the invention
The purpose of the present invention is to provide a kind of no sensitization propofol fat micro emulsion frozen preparations, by following components group
At:
The artificial synthesized phosphatide is it is characterized in that the artificial synthesized phosphatide is the one or more of of Formulas I structure
Mixing；
R2:-CH2-CH2-N+H3 (PE)
-CH2-CH2-N+(CH3)3 (PC)
-C6H(OH)5 (PI)
-CH2COO-CH(N+H3) (PS)
-CH2CHOH-CH 2OH (PG)
Wherein, R2It indicates to be selected from choline (PC), ethanol amine (PE), inositol (PI), glycerol (PG), serine (PS), R and R1
Can be identical or different, in saturation, single insatiable hunger and/or how unsaturated, long chain hydrocarbon groups, such as alkyl, alkenyl, alkynyl, R
And R1Carbochain optional 4~26 carbon of length, the preferably length of carbochain is 6~22 carbon, and the length of more preferable carbochain is 10~20
Carbon.It can be artificial synthesized dipalmitoylphosphatidylcholine (DPPC), artificial synthesized Distearoyl Phosphatidylcholine (DSPC), people
Work synthesizes dilinoleoylphosphatidylcholine, artificial synthesized linolenic acid phosphatidyl choline, artificial synthesized Dioleoyl Phosphatidylcholine；People
Work synthesizes -2 arachadoyl phosphatidyl choline of 1- stearoyl, artificial synthesized 1- palmityl -2- sub-oleoyl phosphatidyl choline, artificial conjunction
At and the one or more such as stearyl glycerol (DSPG), artificial synthesized distearyl ethylethanolamine.
The artificial synthesized fatty acid glycerine fat is the mixing of Formula II one or more；
Wherein, R, R1And R2For can be identical or different, the middle long chain hydrocarbon groups selected from saturation, single insatiable hunger and/or how unsaturated,
Such as alkyl, alkenyl, alkynyl, R, R1And R2Carbochain optional 4~26 carbon of length, preferably the length of carbochain be 6~22 carbon, more
It is preferred that the length of carbochain is 10~20 carbon；It can be artificial synthesized tristerin, artificial synthesized tripalmitin, artificial
Synthesize the one or more of olein, artificial synthesized glyceryl linolenate, artificial synthesized glyceryl linoleate etc..
The artificial synthesized mono fatty acid glyceride is the one or more of mixing of formula III；
Wherein, middle long chain hydrocarbon groups of the R selected from saturation, single insatiable hunger and/or how unsaturated, such as alkyl, alkenyl, alkynyl, R's
The length of carbochain is 16~18 carbon.It can be glycerin monostearate, monopalmitin, glyceryl monolaurate, single oil
The one or more of acid glyceride etc..
The polyethyleneglycol lipid derivates can be polyethylene glycol-distearoylphosphatidylethanolamine, poly- second two
Alcohol-cholesterol, the one or more of polyethylene glycol-fatty acid etc..
The skeletal support agent can be one of lactose, sucrose, maltose, mannitol, sorbierite, xylitol or
It is several.
Preferably, the weight ratio of Propofol and artificial synthesized fatty glyceride is less than 1:15, improves oil mutually relative to third
The ratio of pool phenol is facilitated control Propofol and (is dissolved using larger amount of oil in oily phase dilution agent in relatively low concentration
Drug), enable Propofol more efficient and is adequately dissolve in oily phase and is wrapped in fatty micro emulsion emulsion droplet.
It is highly preferred that the weight ratio of Propofol, artificial synthesized fatty glyceride and artificial synthesized phosphatide is 1:25:(0.8
~3.2) phospholipid ratio, is improved, under the premise of keeping the proportions constant of oily diluent and Propofol, improves the dosage of phosphatide,
To guarantee to improve package efficiency of the Propofol in fatty micro emulsion.
Propofol fat micro emulsion frozen preparation of the present invention, the preparation method is as follows:
Whole process carries out under nitrogen protection.Take the Propofol, artificial synthesized phosphatide, artificial synthesized fatty acid of recipe quantity
The heating stirrings such as glycerolipid and polyethylene glycol phospholipid derivative mix, and separately take appropriate water for injection, and oleic acid and skeleton branch is added
Agent dissolution is supportted, under the conditions of nitrogen protection, oil solution is slowly added in the water phase of cutter high-speed stirred (8000rpm),
Continue 15min, obtains just milk solution.Through high pressure homogenizer homogeneous 7~8 times, pressure 100MPa, pH6.0-8.0 is adjusted, controls partial size
Less than 180nm, reduction is reached using the independent of a variety of methods and being used in combination or basic is removed after micro emulsion frozen preparation redissolves
The Propofol that free propofol and emulsion droplet outer surface are sticked in water phase, filtering, it is filling, prepare lyophilized preparation: subzero 45 DEG C with
2~5h of lower pre-freeze, is warming up to maintenance 22h or more between subzero 30 DEG C to subzero 15 DEG C, and vacuum decompression removes moisture, is warming up to 0
~5 DEG C, maintain 5h to continue vacuum drying and moisture be removed under reduced pressure, be warming up to 25 DEG C, continue vacuum decompression and go out moisture, drying
Freeze-dried emulsion；
Preferably, after the completion of fatty microemulsion homogeneous, the third pool to dissociate in water phase is removed using ultrafiltration or dialysis process
Phenol selects brown cillin bottle filling in step.
The technique of the free propofol of ultrafiltration removal preparation water phase is shown in Fig. 2.Take propofol fat micro emulsion 1000mL (Specific amounts
The design of foundation process units and ultrafiltration column capacity difference is effectively treated and changes), take its water phase of a small amount of sample analysis to swim
From concentration of propofol.Assemble " ultrafiltration production equipment " according to Fig. 2, select the ultrafiltration column core in suitable aperture, selection it is main because
Element can be passed freely through with aqueous solution, and Fat Emulsion cannot be by for Selecting All Parameters.Isotonic buffer solution equilibria ultrafiltration column is used first,
Then propofol fat micro emulsion is slowly inputted into ultrafiltration column, adjustable column pressure.Aqueous solution containing free propofol penetrates ultrafiltration
Column is efficiently separated with propofol fat micro emulsion.The solution of missing is supplemented by buffer solution.Generally pass through 10 times of volumes
Buffer solution exchange ensure that the free propofol in water phase is all removed it is clean.Specific technological parameter, preparation
Processing capacity, buffer solvent exchange capacity must according to the control of the free propofol content in specific equipment and final preparation require and
It is fixed.
It should be noted that the present invention using 1), in prescription use artificial synthetic phospholipid and artificial synthesized fatty acid glycerine
Rouge fundamentally goes the presence for avoiding the sensitization sources such as natural lecithin and soybean oil trace of albumin.2), without using gold
Belong to complex compound EDTA, sulphite or thiosulfate sulfides, eliminates the anaphylactogens such as metal chelating agent and sulfide
Presence.3), using the form of fatty micro emulsion frozen preparation, keep preparation more stable, effectively prevent the oxygen of Propofol and auxiliary material
Change degradation and bacterial growth during preservation.4), using brown cillin bottle as interior packaging material, caused by avoiding because of illumination
The degradation of Propofol and light-catalysed phospholipid oxidation.5), being used alone or in combination using following five kinds of methods, reduces
Free propofol in water phase after micro emulsion frozen preparation redissolves, or the content of Propofol that fatty micro emulsion outer surface is sticked, it is multiple
The encapsulation rate of Propofol does not reduce after molten, and dissociate propofol content≤10 μ g/ml in water phase, and partial size is conformed to less than 180nm
It asks, reduces free propofol to vascular stimulation, no injection pain.
, after the completion of fatty microemulsion is homogeneous five kinds of methods that the present invention describes are: 1), using ultrafiltration (see Fig. 3), dialysis
Or other methods remove the free Propofol in water phase.2) ratio of oily diluent and Propofol, is improved, that is, is controlled
Propofol in oily phase dilution agent be in relatively low concentration (drug is dissolved using larger amount of oil), enable Propofol more
It oily mutually and is wrapped in fatty micro emulsion emulsion droplet added with imitating and being adequately dissolve in.3) phospholipid ratio, is improved, oily diluent is being kept
Under the premise of the proportions constant of Propofol, the dosage of phosphatide is improved, to guarantee to improve packet of the Propofol in fatty micro emulsion
Wrap up in efficiency.4) polyethylene glycol phospholipid derivative (form structure and see schematic diagram 4), is added in formula.Polyethylene glycol phosphatide is derivative
Emulsifying effectiveness both can be enhanced in object, guarantees that Propofol can be effectively wrapped in fatty micro emulsion oil droplet；It again can be in fatty micro emulsion
Polymeric buffer band (Fig. 5 is shown in physical barrier effect) is formed between drop and vascular wall, common fats cream Propofol is very close to blood
Endothelial tube surface, the Propofol of fatty emulsion droplet outer surface is contacted with vascular wall can generate stimulation or initiation inflammation.And poly- second two
Alcohol separate vascular wall after fatty micro emulsion frozen preparation is redissolved, the Propofol on emulsion droplet surface is not contacted with vascular wall, so not
Stimulation can be generated, thus without injection pain.5), the skeletal support agent using disaccharides etc. as lyophilized preparation.Disaccharides etc. is in addition to this
Other than the isotonic agent function of body, they can be reduced in fatty micro emulsion Propofol forming process is attached on fatty micro emulsion drop appearance
Package efficiency of the Propofol in fatty micro emulsion can be improved in the Propofol in face, and furthermore disaccharides etc. can also be in fatty micro emulsion cream
Physics isolation strip is formed between drop and vascular wall, avoid free propofol and vascular wall touches building.
It can be reduced by the novel propofol fat micro emulsion frozen preparation that above-mentioned all methods or Part Methods combine preparation
Or propofol fat emulsion formulation injection stimulation and injection pain are eradicated, the tolerance of patient is improved, there is very important face
Bed meaning.
The present invention by simultaneously use above without sensitization supplementary material and painless solution, reach prepare novel no sensitization,
Novel propofol fat micro emulsion frozen preparation without injection pain.
Specifically embodiment is prepared without sensitization, the novel propofol fat micro emulsion frozen preparation of without pain
Innovative point of the invention is illustrated in order to clearer, and classification provides no sensitization, without the novel of injection pain below
Propofol fat micro emulsion frozen preparation prepares embodiment, and the present invention is described in further detail.
Important analysis method
(1), water phase propofol content detection method after redissolving:
Propofol fat micro emulsion frozen preparation redissolve after in water phase the measurement of propofol content can be used centrifugal process by water phase,
It is oily mutually and after emulsification oxidant layer separation to measure respectively.Emulsification oxidant layer is efficiently separated with water phase using centrifugation in this experiment, then
Fatty micro emulsion water phase drug content is determined using HPLC:
The injection that precision measures after the redissolution of propofol fat micro emulsion frozen preparation is appropriate, makes to obtain 50ug/ml's in measuring bottle
Sample solution is added Chromatographic Pure Methanol to scale, mixes, 0.22 μm of filtering with microporous membrane takes subsequent filtrate, by under content determination item
The measurement of chromatographic condition HPLC method, external standard method calculate preparation of traditional Chinese medicine total concentration Ctotal；Separately take propofol fat micro emulsion frozen system
Injection about 10mL after agent redissolution sets in ultracentrifuge and is centrifuged 1.0h with 30,000rpm, 4 DEG C of temperature, takes lower layer's clarification molten
Liquid takes subsequent filtrate through 0.22 μm of filtering with microporous membrane, measures (Jasco PU- by chromatographic condition HPLC method under content determination item
2089 type quaternary pump high performance liquid chromatographs, Jasco-UV-2075plus detector), external standard method calculates water phase drug concentration
Cwater。
Chromatographic condition: chromatographic column: Kromasil-C18 4.6 × 250mm, 5 μm；Mobile phase: acetonitrile-water (85:15)；Inspection
Survey wavelength: 280nm；Flow velocity: 1.0ml/min；Sample volume: 20 μ l；Column temperature: 25 DEG C.
(2), granularity and determination of particle size distribution
A. instrument
Zeta potential/particle Sizer(NicompTM380ZLS, U.S. PSS.NICOMP).
B. measuring method
It takes this product appropriate, is redissolved with 0.9% sodium chloride injection, and dilute 5000 times, mix, as test solution,
It is measured with Dynamic laser scattering particle size determination method (two annex of Chinese Pharmacopoeia version in 2010, Ⅸ E third method), the partial size of micro emulsion drop
Should be between 10~180nm, the granularity 99% of micro emulsion drop should be at 0.2 μm or less.
(3), propofol fat micro emulsion frozen preparation allergic reaction inspection technique
A. principle
This genealogy of law injects a certain amount of test solution in cavy body, and it is molten that test sample is injected intravenously after separated in time
Liquid is excited, and the case where allergic reaction occurs in observation animal, to determine whether test sample causes animal systemic anaphylaxis.
On approbation cavy answers healthy qualification, and weight 250-350g, female mice should be without pregnant.Before the test and during test,
It should all be raised by normal rearing conditions.The cavy for doing this test must not be reused.
B. reagent
DiprivanTMInjection (commercially available), propofol fat micro emulsion frozen agent (self-control), saline control group (city
Sell), 5% egg white physiological saline.
C. inspection technique
Above-mentioned cavy is taken, is randomly divided into 6 groups, every group 6.The next day every intraperitoneal injection test solution 1ml every time, totally 3
It is secondary, 10 days after final injection, only by hind leg saphena difference injection 2.0ml/, carry out sensitization.Every animal is observed daily
Behavior and sign, for the first time preceding weighing of sensitization and excitation and the weight for recording every animal.It is moved in 30 minutes after observation attack excitation
Whether there is or not symptoms of allergic for object.
D. result judges
Animal allergic reaction series is calculated by 1 requirement of table.The order of reaction is at 2 grades or less, then it is assumed that by the allergy of test product
Pass the test.
1 cavy allergic reaction grading table of table
(4), propofol fat micro emulsion frozen preparation vascular pain evaluation test
Instrument, reagent and animal
A. instrument
Electromyogram recorder (AB-621G, Nihon Kohden Corp.), constant temperature blender with magnetic force (Shanghai intelligence light instrument
Finite instrument company), ten a ten thousandth electronic analytical balances (BP211D Germany Sai Duolisi), the coaxial needle electrode of electromyogram and
Reference electrode (indifferent electrode), digital display thermostat water bath (Fuhua Instrument Ltd. of Jintan City).
B. reagent
DiprivanTMInjection (commercially available), propofol fat micro emulsion frozen agent (self-control), blank Fat Emulsion (self-control) are raw
It manages salt water (commercially available).
C. animal
SD rat, weight 200~250g male, is provided by The Fourth Military Medical University's Experimental Animal Center.
D. experimental method
Male SD rat is divided into 6 groups first, every group 6, etherization is fixed on mouse platform to face upward appearance, removes right rear leg hand
Polyethylene catheter is intubated in rat right femoral artery, while fixed catheter by art area and electrode insertion site hair, exposure femoral artery,
Electromyogram is placed in right rear leg with coaxial needle electrode and reference electrode, and is connected to electromyogram recorder.
The femoral artery of Propofol fat milk sample product that commercially available and embodiment is voluntarily prepared to rat is given respectively, passes through administration sample
The degree of the electromyography evaluation vascular pain at the neighbouring position of the artery of product.Electromyography method evaluates vascular pain according to ginseng
Examine literature method[23].Start electromyography record before propofol fat sample is administered.1 hour after to operation, electromyography wave
Shape is stablized, by being intubated commercially available propofol injection is administered respectively, removes free propofol fatty micro emulsion, highly dissoluble oil third
Moor the 1-27 embodiment samples such as phenol fat micro emulsion, the propofol fat micro emulsion frozen preparation of ratio for improving oil for injection, administration
It records electromyogram respectively afterwards, and calculates area under the peak in electromyogram.
It is administered after commercially available propofol injection 1 hour, the fats emulsion sample (each 0.5ml) of embodiment adjusts pH to 8, meter
Area under peak in calculation electromyography waveform.The value of every rat of each group is measured compared with commercially available reference medicine, to determine its " electromyogram
Area ratio " is indicated with (%), indicates the index of vascular pain.When the index is less than 100%, show and commercially available Propofol
Fat Emulsion Injection mitigates compared to vascular pain.And index (electromyogram area ratio) is smaller, it is better that vascular pain mitigates effect.
(5) it is thin that EDTA, sulphite, the propofol fat micro-emulsion injecta of thiosulfate and micro emulsion frozen preparation is not added
The comparison of bacterium pollution
Experimental group: experimental group is divided into three groups: A group is the third pool that EDTA, sulphite, thiosulfate is not added
Phenol fat microemulsion injection；B group is the propofol fat micro emulsion frozen preparation that EDTA, sulfate is not added；C group is to use nothing
Bacterium physiological saline.
The preparation of test solution: under non-sterile conditions, propofol fat microemulsion solution is prepared according to prescription, is taken a certain amount of
Propofol fat microemulsion injection is prepared, equivalent solution is separately taken to prepare fatty micro emulsion frozen preparation.Bacterium is carried out after the completion of freeze-drying
The comparison of sum.Fatty micro emulsion frozen preparation, uses sterile physiological after taking appropriate propofol fat microemulsion injection respectively and redissolving
10 times of gradient dilutions of salt water.
The comparison of clump count: taking 9 clean glass dishes, B solution, dilution 10 after being inoculated with 1ml A, redissolution respectively2、
104、106The B solution and C of A again and same extension rate, shake up in heats liquefied nutrient agar, cooling solidifying
It is cultivated 24 hours after Gu at 37 DEG C, compares the clump count on culture medium.
Detailed description of the invention
The chemical structure of Fig. 1, Propofol
Fig. 2, Propofol oxidation and polymerization impurity
A:2,6- diisopropyl-Isosorbide-5-Nitrae-benzoquinones
B:3,3,5,5 '-tetra isopropyl xenols
The technique signal of free propofol after Fig. 3, ultrafiltration removal propofol fat micro emulsion frozen preparation redissolve in water phase
Figure.
Schematic diagram after Fig. 4, polyethyleneglycol modified propofol fat micro emulsion frozen preparation redissolve.
The action principle that Fig. 5, polyethyleneglycol modified propofol fat micro emulsion frozen preparation effectively mitigate injection pain is shown
It is intended to.
Fig. 5 A: common fats cream Propofol
Fig. 5 B: polyethyleneglycol modified propofol fat micro emulsion frozen preparation
Area under the electromyogram peak of area and commercial samples under the peak of the electromyogram of Fig. 6, invention laboratory sample method 1-4
Ratio.
1), the sample (embodiment 1) of hyperfiltration process preparation；
2), increase the sample (embodiment 14) of phosphatide dosage preparation；
3), the sample (embodiment 24) prepared using polyethyleneglycol lipid derivates；
4), using the sample (embodiment 10) of oil preparation at high proportion.
Specific embodiment
Method one, the investigation that free propofol after redissolving in water phase is removed using ultrafiltration, dialysis or other methods.
Embodiment 1: ultrafiltration investigates the applicability of common propofol fat micro emulsion
The propofol fat micro emulsion 1000mL for taking any embodiment preparation takes free third pool of its water phase of a small amount of sample analysis
Phenol concentration." ultrafiltration production equipment " is assembled according to Fig. 2, selects the ultrafiltration column core for being suitble to aperture, the principal element of selection is with water-soluble
Free propofol in liquid, especially water phase can pass freely through, and Fat Emulsion cannot be by for Selecting All Parameters.First with isotonic slow
Solution equilibria ultrafiltration column is rushed, propofol fat emulsion is slowly then inputted into ultrafiltration column, adjustable column pressure.Contain free propofol
Aqueous solution penetrates ultrafiltration column, efficiently separates with propofol fat micro emulsion.The solution of missing is supplemented by buffer solution.One
As ensured that by the buffer solution exchange of 10 times of volumes the free propofol in water phase is all removed it is clean.
Embodiment 2: ultrafiltration investigates the applicability of polyethylene glycol propofol fat micro emulsion
The polyethylene glycol propofol fat micro emulsion sample 1000mL prepared according to embodiment 21-24 is taken, takes and analyzes it on a small quantity
Water phase free propofol concentration." ultrafiltration production equipment " is assembled according to Fig. 2, the ultrafiltration column core in suitable aperture is selected, with water-soluble
Liquid can pass freely through, and Fat Emulsion cannot be by for Selecting All Parameters.Isotonic buffer solution equilibria ultrafiltration column is used first, then slowly
By propofol fat emulsion input ultrafiltration column, adjustable column pressure.Aqueous solution containing free propofol penetrates ultrafiltration column, with Propofol
Fatty micro emulsion efficiently separates.The solution of missing is supplemented by buffer solution.Generally pass through the buffer solution of 10 times of volumes
Exchange, which ensures that, all removes the free propofol in water phase completely.
Ultrafiltration will not influence the stability of polyethylene glycol propofol fat micro emulsion, polyethylene glycol will not be caused from fat
Micro emulsion surface falls off.
Method two, different proportion artificial synthesized supplementary material in water phase after redissolution dissociate propofol content investigation.
(1), the proportional region of Propofol and flux oil is investigated
The present invention has carried out verifying to the usage ratio range of listed Propofol and flux oil and has investigated.In technique of the invention
With under the conditions of, the constant rate of the other auxiliary materials of holding, the claims in the present invention Propofol micro emulsion frozen agent is equivalent to containing Propofol
In the unit mass dried frozen aquatic products of 1g, the usage ratio range of flux oil is in 12-35g.Any dosage within the scope of weight content is all
Stable fatty micro emulsion pharmaceutical injection lyophilized preparation can be made in guarantee.
Embodiment 3: the weight ratio of Propofol and artificial synthesized fatty glyceride is 1 ﹕ 12
Prescription:
Propofol 10.0g tripalmitin 120.0g is taken, 12.5g Distearate Phosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 700ml is separately taken, mannitol 22.0g is added.Under nitrogen protection and stirring condition, by third
It moors phenol phosphatide oil solution to be added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous
Pressure is 100MPa, until partial size is less than 180nm, adjusts pH6.0-8.0, and filtering is filling, with brown cillin bottle, preparation freeze-drying system
Agent.
After the propofol fat micro emulsion frozen preparation for taking the above method to prepare redissolves, using in supercentrifugation analysis water phase
Free propofol content.
Embodiment 4: the weight ratio of Propofol and artificial synthesized fatty glyceride is 1 ﹕ 20
Prescription:
Propofol 10.0g tripalmitin 200.0g is taken, 12.5g Distearate Phosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.Under nitrogen protection and stirring condition, by third
It moors phenol phosphatide oil solution to be added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous
Pressure is 100MPa, until partial size is less than 180nm, adjusts pH6.0-8.0, and filtering is filling, with brown cillin bottle, preparation freeze-drying system
Agent.
After the propofol fat micro emulsion frozen preparation for taking the above method to prepare redissolves, using in supercentrifugation analysis water phase
Free propofol content.
Embodiment 5: the weight ratio of Propofol and artificial synthesized fatty glyceride is 1 ﹕ 30
Prescription:
Propofol 10.0g, tripalmitin 300.0g are taken, 12.5g Distearate Phosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.Under nitrogen protection and stirring condition, by third
It moors phenol phosphatide oil solution to be added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous
Pressure is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying
Preparation.
After the propofol fat micro emulsion frozen preparation for taking the above method to prepare redissolves, using in supercentrifugation analysis water phase
Free propofol content.
Embodiment 6: the weight ratio of Propofol and artificial synthesized fatty glyceride is 1 ﹕ 35
Prescription:
Propofol 10.0g, tripalmitin 350.0g are taken, 12.5g Distearate Phosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.Under nitrogen protection and stirring condition, by third
It moors phenol phosphatide oil solution to be added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous
Pressure is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying
Preparation.
After the propofol fat micro emulsion frozen preparation for taking the above method to prepare redissolves, using in supercentrifugation analysis water phase
Free propofol content.
(2), flux oil amount ranges are investigated
Under the premise of guaranteeing that the ratio of Propofol and flux oil does not change, use of the present invention to listed diluent oil
Amount range is verified.The dosage of listed diluent oil is in 5-35% weight content model under the conditions of basic technology of the invention
Any dosage in enclosing all guarantees the novel propofol fat emulsion formulation that stable painless, low injection stimulation can be made.
Embodiment 7: minimum artificial synthesized fatty acid glyceride content is 5% (weight content).
Prescription:
Propofol 2.5g, tripalmitin 50.0g are taken, 12.5g Distearate Phosphatidylcholine is added, heating stirring is about
10-20min is mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.Under nitrogen protection and stirring condition, by the third pool
Phenol phosphatide oil solution is added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous pressure
Power is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying system
Agent.
Embodiment 8: artificial synthesized fatty acid glyceride content is 10.0% (weight content).
Prescription:
Propofol 10g, tripalmitin 100.0g are taken, 12.5g Distearate Phosphatidylcholine is added, heating stirring is about
10-20min is mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.Under nitrogen protection and stirring condition, by the third pool
Phenol phosphatide oil solution is added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous pressure
Power is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying system
Agent.
Embodiment 9: artificial synthesized fatty acid glyceride content is 30.0% (weight content).
Prescription:
Propofol 16.5g, tripalmitin 300.0g are taken, 12.5g Distearate Phosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.Under nitrogen protection and stirring condition, by third
It moors phenol phosphatide oil solution to be added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous
Pressure is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying
Preparation.
Embodiment 10: the artificial synthesized fatty acid glyceride content of highest is 35.0% (weight content).
Prescription:
Propofol 16.5g, tripalmitin 350.0g are taken, 12.5g Distearate Phosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.Under nitrogen protection and stirring condition, by third
It moors phenol phosphatide oil solution to be added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous
Pressure is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying
Preparation.
(3), the investigation of the artificial synthesized phosphatide dosage of emulsifier
Under the premise of guaranteeing that the ratio and flux oil dosage of Propofol and flux oil do not change, the present invention is to listed
The amount ranges of the artificial synthesized phosphatide of emulsifier are verified.The use of listed emulsifier under the conditions of basic technology of the invention
Any dosage within the scope of 0.8-3.2% weight content is measured all to guarantee that the new of stable painless, low injection stimulation can be made
Type propofol fat emulsion formulation.
Embodiment 11: minimum artificial synthesized phosphatide usage amount content is 0.8% (weight content)
Prescription:
Propofol 10.0g, tripalmitin 250.0g are taken, 8.0g Distearate Phosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.Under nitrogen protection and stirring condition, by third
It moors phenol phosphatide oil solution to be added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous
Pressure is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown bottle, preparation freeze-drying system
Agent.
Embodiment 12: artificial synthesized phosphatide usage amount content is 1.25% (weight content)
Prescription:
Propofol 10.0g, tripalmitin 250.0g are taken, 12.5g Distearate Phosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.Under nitrogen protection and stirring condition, by third
It moors phenol phosphatide oil solution to be added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous
Pressure is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying
Preparation.
Embodiment 13: artificial synthesized phosphatide usage amount content is 2.5% (weight content)
Prescription:
Propofol 10.0g, tripalmitin 250.0g are taken, 25g Distearate Phosphatidylcholine is added, heating stirring is about
10-20min is mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.Under nitrogen protection and stirring condition, by the third pool
Phenol phosphatide oil solution is added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous pressure
Power is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying system
Agent.
Embodiment 14: the artificial synthesized phosphatide usage amount content of highest is 3.2% (weight content)
Prescription:
Propofol 10.0g, tripalmitin 250.0g are taken, 32g Distearate Phosphatidylcholine is added, heating stirring is about
10-20min is mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.Under nitrogen protection and stirring condition, by the third pool
Phenol phosphatide oil solution is added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous pressure
Power is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying system
Agent.
(4), using the investigation of different skeletal support agent
Embodiment 15: lactose is 2% (weight content) as skeletal support agent usage amount
Prescription:
Propofol 10.0g, glyceryl linolenate 250.0g are taken, 12.5g dipalmitoylphosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 600ml is separately taken, lactose 20.0g is added.Under nitrogen protection and stirring condition, by the third pool
Phenol phosphatide oil solution is added in lactose aqueous solution, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogenization pressure
PH6.0-8.0 is adjusted until partial size is less than 180nm for 100MPa, filtering is filling, using brown cillin bottle, prepares lyophilized preparation.
Embodiment 16: lactose is 5% (weight content) as skeletal support agent usage amount
Prescription:
Propofol 10.0g, tristerin 250.0g are taken, 12.5g linolenic acid phosphatidyl choline is added, heating stirring is about
10-20min is mixed.Water for injection 600ml is separately taken, lactose 50.0g is added.Under nitrogen protection and stirring condition, by Propofol
Phosphatide oil solution is added in lactose aqueous solution, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogenization pressure is
100MPa adjusts pH6.0-8.0 until partial size is less than 180nm, and filtering is filling, using brown cillin bottle, prepares lyophilized preparation.
Embodiment 17: maltose is 2% (weight content) as skeletal support agent usage amount
Prescription:
Propofol 10.0g, olein 250.0g are taken, 12.5g linoleic acid phosphatidyl choline is added, heating stirring is about
10-20min is mixed.Water for injection 600ml is separately taken, maltose 20.0g is added.Under nitrogen protection and stirring condition, by the third pool
Phenol phosphatide oil solution is added in maltose solution, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous pressure
Power is 100MPa, until partial size is less than 180nm, adjusts pH6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying system
Agent.
Embodiment 18: maltose is 5% (weight content) as skeletal support agent usage amount
Prescription:
Propofol 10.0g, glyceryl linoleate 250.0g are taken, 12.5g dipalmitoylphosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 600ml is separately taken, maltose 50.0g is added.Under nitrogen protection and stirring condition, by third
It moors phenol phosphatide oil solution to be added in maltose solution, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous
Pressure is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying
Preparation.
Embodiment 19: mannitol is 2% (weight content) as skeletal support agent usage amount
Prescription:
Propofol 10.0g, tripalmitin 250.0g are taken, 12.5g Distearate Phosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 600ml is separately taken, mannitol 20.0g is added.Under nitrogen protection and stirring condition, by third
It moors phenol phosphatide oil solution to be added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous
Pressure is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying
Preparation.
Embodiment 20: mannitol is 5% (weight content) as skeletal support agent usage amount
Prescription:
Propofol 10.0g, tripalmitin 250.0g are taken, 12.5g Distearate Phosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 600ml is separately taken, mannitol 50.0g is added.Under nitrogen protection and stirring condition, by third
It moors phenol phosphatide oil solution to be added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogeneous
Pressure is 100MPa, until partial size is less than 180nm, adjusts pH 6.0-8.0, and filtering is filling, uses brown cillin bottle, preparation freeze-drying
Preparation.
Method three is examined using polyethyleneglycol lipid derivates propofol content of dissociating in water phase after preparation redissolves is reduced
It examines
Embodiment 21: the propofol fat micro emulsion frozen preparation of 1% polyethyleneglycol lipid derivates (remembering with weight) is added
Prescription:
Propofol 10.0g, tripalmitin 200.0g are taken, 12.5g Distearate Phosphatidylcholine is added and 10g is (poly-
Ethylene glycol-distearoylphosphatidylethanolamine) DSPE-PEG, heating stirring about 10-20min mixing.Separately take water for injection
Mannitol 22.0g is added in 800ml.Under nitrogen protection and stirring condition, it is water-soluble that mannitol is added in Propofol phosphatide oil solution
In liquid, total amount is adjusted to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogenization pressure 100MPa, than conventional Fat Emulsion system
Agent, partial size are reduced, until particle size range adjusts pH 6.0-8.0 in 50nm-120nm, filtering is filling, uses brown west
Woods bottle, prepares lyophilized preparation.
Embodiment 22: the propofol fat micro emulsion frozen preparation of 5% polyethyleneglycol lipid derivates (remembering with weight) is added
Prescription:
Propofol 10.0g, tripalmitin 200.0g are taken, 12.5g Distearate Phosphatidylcholine is added and 50g is (poly-
Ethylene glycol-distearoylphosphatidylethanolamine) DSPE-PEG, heating stirring about 10-20min mixing.Separately take water for injection
Mannitol 22.0g is added in 800ml.Under nitrogen protection and stirring condition, it is water-soluble that mannitol is added in Propofol phosphatide oil solution
In liquid, total amount is adjusted to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogenization pressure 100MPa, than conventional Fat Emulsion system
Agent, partial size are obviously reduced, until particle size range adjusts pH 6.0-8.0 in 50nm-120nm, filtering is filling, uses brown
Cillin bottle prepares lyophilized preparation.
Embodiment 23: the propofol fat micro emulsion frozen preparation of 10% polyethyleneglycol lipid derivates (remembering with weight) is added
Prescription:
Propofol 10.0g, tripalmitin 200.0g are taken, 12.5g Distearate Phosphatidylcholine is added and 100g is (poly-
Ethylene glycol-distearoylphosphatidylethanolamine) DSPE-PEG, heating stirring about 10-20min mixing.Separately take water for injection
Mannitol 22.0g is added in 800ml.Under nitrogen protection and stirring condition, it is water-soluble that mannitol is added in Propofol phosphatide oil solution
In liquid, total amount is adjusted to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogenization pressure 100MPa, than conventional Fat Emulsion system
Agent, partial size are obviously reduced, until particle size range adjusts pH 6.0-8.0 in 50nm-120nm, filtering is filling, uses brown
Cillin bottle prepares lyophilized preparation.
Embodiment 24: the propofol fat micro emulsion frozen preparation of 15% polyethyleneglycol lipid derivates (remembering with weight) is added
Prescription:
Propofol 10.0g, tripalmitin 200.0g are taken, 12.5g Distearate Phosphatidylcholine is added and 150g is (poly-
Ethylene glycol-distearoylphosphatidylethanolamine) DSPE-PEG, heating stirring about 10-20min mixing.Separately take water for injection
Mannitol 22.0g is added in 800ml.Under nitrogen protection and stirring condition, it is water-soluble that mannitol is added in Propofol phosphatide oil solution
In liquid, total amount is adjusted to 1000ml.Through high pressure homogenizer homogeneous 7-8 times, homogenization pressure 100MPa, than conventional Fat Emulsion system
Agent, partial size are obviously reduced, until particle size range adjusts pH 6.0-8.0 in 50nm-120nm, filtering is filling, uses brown
Cillin bottle prepares lyophilized preparation.
Method four, lyophilized preparation use the investigation of the light durability of colourless cillin bottle and brown cillin bottle
Embodiment 25: the influence using colourless bottle and brown bottle to lyophilized preparation stability
Prescription:
Propofol 10.0g, tripalmitin 200.0g are taken, 12.5g Distearate Phosphatidylcholine, heating stirring is added
About 10-20min is mixed.Water for injection 600ml is separately taken, mannitol 22g is added.Under nitrogen protection and stirring condition, by the third pool
Phenol phosphatide oil solution is added in Osmitrol, adjusts total amount to 100ml.Through high pressure homogenizer homogeneous 7-8 times, homogenization pressure
PH6.0-8.0 is adjusted until partial size is less than 180nm for 100MPa, filtering is filling, and half uses colourless cillin bottle, and half uses
Brown cillin bottle, prepares lyophilized preparation.
The allergic reaction that micro soybean protein or yolk protein are added in method five, novel formulation is investigated
Embodiment 26: adding micro soybean protein in novel formulation, allergic reaction is investigated
Prescription:
Propofol 10.0g, tripalmitin 250.0g are taken, 12.5g Distearate Phosphatidylcholine, soybean protein is added
4mg, heating stirring about 10-20min are mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.In nitrogen protection and stirring
Under the conditions of, Propofol phosphatide oil solution is added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous
7-8 times, homogenization pressure 100MPa, until partial size is less than 180nm, pH 6.0-8.0 is adjusted, filtering is filling, uses brown XiLin
Bottle, prepares lyophilized preparation.
Embodiment 27: adding micro yolk protein in novel formulation, allergic reaction is investigated
Prescription:
Propofol 10.0g, tripalmitin 250.0g are taken, 12.5g Distearate Phosphatidylcholine, yolk protein is added
4mg, heating stirring about 10-20min are mixed.Water for injection 600ml is separately taken, mannitol 22.0g is added.In nitrogen protection and stirring
Under the conditions of, Propofol phosphatide oil solution is added in Osmitrol, adjusts total amount to 1000ml.Through high pressure homogenizer homogeneous
7-8 times, homogenization pressure 100MPa, until partial size is less than 180nm, pH 6.0-8.0 is adjusted, filtering is filling, uses brown XiLin
Bottle, prepares lyophilized preparation.
The propofol fat micro emulsion frozen preparation of various method preparations, allergic reaction and the comparison for reducing injection pain
According to " dissociate in water propofol content measurement after redissolution ", " granularity and determination of particle size distribution " and " third in aforementioned
Moor phenol fat micro emulsion frozen preparation allergy inspection technique " it checks.All embodiments are checked, after product redissolves, in solution
Free propofol aqueous phase content≤4 μ g/ml, Propofol encapsulation rate does not reduce and partial size is respectively less than 180nm and meets the requirements.Allergy
It reacts in the result checked, 0.9% sodium chloride injection control group was attacked in last dose 10 days, and cavy is normal, and nothing is appointed
What allergic reaction occurs, and 5% egg white physiological saline group was attacked in last dose 10 days, cavy occur grabbing first nose, tremble,
Perpendicular hair, expiratory dyspnea, twitch, aconuresis, it is last dead.Death mostly occurred in 2 minutes.Commercially available propofol fat emulsion injection
There is 2 order reaction of an example in liquid large dosage group, grabs nose, trembles, perpendicular hair, cough phenomenon.Make propofol fat micro emulsion frozen system by oneself
Attack is without any symptom, no allergic reaction within agent (embodiment 1-25) last dose 10 days.Embodiment 26,27 is micro- because deliberately adding
Soybean protein and yolk protein are measured, is attacked within last dose 10 days, cavy occurs grabbing nose, trembles, is perpendicular hair, expiratory dyspnea, twitch, small
Fecal incontinence, it is last dead.Death mostly occurred in 2 minutes.It can be seen that the fat prepared using prescription of the invention and preparation method
Micro emulsion frozen preparation can improve the allergic reaction of former preparation, become no allergic reaction novel formulation.
According to aforementioned " important analysis method " neutralization " evaluation test of propofol fat micro emulsion frozen preparation vascular pain "
It specifically describes, gives the femoral artery of Propofol fat micro emulsion frozen sample that commercially available and embodiment is voluntarily prepared to rat respectively, lead to
Cross the degree of the electromyography evaluation vascular pain at the neighbouring position of artery of administration sample.It is administered before propofol fat sample
Start electromyography record.1 hour after to operation, commercially available Propofol rouge is administered by intubation in electromyography waveform stabilization respectively
Fat cream and the embodiment sample of preparation of the embodiment of the present invention, record electromyogram, and calculate the peak in electromyogram respectively after administration
Lower area.The value of every rat of each group is measured compared with commercially available reference medicine, to determine its " electromyogram area ratio ", with (%) table
Show, indicates the index of vascular pain.When the index is less than 100%, show compared with commercially available propofol fat emulsion injection
Vascular pain mitigates.And index (electromyogram area ratio) is smaller, it is better that vascular pain mitigates effect.
Area under the electromyogram peak of area and commercial samples under the peak of the electromyogram of Fig. 6, invention laboratory sample method 1-4
Ratio.
1), the sample (embodiment 1) of hyperfiltration process preparation；
2), increase the sample (embodiment 14) of phosphatide dosage preparation；
3), the sample (embodiment 24) prepared using polyethyleneglycol lipid derivates；
4), using the sample (embodiment 10) of oil preparation at high proportion.
" EDTA, sulphite, the propofol fat micro-emulsion injecta of thiosulfate and freeze-drying is not added to make according in aforementioned
The comparison of agent germ contamination " checks that observation result is visible:
It is inoculated with sterile length of being born in the culture dish of C；It is inoculated in the culture dish of A or B, extension rate is bigger, raw in culture dish
Long bacterial population is fewer；It is inoculated with total number of bacteria in the culture medium of the A of same extension rate and is significantly more than the culture dish for being inoculated with B.It can
After seeing sample preparation into lyophilized preparation, bacterial growth can obviously reduce.
According to " Propofol fat emulsion injection quality standard " to method 7, using colourless bottle and the freeze-drying of brown bottle is used
Preparation, carry out 5 days and 10 days influence factor exposure experiments to light investigation.
As seen from the experiment, more stable using colourless cillin bottle properties of samples using brown cillin bottle ratio.Because of Propofol
It containing phenolic hydroxyl group, is easily oxidized, the degradation of Propofol can be effectively prevented using brown bottle[12]。
In summary as a result, having been effectively removed using Propofol phenol fat micro emulsion frozen preparation prepared by the present invention possible
Sensitization source, no allergic reaction；Reduce the Propofol that water phase is free after redissolving, reduce to vascular stimulation, it will be apparent that mitigates blood vessel
Injection pain, wherein ultrafiltration, polyethylene glycol reduce the effect of pain clearly.Particular note is that the sample of ultrafiltration is basic
On can remove feeling of pain.The method (dosage for increasing phosphatide or oil) for promoting solubility property of the Propofol in solvent can also rise
To certain effect, but effect is obvious not as good as directly removal free drug.Lyophilized preparation is made in sample and solves no antioxidant
Protect the problem of the oxidative degradation of lower Propofol and auxiliary material；Light degradation when storage can be effectively reduced using brown cillin bottle.It is logical
It crosses the above method our available no sensitizations, without the novel propofol fat micro emulsion frozen preparation of injection pain, and makes the system
Agent safety is higher.
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Claims (1)
1. a kind of no sensitization, painless propofol fat micro emulsion frozen preparation, are prepared from the following components:
The preparation method is as follows:
Propofol 10.0g, tripalmitin 200.0g are taken, 12.5g Distearate Phosphatidylcholine and the poly- second two of 150g is added
Alcohol-distearoylphosphatidylethanolamine, heating stirring 10-20min are mixed, and obtain Propofol phosphatide oil solution；Separately take injection
With water 800ml, mannitol 22.0g is added, Osmitrol is obtained, under nitrogen protection and stirring condition, by Propofol phosphorus
Oil solution is added in Osmitrol, adjusts total amount to 1000ml, and through high pressure homogenizer homogeneous 7-8 times, homogenization pressure is
100MPa, until particle size range adjusts pH 6.0-8.0 in 50nm-120nm, filtering is filling, and using brown cillin bottle, preparation is frozen
Dry preparation.
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| CN105287406B (en) * | 2015-11-17 | 2018-12-04 | 西安力邦肇新生物科技有限公司 | A kind of Propofol lipidosome freeze-dried preparation and preparation method thereof |
| CN106214668B (en) * | 2016-07-21 | 2019-12-03 | 西安力邦制药有限公司 | Propofol flexible nano-liposomes patch and its application |
| CN108254450A (en) * | 2016-12-29 | 2018-07-06 | 上海医药集团股份有限公司 | In Propofol/detection method of long chain fat emulsion injection envelop rate |
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| CA2474710A1 (en) * | 2002-02-01 | 2003-08-07 | Shimoda Biotech (Pty) Ltd | Freeze-dried pharmaceutically acceptable inclusion complexes of propofol and cyclodextrin |
| CN101006992A (en) * | 2006-01-27 | 2007-08-01 | 姚瑶 | Propofol freeze-dried emulsion and its preparing method |
| CN102085185A (en) * | 2010-12-07 | 2011-06-08 | 西安力邦制药有限公司 | Formula and preparation method of novel propofol fat emulsion preparation causing no pain and low injection stimulation |
| EP1748759B1 (en) * | 2004-04-27 | 2013-03-27 | Javeri, Indu | Methods of enhancing solubility in water of hydrophobic compounds by micellar dispersions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2474710A1 (en) * | 2002-02-01 | 2003-08-07 | Shimoda Biotech (Pty) Ltd | Freeze-dried pharmaceutically acceptable inclusion complexes of propofol and cyclodextrin |
| EP1748759B1 (en) * | 2004-04-27 | 2013-03-27 | Javeri, Indu | Methods of enhancing solubility in water of hydrophobic compounds by micellar dispersions |
| CN101006992A (en) * | 2006-01-27 | 2007-08-01 | 姚瑶 | Propofol freeze-dried emulsion and its preparing method |
| CN102085185A (en) * | 2010-12-07 | 2011-06-08 | 西安力邦制药有限公司 | Formula and preparation method of novel propofol fat emulsion preparation causing no pain and low injection stimulation |
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