CN106491533A - A kind of stable flurbiprofen axetil composition and preparation method - Google Patents
A kind of stable flurbiprofen axetil composition and preparation method Download PDFInfo
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
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Abstract
The invention discloses a kind of stable flurbiprofen axetil composition and preparation method thereof, said composition contains the additive of active medicinal matter flurbiprofen axetil and least kind, by the innovation of preparation technology program and parameter, shorten the manufacturing cycle, improve composition freeze-thaw stability and heat endurance, drug degradation is reduced, security, the reducing energy consumption of clinical application is improve.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of stable flurbiprofen axetil composition and its preparation side
Method.
Background technology
Flurbiprofen axetil (Flurbiprofen Axet), is the pro-drug of Flurbiprofen, acts on through Carboxylesterase in vivo
Rapid hydrolysis generates Flurbiprofen, suppresses the synthesis of prostaglandin by Flurbiprofen and plays analgesia, anti-inflammatory and refrigeration function.
Due to flurbiprofen axetil water insoluble, therefore the florfenicol residues of clinical practice be emulsion type injection, emulsion-type note
The most frequently used emulsifying agent of liquid is penetrated for phosphatide, phosphatide is very easy to oxidation, need less than -20 DEG C inflated with nitrogen to preserve, prepared in emulsion
In journey, phosphatide is very easy to be oxidized to aldoketones material cause human body hepatic disorder, is required in emulsion similar drug quality standard
Control aldoketones degradation material, it is also that vast researcher has to gram that therefore at present emulsion preparation technology prevents phospholipid oxidation
The technology barrier of clothes.While emulsion belongs to heterogeneous liquid preparation easily produces phenomenon of phase separation impact medicine stability, not
In stable emulsion systems, Flurbiprofen ester hydrolysis generate Flurbiprofen and 1- hydroxyethyls, and the latter is further degraded into second
Acid and formaldehyde, so that affect the security of preparation.How to prevent phospholipids degradation and ensure that emulsion systems stability is urgently to be resolved hurrily
Problem.
The existing at present technique that most simplifies be two steps into newborn method：Flurbiprofen axetil, lecithin add 50-70 DEG C of soybean oil
High speed shear forms oil phase, and glycerine, disodium hydrogen phosphate, citric acid are soluble in water to form water phase.The first step, oil phase under high speed shear
Water is added mutually to make colostrum；Second step, colostrum is high-pressure homogeneous to make homogenizing fluid.121 DEG C of homogenizing fluid, 15min sterilize to form fluorine ratio
Ibuprofen ester emulsion.In terms of florfenicol residues stability is improved, most of researcher employs increase assistant for emulsifying agent, steady
The method for determining agent, belongs to surfactant these additives more and easily causes the clinical safety hidden danger such as haemolysis, such as CN
104706575 A increase high surfactant, antioxidant；104784115 A of CN increase oleic acid, F68,104188905 A of CN
Increase oleic acid, VE, 105919949 A of CN increase oleic acid etc., and oleic acid has haemolysis and causes acidosic risk.Also there is researcher
The thinking of optimize technique is employed, phosphatide is changed to be soluble in the aqueous phase by such as CN102988291A, although improve phosphatide dispersion effect
Really, the dispersion but for the phosphatide for easily aoxidizing in water will aggravate phospholipid oxidation degree significantly, while preparing in colostrum
Due to water-oil phase volume great disparity during emulsification pretreatment, the oil phase added during high speed shear is easy to mutually to be occurred in water
Diffusion, it is difficult to gather mechanical shearing position, shearing machine is oil-in-water to emulsion low into newborn process mechanical efficiency, shows as
Colostrum is fuel-displaced substantially, and after sterilizing, emulsion freeze thawing is unstable, and extremely frigid zones medicine accumulating has great quality risk.
Content of the invention
In order to overcome the disadvantages mentioned above of flurbiprofen axetil fat emulsion injection, the present invention is led in the case where prescription is constant
Innovation emulsification manufacturing process is crossed, keeps phosphatide to be dispersed in oil phase, oil film obstruct phosphatide is formed around phosphatide and is contacted with oxygen；Change
Become the oil phase that generally adopts add water mutually to make colostrum in advance, further high-pressure homogeneous two step emulsifying process for making homogenizing fluid,
Emulsification is realized synchronous under certain flow to oil phase and water through the online step of high pressure homogenizer；Work is prepared by omitting colostrum
Sequence can saving energy consumption, greatly shorten the phosphatide process-cycle, reduce phospholipid oxidation, lift emulsifying effectiveness, novelty by control
Water phase, oil phase flow directly realize a step into breast by homogenizer, so that final emulsion products freeze-thaw stability, drug degradation
Less, phospholipid oxidation is little, improves stability, the security of flurbiprofen axetil emulsion, reducing energy consumption.
A kind of stable flurbiprofen axetil composition of the present invention ultimately forms the fat emulsion in pharmacy, clinical
Above it is used for the analgesia medication of postoperative and cancer.
Technical solution of the present invention is as follows：
A kind of preparation method of stable flurbiprofen axetil composition, the component of said composition include that active medicine fluorine compares Lip river
Fragrant ester, emulsifying agent, oil for injection, osmotic pressure regulator, pH adjusting agent and water for injection etc., preparation method is comprised the following steps：
1), under nitrogen protection, flurbiprofen axetil, emulsifying agent high speed shear is dissolved in oil for injection, oil phase is made；
2) osmotic pressure regulator, pH adjusting agent are dissolved in water for injection, make water phase；
3) under nitrogen protection, by oil phase, water according to flow-rate ratio 1:1-1:2 simultaneous implantation high pressure homogenizer emulsifyings,
Homogenizing fluid is made, control homogenizing process homogeneous liquid temp is less than 30 DEG C；Homogeneous is finished, and adds remaining water phase in homogenizing fluid,
Mix；
4) by step 3) gained homogenizing fluid embedding (for example embedding is in ampoule), sterilizing (such as 121 DEG C, 15min is damp and hot goes out
Bacterium), make florfenicol residues.
In above-mentioned preparation method,
Preferably, in composition flurbiprofen axetil mass fraction be 0.1%-5%, more preferably 1%.
Preferably, in composition oil for injection mass fraction be 5%-20%, more preferably 10%.
Preferably, the oil for injection is selected from soybean oil, midchain oil, fish oil, brucea fruit oil, olive oil, safflower oil, castor-oil plant
One kind in oil, corn oil, more preferably soybean oil.
Preferably, in composition emulsifying agent mass fraction be 1%-3%, more preferably 1.2%.
Preferably, the one kind of the emulsifying agent in lecithin, Fabaceous Lecithin, phosphatidylserine, more preferably
Lecithin.
Preferably, in composition osmotic pressure regulator mass fraction be 1%-3%, more preferably 2.2%.
Preferably, the one kind of the osmotic pressure regulator in glycerine, propane diols, PEG400, more preferably sweet
Oil.
Preferably, the pH adjusting agent is disodium hydrogen phosphate-citric acid, and sodium citrate-acetic acid, in sodium acetate-hydrochloric acid
Any one group of composition buffer salt.
It is further preferred that the pH adjusting agent be disodium hydrogen phosphate-citric acid according to mol ratio 5:The buffering of 1 composition
Salt.
It is further preferred that pH adjusting agent mass fraction described in composition is 0.04%-0.24%, still more preferably
For 0.08%.
Preferably, step 1) high speed shear rotating speed be 8000-16000rpm.
Preferably, step 3) homogeneous low pressure be 80bar, high pressure is 600-900bar.
Preferably, step 3) homogeneous 2-4 time.
Used as a kind of preferred scheme, in the composition, flurbiprofen axetil mass fraction is 1%；The oil for injection is
Soybean oil, mass fraction are 10%；The emulsifying agent is lecithin, and mass fraction is 1.2%；The osmotic pressure regulator is sweet
Oil, mass fraction are 2.2%；The pH adjusting agent be disodium hydrogen phosphate, citric acid according to mol ratio 5:The buffer salt of 1 composition,
Mass fraction is 0.08%.
As a kind of specific scheme, in the composition, contain flurbiprofen axetil 6g, lecithin 7.2g, soybean oil
60mL, glycerine 13.2g, disodium hydrogen phosphate 0.43g, citric acid 0.05g, water for injection 520mL.
As another kind of specific scheme, in the composition, contain flurbiprofen axetil 0.6g, lecithin 6g, soybean oil
30mL, glycerine 6g, disodium hydrogen phosphate 0.215g, citric acid 0.025g, water for injection 550mL.
As another kind of specific scheme, in the composition, contain flurbiprofen axetil 30g, lecithin 18g, soybean oil
120mL, glycerine 18g, disodium hydrogen phosphate 1.29g, citric acid 0.15g, water for injection 430mL.
Specifically, above-mentioned preparation method is comprised the following steps：
1), under nitrogen protection, flurbiprofen axetil, emulsifying agent are dissolved in injection under 8000-16000r/min high speed shears
In oil, oil phase is made；
2) osmotic pressure regulator, pH adjusting agent are dissolved in water for injection, make water phase；
3) under nitrogen protection, by oil phase, water according to flow-rate ratio 1:1-1:2 simultaneous implantation high pressure homogenizer homogeneous are newborn online
Change 2-4 time, make homogenizing fluid, control homogenizing process homogeneous liquid temp is less than 30 DEG C；Homogeneous is finished, and is added surplus in homogenizing fluid
Yu Shuixiang, mixes；
4) by step 3) in ampoule, 121 DEG C, 15min moist heat sterilizations make flurbiprofen axetil note for gained homogenizing fluid embedding
Penetrate liquid.
Present invention additionally comprises the flurbiprofen axetil composition (i.e. parenteral solution) that said method is prepared.
Flurbiprofen axetil composition obtained by the inventive method, on the premise of prescription is constant, is optimized to newborn step, maximum
Limit prevents phospholipid oxidation, greatly improves emulsion particles into newborn effect, improves emulsion heat endurance, freeze-thaw stability, improves
Clinical application security, reduces manufacturing cost.
Specific embodiment
Following examples are used for the present invention to be described, but are not limited to the scope of the present invention.Unreceipted concrete in embodiment
Technology or condition person, according to technology or condition described by document in the art, or are carried out according to product description.Used
Reagent or the unreceipted production firm person of instrument, are the conventional products that can be commercially available by regular distributor.
Cutter FLUKO used below, Germany；Homogenizer GEA Niro Soavi S.P.A, Italy.
Aldehyde material detection method：
Less than 20 DEG C operate.Precision measures this product 10mL and puts in separatory funnel, plus ethanol 5mL, mixes, plus sodium chloride is a little
And ether 20mL, acutely shake.Stratification, upper liquid is transferred in flask, and water layer ether is extracted twice each 10mL,
Merge ether solution.Ether is concentrated into below 40 DEG C with Rotary Evaporators to steam to the greatest extent, plus ethyl acetate rotates again for 2 times and is evaporated, every time
10mL.Residue adds isooctane to make to dissolve and shift to put in 25mL measuring bottles to be diluted to scale with isooctane, plus anhydrous sodium sulfate is de-
Water, filtration, used as need testing solution；Precision measures 10mL and puts in brown tool plug test tube, as need testing solution pipe；Another accurate amount
Take isooctane solution 10mL to put in brown tool plug test tube, as blank tube.Precision adds 0.25% 4- aminoanisoles respectively
Glacial acetic acid solution (face with newly match somebody with somebody) 2mL, shaking, after lucifuge accurately places 10 minutes, immediately according to UV-VIS spectrophotometry
(Chinese Pharmacopoeia two annex IV A of version in 2015), with blank tube solution as blank determination need testing solution at 350nm wavelength
The absorbance (A) of pipe solution, absorbance (A of the isooctane solution for blank determination need testing solution0).
It is calculated as follows.
Computing formula：
In formula：Sampling amounts of the V for test sample, mL
B be need testing solution in grease labelled amount in terms of oil phase, g/mL.
Flurbiprofen axetil degradation impurity detection method：
Chromatographic condition and system suitability test are filler with octadecylsilylated bonded silica gel；With acetonitrile-water-
Glacial acetic acid mixed liquor (1200: 800: 3) be mobile phase, 40 DEG C of column temperature；Detection wavelength is 254nm.Number of theoretical plate is with Flurbiprofen
Ester is calculated, and should be not less than 2000, and flurbiprofen axetil should meet the requirements with the separating degree at internal standard peak, and two mappings of flurbiprofen axetil are stood
The separating degree of body isomers should be greater than 1.0.
Inner mark solution with producing biphenyl, plus solution of every 1mL containing 1mg made by absolute ethyl alcohol, obtains final product.
Determination method learns from else's experience the drying under reduced pressure Flurbiprofen reference substance of 4 hours in right amount, plus absolute ethyl alcohol is made in every 1mL and contained
The solution of 1mg, precision measure 1mL and put in 100mL measuring bottles, accurate addition inner mark solution 2mL, are diluted to scale with absolute ethyl alcohol,
Shake up, as reference substance solution.Precision measures this product 1mL, puts in 100mL measuring bottles, accurate add inner mark solution 2mL, with anhydrous
Ethanol is diluted to scale, shakes up, as need testing solution.Determine according to the method under assay item, precision measures above two
The each 10 μ l of solution, are injected separately into liquid chromatograph, record chromatogram, by internal standard method with calculated by peak area, fluorine-containing in the every 1mL of this product
0.74mg must not be crossed than ibuprofen.
Free-fat assays：
The preparation of reference substance solution takes palmitic acid 0.64g, accurately weighed, puts in 500mL measuring bottles, dissolves simultaneously with normal heptane
Scale is diluted to, is shaken up, precision measures 1mL, put in 20mL tool plug test tubes, accurate addition mixed liquor 5mL shakes 1 minute, places
10 minutes, then precision adds normal heptane 2mL, water 4mL, close plug to spin upside down 10 times respectively, stands more than 15 minutes, makes layering,
Divide and take upper solution, obtain final product.
The preparation precision of need testing solution measures this product 1mL, puts in 20mL tool plug test tubes, accurate addition mixed liquor 5mL,
Shaking 1 minute, places 10 minutes, then respectively accurate add normal heptane and each 3mL of water, spin upside down 10 times, stand 15 minutes with
On, layering is made, is divided and is taken upper solution, obtain final product.
Determination method precision measures reference substance solution and each 3mL of need testing solution, puts in 10mL centrifuge tubes, plus Nile blue refers to
Show liquid 1mL, under logical condition of nitrogen gas, the aobvious lavender of solution is titrated to sodium hydroxide titration liquid (0.01mol/L), by titration knot
Consume titrating solution milliliter number to be corrected needed for fruit Flurbiprofen.In need testing solution, free fatty consumes NaOH drop
The milliliter number for determining liquid (0.01mol/L) cannot be greater than the milliliter number that comparison liquid consumes sodium hydroxide titration liquid (0.01mol/L).Per
1mg Flurbiprofens need to consume sodium hydroxide titration liquid (0.01mol/L) 0.4094mL.
Correlative study is tested
Imported product florfenicol residues (ROPION, Japan) specification prescription is ground with reference to original, supplementary material includes fluorine
Than ibuprofen ester, lecithin, soybean oil, glycerine, disodium hydrogen phosphate, citric acid, technique study is prepared.
1st, into the screening of newborn mode and two phase flow
It is, under water phase high speed shear, oil phase is slowly added to water phase that usual two step is prepared into the colostrum of newborn method, easily causes
Oil phase is difficult to gather shears position, it is impossible to realize effectively emulsifying, and after showing as emulsification, colostrum standing is fuel-displaced rapidly, passes through immediately
The high-pressure homogeneous effect times of second step is so undesirable, makes the degraded of emulsion active ingredient soon, and freeze thawing particle diameter becomes fuel-displaced greatly；The present invention one
Walk into newborn method and realize that water phase, oil phase are fully contacted efficient breast at the even position of homogenizer mechanical shearing breast by way of on-line mixing
Change, form void effect, shearing effect, concrete test method is：Take flurbiprofen axetil 6g, lecithin 7.2g (Japan
Q.P.Corporation, FC Plant) soybean oil 60mL is added, the lower 10000r/min high speed shears of nitrogen protection dissolve oily
Phase；Take glycerine 13.2g, disodium hydrogen phosphate 0.43g, citric acid 0.05g and be dissolved in 520mL water obtaining water phase.Following techniques are pressed respectively
Prepare sample：
Sample 1：In 10000r/min high speed shears, oil phase is slowly added to water and mutually obtains colostrum, colostrum the lower water of nitrogen protection
Through 900bar homogeneous 4 times, in ampoule, 121 DEG C of 15min sterilize to obtain sample 1 for 5mL/ embedding；
Sample 2：After oil phase adds water phase, under nitrogen protection, homogenizer is input into, 350bar homogeneous obtains colostrum for 1 time, and colostrum is passed through
900bar homogeneous 4 times, in ampoule, 121 DEG C of 15min sterilize to obtain sample 2 for 5mL/ embeddings；
Sample 3-6：Under nitrogen protection, oil phase, aqueous phase stream amount is controlled respectively for 2:1、1:1、1:2、1:3 is synchronous through high pressure
The 3 times emulsification of the online 900bar homogeneous of homogenizer, adds remaining water mutually to mix, and in ampoule, 121 DEG C of 15min go out for 5mL/ embedding
Bacterium obtains sample 3-6.Taking 1-6 samples carries out freezing-thawing test：2 days, 40 DEG C of high temperature 2 days are freezed in -18 DEG C, is circulated 3 times.Using
2000 laser particle size analyzers of Mastersizer detect particle diameter, investigate proterties after shear-mixed, proterties, particle diameter and jelly after sterilizing
Melt rear particle diameter and see the table below Y1.
Table Y1
As a result show, the two steps breast of shearing, homogeneous after oil phase adds water phase and oil phase mixed with water in shear history
After change method freeze thawing, particle diameter increases substantially；Oil phase mutually presses 1 with water:1-1:2 flows injection, one step of homogenizer can be played preferably into breast
Emulsifying effectiveness, can ensure the freeze-thaw stability of emulsion.
2nd, lecithin dissolution mechanism contrast test
Preserve as lecithin requires less than -20 DEG C, even if also easily oxidation, hydrolysis at normal temperatures, not only reduces its breast
Change effect, and the aldehyde type impurities produced by phospholipids degradation also seriously threatens human health, therefore must prevent in emulsion process
Phosphatide and oxygen and contact with moisture, this experiment is using on-line shearing emulsifying process, control oil phase, water phase 1:1 flow, have studied phosphorus
Fat dissolves gained emulsion aldehyde matter content difference in water phase and in oil phase.Specifically test method is：Take flurbiprofen axetil 6g to add
Enter soybean oil 60mL, stirring and dissolving obtains oil phase；Take glycerine 13.2g, lecithin 7.2g, disodium hydrogen phosphate 0.43g, citric acid
0.05g is dissolved in 520mL water, and the lower 10000r/min high speed shears of nitrogen protection obtain water phase.Oil phase, water phase 1:The injection of 1 flow is high
The online 900bar homogeneous of pressure homogenizer 3 times, in ampoule, 121 DEG C of 15min sterilize to obtain sample 7, take 7 He of sample for 5mL/ embedding
Aforementioned sample 4 determines the amount of aldehyde material with UV detector, as a result see the table below Y2.
Table Y2
| Sample number | Phosphatide dissolution mechanism | Particle diameter after sterilizing | The amount of aldehyde material |
| 4 | Phosphatide is dissolved in oil phase | 208nm | 1.73 |
| 7 | Phosphatide is soluble in the aqueous phase | 211nm | 6.74 |
Knowable to upper table Y2, phosphatide adds oil phase to considerably reduce the generation of phospholipid oxidation product.
It is exemplified below specific embodiment and flurbiprofen axetil composition of the present invention and preparation method thereof is described, tested number is about
600mL, but the present invention is not limited in following embodiments.
Embodiment 1
Under nitrogen protection, flurbiprofen axetil 6g, lecithin 7.2g is taken high in cutter (FLUKO, Germany) 13000r/min
60mL soybean oils are dissolved under speed shearing obtain oil phase；Take glycerine 13.2g, disodium hydrogen phosphate 0.43g, citric acid 0.05g and be dissolved in 520mL
Water phase is obtained in water for injection.Under nitrogen protection, homogenizer (GEA Niro Soavi S.P.A, Italy) low pressure 80bar high pressure
900bar, process homogeneous liquid temp control oil phase, aqueous phase stream amount for 1 less than 30 DEG C:1 simultaneous implantation high pressure homogenizer is online
Emulsification 2 times, adds remaining water mutually to mix to obtain homogenizing fluid, and 5mL/ inflated with nitrogen embedding puts rotary water-bath sterilization cabinet in ampoule
121 DEG C, 15min sterilizings.
Embodiment 2
Under nitrogen protection, 8000r/min is at a high speed in cutter (FLUKO, Germany) to take flurbiprofen axetil 0.6g, lecithin 6g
30mL soybean oils are dissolved under shearing obtains oil phase；Take glycerine 6g, disodium hydrogen phosphate 0.215g, citric acid 0.025g and be dissolved in 550mL notes
Penetrate with water water phase.Under nitrogen protection, homogenizer (GEA Niro Soavi S.P.A, Italy) low pressure 80bar high pressure
600bar, process homogeneous liquid temp control oil phase, aqueous phase stream amount for 1 less than 30 DEG C:1 simultaneous implantation high pressure homogenizer is online
Emulsification 4 times, adds remaining water mutually to mix to obtain homogenizing fluid, and 5mL/ inflated with nitrogen embedding puts rotary water-bath sterilization cabinet in ampoule
121 DEG C, 15min sterilizings.
Embodiment 3
Under nitrogen protection, flurbiprofen axetil 30g, lecithin 18g is taken high in cutter (FLUKO, Germany) 16000r/min
120mL soybean oils are dissolved under speed shearing obtain oil phase；Take glycerine 18g, disodium hydrogen phosphate 1.29g, citric acid 0.15g and be dissolved in 430mL
Water phase is obtained in water for injection.Under nitrogen protection, homogenizer (GEA Niro Soavi S.P.A, Italy) low pressure 80bar high pressure
800bar, process homogeneous liquid temp control oil phase, aqueous phase stream amount for 1 less than 30 DEG C:2 simultaneous implantation high pressure homogenizers are online
Emulsification 3 times, adds remaining water mutually to mix to obtain homogenizing fluid, and 5mL/ inflated with nitrogen embedding puts rotary water-bath sterilization cabinet in ampoule
121 DEG C, 15min sterilizings.
Embodiment 4
Under nitrogen protection, flurbiprofen axetil 6g, Fabaceous Lecithin 7.2g is taken, high in cutter (FLUKO, Germany) 13000r/min
60mL midchain oils are dissolved under speed shearing obtain oil phase；Take propane diols 13.2g, sodium acetate 0.44g, hydrochloric acid 0.05mL and be dissolved in 520mL notes
Penetrate with water water phase.Under nitrogen protection, homogenizer (GEA Niro Soavi S.P.A, Italy) low pressure 80bar high pressure
800bar, process homogeneous liquid temp control oil phase, aqueous phase stream amount for 1 less than 30 DEG C:1 simultaneous implantation high pressure homogenizer is online
Emulsification 3 times, adds remaining water mutually to mix to obtain homogenizing fluid, and 5mL/ inflated with nitrogen embedding puts rotary water-bath sterilization cabinet in ampoule
121 DEG C, 15min sterilizings.
Embodiment 5
Under nitrogen protection, flurbiprofen axetil 6g, phosphatidylserine 7.2g is taken in cutter (FLUKO, Germany) 10000r/
60mL fish oil is dissolved under min high speed shears obtains oil phase；Take PEG40012g, sodium citrate 0.46g, acetic acid 0.02g are dissolved in 520mL
Water phase is obtained in water for injection.Under nitrogen protection, homogenizer (GEA Niro Soavi S.P.A, Italy) low pressure 80bar high pressure
900bar, process homogeneous liquid temp control oil phase, aqueous phase stream amount for 1 less than 30 DEG C:2 simultaneous implantation high pressure homogenizers are online
Emulsification 3 times, adds remaining water mutually to mix to obtain homogenizing fluid, and 5mL/ inflated with nitrogen embedding puts rotary water-bath sterilization cabinet in ampoule
121 DEG C, 15min sterilizings.
Embodiment 6
Under nitrogen protection, flurbiprofen axetil 6g, lecithin 12g is taken, high in cutter (FLUKO, Germany) 13000r/min
90mL corn oils are dissolved under speed shearing obtain oil phase；Take glycerine 13.2g, disodium hydrogen phosphate 0.41g, citric acid 0.05g and be dissolved in 480mL
Water phase is obtained in water.Under nitrogen protection, homogenizer (GEA Niro Soavi S.P.A, Italy) low pressure 80bar high pressure 800bar,
Process homogeneous liquid temp controls oil phase, aqueous phase stream amount for 1 less than 30 DEG C:1 simultaneous implantation high pressure homogenizer online-emulsification 4 times,
Add remaining water mutually to mix to obtain homogenizing fluid, 5mL/ inflated with nitrogen embedding in ampoule, put 121 DEG C of rotary water-bath sterilization cabinet,
15min sterilizes.
Comparative example 1
Under nitrogen protection, flurbiprofen axetil 6g, lecithin 7.2g is taken, high in cutter (FLUKO, Germany) 13000r/min
60mL soybean oils are dissolved under speed shearing obtain oil phase；Take glycerine 13.2g, disodium hydrogen phosphate 0.41g, citric acid 0.05g and be dissolved in 520mL
Water phase is obtained in water for injection；Under nitrogen protection, oil phase is slowly added into during water phase 13000r/min high speed shear and makes colostrum；
Homogenizer (GEA Niro Soavi S.P.A, Italy) low pressure 80bar high pressure 800bar, process homogeneous liquid temp are less than 30
DEG C, colostrum injection high pressure homogenizer homogeneous is obtained homogenizing fluid for 3 times, 5mL/ inflated with nitrogen embedding puts rotary water-bath in ampoule
121 DEG C of sterilizing cabinet, 15min sterilizings.
Comparative example 2
Under nitrogen protection, take flurbiprofen axetil 6g and be dissolved in 60mL soybean oils and obtain oil phase；Take glycerine 13.2g, disodium hydrogen phosphate
0.41g, citric acid 0.05g are dissolved in 520mL waters for injection, under nitrogen protection, add lecithin 7.2g, in cutter
Water phase is obtained under (FLUKO, Germany) 13000r/min high speed shears；Oil is slowly added into during water phase 13000r/min high speed shear
Colostrum is mutually made；Homogenizer (GEA Niro Soavi S.P.A, Italy) low pressure 80bar high pressure 800bar, process homogenizing fluid
Temperature is less than 30 DEG C, by colostrum injection high pressure homogenizer homogeneous 3 times homogenizing fluid, 5mL/ inflated with nitrogen embedding in ampoule,
Put 121 DEG C of rotary water-bath sterilization cabinet, 15min sterilizings.
Flurbiprofen axetil composition prescription of the present invention is simple, and technique simplifies, and improves product heat endurance, freeze-thaw stability
Prominent effect is produced in terms of property, these effects will be verified in following test examples.
1 florfenicol residues hot test of test example
According to national drug stability study technological guidance's principles and requirements, Example 1, comparative example 1,2 gained of comparative example
The original of flurbiprofen axetil emulsion and Japanese scientific research Industrial Co., Ltd grinds florfenicol residues (ROPIONTM, 155340), in
Place 10 days in 60 DEG C of study on the stability instrument, after 10 days, take out observation proterties, detection flurbiprofen axetil degradation impurity, aldehydes
Matter, free fatty acid content.Test by aforementioned detection method, investigate result and see the table below S1.
Table S1
Knowable to upper table S1 achievement data, either phosphatide be dissolved in oil be also dispersed in water, by oil phase addition water mutually make
After colostrum, two steps of emulsifying again assume obvious thermal instability into newborn method gained emulsion, and one step of flow is into breast in proportion
Method gained emulsion stability significantly breaks through.
2 florfenicol residues freezing-thawing test of test example
The original of Example 3, comparative example 1,2 gained emulsion of comparative example and Japanese scientific research Industrial Co., Ltd grinds Flurbiprofen
Ester injection (ROPIONTM, 155340) freeze in -20 DEG C and heat 2 days for 2 days, 40 DEG C, be repeated 3 times, first and third taking-up sight afterwards
Emulsion proterties after freeze thawing is examined, particle diameter is detected, as a result be see the table below S2.
Table S2
From the experimental results, comparative example is difficult to tolerate freeze thawing change, and 3 florfenicol residues of embodiment are ground with day basis
The feature of white " milky " liquid is maintained after ROPION freeze thawing, especially grinds particle diameter with day basis than resulting composition particle diameter of the present invention
Substantially do not affected by freeze thawing, more preferable security is shown to the change of extremely frigid zones temperature.
3 florfenicol residues storage stability test of test example
Example 1, comparative example 2, day basis grind ROPION and place 24 months in 30 DEG C ± 2 DEG C, investigate known degraded miscellaneous
Matter Flurbiprofen, as a result see the table below S3.
Table S3
From investigating in terms of data, require that 30 DEG C ± 2 DEG C investigation degradation impurities should mistake according to medicine normal temperature storage condition
The bound requirements of 0.74mg/mL, embodiment 1 grind ROPION than having more stability in 24 months effect phases, effectively with comparative example 2, original
Property, assume obvious clinical benefit.
Although, above the present invention is described in detail with a general description of the specific embodiments,
On the basis of the present invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Cause
This, these modifications or improvements, belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1. a kind of preparation method of stable flurbiprofen axetil composition, the component of said composition include active medicine Flurbiprofen
Ester, emulsifying agent, oil for injection, osmotic pressure regulator, pH adjusting agent and water for injection, it is characterised in that preparation method include with
Lower step：
1), under nitrogen protection, flurbiprofen axetil, emulsifying agent high speed shear is dissolved in oil for injection, oil phase is made；
2) osmotic pressure regulator, pH adjusting agent are dissolved in water for injection, make water phase；
3) under nitrogen protection, by oil phase, water according to flow-rate ratio 1:1-1:2 simultaneous implantation high pressure homogenizer emulsifyings, make
Homogenizing fluid, control homogenizing process homogeneous liquid temp are less than 30 DEG C；Homogeneous is finished, and adds remaining water phase, mix in homogenizing fluid；
4) by step 3) gained homogenizing fluid embedding, sterilize, make florfenicol residues.
2. preparation method according to claim 1, it is characterised in that
Step 1) high speed shear rotating speed be 8000-16000rpm；And/or,
Step 3) homogeneous low pressure be 80bar, high pressure is 600-900bar；And/or,
Step 3) homogeneous 2-4 time.
3. preparation method according to claim 1 and 2, it is characterised in that
The oil for injection is in soybean oil, midchain oil, fish oil, brucea fruit oil, olive oil, safflower oil, castor oil, corn oil
One kind；And/or,
The one kind of the emulsifying agent in lecithin, Fabaceous Lecithin, phosphatidylserine；And/or,
The one kind of the osmotic pressure regulator in glycerine, propane diols, PEG400；And/or,
The pH adjusting agent be disodium hydrogen phosphate-citric acid, sodium citrate-acetic acid, any one group of composition in sodium acetate-hydrochloric acid
Buffer salt.
4. preparation method according to claim 3, it is characterised in that the pH adjusting agent is disodium hydrogen phosphate-citric acid
According to mol ratio 5:The buffer salt of 1 composition.
5. the preparation method according to any one of claim 1-4, it is characterised in that
In the composition, flurbiprofen axetil mass fraction is 0.1%-5%, and oil for injection mass fraction is 5%-20%, emulsifies
Agent mass fraction is 1%-3%, and osmotic pressure regulator mass fraction is 1%-3%, and pH adjusting agent mass fraction is 0.04%-
0.24%.
6. preparation method according to claim 5, it is characterised in that
In the composition, flurbiprofen axetil mass fraction is 1%, and oil for injection mass fraction is 10%, emulsifying agent mass fraction
For 1.2%, osmotic pressure regulator mass fraction is 2.2%, and the pH adjusting agent mass fraction is 0.08%.
7. preparation method according to claim 1 and 2, it is characterised in that
In the composition, flurbiprofen axetil mass fraction is 1%；The oil for injection is soybean oil, and mass fraction is 10%；
The emulsifying agent is lecithin, and mass fraction is 1.2%；The osmotic pressure regulator is glycerine, and mass fraction is 2.2%；Institute
State pH adjusting agent for disodium hydrogen phosphate, citric acid according to mol ratio 5:The buffer salt of 1 composition, mass fraction is 0.08%.
8. preparation method according to claim 1 and 2, it is characterised in that
Contain flurbiprofen axetil 6g, lecithin 7.2g, soybean oil 60mL, glycerine 13.2g, disodium hydrogen phosphate in the composition
0.43g, citric acid 0.05g, water for injection 520mL；Or,
Contain flurbiprofen axetil 0.6g, lecithin 6g, soybean oil 30mL, glycerine 6g, disodium hydrogen phosphate in the composition
0.215g, citric acid 0.025g, water for injection 550mL；Or,
Contain flurbiprofen axetil 30g, lecithin 18g, soybean oil 120mL, glycerine 18g, disodium hydrogen phosphate in the composition
1.29g, citric acid 0.15g, water for injection 430mL.
9. the preparation method according to any one of claim 1-8, it is characterised in that comprise the following steps：
1), under nitrogen protection, flurbiprofen axetil, emulsifying agent are dissolved in oil for injection under 8000-16000r/min high speed shears
In, make oil phase；
2) osmotic pressure regulator, pH adjusting agent are dissolved in water for injection, make water phase；
3) under nitrogen protection, by oil phase, water according to flow-rate ratio 1:1-1:2 simultaneous implantation high pressure homogenizer homogeneous online-emulsification 2-
4 times, homogenizing fluid is made, control homogenizing process homogeneous liquid temp is less than 30 DEG C；Homogeneous is finished, and adds remaining water in homogenizing fluid
Phase, mixes；
4) by step 3) in ampoule, 121 DEG C, 15min moist heat sterilizations make flurbiprofen axetil injection for gained homogenizing fluid embedding
Liquid.
10. flurbiprofen axetil composition obtained in any one of claim 1-9 methods described.
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| CN102988291A (en) * | 2012-12-13 | 2013-03-27 | 哈药集团技术中心 | Flurbiprofen axetil fat emulsion injection composition and preparation method thereof |
| US20130189348A1 (en) * | 2010-10-28 | 2013-07-25 | Pacira Pharmaceuticals, Inc. | Sustained release formulation of a non-steroidal anti-inflammatory drug |
| CN104490779A (en) * | 2014-12-26 | 2015-04-08 | 北京蓝丹医药科技有限公司 | Flurbiprofen axetil fat emulsion injection |
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| US20130189348A1 (en) * | 2010-10-28 | 2013-07-25 | Pacira Pharmaceuticals, Inc. | Sustained release formulation of a non-steroidal anti-inflammatory drug |
| CN102988291A (en) * | 2012-12-13 | 2013-03-27 | 哈药集团技术中心 | Flurbiprofen axetil fat emulsion injection composition and preparation method thereof |
| CN104490779A (en) * | 2014-12-26 | 2015-04-08 | 北京蓝丹医药科技有限公司 | Flurbiprofen axetil fat emulsion injection |
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| CN110870850A (en) * | 2018-09-04 | 2020-03-10 | 武汉大安制药有限公司 | Flurbiprofen axetil injection and preparation method and application thereof |
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