CN107773533A - A kind of new thrombin inhibitor and preparation method thereof - Google Patents
A kind of new thrombin inhibitor and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of new thrombin inhibitor and preparation method thereof.A kind of argatroban emulsion, it includes argatroban, oil phase, emulsifying agent, osmotic pressure regulator, wherein, described oil phase is the mixture of long-chain oil and median chain triglyceride oil, mixture, the mixture or structure triglyceride of median chain triglyceride oil and structure triglyceride of long-chain oil and structure triglyceride.Argatroban emulsion prepared by the present invention has the advantages that envelop rate and medicament contg are high, and particle diameter is small, and particle diameter distribution is uniform and stability is good, and the quality of the pharmaceutical preparations is excellent.
Description
Technical field
The present invention relates to a kind of new thrombin inhibitor, belong to field of medicaments.
Background technology
Entitled (2R, the 4R) -4- methyl isophthalic acids of argatroban (argatroban) chemistry-[N- ((R, S) -3- methyl isophthalic acids, 2,3,
4- tetrahydrochysene -8- quinoline sulfonyl)-L- arginyl-s] -2 piperidine carboxylic acid is a kind of novel anticoagulation medicine.Clinical research shows
Show, argatroban has many medical applications：1st, it is evident in efficacy to acute ischemic cerebral apoplexy, to the disturbance of consciousness, intelligence
Obstacle and nervous symptoms improve obvious, can reduce sequela, and can prevent deep vein thrombosis, myocardial infarction,
Headstroke；2nd, there is preferable therapeutic action to thrombotic diseases, to improving atherosclerotic occlusive disease and Buerger's disease
Charcot's syndrome symptom, promote ulcer healing to have better effects, and ankle-upper arm index of patient can be significantly improved, reduce and cut
Limb danger 3, intervene and control available for heparin-induced thrombocytopenia, the thrombolysis of acute myocardial infarction AMI and percutaneous coronary
Treat；4th, in addition, argatroban, which is also used as anticoagulant, is applied to haemodialysis.On the whole, argatroban, which has, works
Rapidly, metabolism it is fast, in vivo without accumulation, few side effects, hemorrhage risk is low, security is good, duplicate injection better tolerance etc. is many
Advantage, its clinical practice and the prospect of marketing are very wide.
Argatroban poorly water-soluble, the solubility in water is only capable of reaching 0.8~0.9mg/mL, therefore is prepared into liquid system
The auxiliary material with solubilization need to be added during agent.At present, the primary formulation form of argatroban is parenteral solution, wherein containing mostly
The solubilizer such as ethanol, propane diols, D-glucitol.For example each milliliter contains in the product of Mitsubishi Pharmaceutical Co., Ltd production
There are argatroban 5mg, absolute ethyl alcohol 150mg, concentrated glycerin 450mg；The product of Par Pharmaceutical Inc companies production
In each milliliter contain argatroban 100mg, D-glucitol 300mg, absolute ethyl alcohol 400mg.It is a large amount of in these injection products
Using solubilizer, there is obvious harm to human body：Blood vessel is stimulated during injection, easily causes injection site pain, and it is repeated multiple times
Injection also easily causes blood vessel phlebitis；And solubilizer ethanol belongs to the inhibitor of central nervous system, and the intake of high concentration can
To cause spinal cord reaction to reduce, addicted to saliva, forgetful, hypothermia, hypoglycemia, stupor is numb, respiration inhibition, cardiovascular failure；This
Outside, solubilizer easily passes through human erythrocyte membrane, causes erythrodegeneration or haemolysis.
To solve the problems, such as argatroban dissolubility difference in water, while the use of solubilizer, patent is reduced or avoided
EP0608831 provides another scheme, and argatroban is prepared into emulsion.The patent is used as oil phase using long-chain oil, such as big
Soya-bean oil, olive oil etc.；Compared to median chain triglyceride oil, emulsion aging and the speed assembled, gained can be slowed down using long-chain oil
Emulsion stability is more preferable.However, solubility of the long-chain oil in water is small compared with middle chain, it is unfavorable for improving the content of medicine in emulsion；
Moreover, long-chain oil has the characteristics that molecular weight is big, hydrolysis is slow, if long-term use of have certain hepatotoxicity wind agitation, while easily occur high
Triglyceride, and to the functional infringement of other important organs such as immune system, body is injured obvious.
Therefore it provides the argatroban emulsion that a kind of medicament contg is high, good stability and security are good, becomes one
Urgent problem to be solved.
The content of the invention
It is an object of the invention to provide a kind of argatroban emulsion and preparation method thereof.
The invention provides a kind of argatroban emulsion, mainly by argatroban, oil phase, emulsifying agent, osmotic pressure regulator
Composition, wherein, described oil phase is the mixture of long-chain oil and median chain triglyceride oil, long-chain oil and structure triglyceride
Mixture, the mixture of median chain triglyceride oil and structure triglyceride or structure triglyceride.
Further, described argatroban emulsion is mainly made up of the composition of following weight proportion：
Further, the weight proportion of the oil phase is 20~40 parts.
Further, described oil phase is the mixture of long-chain oil and median chain triglyceride oil.
Further, described oil phase is that mass ratio is (0.2~5):1 long-chain oil：The mixing of median chain triglyceride oil
Thing, long-chain oil：Mixture, the median chain triglyceride oil of structure triglyceride：The mixture of structure triglyceride is
Structure triglyceride.
Further, described oil phase is that mass ratio is 1:The mixture of 1 long-chain oil and median chain triglyceride oil.
Further, described long-chain grease separation is from soybean oil, olive oil, castor oil, peanut oil, corn oil or rapeseed oil
One or more kinds of mixtures.
Further, the one kind of described emulsifying agent in phosphatide, Tween 80, poloxamer, Emulsifier EL-60
It is or several.
Further, the one kind or several of described phosphatide in egg yolk lecithin, soybean lecithin, hydrogenated soya phosphatide
Kind.
Further, described phosphatide is egg yolk lecithin.
Further, described osmotic pressure regulator is glycerine.
Further, it is also comprising one or more of auxiliary materials in pH adjusting agent, antioxidant, preservative, stabilizer.
The invention provides a kind of preparation method of the argatroban emulsion, comprise the following steps：
A, oil phase and emulsifying agent are taken, is well mixed；
B, by one kind in argatroban, organic solvent and osmotic pressure regulator, antioxidant, preservative, stabilizer or
Several auxiliary materials are well mixed, and obtain organic phase；
C, the preparation of colostrum：Oil phase is well mixed with organic phase, organic solvent is removed, adds water, is stirred, pH is adjusted, obtains
To colostrum；
D, the preparation of essence breast：Colostrum is moved into homogenizer, pressure-even pulp crusher or separating apparatus, homogenizes, produces.
Further, the pH value of step c regulation colostrum is to 7~10.
Further, described organic solvent boiling point is less than 100 DEG C.
Further, described organic solvent is selected from one or both of ethanol, methanol, chloroform, dichloromethane, acetonitrile
Mixture above.
Other conventional auxiliary materials as fat emulsion, such as pH adjusting agent, antioxidant/reducing agent, preservative, stabilizer
Line option can be entered according to common knowledge.PH adjusting agent：, sodium hydroxide, sodium citrate, sodium acid carbonate, disodium hydrogen phosphate etc.；It is stable
Agent：Oleic acid, enuatrol, cholic acid, sodium taurocholate, deoxycholic acid, NaTDC etc.；Antioxidant/reducing agent：Vitamin E, it is anti-bad
Hematic acid etc..
The invention provides a kind of argatroban emulsion, have the advantages that：
1st, solubilizer is not contained in argatroban emulsion of the present invention, significantly improves security, drug administration by injection position stimulates
Property tests confirmation, and it is acted on without obvious vascular stimulation, and suitably intravenous injection uses, and preferably overcomes current Ah add'sing song
The defects of class's injection excitant is stronger.
2nd, argatroban emulsion of the present invention is with the mixture, long-chain oil and structure glycerine of long-chain oil and median chain triglyceride oil
The mixture of three acid esters, the mixture of median chain triglyceride oil and structure triglyceride or structure triglyceride are as oil
Phase, on the basis of essential fatty acid is provided, have the characteristics that accretion rate is fast, little effect lipoprotein metabolism, toxic side effect
It is small, improve human administration's security.
3rd, argatroban emulsion of the present invention has envelop rate and medicament contg high, and particle diameter is small, and particle diameter distribution is uniformly and stably
The advantages that property is good, the quality of the pharmaceutical preparations is excellent.
Obviously, according to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, do not departing from
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The embodiment of form by the following examples, the above of the present invention is remake further specifically
It is bright.But the scope that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Embodiment
The raw material that is used in the specific embodiment of the invention, equipment are known product, are obtained by buying commercially available prod.
The preparation method of the argatroban emulsion of the present invention of embodiment 1
Weigh soybean oil/median chain triglyceride oil (mass ratio 0.2:1) common 8.0g and egg yolk lecithin 1.0g, heating,
Stirring is to being completely dissolved to obtain oil phase.Glycerine 0.4g, ethanol 2mL, argatroban 0.02g are mixed, stirring is to being completely dissolved, mix
Uniformly, organic phase is obtained.Oil phase is well mixed with organic phase, in being spin-dried for ethanol on Rotary Evaporators；Add water for injection
To 200mL, aquation mixing；Stirring；PH value is adjusted to 7.0 with sodium hydroxide, and colostrum is made.Obtained colostrum is moved into homogenizer
In, homogenize, obtain smart breast.Nitrogen charging, embedding, sterilizing, are produced.
The preparation method of the argatroban emulsion of the present invention of embodiment 2
Weigh olive oil/median chain triglyceride oil (mass ratio 1:1) common 20.0g and egg yolk lecithin 3.0g, heating are stirred
Mix to being completely dissolved to obtain oil phase.Glycerine 15.0g, dichloromethane 10mL, argatroban 0.20g are mixed, stirring to being completely dissolved,
It is well mixed, obtain organic phase.Oil phase is well mixed with organic phase, heating evaporation removes dichloromethane；Add injection
Water to 200mL, aquation mixes；Stirring；PH value is adjusted to 8.0 with sodium hydroxide, and colostrum is made.Obtained colostrum is moved into homogeneous
In machine, homogenize, obtain smart breast.Nitrogen charging, filling, sterilizing, are produced.
The preparation method of the argatroban emulsion of the present invention of embodiment 3
Weigh median chain triglyceride oil/structure triglyceride (mass ratio 4:1) common 60.0g and egg yolk lecithin
8.0g, heating stirring is to being completely dissolved to obtain oil phase.Glycerine 40.0g, chloroform 8mL, argatroban 2.00g are mixed, stirred to complete
Fully dissolved, it is well mixed, obtains organic phase.Oil phase is well mixed with entering organic phase, is evaporated under reduced pressure and removes chloroform；Add note
Penetrate with water to 200mL, aquation mixing；Stirring；PH value is adjusted to 7.5 with sodium hydroxide, and colostrum is made.Obtained colostrum is moved into
In pressure-even pulp crusher, homogenize, obtain smart breast.Nitrogen charging, filling, sterilizing, are produced.
The preparation method of the argatroban emulsion of the present invention of embodiment 4
Weigh median chain triglyceride oil/structure triglyceride (mass ratio 0.75:1) common 20.0g and soybean lecithin
6.0g, heating stirring is to being completely dissolved to obtain oil phase.Glycerine 8.0g, methanol 5mL, argatroban 0.50g are mixed, stirred to complete
Dissolving, it is well mixed, obtains organic phase.Oil phase is well mixed with organic phase, heating water bath, in being spin-dried for first on Rotary Evaporators
Alcohol；Water for injection is added to 200mL, aquation mixing；Stirring；PH value is adjusted to 8.5 with sodium hydroxide, and colostrum is made.Will system
The colostrum obtained is moved into pressure-even pulp crusher, is homogenized, is obtained smart breast.Nitrogen charging, filling, sterilizing, are produced.
The preparation method of the argatroban emulsion of the present invention of embodiment 5
Weigh castor oil/structure triglyceride (mass ratio 5:1) common 36.0g and hydrogenated soya phosphatide 5.0g, heating
Stirring is to being completely dissolved to obtain oil phase.Glycerine 20.0g, methanol 10mL, argatroban 1.00g are mixed, stirring is to being completely dissolved, mix
Close uniformly, obtain organic phase.Oil phase is well mixed with organic phase, heating water bath, in being spin-dried for methanol on Rotary Evaporators；Again plus
Enter water for injection to 200mL, aquation mixing；Stirring；PH value is adjusted to 10.0 with sodium hydroxide, and colostrum is made.By made from just
Breast is moved into separating apparatus, is homogenized, is obtained smart breast.Nitrogen charging, filling, sterilizing, are produced.
The preparation method of the argatroban emulsion of the present invention of embodiment 6
Weigh peanut oil/structure triglyceride (mass ratio 5:1) common 36.0g and egg yolk lecithin 5.0g, heating are stirred
Mix to being completely dissolved to obtain oil phase.Glycerine 20.0g, methanol 10mL, argatroban 1.00g are mixed, stirring is to being completely dissolved, mix
Uniformly, organic phase is obtained.Oil phase is well mixed with organic phase, heating water bath, in being spin-dried for methanol on Rotary Evaporators；Add
Water for injection to 200mL, aquation mixes；Stirring；PH value is adjusted to 10.0 with sodium hydroxide, and colostrum is made.By obtained colostrum
Move into separating apparatus, homogenize, obtain smart breast.Nitrogen charging, filling, sterilizing, are produced.
The preparation method of the argatroban emulsion of the present invention of embodiment 7
Weigh corn oil/structure triglyceride (mass ratio 5:1) common 36.0g and soybean lecithin 5.0g, heating stirring
To being completely dissolved to obtain oil phase.Glycerine 20.0g, methanol 10mL, argatroban 1.00g are mixed, stirring is equal to being completely dissolved, mixing
It is even, obtain organic phase.Oil phase is well mixed with organic phase, heating water bath, in being spin-dried for methanol on Rotary Evaporators；Add note
Penetrate with water to 200mL, aquation mixing；Stirring；PH value is adjusted to 10.0 with sodium hydroxide, and colostrum is made.Obtained colostrum is moved
Enter in separating apparatus, homogenize, obtain smart breast.Nitrogen charging, filling, sterilizing, are produced.
The preparation method of the argatroban emulsion of the present invention of embodiment 8
Weigh rapeseed oil/structure triglyceride (mass ratio 1:1) common 40.0g and egg yolk lecithin 10.0g, heating are stirred
Mix to being completely dissolved to obtain oil phase.Glycerine 35.0g, acetonitrile 15mL, argatroban 1.60g will be weighed to mix, stirring to be completely dissolved,
It is well mixed, obtain organic phase.Oil phase is well mixed with organic phase, heating evaporation removes acetonitrile；Add water for injection extremely
200mL, aquation mixing；Stirring；PH value is adjusted to 9.5 with sodium hydroxide, and colostrum is made.Obtained colostrum is moved into separating apparatus
In, homogenize, obtain smart breast.Nitrogen charging, filling, sterilizing, are produced.
The preparation method of the argatroban emulsion of the present invention of embodiment 9
Structure triglyceride 28.0g and egg yolk lecithin 4.0g is weighed, heating stirring is to being completely dissolved to obtain oil phase.Will be sweet
Oily 28.0g, dichloromethane 20mL, argatroban 0.30g mixing, stirring are well mixed to being completely dissolved, obtain organic phase.Will
Oil phase is well mixed with organic phase, and heating evaporation removes dichloromethane；Water for injection is added to 200mL, aquation mixing；Stir
Mix；PH value is adjusted to 8.0 with sodium hydroxide, and colostrum is made.Obtained colostrum is moved into homogenizer, homogenizes, obtains smart breast.Fill
Nitrogen, filling, sterilizing, are produced.
Comparative example 1 prepares argatroban fat emulsion according to EP0308831 embodiments 1
Tween 0.5g is dissolved in 95mL waters for injection, then 0.18g argatrobans are added and dissolved, obtains aqueous phase.Will
0.02g argatrobans are added in 0.5g oleic acid and 4.5g saualanes, are well mixed, are obtained oil phase.Aqueous phase addition oil phase is mixed
Close, the fat emulsion of argatroban is made by ultrasonic generator for obtained emulsion particulate.Nitrogen charging, filling, sterilizing, you can.
Comparative example 2 prepares argatroban fat emulsion according to EP0308831 embodiments 3
The dissolving saccharose ester 0.5g in 95mL waters for injection, then 0.18g argatrobans are added and dissolved, obtain aqueous phase.Will
0.02g argatrobans are added in water/ethanol (9:1) in mixed liquor 0.5mL and 4.5g saualanes, it is well mixed, obtains oil phase.Will
Aqueous phase adds oil phase mixing, and the fat emulsion of argatroban is made by ultrasonic generator for obtained emulsion particulate.Nitrogen charging, filling
Dress, sterilizing, you can.
Comparative example 3 prepares argatroban according to CN102784382 embodiments 1 and contains alcohol injection
Absolute ethyl alcohol 30g, propane diols 50g are taken, stirs to form stable solution system, adds main ingredient argatroban
1g, stirring are completely dissolved main ingredient, and solution becomes clear and bright, adds water for injection to be settled to 200mL, are well mixed obtained formulation soln.
Filtering, embedding, sterilizing.
Beneficial effects of the present invention are proved below by way of experimental example.
The drug administration by injection position excitant contrast test of experimental example 1
New zealand rabbit 32 is taken, is randomly divided into 8 groups.First group by 2mg/kg rabbit rights auricular vein injection embodiment 2
Sample, as control, the 3rd group is pressed 2mg/kg for the emulsion for injection blank sample of embodiment 2 of the identical administered volume of second group of injection
Rabbit right auricular vein injects the sample of comparative example 1, the parenteral solution blank sample of comparative example 1 of the 4th group of identical administered volume of injection
As control, the 5th group of sample by 2mg/kg rabbit rights auricular vein injection comparative example 2, the 6th group of identical administered volume of injection
The parenteral solution blank sample of comparative example 2 as control, the 7th group by 2mg/kg rabbit rights auricular vein injection comparative example 3 sample
Product, the parenteral solution blank sample of comparative example 3 of the 8th group of identical administered volume of injection is as control.One to eight groups are respectively in left ear
Edge is injected intravenously isometric physiological saline and makees itself negative control.Each group is administered once daily, successive administration 4 weeks, before daily administration
And 48h~72h after last time administration, visually observe whether injection site and surrounding tissue there are the stimulations such as redness, hyperemia to show
As.After observation period terminates, injection site and surrounding tissue are done into pathological section, histological examination is carried out, the results are shown in Table 1.
The vascular stimulation tests result of table 1
Experimental result：Containing alcohol in the argatroban ejection preparation prepared according to comparative example 2,3, has strong impulse to blood vessel
Effect；And argatroban emulsion prepared by the embodiment of the present invention 2 is then without obvious excitant.
The dosage form of experimental example 2, particles size and distribution detection
The argatroban prepared in above-described embodiment 1-9 and comparative example 1,2 is determined with Malvern ZS90 laser particle analyzers
Outward appearance, dewatering ability, particle diameter, the size distribution situation of Fat Emulsion.Wherein PDI values are particle diameter polydispersity index, and its value is smaller
Representative diameter is more homogeneous.It the results are shown in Table 2.
The argatroban emulsion form of table 2, particles size and distribution testing result
Experimental result：Argatroban Fat Emulsion particle diameter is larger made from comparative example 1,2, and polydispersity index is more than 0.5,
Particle diameter distribution is uneven.
In contrast, argatroban Fat Emulsion outward appearance made from the embodiment of the present invention 1~9 is in homogeneous milky；4000r/
Lamination is had no after min centrifugations 30min, and does not observe oil droplet generation, shows its good stability；Average grain diameter is in 358nm
(pharmacopoeial requirements intravenous injection average grain diameter is between 50-1000nm) below, polydispersity index shows it below 0.245
Particle diameter is smaller, and particle diameter distribution is highly uniform, and suitable injection uses.
The measure of the free drug content of experimental example 3 and envelop rate
The Fat Emulsion for respectively preparing embodiment 1-9 and comparative example 1-2 by volume, emulsion：5% glucose (or it is raw
Manage salt solution)=1：4 volume dilutions, it is fitted into 250mL beakers.Load 2.6% in each bag filter (molecular weight 8000~14000)
(w/v) glycerine water solution (isotonic dialysis) 5mL, 3 bag filters are put into each beaker.Stirring dialysis 24 hours.Take out saturating
Bag is analysed, HPLC determines bag filter drug concentration after centrifugation.It the results are shown in Table 3.
The measurement result of the free drug content of table 3 and envelop rate
| Group | Free drug ratio (%, w/w) | Envelop rate (%, w/w) |
| Embodiment 1 | 4.84 | 95.16 |
| Embodiment 2 | 2.70 | 97.30 |
| Embodiment 3 | 3.75 | 96.25 |
| Embodiment 4 | 6.45 | 93.55 |
| Embodiment 5 | 3.59 | 96.41 |
| Embodiment 6 | 3.89 | 96.11 |
| Embodiment 7 | 4.12 | 95.88 |
| Embodiment 8 | 7.29 | 92.71 |
| Embodiment 9 | 4.21 | 95.79 |
| Comparative example 1 | 3.23 | 96.77 |
| Comparative example 2 | 10.97 | 89.03 |
Result above shows that argatroban Fat Emulsion envelop rate prepared by embodiment 1~9 dissociates more than 92%
Medicament contg is minimum only to account for 2.70%, it was demonstrated that prescription of the present invention and preparation technology are reasonable, can high productivity obtain argatroban breast
Agent.
The stability test of experimental example 4
The sample of embodiment 2, comparative example 1, comparative example 2 is carried out into 6 months accelerated stabilities to investigate.Sample places condition
40 DEG C ± 2 DEG C of temperature, humidity RH75% ± 5%.Content investigation and relevant thing have been carried out to sample using high performance liquid chromatography
Matter is investigated.It the results are shown in Table 4-6.
The sample accelerated stability test result of 4 embodiment of table 2
The sample accelerated stability test result of 5 comparative example of table 1
The sample accelerated stability test result of 6 comparative example of table 2
Result above shows that the sample of the embodiment of the present invention 2 is after the experiment by accelerating June, average grain diameter and granularity
Changes in distribution is smaller, and impurity content is almost unchanged, and stability is very good；And preparation (the contrast prepared according to prior art
Example 1, comparative example 2) sample, average grain diameter and size distribution change more greatly, and the growth of total impurities is notable, and stability is relatively
Difference.
The hemolytic of experimental example 5 is tested
The preparation of 2% red blood cell suspension：Healthy rabbits blood 20mL is taken, is put into the conical flask containing bead and shakes
10min, fibrinogen is removed, makes into defibrinated blood.Add 0.9% sodium chloride solution 200mL, shake up, 1000~1500rpm
Centrifugation 15 minutes, removes supernatant, and the red blood cell of precipitation washs 2~3 according to the method described above with 0.9% sodium chloride solution again
It is secondary, untill the not aobvious red of supernatant.Gained red blood cell is made into 0.9% sodium chloride solution to 2% suspension, for experiment
With.
The preparation of tested material：Argatroban injection sample normal saline is taken into the molten of the argatroban containing 1mg/mL
Liquid, it is standby.
Test method：Clean tube 7 is taken, is numbered, No. 1-5 pipe be test sample pipe, and it is negative control pipe to manage for No. 6,7
Number pipe is positive control pipe.2% red cell suspension, 0.9% sodium chloride solution or distillation are sequentially added as shown in the testing program of table 7
Water, after mixing, put in 37 DEG C ± 0.5 DEG C of insulating box and incubated immediately, start after observation in 15 minutes 1 time, 1 hour,
Observed 1 time every 1 hour, overview 3 hours.
The hemolytic testing program of table 7
| Test tube number | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| 2% cell suspension/mL | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
| 0.9% sodium chloride solution/mL | 2.0 | 2.1 | 2.2 | 2.3 | 2.4 | 2.5 | / |
| Distilled water/mL | / | / | / | / | / | / | 2.5 |
| Tested material/mL | 0.5 | 0.4 | 0.3 | 0.2 | 0.1 | / | / |
Laboratory sample：
Sample 1：0 month sample of normal temperature of embodiment 5
Sample 2：The normal temperature sample in December of embodiment 5
Sample 3：40 DEG C of embodiment 5 accelerate sample in June
Sample 4：0 month sample of normal temperature of embodiment 6
Sample 5：The normal temperature sample in December of embodiment 6
Sample 6：40 DEG C of embodiment 6 accelerate sample in June
Sample 7：0 month sample of normal temperature of embodiment 7
Sample 8：The normal temperature sample in December of embodiment 7
Sample 9：40 DEG C of embodiment 7 accelerate sample in June
Sample 10：0 month sample of normal temperature of comparative example 1
Sample 11：The normal temperature sample in June of comparative example 1
Sample 12：40 DEG C of comparative example 1 accelerate sample in June
As a result observe：If the solution in experiment is in clear and bright red, ttom of pipe is acellular to be remained or has a small amount of red blood cell to remain, table
It is bright to have haemolysis；Such as red blood cell whole sinking, supernatant fluid achromatism and clarity, show that no haemolysis occurs.If have in solution reddish brown
Color or rufous flocculent deposit, do not disperse after shaking, show there is red blood cell condensation., can if any the phenomenon of red blood cell condensation
Further judge it is true cohesion or pseudo agglutination by the following method.If condensation product and can after test tube vibration is dispersed, or will cohesion
Thing is placed on slide, and 2 0.9% sodium chloride solutions of drop are added dropwise at slide edge, puts micro- Microscopic observation, condenses red blood cell energy
It is pseudo agglutination by the person of breaking up, if condensation product is not shaken and dissipates or not by the person of breaking up be really to condense on slide.It the results are shown in Table 8.
The hemolytic result of the test of table 8
| Test tube number | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| Sample 1 | - | - | - | - | - | - | + |
| Sample 2 | - | - | - | - | - | - | + |
| Sample 3 | + | + | + | + | + | - | + |
| Sample 4 | - | - | - | - | - | - | + |
| Sample 5 | - | - | - | - | - | - | + |
| Sample 6 | - | - | - | - | - | - | + |
| Sample 7 | - | - | - | - | - | - | + |
| Sample 8 | - | - | - | - | - | - | + |
| Sample 9 | + | + | + | + | + | - | + |
| Sample 10 | - | - | - | - | - | - | + |
| Sample 11 | + | + | + | + | + | - | + |
| Sample 12 | + | + | + | + | + | - | + |
(note："-" indicates no haemolysis, and "+" indicates haemolysis)
Result of the test shows, comparative example 1 has just occurred haemolysis under conditions of 6 months in normal temperature, and embodiment 5,
6th, 7 sample does not still have haemolysis under the conditions of the normal temperature placement of 12 months, illustrates invention formulation prescription and prepares work
Skill is significantly better than prior art EP0308831.
Simultaneously as can be seen that the haemolysis situation of the sample of embodiment 6 using egg yolk lecithin as emulsifying agent is better than with hydrogenation
Embodiment 7 of the soybean lecithin as the embodiment 5 of emulsifying agent and using soybean lecithin as emulsifying agent.
Claims (10)
- A kind of 1. argatroban emulsion, it is characterised in that mainly it is made up of argatroban, oil phase, emulsifying agent, osmotic pressure regulator, Wherein, described oil phase is the mixing of the mixture of long-chain oil and median chain triglyceride oil, long-chain oil and structure triglyceride Thing, the mixture of median chain triglyceride oil and structure triglyceride or structure triglyceride.
- 2. argatroban emulsion as claimed in claim 1, it is characterized in that being mainly to be made up of the composition of following weight proportion：
- 3. argatroban emulsion as claimed in claim 1 or 2, it is characterized in that：Described oil phase is long-chain oil and medium chain triglyceride The mixture of three acid esters.
- 4. the argatroban emulsion as described in claims 1 to 3 any one, it is characterized in that：Described long-chain grease separation is from soybean Mixture more than one or both of oil, olive oil, castor oil, peanut oil, corn oil or rapeseed oil.
- 5. argatroban emulsion as claimed in claim 1 or 2, it is characterized in that：Described emulsifying agent be selected from phosphatide, Tween 80, One or more in poloxamer, Emulsifier EL-60.
- 6. argatroban emulsion as claimed in claim 5, it is characterized in that：Described phosphatide is selected from egg yolk lecithin, soybean phosphorus One or more in fat, hydrogenated soya phosphatide.
- 7. argatroban emulsion as claimed in claim 6, it is characterized in that：Described phosphatide is egg yolk lecithin.
- 8. argatroban emulsion as claimed in claim 1, it is characterized in that：Described osmotic pressure regulator is glycerine.
- 9. the argatroban emulsion as described in claim 1~8 any one, it is characterized in that：It is also comprising pH adjusting agent, antioxygen One or more of auxiliary materials in agent, preservative, stabilizer.
- 10. the preparation method of argatroban emulsion described in a kind of claim 1~9 any one, it is characterized in that：Including following step Suddenly：A, oil phase and emulsifying agent are taken, is well mixed；B, by the one or more in argatroban, organic solvent and osmotic pressure regulator, antioxidant, preservative, stabilizer Auxiliary material is well mixed, and obtains organic phase；C, the preparation of colostrum：Oil phase is well mixed with organic phase, organic solvent is removed, adds water, is stirred, adjusts pH, is obtained just Breast；D, the preparation of essence breast：Colostrum is moved into homogenizer, pressure-even pulp crusher or separating apparatus, homogenizes, produces.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0608828A1 (en) * | 1993-01-25 | 1994-08-03 | Mitsubishi Chemical Corporation | Compositions containing argatroban analogs |
| EP0608831A1 (en) * | 1993-01-25 | 1994-08-03 | Mitsubishi Chemical Corporation | Compositions containing argatroban analogs |
| CN101257890A (en) * | 2005-09-01 | 2008-09-03 | 巴克斯特国际公司 | Argatroban formulation comprising an acid as solubilizer |
| CN102366410A (en) * | 2011-09-14 | 2012-03-07 | 海南灵康制药有限公司 | Argatroban liposome injection |
-
2016
- 2016-08-26 CN CN201610739821.6A patent/CN107773533A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0608828A1 (en) * | 1993-01-25 | 1994-08-03 | Mitsubishi Chemical Corporation | Compositions containing argatroban analogs |
| EP0608831A1 (en) * | 1993-01-25 | 1994-08-03 | Mitsubishi Chemical Corporation | Compositions containing argatroban analogs |
| CN101257890A (en) * | 2005-09-01 | 2008-09-03 | 巴克斯特国际公司 | Argatroban formulation comprising an acid as solubilizer |
| CN102366410A (en) * | 2011-09-14 | 2012-03-07 | 海南灵康制药有限公司 | Argatroban liposome injection |
Non-Patent Citations (2)
| Title |
|---|
| 孟胜男 等: "《药剂学》", 31 January 2016, 中国医药科技出版社 * |
| 黄德骧 等: "《临床静脉营养》", 31 January 1994, 上海医科大学出版社 * |
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