CN105769764B - Aspartic acid fat emulsion injection and preparation method - Google Patents
Aspartic acid fat emulsion injection and preparation method Download PDFInfo
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- CN105769764B CN105769764B CN201410823457.2A CN201410823457A CN105769764B CN 105769764 B CN105769764 B CN 105769764B CN 201410823457 A CN201410823457 A CN 201410823457A CN 105769764 B CN105769764 B CN 105769764B
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Abstract
The invention belongs to technical field of medicine.The invention discloses a kind of aspartic acid fat emulsion injections.Aspartic acid 0.05~0.25%, injection soybean oil 10~30%, injection egg yolk lecithin 1.0~1.5% or the injection soybean lecithin of said preparation including content % O.8~1.5%, glycerol for injection 2.0~2.5%, water for injection add to 100ml.Invention formulation has good effect to mending potassium, can improve human body potassium content in a short time, and high-energy nutrition can be provided for body.It is small to the irritation object pain degree of vein during use.The present invention provides preparation methods.
Description
Technical field
The invention belongs to technical field of medicine.More particularly to a kind of aspartic acid fat emulsion injection and preparation side
Method.
Background technology
Potassium is intracellular dominant cation, required for cells survival.Diagnostic value can clinically cause various illnesss,
Such as severe arrhythmia, the neuro-muscular disorders such as myasthenia, paralysis, respiratory insufficiency, long-term Diagnostic value causes renal tubule to damage
Wound（Diagnostic value nephrosis）.The sylvite clinically applied is divided into inorganic potassium salt and potassium salt.Inorganic potassium salt is potassium chloride, potassium phosphate
Deng；Potassium salt is potassium acetate, aspartic acid, potassium glutamate, potassium citrate etc..Mending potassium drug can be according to the cause of disease and morbidity machine
System is different and is selected.
L-aminobutanedioic acid is very strong to the affinity of cell, can as potassium ion carrier and provide energy for it, return to it
Into the cell, intracellular potassium concentration is improved.Substantial amounts of clinical data, documents and materials prove that this product has rapid-action, short treating period
The characteristics of.
Intravenous route is most common benefit potassium mode, suitable for the patient of severe hypopotassaemia, can in time, quickly be corrected low
Potassium mass formed by blood stasis reduces the generation of complication, clinical generally to use high concentration potassium.It is general to select peripheral vein and central vein,
Its advantage is to promote serum potassium rapidly, prevents influence of the low potassium to myocardium irritability and antiotasis.
Intravenously administrable may cause injection site pain, and severe patient causes thrombophlebitis.Cause the main original of pain
Because potassium ion is the induced pain factor, input after blood vessel in addition to the physical stimulation of itself, potassium ion acts on nerve after entering tissue
Tip receptor makes its depolarising, causes pain.Potassium ion can also directly stimulate blood vessel upper wall, and pass through blood vessel upper wall
Sympathetic nerve causes subcutaneous and epidermal tissue's myoelectricity outburst ripple, the aggravation of unicast releasability to touch free nerve ending and cause thorn
Severe Pain and Rediating Pain.In addition, still cause nerves within the body medium, such as the liter that adrenaline, serotonin substance are different degrees of
Height, so as to which site of puncture be caused pain occur.The speed that intravenous potassium supplement pain degree and potassium concn are proportionate and instil is in just
Than.By clinical observation, venoclysis sylvite, Most patients master, which is stated at inserting needle, different degrees of pain, and some is difficult because of pain
Bear and terminate injection.
The foreign drug big to vein irritating such as arcotic Propofol relies on rice ester etc. to be dissolved in oil phase
In oil in water emulsion is made with reduce the incidence of phlebitis just and mitigate pain.Aspartic acid fat is prepared in present invention research
Fat emulsion injection can mitigate vascular stimulation while potassium is mended.
The content of the invention
The technical problems to be solved by the invention are to overcome above-mentioned shortcoming, design the novel formulation of aspartic acid,
Drug effect is improved, lowers side effect
The present invention provides a kind of aspartic acid fat emulsion injection, weight/volume % (g/ml) groups of the parenteral solution
As aspartic acid 0.05~0.25%, injection soybean oil 10~30%, phosphatide selection injection egg yolk lecithin 1.0~
1.5% or injection soybean lecithin 0.8~1.5%, glycerol for injection 2.0~2.5%, water for injection add to 100ml.
The parenteral solution of the present invention is oil in water emulsion, 250ml：250mg, dosage every time for aspartic acid 250~
750mg.Confirm that its vein irritating and the existing preparation of pain degree ratio mitigate through pharmacological testing.And because this preparation uses soybean
Oil makees solvent, lecithin makees emulsifier, make its can also be provided in clinical treatment the nutrition such as human body thermal energy and essential fatty acid into
Part, still there is professional Medical Degree.
The potassium aspartate injection of the present invention is as follows to ANIMAL PAIN and vascular stimulation result of the test：
1st, tested material：
Preparation method：10% fat emulsion injection contains containing 0.1% aspartic acid (No. I), 20% fat emulsion injection
0.1% aspartic acid (No. II) and 20% fat emulsion injection contain 6% dextrorotation candy acid anhydride and 0.1% aspartic acid (No. III)
Three samples use stoste.With reference to product original potassium aspartate injection with normal saline dilution, L-aminobutanedioic acid potassium concn from
0.5% is diluted to 0.1% (IV).
2nd, content of the test：
(1) mouse writhing is tested：
Experimental animal：Kunming mice, every group of experiment 10.20, half male and half female.
Dosage and administration route：I, II and No. III three aspartic acid fat emulsion injection sample uses stoste
1ml/ mouse, i.e. 1mg/ mouse.With reference to product original potassium aspartate injection, using aspartic acid after normal saline dilution
Concentration 1ml/1m IV samples, administration concentration are also 1ml/ mouse, i.e. 1mg/ mouse.Each sample test solution uses abdominal cavity
Approach is administered.(remarks：Routinely the volume of abdominal channels administration is 0.5ml/ mouse, trial test of this experiment find by
If examination object does not occur " writhing " reaction to 0.5ml/0.5mg/ mouse.To strengthen the stressed condition of tested material, it is administered
Volume increases to 1ml/ mouse).
Mouse writhing test method：Under the conditions of 20 DEG C ± 2 DEG C of room temperature, it will be injected by test solution in mouse peritoneal, and make mouse
Cause abdomen deep, large area and lasting pain reaction due to stimulation.Statistical observation each group mouse 0~15 minute and 15~
The number of " writhing " (abdomen indent, trunk and back leg are upheld, hips up) is generated in 30 minutes, is caused with each group mouse and " turned round
The number of body ", is counted.
Mouse writhing result of the test：Three are screened I, II, No. III three aspartic acid fat emulsion injection samples pair
Mouse writhing stimulation is not reacted substantially, they stimulate mouse writhing fairly obvious less than former potassium aspartate injection
IV.Refer to table 1.
Table l mouse writhings test (1) n=5；(2)n=10
Note：1st, in parantheses 1 and 2 experimental result twice is represented respectively
2nd, test every group of mouse 10 for the 1st time, the 2nd time every group 20, equal half male and half female.
(2) mouse hot-plate causes Pain test：
Experimental animal：Kunming mice, 20 ± 2 grams of weight, every group of experiment 10--, 20, half male and half female.
Dosage and administration route：I, No. II three aspartic acid fat emulsion injection samples of II and I use stoste 0.
3ml/ mouse, i.e. 0.3mg/ mouse.No. IV administration concentration of reference substance is also 0.3ml/ mouse, i.e. 0.3mg/ mouse.
Each sample experiment is using toes subcutaneous administration behind the right side.
Mouse hot-plate causes Pain test method：After 0.03ml test solutions are subcutaneously injected in toes after mouse, 20 DEG C ± l DEG C is placed in
On hot plate, there is the number of pain, acquired results and original after there is the time of pain reaction and administration in observation mouse in 5 minutes
Aspartic acid emulsion injection is calculated more as the following formula.
The standard drafted：Lick No. 12 points of meter of foot
Carry No. 11 point of meter of foot
Above-mentioned action is continued to exceed 5 minutes and added up 1 time
There is stimulation time：Start to occur licking foot or carry the sufficient time (second)
The percentage that inhibition stimulates=[(positive group stimulates a test group of scoring to stimulate score)/positive group stimulation meter] point ×
100%
There is rate elongation=[(test group the positive group of stimulation time one occurs and stimulation time occurs)/positive group of stimulation time
There is stimulation time】× 100%
Hot plate method in mice causes Pain test result：I, II, No. III three potassium aspartate injection samples pair being screened
Mouse hot-plate causes pain reaction to occur the time stimulated or pain for the first time all
Significantly lower than former aspartic acid emulsion injection reference substance IV, the results detailed in Table 2,3,4.
Mouse hot-plate is tested：
Table 2：N=10 (half male and half female)
Table 3
Note 1：Data above is compared with former potassium aspartate injection.
(3) irritant test of rabbit auricular vein continuous drip：
Experimental animal：Rabbit No. 6,2.5 ~ 3.0kg of weight, male.
Dosage and administration route：I samples are instiled daily with 20 ~ 25ml/1h auricular veins, daily administration amount 10mg/kg,
Successive administration 8 days, accumulated dose 80mg/kg.Reference substance IV samples, with identical dose regimen.Negative control group is
Physiological saline.
Rabbit auricular vein irritant test result：
Gross examination of skeletal muscle：Administration has no apparent auricular vein stimulate the reaction in first 3 days, until the 5th day each group occurs in various degree
Stimulation.Find that tetanic stimulation shape occurs in the ear edge of former aspartic acid breast group during administration.Improved preparation is gone out
Existing degree is very light.
Pathological observation：Each group ear edge divides equally 6 sections of observations.Aspartic acid fat emulsion injection (vein use) though with the former door winter
Propylhomoserin potassium emulsion injection has similar vascular stimulation symptom, but stimulates lesser extent, and has no thrombosis；And stimulate hair
Also more former aspartic acid emulsion injection is small to raw scope.
Note：This experiment carries out on the basis of both the above experiment, therefore has only selected 10% L-aminobutanedioic acid
Potassium fat emulsion injection (vein with) compares.
Pharmacology irritant test conclusion：Three prescription aspartic acid fat emulsion injections (vein use) are to selected 3 kinds
Animal causes pain and causes the experiment that model is stimulated to carry out, and can reflect the newly-designed more former door of aspartic acid fat milk transfusion
Winter propylhomoserin potassium emulsion injection can significantly mitigate pain and vascular stimulation.
It is a further object of the present invention to provide the preparation method of above-mentioned aspartic acid fat emulsion injection, this method is
Under inert gas shielding, by injection yolk phospholipid (or injection soybean lecithin) and aspartic acid high-speed stirred to equal
It is even that oil phase is made.Separately glycerol for injection addition is filled in appropriate water for injection container, after mixing filtering be heated to 40 to clear and bright
~70 DEG C：Water phase is made, oil phase and water are mutually mixed under high velocity agitation platform and with 10% sodium hydroxide solution adjusting pS values 8.0~
10.0, it adds to the full amount of water for injection and emulsifies colostrum to milk particle passed examination (particle repeatedly through two step high pressure homogenizers<1 u with
Under to account for more than 97%, filling in 250~500ml glass bottles through filtering with microporous membrane again, add logical nitrogen, rubber plug, roll and be placed on swinging
Steam sterilizing
115 DEG C of 30 points of sterilizings in device.After inspection desk lattice aspartic acid fat emulsion injection.
The quality of the pharmaceutical preparations of the present invention is as follows：
1st, character：This product is white emulsion liquid,
2nd, differentiate
3 ware of this product is taken, puts and adds ethyl alcohol 11Ill in test tube, slowly add 1% vanilla circle place displaing amaranth after shaking up along tube wall
Ring shows violet after shaking up
The retention time at test samples peak should be with the retention time at reference substance peak in the chromatogram recorded under assay item
Unanimously.
3rd, inspection item：PI-I values, related substance, free fatty, milk particle size, pyrogen, sterile and related injection
Every regulation under.
4th, ancient measure is determined：Chinese scholartree perfume (or spice) alkene hits measure using gas-chromatography i
5th, Related substances separation mainly checks free fatty (using chemical determination) and relative substance (using gas phase color
Spectrometry measures).
6th, stability test:
Aspartic acid Fat Emulsion (illumination, 40 DEG C, 60 DEG C, 80 DEG C accelerate 10 days) midship DEG C constant temperature accelerate three months after,
Content is without significant change, and free fatty acid level and PH are varied from time tall building temperature, i.e. pH is in a slight decrease, free-fat
Acid value increased, but can meet ordered quality standard.Other such as appearances, milk particle the size that has no significant change tentatively are demonstrate,proved
Bright this product can be stablized 2 years or so in room temperature storage.
Specific embodiment：
Embodiment one：
Under nitrogen protection, 120 g of injection soybean oil is weighed, is heated to 70 DEG C, adds in injection egg yolk lecithin 13
Oil phase is made to uniform in 0.8 g of g and aspartic acid, high-speed stirred.Separately by 23 g of glycerol for injection, appropriate injection is added in
Colostrum is mixed and made into oil phase under high velocity agitation after 60 DEG C of filterings are heated to after water mixing, then with 10% sodium hydroxide solution
PH value 9.5 is adjusted, 1000ml is injected water to and emulsifies colostrum to milk particle passed examination (grain repeatedly through two step high pressure homogenizers
Son<1 below u accounts for more than 97%), then through filtering with microporous membrane, filling in 250~500ml glass bottles, logical nitrogen jumps a queue, rolls lid
115 DEG C of 30 points of sterilizings in swinging steam sterilizer.After passed examination aspartic acid fat emulsion injection.
Embodiment two：
Under nitrogen protection, 200 g of injection soybean oil is weighed, is heated to 60 DEG C, adds in 1.5 g of elemene, high-speed stirring
It mixes to uniform, oil phase is made.Separately by 22 g of glycerol for injection, added under high velocity agitation after adding in appropriate water for injection mixing
70 DEG C are heated to after 8 g mixings of injection soybean lecithin, is mixed and made into colostrum with oil phase under high velocity agitation, and with 10% hydrogen-oxygen
Change sodium solution and adjust pH value 8.5, the 1000ml that adds to the full amount of water for injection emulsifies colostrum repeatedly to breast through two step high pressure homogenizers
Grain passed examination (particle<1 below u accounts for more than 97%), then it is filling in 250~500ml glass bottles through filtering with microporous membrane, lead to
Nitrogen jumps a queue, rolls and be placed in swinging steam sterilizer 1 15 DEG C of 30 points of sterilizings.After passed examination aspartic acid Fat Emulsion
Parenteral solution.
Embodiment three：
Under nitrogen protection, 1 50 g of injection soybean oil is weighed, is heated to 80 DEG C, adds in injection egg yolk lecithin
Oil phase is made to uniform in 1.2 g of 14g and aspartic acid, high-speed stirred.Separately by 24 g of glycerol for injection, appropriate injection is added in
Be heated to after water mixing 50 ~ C filtering after colostrum is mixed and made into oil phase under high velocity agitation, it is then molten with lO% sodium hydroxides
Liquid adjusts pH value 8.5, injects water to 1000ml and emulsifies colostrum to milk particle passed examination repeatedly through two step high pressure homogenizers
(particle<1 below u, then filling in 250~500ml glass bottles through filtering with microporous membrane, logical nitrogen jump a queue, roll and be placed on swinging steaming
115 DEG C of 30 points of sterilizings in vapour sterilizer.Passed examination aspartic acid Fat Emulsion.
Claims (2)
1. a kind of aspartic acid fat emulsion injection, it is characterised in that the weight/volume % (g/ml) of the parenteral solution, which is formed, is
Aspartic acid 0.05~0.25%, injection soybean oil 10~30%, phosphatide selection injection egg yolk lecithin 1.0~
1.5% or injection soybean lecithin 0.8~1.5%, glycerol for injection 2.0~2.5%, water for injection add to 100ml.
2. a kind of a kind of preparation method of aspartic acid fat emulsion injection as described in claim 1, it is characterised in that should
Method is under inert gas shielding, by injection phosphotide and aspartic acid high-speed stirred to oil phase uniformly is made, separately will
Glycerol for injection addition is filled in appropriate water for injection container, after mixing filtering be heated to 40~70 DEG C and water phase be made to clear and bright,
Under high velocity agitation by oil phase it is mixed with water be made colostrum and with 10% sodium hydroxide solution adjust pH value 8.0~10.0, add
Water for injection is emulsified colostrum repeatedly to milk particle passed examination, particle through two step high pressure homogenizers to full dose<Below 1u accounts for 97%
More than, filling in 250~500ml glass bottles then through filtering with microporous membrane, logical nitrogen plus rubber plug roll and are placed on swinging steam sterilizing
115 DEG C of 30 points of sterilizings in device, after passed examination aspartic acid fat emulsion injection.
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Citations (4)
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|---|---|---|---|---|
| US6281175B1 (en) * | 1997-09-23 | 2001-08-28 | Scimed Life Systems, Inc. | Medical emulsion for lubrication and delivery of drugs |
| CN101244037A (en) * | 2007-02-12 | 2008-08-20 | 广州富邦医药科技有限公司 | High concentration middle/long fatty milk injection for injection and preparing method thereof |
| 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 |
| CN102961397A (en) * | 2012-12-05 | 2013-03-13 | 海南百思特医药科技有限公司 | Pharmaceutical composition of fat emulsion injection and compound amino acid injection |
-
2014
- 2014-12-26 CN CN201410823457.2A patent/CN105769764B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6281175B1 (en) * | 1997-09-23 | 2001-08-28 | Scimed Life Systems, Inc. | Medical emulsion for lubrication and delivery of drugs |
| CN101244037A (en) * | 2007-02-12 | 2008-08-20 | 广州富邦医药科技有限公司 | High concentration middle/long fatty milk injection for injection and preparing method thereof |
| 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 |
| CN102961397A (en) * | 2012-12-05 | 2013-03-13 | 海南百思特医药科技有限公司 | Pharmaceutical composition of fat emulsion injection and compound amino acid injection |
Non-Patent Citations (3)
| Title |
|---|
| 丙泊酚载药脂肪乳的处方及工艺研究;张会丽，等;《天津药学》;20071031;第19卷(第5期);第31-33页 * |
| 载药脂肪乳注射液的研究进展;赵明明，等;《沈阳药科大学学报》;20101231;第27卷(第12期);第1014-1022页 * |
| 静脉注射用门冬氨酸洛美沙星脂肪乳剂的制备;马法洋，等;《中国医药科学》;20130131;第3卷(第2期);第50-51页 * |
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