CN105769827B - For animal clearing away heat and alleviating pain flunixin meglumine plastics and preparation method thereof - Google Patents
For animal clearing away heat and alleviating pain flunixin meglumine plastics and preparation method thereof Download PDFInfo
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Abstract
The invention discloses one kind being used for animal clearing away heat and alleviating pain flunixin meglumine plastics, it is the plastics made of the following raw material：80 120g/L of flunixin meglumine, 124 20 40g/L of polyvinyl alcohol, 20 40mL/L of water-solubleazone, 80 120mL/L of N methyl pyrrolidones, 80 120mL/L of glycerine, solvent are Tris HCL buffer solutions.The invention also discloses the preparation methods of above-mentioned plastics.Transdermal agent prepared by the present invention have many advantages, such as good film-forming property, can slow release drug, analgesia of bringing down a fever, curative effect persistently, stress be small.Inventive formulation and production method are unique, and therapeutic effect is notable, can form protective film, and film inner layer Medicated Permeation absorbs, and film outer layer plays a protective role, will not voluntarily fall off, and has the advantages that dashing agent is incomparable.
Description
Technical field
The present invention relates to one kind for animals clearing away heat and alleviating pain flunixin meglumine plastics such as pig rabbit and preparation method thereof, belongs to
In animal formulation technical field.
Background technology
Fever is a kind of common sympton of domestic animal, does not only result in physiological function decline, and domestic animal growth is also suppressed,
Production performance reduces, and generation can be mixed with infectious diseases, the formation cad pig for causing piglet, sow dead, not dead.Fever
It is usually associated with pain, especially inflammation again and causes red and swollen heat pain and dysfunction, seriously affects animal productiong, gives aquaculture
Bring economic loss.Therefore, the use of antipyretic analgesics is more frequent.Currently, antipyretic common analgin injection, aminopyrine
Antipyretic response is less notable, and needs to inject pig by head, and use is very inconvenient, and an apparent disadvantage exactly needs
It to arrest, inject by head, this is again once stress for the pig natively to fall ill.Aulin is a kind of novel antipyretic
Object has preferable antipyretic response, it is a kind of nonsteroidal analgesic-antipyretic, is increasingly taken seriously, and someone uses at present
Nimesulide In Healthy Volunteers, granule etc., but aulin is not soluble in water, needs alcohol-soluble solvent that could dissolve, and production cost is high.Fluorine
The pungent meglumine of Buddhist nun belongs to water soluble drug, has good antipyretic-antalgic effect, effect widely used in animal and veterinary field
Fruit is good.But current flunixin meglumine for animals only has injection type, and when use must fix animal and be injected, time-consuming to take
Power, and easily to animal cause stress, be also not easy to eliminate after there is side effect.
Invention content
Technical problem to be solved by the invention is to provide it is a kind of it is water-soluble, easy to use, irritation is small, curative effect is reliable
, the safe flunixin meglumine plastics for animals clearing away heat and alleviating pains such as pig rabbits, substituted on veterinary clinic using not with this
Convenient injection type and peroral dosage form, reduction stress and its side effect.
The present invention also technical problems to be solved are to provide the preparation method of above-mentioned flunixin meglumine plastics.
In order to solve the above technical problems, the technical solution adopted by the present invention is as follows：
One kind being used for animal clearing away heat and alleviating pain flunixin meglumine plastics, it is the plastics made of the following raw material：
Flunixin meglumine 80-120g/L, -124 20-40g/L of polyvinyl alcohol, water-solubleazone 20-40mL/L, N- first
Base pyrrolidones 80-120mL/L, glycerine 80-120mL/L, solvent is Tris-HCL buffer solutions.
Wherein, the Tris-HCL buffer solutions be 0.05M, the Tris-HCL buffer solutions of pH 7.2-7.4, preferably
The Tris-HCL buffer solutions of 0.05M, pH 7.4.
It is above-mentioned to be used for the animal clearing away heat and alleviating pain flunixin meglumine plastics preferably plastics made of the following raw material：Fluorine Buddhist nun
Pungent meglumine 100g/L, polyvinyl alcohol -12430g/L, water-solubleazone 30mL/L, N-Methyl pyrrolidone 100mL/L, glycerine
100mL/L, solvent are Tris-HCl buffer solutions.
The above-mentioned preparation method for animal clearing away heat and alleviating pain flunixin meglumine plastics, it includes the following steps：
1. weighing the polyvinyl alcohol -124 of formula ratio, the Tris-HCl buffer solutions that 1/2 formula ratio is added impregnate 2-4h (preferably
It after 2h), is stirred under the conditions of 75-85 DEG C (preferably 80 DEG C) to being completely dissolved, obtains -124 solution of polyvinyl alcohol, kept the temperature at 75-85 DEG C
(preferably 80 DEG C) are spare；
2. measuring the glycerine of formula ratio, step 1. -124 solution of polyvinyl alcohol obtained is added, it is stirring while adding, until complete
Fully dissolved, solution heat preservation are spare at 75-85 DEG C (preferably 80 DEG C)；
3. measuring the water-solubleazone of formula ratio, step is added 2. in solution obtained, it is stirring while adding, until completely molten
Solution, solution heat preservation are spare at 75-85 DEG C (preferably 80 DEG C)；
4. measuring the N-Methyl pyrrolidone of formula ratio, step is added 3. in solution obtained, it is stirring while adding, until complete
Fully dissolved, solution heat preservation are spare at 75-85 DEG C (preferably 80 DEG C)；
5. weighing the flunixin meglumine of formula ratio, the Tris-HCl buffer solutions of 1/4 formula ratio are added, are placed in 50-60 DEG C
Under the conditions of, to being completely dissolved, solution heat preservation is spare at 50-60 DEG C (preferably 55 DEG C) for stirring；
6. by step, 5. step is added 4. in solution obtained in flunixin meglumine solution obtained, stirring while adding, directly
To being completely dissolved, it is spare that solution is maintained at 75-85 DEG C (preferably 80 DEG C)；
7. be added in the solution 6. obtained to step the Tris-HCl buffer solutions of 1/4 formula ratio to get.
Step 2., 3., 4., 5. and 6. in, mixing speed be 10~30r/min.
Step 4. in, step is added 3. in solution obtained in N-Methyl pyrrolidone in 1 minute.
Step 7. after, filtered while hot with two layers of sterile gauze, natural cooling.
The present invention is using flunixin meglumine as raw material, with polyvinyl alcohol -124 for film forming agent, N-Methyl pyrrolidone, water
Dissolubility azone is transdermal enhancer, and glycerine adjusts acid-base value with Tris-HCl buffer solutions and fill as transdermal enhancer, moisturizer and plasticizer
Work as solvent, maintain the pH value of plastics between 7.0-7.4, is prepared by certain process.
The present invention has carried out the research for the method that plastics are prepared with flunixin meglumine, is screened by vitro transdermal test
The suitable transdermal enhancer for promoting drug absorption has carried out the film-formation result experiment of plastics, it is determined that plastics matrix it is reasonable
Formula, manufactured plastics are stablized, safety；Using pig, rat and rabbit as research object, experimental observation has rated production of the present invention
The clearing away heat and alleviating pain effect of product.
Advantageous effect：Compared with prior art, the present invention having following advantage：
1, the transdermal agent for preparing of the present invention have good film-forming property, can slow release drug, analgesia of bringing down a fever, curative effect persistently,
Stress be small the advantages that.Inventive formulation and production method are unique, and therapeutic effect is notable, can form protective film, and film inner layer drug oozes
It absorbs thoroughly, film outer layer plays a protective role, will not voluntarily fall off, and can remove at any time, and film, very convenient to use at any time, has
The incomparable advantage of dashing agent.Manufactured plastics are stable, transparent, are in a liquid state, and can be sprayed and are administered by pressure packing container.
2, plastics are made in flunixin meglumine, then can direct spraying administration, be not required to arrest fixed animal, be not required to inject
Or feed, it is easy to use, and drug reduces drug effect through liver first-pass effect first unlike oral feed, and once go out
Existing side effect only needs to remove medicine film.Protection can be formed after manufactured flunixin meglumine plastics spraying animal skin
Film has protection slow releasing function, did not only fall out, but also with long-acting.
Description of the drawings
Fig. 1 flunixin meglumine standard curves.
Fig. 2 various concentrations PVA124 film forming presentation quality observations, wherein a --- contain 2%PVA-124；B --- contain 3%
PVA-124；C --- contain 4%PVA-124；D --- contain 5%PVA-124.
Fig. 3 flunixin meglumine plastics analgesic test result (n=5).
Fig. 4 flunixin meglumines plastics (content 10%) are to the antipyretic test result of rat (n=4).
Fig. 5 flunixin meglumines plastics (content 10%) are to the antipyretic test result of rabbit (n=6).
Antipyretic test result (n=4) of Fig. 6 flunixin meglumines plastics to pig.
Specific implementation mode
According to following embodiments, the present invention may be better understood.However, as it will be easily appreciated by one skilled in the art that real
It applies content described in example and is merely to illustrate the present invention, without sheet described in detail in claims should will not be limited
Invention.
Embodiment 1：
For the animal clearing away heat and alleviating pain flunixin meglumine plastics preferably plastics made of the following raw material：Flunixin Portugal
Methylamine 100g/L, polyvinyl alcohol -12430g/L, water-solubleazone 30mL/L, N-Methyl pyrrolidone 100mL/L, glycerine
100mL/L, solvent are the pH7.4Tris-HCl buffer solutions of 0.05M.
The production method that above-mentioned each component is made to plastics of the present invention is (by 1000 milliliters of volume calculations)：
1. at room temperature in 25 DEG C, preparing the Tris hydrochloride buffers (pH7.4) of 0.05mol/1；
2. weighing polyvinyl alcohol -124 30g, it is placed in the clean beaker of appropriate volume, the Tris of 500ml 0.05M is added
It after hydrochloride buffer impregnates 2h, sets 80 DEG C of water-baths and is slowly stirred and be completely dissolved, obtain -124 solution of polyvinyl alcohol, be maintained at 80 DEG C of water
It is spare in bath；
3. measuring glycerine 100ml, being slowly added to step, 2. solution obtained, side edged are slowly stirred, mixing speed 10
~30r/min until dissolve each other completely, and transparent, solution is maintained at spare in 80 DEG C of water-baths；
4. measuring water-solubleazone 30ml, step is added 3. in -124 solution of polyvinyl alcohol obtained, it is stirring while adding, it stirs
It is 10~30r/min to mix speed, until being completely dissolved, is maintained at spare in 80 DEG C of water-baths；
5. measuring N-Methyl pyrrolidone 100ml, step is slowly added to 4. in solution obtained, is added in 1 minute, side
Edged stirs, and mixing speed is 10~30r/min, until dissolve each other completely, it is transparent, it is maintained at spare in 80 DEG C of water-baths；
6. weighing flunixin meglumine 100g, the Tris hydrochloride buffers of the 0.05mol/l of 250ml or so are added
(pH7.4), it is placed in 55 DEG C of water-baths, is slowly stirred, mixing speed is 10~30r/min, until being completely dissolved, rests on 55 DEG C
It is spare in water-bath；
7. by step, 6. flunixin meglumine solution obtained is slowly added to the step 5. mixing of polyvinyl alcohol -124 obtained
It in solution, is slowly stirred, mixing speed is 10~30r/min, until being completely dissolved, this solution is maintained at standby in 80 DEG C of water-baths
With；
8. being slow added into Tris hydrochloride buffers is settled to 1000ml to get flunixin meglumine plastics product.
9. being filtered while hot with two layers of sterile gauze, natural cooling obtains flunixin meglumine plastics.
Embodiment 2：
1, flunixin meglumine acute toxicity test (LD50It measures)
(1) mouse intramuscular injection LD50It measures
Trial test：The high dose group dosage that experiment is proposed according to the analysis of flunixin meglumine is 600mg/kg, by 3
~5 times of multiple successively decrease setting 5 groups, every group of dosage be respectively 600mg/kg, 200mg/kg, 150mg/kg, 120mg/kg,
66.7mg/kg is followed successively by 1~5 group from low dosage to high dose.4 small white mouses of every group of selection, half male and half female, intramuscular injection 0.1ml/
Each dosage group solution of 10g, optionally with 4 small white mouses, blank solvents of the intramuscular injection 0.1ml/10g without flunixin meglumine, observation
The death condition of each group small white mouse counts simultaneously analysis result.
Trial test result (is shown in Table 1)
1 various dose flunixin meglumine of table injects necrology to small white mouse
From trial test result it is found that 600mg/kg dosage groups small white mouse is all dead, 66.7mg/kg dosage groups and 120mg/
Kg dosage group small white mouses do not occur death, accordingly, it can be determined that 4/4 lethal dose of flunixin meglumine is 600mg/kg, 0/4 causes
Dead dosage is 120mg/kg.
Formal test：Foundation《Veterinary drug guideline》The ratio of regulation, 4/4 lethal dose and 0/4 lethal dose is 3~10
When, if 5~7 groups, therefore experiment is set as 5 groups.It is 1.5 to acquire two adjacent groups dose ratio (r) according to formula, is obtained with trial test
Dosage of 4/4 lethal dose as formal test high dose group, it is respectively 400mg/ to acquire other each dosage group dosage by r values
Kg, 266.7mg/kg, 177.8mg/kg, 118.5mg/kg are set as 1~5 group successively from low dosage to high dose.It separately will not be fluorine-containing
The solvent of the pungent meglumine of Buddhist nun is set as control group.
Select the small white mouse 48 of health, half male and half female.Prepare each dosage group solution, every group of small white mouse intramuscular injection 0.1ml/
10g is observed continuously 7 days, and statistical result (is shown in Table 2).
2 flunixin meglumine LD of table50Test result
Median lethal dose LD50Computational methods：
Formula LD50=log-1[Xm-I(∑P-0.5)]
Xm：The logarithm of maximum dose group dosage；
I：The logarithm of the ratio between two adjacent groups dosage high dose and low dosage；
P：Each group mortality of animals；
∑P：The summation of each group mortality of animals
It is calculated by formula,
Flunixin meglumine mouse intramuscular injection LD50For 308.6mg/kg.
(2) rat intramuscular injection LD50It measures
Trial test：The high dose group dosage that experiment is proposed according to the analysis of flunixin meglumine is 425mg/kg, by 3
~5 times of multiple, which successively decreases, sets 5 groups, and every group of dosage is respectively 425mg/kg, 141.67mg/kg, 106.25mg/kg, 85mg/
Kg, 47.23mg/kg are followed successively by 1~5 group from low dosage to high dose.4 rats of every group of selection, half male and half female, intramuscular injection
Each dosage group solution of 0.5ml/100g, optionally with 4 rats, the blank that intramuscular injection 0.5ml/100g is free of flunixin meglumine is molten
The death condition of each group rat is observed in agent, counts simultaneously analysis result.
Trial test the results are shown in Table 3.
3 various dose flunixin meglumine of table injects necrology to rat
From trial test result it is found that 425mg/kg dosage groups small white mouse is all dead, 47.23mg/kg dosage groups rat is not
There is death, accordingly, it can be determined that 4/4 lethal dose of flunixin meglumine is 425mg/kg, 0/4 lethal dose is 47.23mg/
kg。
Formal test：Foundation《Veterinary drug guideline》The ratio of regulation, 4/4 lethal dose and 0/4 lethal dose is 3~10
When, if 5~7 groups, therefore experiment is set as 6 groups.It is 1.3 to acquire two adjacent groups dose ratio (r) according to formula, is obtained with trial test
Dosage of 4/4 lethal dose as formal test high dose group, it is respectively 326.9mg/ to acquire other each dosage group dosage by r values
Kg, 217.9mg/kg, 145.3mg/kg, 96.9mg/kg, 64.8mg/kg are set as 1~6 group successively from low dosage to high dose.
The solvent without flunixin meglumine is separately set as control group.
Select the rat 56 of health, half male and half female.Prepare each dosage group solution, every group of rat intramuscular injection 0.5ml/100g,
7 days are observed continuously, statistical result.
Test result is shown in Table 4.
4 flunixin meglumine LD of table50Test result
Median lethal dose LD50Computational methods：
Formula LD50=log-1[Xm-I(∑P-0.5)]
Xm：The logarithm of maximum dose group dosage；
I：The logarithm of the ratio between two adjacent groups dosage high dose and low dosage；
P：Each group mortality of animals；
∑P：The summation of each group mortality of animals
It is calculated by formula, flunixin meglumine rat intramuscular injection LD50For 206.0mg/kg.
Conclusion：According to the acute toxicity tests of rat and mouse, flunixin meglumine belongs to low toxicity level drug.Therefore this
Research product flunixin meglumine plastics are used in the preparation that animal belongs to security level.
2, the screening test of transdermal enhancer
Can N-Methyl pyrrolidone, water-solubleazone belong to transdermal enhancer, and glycerine has plasticising, a moisture-keeping function, but with
Flunixin meglumine dissolves each other and what ratio can most promote the absorption of flunixin meglumine to be required for carrying out test evaluation, obtains
Best transdermal enhancer combination.
In view of water-solubleazone, glycerine, N-Methyl pyrrolidone inherently have preferable water solubility, therefore test
Main purpose will consider to promote effect preferable, while the higher water-solubleazone dosage of cost is few, this research and design is following several
A combination：
Combination 1：Flunixin meglumine 1g+N- methyl pyrrolidone 5ml, 100 milliliters are settled to water dissolution；
Combination 2：Flunixin meglumine 1g+N, N- dimethyl-2-imidazolinone 5ml+ glycerine 8ml, are settled to water dissolution
100 milliliters；
Combination 3：Flunixin meglumine 1g+ water-solubleazone 2ml+N- methyl pyrrolidone 6ml+ glycerine 8ml, use water dissolution
It is settled to 100 milliliters；
Combination 4：Flunixin meglumine 1g+ water-solubleazone 3ml+N- methyl pyrrolidone 10ml+ glycerine 10ml, use are water-soluble
Solution is settled to 100 milliliters.
Test method：
The measurement of absorbing wavelength：Appropriate flunixin meglumine is taken, certain density solution is configured to pure water, is with pure water
Control, ultraviolet spectra is scanned within the scope of 100~900nm, determines flunixin meglumine maximum absorption wavelength at 282nm, and
Pure water is without absorption value at this wavelength.Therefore, wave is absorbed using 282nm wavelength as the measurement for measuring flunixin meglumine content
It is long.
The foundation of standard curve：The accurate flunixin meglumine for weighing 0.01g, 100ml is settled to get 100 μ with pure water
The flunixin meglumine stock solution of g/ml.Then 10 are diluted to pure water, 20,30,40, the flunixin meglumine of 50ug/ml it is molten
Liquid measures its absorbance, and using absorbance as ordinate (Y), flunixin meglumine content is abscissa (X), makees linear equation, i.e.,
Flunixin meglumine content measuring standard curve is obtained, sees Fig. 1.
Y=0.02641X-0.0165 (R2=0.99931)
The preparation of mouse isolated skin：By mouse break neck put to death after with shaver by mouse back skin hair remove, take
Without damaged skin, physiological saline rinses not muddy to liquid repeatedly, and then isolated skin is placed in physiological saline, 4 DEG C of preservations
It is spare.
The preparation of receiving liquid and release liquid：Combined according to above-mentioned four kinds, the mixed solution in said combination as release liquid,
1. combination is pure water with the receiving liquid of combination 2.；3. combination is 30% ethyl alcohol with the receiving liquid of combination 4..Control group release liquid is
The solution for the transdermal enhancer containing various concentration for being not added with flunixin meglumine equally prepared with pure water.
The in vitro transdermal test of flunixin meglumine, receiving liquid 15ml, release liquid are carried out using intelligent penetrating absorption instrument
2ml, temperature (37.0 ± 0.5) DEG C, rotating speed 150r/min.Respectively 1 after transdermal beginning, 2,4,6,8,10,12h when from reception tank
5ml is sampled, measures its absorbance by blank control of control group, and add the ethyl alcohol titer of same amount.By the absorbance measured,
It substitutes into flunixin meglumine standard curve and calculates the Percutaneous permeability (Q) that each time point flunixin meglumine penetrates.
Q=(VCn+ ∑sn-1 I=1CiVi)/A
In formula：Q is unit accumulated time transit dose, and V is reception tank volume, and A is transdermal diffusion area, and Cn takes for n-th
The concentration of receiving liquid when sample, Ci are the concentration of receiving liquid when ith samples, and Vi is sampling amount.With unit interval Percutaneous permeability Q
Linear regression is carried out to time t, the slope (K) of gained equation is infiltration coefficient [unit is μ g/ (cm2.h)], which can be anti-
Answer the percutaneous rate of drug.
(6) statistical procedures：Data use average ± standard deviation (X ± SD) to indicate, SPASS17.0 is used in combination to carry out Dan Yin
Plain variance analysis.
Test result is shown in Table 5.
The Percutaneous permeability of 12 hours (h) of the lower flunixin meglumine of the different transdermal enhancer combinations of table 5
Note：With data line mark letter without identical person's significant difference (P ＜ 0.05).
Combination 1：Flunixin meglumine 1g+N- methyl pyrrolidones 5ml；Combination 2：Flunixin meglumine 1g+N, N- diformazan
Base -2- imidazolone 5ml+ glycerine 8ml；Combination 3：Flunixin meglumine 1g+ water-solubleazone 2ml+N- methyl pyrrolidones 6ml
+ glycerine 8ml；Combination 4：Flunixin meglumine 1g+ water-solubleazone 3ml+N- methyl pyrrolidone 10ml+ glycerine 10ml
In terms of the result saturating from rush, water-solubleazone 3ml and N-Methyl pyrrolidone 10ml and glycerine 10ml promote saturating effect most
It is good, but this combination can also continue to optimize.
3, the screening of film forming agent concentration
--- testing program：It is that filmogen is screened with polyvinyl alcohol -124 (PVA-124).Using 100ml as film
Agent solution constant volume, using water-solubleazone 3ml, N-Methyl pyrrolidone 10ml and glycerine 10ml as transdermal enhancer portfolio ratio,
Using 10 grams of flunixin meglumines as main ingredient, with 0.05M Tris-HCL buffer solutions (pH7.4) for solvent, respectively with 1%, 2%,
3%, 4% and 5% polyvinyl alcohol -124 is filmogen, carries out plastics trial-production, is commented according to film formation time, quality of forming film
Sentence, the factors such as character observation (whether being colourless or yellowish clear liquid), viscosity and pH value carry out comprehensive analysis, determine fluorine
The proper ratio of the pungent meglumine plastics matrix of Buddhist nun.
--- preparation method and process：The flunixin meglumine film of various concentration is prepared according to following operating procedure respectively
Agent.
1. at room temperature in 25 DEG C, preparing the Tris hydrochloride buffers (pH7.4) of 0.05mol/l；
2. weighing polyvinyl alcohol -124 1g, 2g, 3g, 4g and 5g respectively, it is placed in the clean beaker of appropriate volume, respectively
After the Tris hydrochloride buffers immersion 2h of 50ml 0.05mol/1 is added in room temperature, sets 80 DEG C of water-baths and be slowly stirred dissolving, obtain poly-
- 124 solution of vinyl alcohol is maintained at spare in 80 DEG C of water-baths；
3. measuring glycerine 10ml, being slowly added to step, 2. solution obtained, side edged are slowly stirred, mixing speed is 10~
30r/min is transparent up to dissolving each other completely；
4. measuring water-solubleazone 3ml, step is added 3. in -124 solution of polyvinyl alcohol obtained, it is stirring while adding, it stirs
It is 10~30r/min to mix speed, until being completely dissolved, is maintained at spare in 80 DEG C of water-baths；
5. measuring N-Methyl pyrrolidone 10ml, step is slowly added to 4. in solution obtained, is added in 1 minute, side
Edged stirs, and mixing speed is 10~30r/min, until dissolve each other completely, it is transparent, it is maintained at spare in 80 DEG C of water-baths；
6. weighing flunixin meglumine 10g, the Tris hydrochloride buffers of 25ml or so are added, are placed in 55 DEG C of water-baths, delays
Slow stirring, mixing speed is 10~30r/min, until dissolving, rests on spare in 55 DEG C of water-baths；
7. by step, 6. flunixin meglumine solution obtained is slowly added to the step 5. mixing of polyvinyl alcohol -124 obtained
It in solution, is slowly stirred, mixing speed is 10~30r/min, until dissolving, is maintained at spare in 80 DEG C of water-baths by this solution；
8. being slow added into Tris hydrochloride buffers is settled to 100ml, flunixin meglumine plastics product is obtained.
9. with two layers of sterile gauze filtering to get flunixin meglumine plastics.
10. the physicochemical character (whether in colourless or yellowish) of plastics made of checking, whether pH value is (in 7.0-
7.6) between.
By the above operating process, 1%, 2%, 3%, 4% and 5% flunixin meglumine plastics have been respectively obtained.It will
The plastics obtained are examined for clarity character, viscosity and quality of forming film.
--- test result
1. flunixin meglumine plastics clarity property determination result prepared by various concentration PVA-124：By measuring,
It is in the yellowish liquid of homogeneous and transparent containing flunixin meglumine plastics made from 1%, 2%, 3%, 4%PVA124, there is one
Fixed viscosity, the flunixin meglumine plastics containing 5%PVA124 are in yellowish muddiness, and PVA124 dissolvings not exclusively (are shown in Table
6).The result shows that it is clear and bright to meet physical and chemical index containing flunixin meglumine plastics made from 1%, 2%, 3%, 4%PVA124
The requirement of degree.
The clear and bright property determination of flunixin meglumine plastics prepared by 6 various concentration PVA124 of table
| PVA-124 concentration | 1% | 2% | 3% | 4% | 5% |
| Clear and bright character | Clear and bright micro- Huang | Clear and bright micro- Huang | Clear and bright micro- Huang | Clear and bright micro- Huang | Muddy micro- Huang |
2. flunixin meglumine plastics viscosity measurements prepared by various concentration PVA-124：With reference to novel chiral synthon development
Guideline, with the 1ml pipettes (import internal diameter, exit inside diameter) of standard, pipette samples 1ml, calculating are vertically released respectively
Time number of seconds needed for 0.5ml, and make comparisons.As a result：With the raising of PVA-124 concentration, the vertical time for releasing 0.5ml prolongs
It is long, show the increasing with PVA-124 concentration, plastics viscosity is increasing, and the viscosity measured at different temperatures also has
Institute is different, and the speed that same dose is discharged at 25 DEG C is significantly shorter than speed at 15 DEG C and 25 DEG C.It the results are shown in Table 7.It will be different dense
It spends spray equipment pilot scale of the flunixin meglumine plastics equipped with pump head prepared by PVA-124 to spray, finds 1%, 2%, 3%, 4%
Flunixin meglumine plastics made from PVA124 are easier to spray.Flunixin meglumine plastics made from 5%PVA124
Because film forming agent dissolving is not complete, should not be prepared as suitable concentration.
Flunixin meglumine plastics viscosimetric analysis prepared by 7 various concentration PVA-124 of table
3. flunixin meglumine plastics film formation time prepared by various concentration PVA-124 measures.Difference obtained is dense
The separately sampled 1ml of flunixin meglumine plastics prepared by degree PVA-124 is spread evenly across on clean the back of the hand, observes and records shape
The time of film forming.It the results are shown in Table 8.The result shows that with the increasing of PVA-124 contents, film formation time extends, when PVA-124 contains
Amount for 1% when can not form a film, the excessive concentration that just seems when PVA-124 contents reach 5% and cannot be completely dissolved.
Flunixin meglumine plastics film formation time prepared by 8 various concentration PVA-124 of table
Note：11 ＇ 3 " expressions 3 seconds 11 minutes, and so on.
4. flunixin meglumine plastics quality of forming film analysis prepared by various concentration PVA-124
Plastics containing 1%PVA-124：One layer of relatively thin membranoid substance is only formed, cannot be opened, is not formed complete
Film.
Plastics containing 2%PVA-124：One layer of complete film can be formed, skin anchorage is good, but there is fracture in while opening
Phenomenon illustrates that flexibility is slightly insufficient.
Plastics containing 3%PVA-124：One layer of complete film is formed, skin anchorage is good, flexible when can completely open
Property is good.
Plastics containing 4%PVA-124：One layer of complete film is formed, skin anchorage is good, flexible when can completely open
Property is good.
Plastics containing 5%PVA-124：Although forming a film good toughness, PVA-124 fails to be completely dissolved, though film is molded,
Skin anchorage is poor, it is easy to just open quickly, practical application is possible to fall off at any time.
It can be seen that the film forming agent 3% in more satisfactory flunixin meglumine plastics matrix is proper, suitable model
Enclose 2%-4%.
5. plastics acid-base value measures：After measured, the flunixin meglumine plastics pH value that prepared by various concentration PVA-124
Between 7.2-7.6, meet the dissolving requirement of flunixin meglumine.
It is according to the above experiment and analysis, entire plastics ideal formulations：
Polyvinyl alcohol -1243g, water-solubleazone 3mL, N-Methyl pyrrolidone 10mL, glycerine 10mL, 0.05M Tris-
HCL (pH7.4) buffer solution is settled to 100mL.
The flunixin meglumine plastics character of preparation is shown in Fig. 2.
4, flunixin meglumine plastics observe mouse analgesic test
Following experiment is carried out with the plastics that embodiment 1 is prepared.
--- test method
(1) Basic Pain Threshold value measures
It is (55.0 ± 0.5) DEG C by the temperature setting of thermostat water bath using hot plate method, room temperature is controlled at 13 ± 18 DEG C,
Female mice (20 ± 2g of weight) is placed in observation mouse on hot plate and licks the sufficient time, Basic Pain Threshold value (unit is measured with stopwatch：
Second), it measures 2 times altogether, is spaced 5min, calculate Basic Pain Threshold value average value and record.Basic Pain Threshold value is chosen in 5~30s
Female mice is as test mice.
(2) experimental animal grouping and administration
Above-mentioned qualified mouse is randomly divided into 3 groups, respectively flunixin meglumine plastics group, aspirin group and blank
Group.Flunixin meglumine plastics group mouse back shaving smears 0.1ml/ flunixin meglumine plastics；Aspirin group
Gavage 4% aspirin solutions of 0.1ml；Blank group is without any processing.
Upon administration 15,30,60,120min measures each group mouse pain threshold and records respectively, with average ± standard deviation
It indicates.
As a result：It is shown in Table 9 and Fig. 3.For mouse after medication 15min, flunixin meglumine plastics group and aspirin group are small
Mouse pain threshold increased, and two group differences are not notable；After medication 30min and 60min, flunixin meglumine plastics group and
Aspirin group significantly increases, and flunixin meglumine plastics group mouse pain threshold is higher than aspirin group；Medication 120min
Afterwards, flunixin meglumine plastics group and aspirin group mouse pain threshold difference is not notable.The result shows that flunixin meglumine
(flunixin meglumine) plastics can significantly improve pain threshold, to play analgesic activity.
9 flunixin meglumine plastics of table are to mouse analgesic test result (n=5)
Flunixin meglumine group and aspirin group respectively with blank group ratio.* the significance of equal value difference is 0.05, * *
Significance is 0.01.
The result shows that flunixin meglumine plastics have preferable analgesic effect, and analgesic effect is better than aspirin.
5. flunixin meglumine plastics are to rat heat-clearing effect observation
Following experiment is carried out with the plastics that embodiment 1 is prepared.
It chooses healthy male SD rat (weight 210-240g) and carries out 3-5 days, adaptability thermometric 3 times a day, until surveying
Warm numerical stability surveyed rat temperature 3 times in the experiment same day before experiment, took its average value as basic body temperature, if wherein body temperature
More than 38.3 DEG C or rat of the adjacent difference of body temperature twice more than 0.5 DEG C is eliminated.
The foundation of rat fever model：The qualified male SD rat filtered out is divided into 3 groups, flunixin meglumine plastics
Group, fabricate-heat not medication group and control group.To flunixin meglumine plastics group, fabricate-heat not medication group back shaving, dorsal sc
Multi-point injection yeast suspension 0.6ml/ is divided only to survey a body temperature per 1h, wait for that rat temperature rises to the normal body temperature temperature difference 0.5
DEG C or more and maintain stablize be modeling success.
Take 4 healthy rats as a control group, it is without any processing；Take 4 successful rats of fabricate-heat as fluorine Buddhist nun respectively
Pungent meglumine plastics group and fabricate-heat not medication group smear 0.5ml/ fluorine Buddhist nun at the shaving of flunixin meglumine plastics group back
Pungent meglumine plastics (content 10%), and 1 after medication, 2,3,4h measures and rat temperature and records；Fabricate-heat not medication group is big
The same point in time measurement body temperature of mouse simultaneously records.It the results are shown in Table 10 and Fig. 4.
10 flunixin meglumine plastics (abbreviation FM) of table are to rat heat-clearing test result (n=4)
Every group it is corresponding with blank group compared with * p ＜ 0.05, * * p ＜ 0.01
6. flunixin meglumine plastics are to rabbit heat-clearing effect observation
Following experiment is carried out with the plastics that embodiment 1 is prepared.
The new zealand white rabbit of healthy weight 2kg or so to be raised seven days, daily morning and afternoon respectively surveys body temperature once and records,
All body temperature could be used as test animal at 38 DEG C -39.6 DEG C and every rabbit of 4 hours body temperature deviations no more than 0.4 DEG C.It takes and makes
Hot successfully experiment rabbit is randomly divided into 3 groups, and the 1st group antipyretic with plastics, the 2nd group of fabricate-heat not medication, and the 3rd group does not have to not generate heat
Medicine control group, it is without any processing, rabbit body temperature is surveyed before testing, yeast suspension is subcutaneously injected to experiment rabbit, after injection per hour
Per anum surveys a rabbit body temperature, waits for that body temperature rises to and the as fabricate-heat success at 0.5 DEG C or more of the normal body temperature temperature difference.Every rabbit back of the body
Portion's shaving, by administration 2.5ml is smeared per kg weight, respectively upon administration 1,2,3,4,5h survey rabbit body temperature, measurement of bldy temperature selects mark
Accurate mercurial thermometer records each timing node body temperature, carries out statistical analysis.
11 are the results are shown in Table, there is preferable antipyretic response to fever rabbit from the visible flunixin meglumine plastics of result, have
It closes antipyretic trend and sees Fig. 5.
11 flunixin meglumine plastics (FM) of table are to the antipyretic test result of rabbit (n=6)
Compared with every group corresponding with blank group：* p ＜ 0.05, * * p ＜ 0.01
7. flunixin meglumine plastics are to the antipyretic experimental observation for the piglet that generates heat
Following experiment is carried out with the plastics that embodiment 1 is prepared.
The foundation of piglet fever model：Healthy white piglet (length is miscellaneous) (8~10kg of weight) subcutaneous abdomen divides multi-point injection
High pressure sterilization skim milk 2ml/kg waits for that body temperature rises to and the as fabricate-heat success at 0.5 DEG C or more of the normal body temperature temperature difference.
Test method：The long miscellaneous white piglets of 4 health of selection are without any processing as blank group；From fever model at
12 are chosen in the piglet of work(, are randomly divided into 3 groups, respectively flunixin meglumine low dose group, flunixin meglumine high dose
Group and fabricate-heat not medication group, flunixin meglumine low dose group is after piglet ear and groin smears the Flunixin Portugal of 0.5ml/kg
Methylamine plastics；Flunixin meglumine high dose group smears the painting of 1.0ml/kg flunixin meglumines after piglet ear and at groin
Film；Fabricate-heat not medication group not medication, respectively 1 after medication, 2,3,4h measure and temperature of pig body and record, the results are shown in Table 12 and Fig. 6.
12 flunixin meglumine plastics of table are to fever piglet heat-clearing test result (n=3)
The significance of difference：Compared with all corresponding with blank group, * significances are that 0.05, * * significances are 0.01.
Claims (7)
1. one kind being used for animal clearing away heat and alleviating pain flunixin meglumine plastics, which is characterized in that it is made of the following raw material
Plastics：
Flunixin meglumine 80-120g/L, -124 20-40g/L of polyvinyl alcohol, water-solubleazone 20-40mL/L, N- methyl pyrrole
Pyrrolidone 80-120mL/L, glycerine 80-120mL/L, solvent are Tris-HCL buffer solutions.
2. according to claim 1 be used for animal clearing away heat and alleviating pain flunixin meglumine plastics, which is characterized in that described
Tris-HCL buffer solutions are 0.05M, the Tris-HCL buffer solutions of pH 7.2-7.4.
3. it is according to claim 1 be used for animal clearing away heat and alleviating pain flunixin meglumine plastics, which is characterized in that it be by
Plastics made of the following raw material：Flunixin meglumine 100g/L, polyvinyl alcohol -124 30g/L, water-solubleazone 30mL/L,
N-Methyl pyrrolidone 100mL/L, glycerine 100mL/L, solvent are Tris-HCl buffer solutions.
4. the preparation method described in claim 1 for animal clearing away heat and alleviating pain flunixin meglumine plastics, which is characterized in that
It includes the following steps：
1. the polyvinyl alcohol -124 of formula ratio is weighed, after the Tris-HCl buffer solutions immersion 2-4h of 1/2 formula ratio is added, 75-85
It is stirred under the conditions of DEG C to being completely dissolved, obtains -124 solution of polyvinyl alcohol, heat preservation is spare at 75-85 DEG C；
2. measuring the glycerine of formula ratio, step 1. -124 solution of polyvinyl alcohol obtained is added, it is stirring while adding, until completely molten
Solution, solution heat preservation are spare at 75-85 DEG C；
3. measuring the water-solubleazone of formula ratio, step is added 2. in solution obtained, it is stirring while adding, until be completely dissolved,
Solution heat preservation is spare at 75-85 DEG C；
4. measuring the N-Methyl pyrrolidone of formula ratio, step is added 3. in solution obtained, it is stirring while adding, until completely molten
Solution, solution heat preservation are spare at 75-85 DEG C；
5. weighing the flunixin meglumine of formula ratio, the Tris-HCl buffer solutions of 1/4 formula ratio are added, are placed in 50-60 DEG C of condition
Under, to being completely dissolved, solution heat preservation is spare at 50-60 DEG C for stirring；
6. by step, 5. step is added 4. in solution obtained in flunixin meglumine solution obtained, stirring while adding, until complete
Fully dissolved, solution be maintained at 75-85 DEG C it is spare；
7. be added in the solution 6. obtained to step the Tris-HCl buffer solutions of 1/4 formula ratio to get.
5. preparation method according to claim 4, which is characterized in that step 2., 3., 4., 5. and 6. in, mixing speed is
10~30r/min.
6. preparation method according to claim 4, which is characterized in that step 4. in, N-Methyl pyrrolidone is in 1 minute
Addition step is 3. in solution obtained.
7. preparation method according to claim 4, which is characterized in that step 7. after, while hot with two layers of sterile gauze
Filtering, natural cooling.
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