A kind of water solublity synergistic composition containing amoxicillin and application thereof
Technical field
The invention belongs to field of veterinary medicine preparation, be specifically related to a kind of water solublity synergistic composition containing amoxicillin and answer
With.
Background technology
Since nineteen forty-one penicillin medicine comes out, penicillin medicine is just strong, anti-with its high-efficiency low-toxicity, selectivity
The other medicines such as bacterium spectrum is wide, distribution in vivo is good are difficult the advantage substituted, and no matter are Human clinical, or at animal clinical, all
Obtain worldwide extensive application, create huge social benefit.
Amoxicillin is a kind of the most frequently used semi-synthetic penicillins wide spectrum beta-lactam antibiotic, and the mechanism of action is medicine
The beta-lactam nucleus in thing molecule transpeptidase in bacterial body is combined and is allowed to inactivate, and cuts off thalline and relies on transpeptidase synthesis sugar poly-
Peptide is used for building the unique channel of cell wall, makes bacterial cell rapidly become spheroplast and ruptures dissolving, and thalline is finally because of cell
Wall loses, and moisture content constantly permeates and spalling is dead.Most of pathogenic G+ bacterium and G-bacterium (including coccus and bacillus) are all had by force
Big antibacterial and bactericidal action.Wherein to the Streptococcus such as streptococcus pneumoniae, Hemolytic streptococcus, do not produce penicillinase Fructus Vitis viniferae ball
The aerobic gram positive coccus such as bacterium, enterococcus faecalis, escherichia coli, proteus mirabilis, Salmonella, hemophilus influenza, pouring
The strain of not beta-lactamase-producing and the helicobacter pylori of the aerobic gram-negative bacterias such as sick Neisseria have good antibacterial activity.Ah
After Amdinocillin is administered orally by animal, at gastric stable under acidic conditions, gastrointestinal absorption rate reaches 90%, and the ability of penetration cell wall
More higher than similar antibiotic, therefore it is one of current widely used oral semisynthetic penicillin, animal clinical is mainly used
In preventing and treating sensitive microbial digestive tract, respiratory tract infection.
But, there are some self-defects in amoxicillin in clinical practice, limits its range of application, be mainly manifested in
The following aspects:
One, amoxicillin is the most unstable, is susceptible to decomposition reaction, thus loses antibacterial activity.Intensive
Change in breeding process, drinking water administration mode because easy to operate, labour cost is low, environmental pollution is little, be suitable for colony's administration etc.
Advantage and enjoy favor.Amoxicillin, because the most easily decomposing, must be finished when using drinking water administration at short notice,
Not so drug effect can be had a greatly reduced quality, and this makes troubles to clinical application, also increases drug cost.
Two, amoxicillin absorbed following oral administration is fast, and protein binding rate is low, and the half-life is short, will soon want from internal metabolism
Maintain drug level, extend action time, it is necessary to shorten dosage period, increase administration frequency.This shortcoming also gives disease in cultivation
Sick prevention and control are made troubles, and increase control and prevention of disease cost.
Three, along with the clinical practice of amoxicillin, Resistant strain produces the most therewith.The beta-lactamase that Resistant strain produces
Amoxicillin can be decomposed so that it is lose antibacterial activity.Particularly at the penicillin that the Clinical practice time is the longest, its drug resistance is the tightest
Weigh, and these Resistant strains exist cross resistance to the amoxicillin being all beta-lactam.
For the problems referred to above, Authorization Notice No. is that the China of CN102846605B (patent No. ZL201210274070.7) is special
Profit, discloses a kind of pharmaceutical composition and preparation technology thereof and application, and pharmaceutical composition includes the component of following weight portion: A Mo
XiLin 5~15 weight portion, clavulanate potassium 1~5 weight portion, ambroxol hydrochloride 1~5 weight portion;Also disclose described medicine group
Compound is in preparation treatment animal respiratory infectious disease, the especially medicine of porcine contagious pleuropneumonia, Haemophilus parasuis
Application in thing.This invention also discloses the preparation method of a kind of compound amoxicillin soluble powder, described amoxicillin
The formula of soluble powder consists of: amoxicillin 5~15 weight portion, clavulanate potassium 1~5 weight portion, ambroxol hydrochloride 1~5
Weight portion, anhydrous glucose 75~93 weight portion;With equal increments principle by above-mentioned each raw material mix homogeneously, to obtain final product.Above-mentioned specially
Although the technical scheme that profit is provided can effectively solve amoxicillin drug resistance problems, but it is water-soluble not solve amoxicillin
The problem that property is poor, aqueous solution is unstable, metabolism is fast.Meanwhile, clavulanate potassium draw moist by force, propose higher to production environment
Requirement, adds production cost.
Summary of the invention
In place of it is an object of the invention to overcome the deficiencies in the prior art, it is provided that a kind of water solublity containing amoxicillin increases
Effect compositions and application thereof, said composition can strengthen the Clinical practice effect of amoxicillin.
One of the technical solution adopted for the present invention to solve the technical problems is:
A kind of water solublity synergistic composition containing amoxicillin, it includes according to the mass fraction: amoxicillin 10~30 parts,
Sulbactam sodium 1~30 parts, sodium benemid 1~11 parts, EDTA-2Na 1~15 parts, PVP-K30 1~10 parts, PEG-6000 1~
10 parts, SDS 1~30 parts, lactose 1~40 parts.
In one embodiment: it includes according to the mass fraction: amoxicillin 9~11 parts, sulbactam sodium 4~6 parts, sodium benemid
3~4 parts, EDTA-2Na 9~11 parts, PVP-K30 2~3 parts, PEG-6000 4~6 parts, SDS 24~26 parts, lactose 38~
40 parts.
In one embodiment: it includes according to the mass fraction: amoxicillin 14~16 parts, sulbactam sodium 7~8 parts, probenecid
Sodium 4~6 parts, EDTA-2Na 9~11 parts, PVP-K30 3~4 parts, PEG-6000 7~9 parts, SDS 19~21 parts, lactose 30
~32 parts.
In one embodiment: it includes according to the mass fraction: amoxicillin 19~21 parts, sulbactam sodium 9~11 parts, probenecid
Sodium 7~9 parts, EDTA-2Na 9~11 parts, PVP-K30 4~6 parts, PEG-6000 9~11 parts, SDS 14~16 parts, lactose 21
~23 parts.
In one embodiment: it is the superfine powder form of particle diameter 6~14 μm, each component super micron mill can be ground into
It is mixed to get after particle diameter 1000~2000 mesh (i.e. particle diameter 6.5~13 μm).
The two of the technical solution adopted for the present invention to solve the technical problems are:
A kind of preparation including the above-mentioned water solublity synergistic composition containing amoxicillin, such as powder, granule, liquid system
The pharmaceutically acceptable preparations such as agent such as oral liquid etc., tablet such as disintegrating tablet;Above-mentioned preparation can be by described containing amoxicillin
Water solublity synergistic composition individually or is combined employing conventional method with at least one pharmaceutically acceptable adjuvant or pharmaceutical carrier
Prepare;Can also be by the water solublity synergistic composition list containing amoxicillin described in the superfine powder form of particle diameter 6~14 μm
Solely or be combined employing conventional method to prepare with at least one pharmaceutically acceptable adjuvant or pharmaceutical carrier.
Described pharmaceutically acceptable adjuvant such as includes diluent, solvent, excipient, absorbent, wetting agent, bonding
Agent, disintegrating agent, lubricant, solubilizing agent, emulsifying agent, suspending agent, surfactant, film former, propellant, antioxidant, correctives,
Aromatic, antibacterial, preservative etc.;Described pharmaceutically acceptable pharmaceutical carrier refers to support medicine, and has change
Medicine enters mode and the distribution in vivo of human body, and Drug controlled release speed reaches controlled release or slow release, and drug targeting is defeated
Deliver to the system of the effect such as target organ, such as include liposome, microsphere, microcapsule, solid dispersion, micelle, microemulsion, gel,
Spacetabs type carrier, control release type carrier, targeting vector, nano-particle material etc..
The three of the technical solution adopted for the present invention to solve the technical problems are:
The above-mentioned water solublity synergistic composition containing amoxicillin is at preparation prevention and/or the veterinary medicine for the treatment of bacterial infection
Purposes on thing, not only includes directly applying to above-mentioned by the water solublity synergistic composition containing amoxicillin of one of technical scheme
Purposes, it is also possible to the formulation application including the described water solublity synergistic composition containing amoxicillin by the two of technical scheme is in upper
State purposes.
In one embodiment: described bacterial infection include respiratory tract infection, digestive tract infection, skin and soft tissue infection,
Urogenital infections.
In one embodiment: described administration object is mammal such as pig, cattle, sheep, horse etc., or poultry such as chicken,
Duck, goose, pigeon etc..
In one embodiment: the described water solublity synergistic composition containing amoxicillin is administered by water way.
The technical program is compared with background technology, and it has the advantage that
One, the compositions of the present invention passes through micronizing and suitable cosolvent, adds amoxicillin and water engaging surface
Long-pending, increase it and disperse in water and dissolve, thus can be administered in the way of using drinking-water, it is possible to meet colony of plant and be administered
Demand.
Two, the composition solution of the present invention is stable.Conventional amoxicillin single preparations of ephedrine, unstable in aqueous, hold
Degradable and lose antibacterial activity, mainly due to caused by the metal cation in drinking-water, such as magnesium ion, calcium ion etc..This group
Compound can effectively get rid of these Cation Interferences, and protection amoxicillin is not the most destroyed and loses antibacterial activity.
Three, the compositions blood drug level of the present invention is held time length.Conventional amoxicillin single preparations of ephedrine, metabolism is fast, effectively
Blood drug level is held time short, must increase medicine frequency to maintain blood drug level, add drug cost during Clinical practice.This
Compositions reaches to extend effective blood drug concentration by suppression amoxicillin in renal metabolism speed and holds time, and plays potentiation and makees
With.
Four, the compositions of the present invention is highly resistant to the hydrolysis of beta-lactamase.Currently, because amoxicillin drug resistance day by day
Seriously, clavulanate potassium, as beta-lactamase inhibitor, is widely used in the compatibility of amoxicillin.But clavulanate potassium is difficult to
Preserving, the easy moisture absorption, see that light easily decomposes, and aqueous solution is unstable, these shortcomings propose tightened up to production and the use of product
Requirement.This compositions can not only effectively suppress the beta-lactamase destruction to amoxicillin, and to production and use
Environment does not has rigors.
Detailed description of the invention
Present disclosure is illustrated below by embodiment:
Embodiment 1
The water solublity synergistic composition containing amoxicillin of the present embodiment includes according to the mass fraction:
10 parts, amoxicillin,
Sulbactam sodium 5 parts,
Sodium benemid 3.5 parts,
EDTA-2Na 10 parts,
PVP-K30 2.5 parts,
PEG-6000 5 parts,
SDS 25 parts,
Lactose 39 parts.
Said components is ground into by super micron mill the superfine powder of particle diameter 1000 mesh (i.e. particle diameter 13 μm), then with three-dimensional
Mixer mix homogeneously, obtains the soluble powder that can be used directly on veterinary clinic.
Take above-mentioned powder and carry out aqueous solution stability test:
Above-mentioned powder is made into drinking water respectively with conventional amoxicillin soluble powder and containing amoxicillin concentration is
The solution of 100ml:10mg, stands, respectively Determination of amoxicillin in different time detection solution, and result is following, and (result is marked
The percent of the amount of showing 100ml:10mg represents):
As can be known from the results, common amoxicillin aqueous solution is unstable, degradable, and the compositions powder that the present embodiment obtains
Solution-stabilized, even if Determination of amoxicillin only declines 3% after 24 hours, and Ah not in conventional amoxicillin soluble powder solution
XiLin content have dropped 93%.When the compositions powder of the present embodiment uses water way to be administered, amoxicillin degraded is slowly, no
Using effect can be affected, and have a strong impact on because of amoxicillin fast degradation when conventional amoxicillin soluble uses drinking water administration
Using effect.
Embodiment 2
The water solublity synergistic composition containing amoxicillin of the present embodiment includes according to the mass fraction:
15 parts, amoxicillin,
Sulbactam sodium 7.5 parts,
Sodium benemid 5 parts,
EDTA-2Na 10 parts,
PVP-K30 3.5 parts,
PEG-6000 8 parts,
SDS 20 parts,
Lactose 31 parts.
Said components is ground into by super micron mill the superfine powder of particle diameter 1000 mesh (i.e. particle diameter 13 μm), mixes by flute profile
Conjunction machine mix homogeneously, adds 50% ethanol solution of component total amount 1/10, and stirring is made soft material, then made granule with granulator,
45 DEG C of drying in an oven, make the spendable granule of veterinary clinic.
Take above-mentioned granule and carry out animal metabolism test.
Selecting 10 health pig (body weight about about 30kg), weigh and record, be bisected into two groups at random, one group is comparison
Group, one group is test group.Matched group is solvable with folk prescription amoxicillin to pig by the dosage of every 1kg body weight 10mg amoxicillin
Property powder drinking-water, test group by every 1kg body weight 10mg amoxicillin dosage to pig with the present embodiment prepare granule drink
Water, control water 2 hours before drinking-water, it is ensured that medicine all absorbs, fasting during test, the most freely drinks water.Every pig is respectively in medication
Latter 0.25,0.5,0.75,1,2,3,4,5,6,7,8 hours venous blood collection 3ml, put in the centrifuge tube containing heparin sodium, mixing, and 4000
Rev/min centrifugal, separated plasma, use Determination of amoxicillin in high performance liquid chromatography detection blood plasma.Different time respectively organizes blood
Concentration meansigma methods is as follows:
As can be seen from the above data, the highest meansigma methods that test group blood drug level is occurred is higher than matched group, >=1 μ g/
The meansigma methods of ml is held time ratio comparison group leader, and last surveyed blood drug level meansigma methods of taking a blood sample is higher than matched group.These are all
Being because test group drug renal accretion rate slow, in blood caused by time of staying length, medicine is the longest at blood residence,
Duration of efficacy is the longest, and medication efficiency is the highest.
Embodiment 3
The water solublity synergistic composition containing amoxicillin of the present embodiment includes according to the mass fraction:
20 parts, amoxicillin,
Sulbactam sodium 10 parts,
Sodium benemid 8 parts,
EDTA-2Na 10 parts,
PVP-K30 5 parts,
PEG-6000 10 parts,
SDS 15 parts,
Lactose 22 parts.
Said components is ground into by super micron mill the superfine powder of particle diameter 2000 mesh (i.e. particle diameter 6.5 μm), then with three
Dimension mixer mix homogeneously, obtains the soluble powder that can be used directly on veterinary clinic.
Take above powder and carry out clinical trial.
The healthy ablactational baby pig just hived off being randomly divided into three groups, makees blank group for one group, one group compares group, and one group is tried
Testing group, three groups all use identical feeding manner to raise.Blank group does not throw in any medicine, and matched group presses 1000ml in drinking-water
Drinking-water adds the ratio interpolation folk prescription amoxicillin powder of 100mg amoxicillin and carries out free drinking-water, and test group is pressed in drinking-water
1000ml drinking-water adds the ratio of 100mg amoxicillin and adds the powder that the present embodiment prepares and add and carry out free drinking-water, every 10 days
Concentrating drinking-water 5 days, the test period is 20 days.Morbidity pig i.e. carries out isolation treatment after finding.
Result record is as follows:
Group |
Test head number |
Morbidity head number |
Sickness rate |
Blank group |
65 |
27 |
41.53% |
Matched group |
60 |
13 |
21.66% |
Test group |
59 |
5 |
8.47% |
Ablactational baby pig is jumped period, and because feedstuff, temperature, environment etc. change, irritability dysentery or diarrhea disease percentage are high.Test
In, the blank group sickness rate not using medicinal health-care is 41.53%, uses the matched group morbidity of folk prescription amoxicillin powder health care
Rate is 21.66%, and the experimental group sickness rate using the powder health care of the present embodiment is 8.47%.As can be seen from the above results,
The powder that the technical program is configured is more higher than folk prescription amoxicillin powder clinic antibacterial action, has good preventive effect.
The above, only present pre-ferred embodiments, therefore the scope that the present invention implements can not be limited according to this, i.e. depend on
The equivalence change that the scope of the claims of the present invention and description are made with modify, all should still belong in the range of the present invention contains.