CN103327984B - Be included in NSAID and the antibiotic Injectable composition that is used for the treatment of mastitis in non-aqueous solvent - Google Patents
Be included in NSAID and the antibiotic Injectable composition that is used for the treatment of mastitis in non-aqueous solvent Download PDFInfo
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- CN103327984B CN103327984B CN201280005989.4A CN201280005989A CN103327984B CN 103327984 B CN103327984 B CN 103327984B CN 201280005989 A CN201280005989 A CN 201280005989A CN 103327984 B CN103327984 B CN 103327984B
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- inflammatory drug
- nsaid
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A—HUMAN NECESSITIES
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Be used for the treatment of the Injectable composition of infected by microbes in animal's mammary gland, wherein, described composition comprises a) anti-inflammatory drug of non-steroidal (NSAID); B) be selected from the antibiotic of beta-lactam antibiotic and macrolide antibiotic; It is characterized in that described composition comprises non-aqueous solvent, and NSAID and antibiotic in composition is dissolved in this non-aqueous solvent.
Description
Technical field
The present invention relates to the composition for treatment of infection, although and nonspecific ground its most preferably for the treatment of mastitis.
Background technology
The present invention will discuss a kind of method, can treat the infection in animal by the method.
Should relate to domestic animal although spread all over this description, the treatment of for example cow, but be understood that, the present invention's principle behind can be applicable to other animals, comprise the mankind. spread all over this description, the instantiation relevant to the treatment of mastitis is provided. it will also be appreciated that the scope of the invention is not limited to mastitis, and can relate to the bacterial infection in any type of animal substantially.
Spread all over this description and should refer to that at this character is bacteroidal infection, and be particularly related to the mastitis being produced by this bacterial infection.
Conventionally, antibiotic is introduced to animal with antagonism bacterial infection. this can be by various methods of administration, comprises oral and local. it is for example, by (breast) surrounding injection in infected position that one is preferably used.
The antibiotic demand of administration is expensive.
First, medicine itself is expensive.
Secondly, in the situation of mastitis that for example adversely affects the production of milk breast, there is dry up's phase (milkwithholding time), wherein by throwing aside, contaminated milk is newborn to be wasted the production of animal milk breast. in cows, this can cause the loss of annual several thousand dollars. similarly, have such regulation, it is controlled the animal product of the animal from having used in the recent period antibiotic therapy is introduced to food chain (birds, beasts and eggs or meat).
Therefore, if can provide for bacterial infection effectively and there is the antibiotic therapy of the shortest downtime for the milk breast of throwing aside, will be, desirable.
Mastitis is the disease that cost is high, it all affects the level of production of animal in short-term (cow's milk) and long-term (Production Life of shortening and superseded risk early), and lose the happiness of animal, and improve the pressure of animal processor (milker)-particularly during the highest lactation.
Need to find administration more easily, and be still effective new treatment. this can produce better compliance and better treatment results (cure rate).
If reach the active matter of enough high concentrations with treatment malignant bacteria, with respect to the breast internal therapy of only treating Yi Geru district, injectable antibiotic has advantages for the treatment of whole Si Geru district (quarters of theudder).
Suppress the required antibiotic MIC (MIC) of specific bacteria and represent the aimed concn .The product that can not reach preferable MIC may not cure mastitis infection. for mastitis treatment product
Such as, staphylococcus aureus (Staphylococcus aureus) can cause the mammary gland being difficult to cure
Inflammation, and to this, routine draws up the prescription of the product containing tylosin.But, the most also do not have
Carry out setting up for the tylosin work to the MIC of staphylococcus aureus.Most of MIC make
Setting up with erythromycin, it is relatively infrequently in the treatment of mastitis.
Report that erythromycin is 0.5 μ g/ml to the MIC of staphylococcus aureus, and tylosin is to gold
The MIC of Staphylococcus aureus is 2 μ g/ml.Substantially, this demonstrates the need for effectively treating golden yellow Portugal
The concentration of the tylosin of grape coccus is about 4 times needed for erythromycin.
It practice, pharmacokinetic has shown the tylosin injectable of over the course for the treatment of 20%
Preparation only reaches the peak concentration of about 1.4 μ g/ml, thus can not reach required treatment concentration (MIC).
Thus, it is desirable to be administered larger dose and/or the active matter (> 20% of higher concentration) to reach higher than MIC
Milk breast concentration.
Accordingly, it would be desirable to the antibiotic therapy that research and development improve is (not only for tylosin, and for other
Antibiotic) to help prevent the active matter (> 20% to larger dose or higher concentration) demand, to reach
Not only for staphylococcus aureus, but also MIC necessary to the reason that other antibacterial is infected.
Furthermore, it is necessary to research and development compositions, wherein comprise excipient or extra active matter to help antibiosis
Element more effectively works when treating bacterial infection.
Past, it has been found that NSAID with the co-administered of antibiotic therapy is in improvement antibiotic response
Effectively.But, the combination of these active matters to be had any problem in stable compositions, this causes leading to
Often two kinds of active matters are individually delivered.This is typically inconvenient, and comprises NSAID by preferably providing
Single compositions with antibiotic.
Animal happiness is considered be also likely to be important.The infection of such as mastitis is painful.
Therefore, having turned into the not only use activating agent that routine operation is, such as NSAID treats infection, and
Treat associated pain.This therapeutic alliance is relatively new in the industry.
US 2005/0277634 discloses NSAID (meloxicam) and antibiotic (penethacillin) is combined in
To treat mastitis in injection mixed suspension preparation.They discuss working in coordination with between NSAID and antibiotic
Reaction, its generation needs the antibiotic of lower loading to reach the effect of the content higher than MIC.Preferably
Ground, in compositions, the concentration of NSAID is the highest, and the effect that antibiotic demonstrates is the best.
But, obvious shortcoming is existed for mixed suspension preparation.These shortcomings include may caking, use
The absorption that front dispersion problem, delivery difficulty, injection rear reaction/pain and active matter is the best.
Thus, will preferably provide NSAID and antibiotic combinations as stable liquid composite.Additionally, carry
To be useful for loading NSAID to improve the liquid composite of the effectiveness of antibiotic.But, by
In those obvious problems such as discussed above, this is the most unrealized.
Generally, the obvious problem that compositions injectable to many is relevant is probably at intramuscular or subcutaneous
Appearance position reaction during delivery, animal caused and/or pain.
Position reaction and pain during this injection are generally attributable to activating agent, such as antibiotic tylosin
Element.But, this problem can be by other excipient in compositions, it is common that rise activating agent carrier or
The solvent of solubilizing agent effect and increase the weight of.This problem is recorded in survey article in detail, Strickley et al.,
Pharmaceutical Research, Vol., 21No.22004 February, entitled " Solubilizing
Excipients in Oral and Injectable Formulations”。
For this reason, veterinary chemist is often intended to develop as solution, and has in Injectable composition
There is the compositions of the solvent of alap concentration and/or volume.Reach relatively as a result of which it is, this can reduce
The ability of the activating agent of high concentration, reduces compositions stability generally, and finally reduction animal can
The treatment successful of energy.
Therefore, veterinary chemist be preferably used waterborne compositions with avoid injection time position reaction and
Pain.
Although this is reducing side effect, such as it is effective in position reaction/pain when delivering, but
Waterborne compositions can cause again the instability of activating agent, causes shorter the depositing the time limit (and of compositions
Whole bioavailability).It also can limit the ability of the surfactant concentration keeping higher.Then such as US
Discuss in 2005/0277634, it may be necessary to restore it as suspensoid.
WO 02/41899 (WO ' 899) discloses to comprise and is dissolved in the antibiotic of solvent and watering of analgesics
Sprinkle (pour-on) or Injectable composition.But, (florfenicol, celebrating are the most mould for the antibiotic of exemplary types
Element and oxytetracycline) compositions paid close attention to the present invention, i.e. beta-lactam is different with macrolide.
It practice, known beta-lactam and macrolide antibiotic are particularly unstable, and it is prone to
With NSAID, such as flunixin reaction.Although be difficult to by beta-lactam and macrolide antibiotic with
NSAID combines, but right and wrong during the microorganism as found in mastitis is infected treated by this antibiotic
The most effective.
The many compositionss of the such stability data not provided in WO ' 899, i.e. hint, particularly
Those compositionss (compositions as in embodiment 4) with greater activity agent concentration will not be to store surely
Fixed.It practice, the research that the present inventor is carried out has shown that similar compositions is unstable.
Present invention aim to address problem above or at least provide effective selection to the public.
The all documents will addressed in this specification, quote including any patents or patent applications and are incorporated to this
Literary composition.Do not promise to undertake that any document constitutes prior art.Documents shows what their author was claimed,
And the applicant retains accuracy and the right of certainty querying described document.It is expressly understood that ground
It is although that, open herein by reference to some prior aries, the document was not constituted for appointing in these documents
Holding of one part constituting common knowledge of the prior art in New Zealand or what other countries in office
Promise.
Throughout this specification, term " comprises/includes " or its modification be understood to expression forgive described key element,
Integer or step or the combination of key element, integer or step, but do not forgive any other key element, integer
Or step or the combination of key element, integer or step.
Other aspects of the present invention and advantage will seem clear from the following description provided the most by way of example
Chu.
Summary of the invention
According to the first aspect of the invention, it is provided that when the microorganism in the mammary gland for treating animal is infected
Time Injectable composition,
Wherein, described compositions comprises
A. nonsteroidal anti-inflammatory drug (NSAID)；
B. selected from beta-Lactam antibiotic and the antibiotic of macrolide antibiotic；
It is characterized in that:
Described compositions comprises non-aqueous solvent, and
NSAID and antibiotic in described compositions are dissolved in described non-aqueous solvent.
According to a further aspect in the invention, it is provided that the method that the inside microorganism for the treatment of animal is infected,
It is characterized in that
By drug administration by injection compositions substantially as described above.
According to a further aspect in the invention, it is provided that compositions is used in preparation substantially as described above
Purposes in the medicine that treatment microorganism is infected.
The method preparing medicine substantially as described above, is characterised by adding at least to described compositions
A kind of non-aqueous solvent.
The discussion of the advantage that the present invention provides
The inventor have discovered that at infection site and obvious inflammation around can hinder the effective of antibiotic
Property, because it reducing the ability reaching and acting on antibacterial.
In the past, it is administered NSAID the most more with treatment inflammation and/or pain.The inventor have discovered that
By the important association that NSAID is administered together with antibiotic in single injectable compositions
Same effect.This synergy can make this antibiotic compared to by individually dosed for this antibiotic more effectively.Phase
As, the inventor have discovered that the combination of NSAID and antibiotic has the association of enhancing in unitary agent
Same effect, if using NSAID and antibiotic therapy animal in two single preparations, then it is not deposited
?.This ability that may be partly due to provide two kinds of active matters in stable compositions together.
Present inventor considered that the binding mode being not limited to propose, cooperative interaction can result from
NSAID reduces at infection site and the inflammation of surrounding (in the case of mastitis at mammary gland) so that
NSAID can make antibiotic effectively be distributed in other inflammatory components.
Additionally, synergy can be partly due to NSAID combines endotoxin (endotoxemia), this
Inventor additionally finds that it hinders the effectiveness of antibiotic.
Such as, endotoxic gram negative bacteria is produced relevant to mastitis.This antibacterial can be caused entirely
The disease (heating and endotoxemia) of body.Although in New Zealand, this is the most uncommon (low at present
In the sickness rate of 1%), but the use that feedstuff pad (feed-pads) and herd room (herd homes) increase
It is likely to result in the sickness rate of the higher mastitis caused by gram-negative pathogens.Accordingly, it is desirable to
The preparation of the present invention will become infection in future, such as the important a member in the therapeutic scheme of mastitis.
Additionally, due to NSAID can act on and reduce fever (heating) so that antibiotic effectiveness and
Safety/the comfortableness of animal is more preferable, so synergy can further enhance.
In some NSAID and antibiotic process of the test, the present inventor describes the most collaborative
Effect.After carrying out above experiment, and determining advantageous effects, those skilled in the art are by clear
This synergy can be intended for the antibiotic of common type, and is not only those particular instances of test.
Such as, will expect that all of beta-lactam and macrolide antibiotic will displays when combining with NSAID
Go out identical synergy.The antibiotic of known both types has similar binding mode (cell egg
Synthesize suppression in vain).
Another important advantage of this combination that the inventors discovered that can be that NSAID can improve animal
Happiness, this owing to reduce may by compromised internal, such as mastitis produce pain and inflammation.
Furthermore it is possible to provide two kinds of different active matters to can help to overcome many in a combination preparation
The demand of the delivery of individual compositions, compositions storage, cost, packaging etc..The present inventor is it can be found that have
Help the specific solvent type of two kinds of active matters combination, and have been found that before both active matters the most difficult
To combine in stable solution.Suspensoid is used to be combined in single compositions by this active matter in the past.
As discussed below, the inventors discovered that and live owing to the concentration of NSAID increases the both caused
The most expected other synergy between property thing.
Improving the purpose of NSAID concentration is to improve synergy that the present inventor is originally found to assist
Improve the antibiotic effectiveness of infection site.
Activating agent has according to being established as effective recommended dose.Thus, when two kinds of activating agents of combination
Time, this combination should provide the suitable dose of each activating agent.Such as, for a kind of certain antibiotics (such as
Tylosin, 10mg/kg) recommended dose, the tylosin concentration of 20% is usually used in compositions.This height
The tylosin of concentration is generally probably the limiting factor in said composition, because it is likely to result in injection
Time obvious stimulation.In order to provide the dosage together of NSAID (such as ketone ibuprofen), preferably 6%
The concentration of w/v.It practice, the compatibility of the dosage between the various active thing used is probably
Active compound successfully provides an importance of correct active matter amount when administered.
But, when the present inventor attempts providing the compositions containing 6% ketone ibuprofen, there is aqueous molten
The compositions of agent is unstable.The NSAID tested for other, if needed for reflection recommended dose
Comprise NSAID under concentration, then in waterborne compositions, similarly find the best stability.
Being not intended to recover to suspensoid, the present inventor needs to consider other approach.
In order to make up the concentration that NSAID increases, the present inventor uses non-aqueous solvent system to attempt providing
Compositions stable in solution under various conditions (the such as temperature higher than 4 DEG C).But, such as ability
Territory is generally understood that, it is contemplated that recover to nonaqueous solvent will cause when delivering relative to waterborne compositions
The position reaction increased and/or pain.
But from the research of the present inventor, unexpectedly, find that this position reaction/pain does not increase
To exceeding discovery in commercial composite (waterborne compositions, such as Tylan and Ketofen).
It is not intended to be limited to specific binding mode, it is contemplated that the NSAID of increase helps to alleviate synergistically
Inflammation/the pain of local, injection site.Therefore, the additional quantity of NSAID may react on and generally will increase
Position reaction during big injection and more irritating solvent of pain.
Therefore, unexpectedly, the inventors discovered that antibiotic and NSAID can together be included in steady
In fixed liquid composite, have than the bigger increase that can be usually reached when combining with water-based system
NSAID concentration.It is essential that this can realize and do not cause relative to industrial standard thing (Tylan and
Ketofen) the position reaction increased when delivering or pain.
The downstream effects of this discovery is the concentration (and final dose) that can increase NSAID, even antibiotic
And position reaction/pain extra when not causing delivery.For infecting, also can strengthen this synergy,
Improve overall therapeutic result.
The preferred embodiment of compositions
There is provided the compositions of the present invention as injectable liquid preparation.Throughout this specification, term " liquid
Body preparation " it is understood to mean that any treatment preparation with " injectable " denseness.This is many agricultures
The people and the preferred mode of administration of veterinary, particularly when treatment infection site, such as during mammary gland (mastitis),
The local application of NSAID can have the biggest effect.Preferably, liquid preparation is in relatively low temperature
Under there is injectable viscosity.
This liquid preparation is solution.This should represent that the most all of excipient and activating agent are substantially soluble in
Not in the compositions of suspensoid in solution.As previously discussed, solvent provides many to be better than suspensoid
Advantage.Such as, the problem that there is not caking, again suspendible or injections difficult.
This solution can have one or more phase.
Nonsteroidal anti-inflammatory drug
Throughout this specification, term " nonsteroidal anti-inflammatory drug " (NSAID) should represent and not use steroidal
Any medicine with anti-inflammatory effects of compound or reactive compound.
There is many different types of NSAID well known in the prior art.Within the scope of this invention should
Understand any one or the combination that use known NSAID or those found in the future.
Preferably, NSAID selected from carprofen, naproxen, ibuprofen, ketone ibuprofen,
Come than Luo Xikang, voltaren see diclofenac, etodolac, flunixin, deracoxib, meloxicam, plug
Examine former times, rofecoxib and combinations thereof.
Most preferably, NSAID is selected from flunixin, carprofen, ketone ibuprofen and combinations thereof.
The inventors discovered that, when with antibiotic combinations required for protection, these NSAID demonstrate
Big synergy.Additionally, these NSAID all demonstrate it is cattle from drug effect and safety perspective
Effective antiinflammatory in medicine.
Preferably, NSAID is present in liquid preparation with the concentration of 1-15%w/v.As previously discussed,
It may be preferred to the concentration improving NSAID to improve the synergy between two kinds of active matters.Although this
The advantage of sample will be expected very much, but as long as cannot realize stablizing compositions in such solution
Combine, not to mention described compositions does not demonstrate bigger portion compared to waterborne compositions when delivering
Position reaction/pain.
Preferably, NSAID flunixin meglumine is present in compositions with the concentration of about 7.3%w/v
In.This can provide the flunixin of about 4.4% in compositions.This is according to the agent combined with tylosin
Dose rate.
Each NSAID preferably the most substantially concentration may also depend upon its antiinflammatory drug effect and safety overview and
The antibiotic concentration used in compositions.
Preferably, NSAID meloxicam is present in compositions with the concentration of about 1%w/v.
Preferably, NSAID carprofen is present in compositions with the concentration of about 3%w/v.
Preferably, NSAID ketone ibuprofen is present in compositions with the concentration of about 4%-10%w/v.
Such as, when the concentration of tylosin antibiotic is 20%w/v in the composition, corresponding ketone group cloth
The concentration of ibuprofen is preferably 6%w/v.If the concentration of tylosin increases to 30%w/v, ketone group cloth
The preferred concentration of ibuprofen is 9%w/v.
Alternatively, NSAID is selected from the antiinflammatory of native form.Such as, these can include that Jadeite Mussel carries
Take thing, ω 3 etc..
Antibiotic
Throughout this specification, term antibiotic should represent (sterilization) and/or the suppression antibacterial killing antibacterial
(antibacterial) material of growth or compound, the most natural, synthesis or semisynthetic.
Antibiotic in compositions is selected from macrolide and beta-Lactam antibiotic.
Throughout this specification, term " macrolide " antibiotic should represent because of exist can connect one or
Multiple desoxy sugars, it is common that the macrolide ring of cladinose and desosamine and active any
Antibiotic.Lactonic ring is typically 14,15 or 16 rings.
Macrolide antibiotics is generally used in veterinary drug, and thinks have identical binding mode.According to
Thinking, the binding mode of macrolide antibiotic includes such as by hindering ribosomal translation to disturb
Protein synthesis.
Preferably, macrolide antibiotics is selected from azithromycin, clarithromycin, dirithromycin, red
Mycin, Roxithromycin, Ketek, carbomycinA, josamycin, kitasamycin, midecamycin/
Midecamycin acetate, oleandomycin, spiramycin, triacetyloleandomycin and tylosin
(tylosin/tylocine)。
Most preferably, macrolide antibiotic is tylosin.
Tylosin is a kind of macrolide antibiotics, to treat on a large scale in species in veterinary drug
Bacterial infection, and there is the high margin of safety.Another advantage of tylosin is that it is at Xin Xi
Orchid is licensed for the treatment of mastitis.
Tylosin has the activity for resisting gram-positive antibacterial of wide spectrum, including staphylococcus
(Staphylococci), streptococcus (Streptococci), corynebacterium (Corynebacteria) and Erysipelothrix
(Erysipelothrix).It also has for gram-negative Campylobacter coli (Campylobacter
And the activity of some spirillums (spirochaetes) coli).Mycoplasma (Mycoplasma) species are also had by it
Active.
Injectable tylosin preparation can cause the pain around injection site, inflammation and pruritus.Cause
This, it is important to be able to reduce above side effect during injection tylosin.There is provided antibiotic such as together
Tylosin and NSAID have extra advantage, and NSAID can help to avoid the pair of tylosin
Effect.Synergy between when being administered in a preparation by NSAID and antibiotic can help this
The reduction of side effect.Throughout this specification, term " beta-lactam " antibiotic should represent and is included in it
Any antibiotic of beta-lactam nucleus in structure.Such as, this can include penicillin derivative (penam),
Cephalosporin (cephem), monobactam and carbapenem.
It is believed that the binding mode of beta-Lactam antibiotic includes the cell wall of attack bacteria.Beta-lactam
Antibiotic can be with beta-lactamase inhibitor, and such as clavulanic acid provides together.
Preferably, beta-Lactam antibiotic is penethacillin.In recent research, find penethacillin
There is the drug effect (be particularly preferred for the class of antibiotic of the present invention) similar to tylosin.
It is both that beta-lactam and macrolide antibiotic are better than the Common advantages of other class of antibiotic
The antibiotic of type is all weak base, and is lipophilic.This can produce in body fluid such as milk Ruzhong and compare blood
Higher concentration in slurry.Thus, they are easier to reach higher than minimum suppression than alipotropic compound
The concentration of concentration (MIC).
Unexpectedly, these class of antibiotic seem to demonstrate synergy with NSAID.But
Other class of antibiotic are not observed this synergy.Preferably, antibiotic with 10-35%w/v,
And most preferably it is present in liquid preparation with the concentration of about 20.0-30.0%w/v.
Generally, it is less that higher antibiotic concentration will result in the antibiotic volume that unit dose need to be administered, its
Can be more convenient for peasant, and make meiofauna more comfortable.By improving the NSAID in compositions
Level, also can improve the antibiotic concentration in compositions, and position reaction when not improving delivery (with
The present invention recovers similar to the effect found during non-aqueous solvent, and it is it is also contemplated that cause the position of increase anti-
Should/pain).
Such as, treat for staphylococcus aureus if the present inventor knows, then antibiotic (example
Such as tylosin) amount can improve to 60%w/v to reach minimum inhibitory concentration (MIC).
Preferably, in liquid preparation, the ratio of NSAID and antibiotic (w/v) is about 1:3 respectively.If
NSAID is flunixin, then this can be particularly suitable ratio.If but NSAID is different
The NSAID of type, such as meloxicam or carprofen, then this variable-scale.
Solvent
Throughout this specification, term " solvent " should represent any solvent being present in compositions or not
Combination with solvent.
Preferably, described solvent has one or more following character:
-non-aqueous；
The dielectric point (dielectric point) of 30 it is more than at-25 DEG C；
-boiling point higher than 100 DEG C；And/or
-classify as dipolar aprotic solvent.
Most preferably, described compositions is the most nonaqueous.The present inventor tests various different
Waterborne compositions, finds them in the case of a high temperature, and the most highly unstable.
For example, it was discovered that tylosin and NSAID are the most unstable when combining in aqueous formulation.If but
The combination of NSAID and antibiotic is combined in system based on non-aqueous solvent, then said composition keeps
Stable, the most at a lower temperature (such as 2-15 DEG C).
Find that the compositions that waterborne compositions becomes only comprising non-aqueous solvent can provide molten most effectively
Compositions stable in liquid.Additionally, complete nonaqueous solvent compositions makes the present inventor by NSAID
Concentration increase to exceed concentration the most possible in water-based system.Can not be pre-although increasing position reaction
Phase, but this does not occur in the research that the present inventor is carried out.
The dielectric point at the 25 DEG C non-aqueous solvent more than 30 also demonstrates the stability for compositions
It is favourable.Non-aqueous solvent, such as ethanol (having the dielectric point of 25) is the best for the present invention
Solvent, and the dissolubility/stability of the solvent phase same level being more than 30 with dielectric point is not provided.In advance
The beneficial effect that the solvent of phase similar type will have like.
Most preferably, non-aqueous solvent has the dielectric point of 30-50.Find propylene glycol (32.1), NMP
(32.2), DMSO (46.7) and DMA (38) improves the stability of active matter.Unexpectedly,
Do not find compared with waterborne compositions this solvent increase deliver time position react/pain (be probably by
In the second level discussed above synergy).The useful effect that the solvent of expection similar type will have like
Really.
Similarly, additionally find that the boiling point non-aqueous solvent higher than 100 DEG C provides the stability improved,
And also position reaction when not increasing delivery.Furthermore, second alcohol and water is all the best solvent.Otherwise
Find solvent, such as propylene glycol (BP=188 DEG C), glycerol formal (BP=190-195 DEG C), NMP
(BP=202-204 DEG C), DMSO (BP=189 DEG C), DMA (BP=164-166 DEG C) have above begging for
The advantage of opinion.The beneficial effect that the solvent of expection similar type will have like.
It moreover has been found that comprise at least one non-aqueous solvent that broad category is dipolar aprotic solvent
It is particularly advantageous.For example, it was discovered that it is very that NMP does not increase position reaction for improving stability
Effective solvent, although it is considered as zest solvent, and causes position during injection to react.
Preferably, non-aqueous solvent is selected from METHYLPYRROLIDONE (NMP), glycerol formal, propylene glycol
And benzyl alcohol.
Stable compositions and make NSAID concentration increase on be found particularly effective solvent such as
NMP and propylene glycol are known which are high stimulus object during injection too.Therefore, it is the most unexpectedly
Finding when injectable composition, these solvents do not cause the position of increase to react.
Preferably, liquid preparation comprises the non-aqueous solvent that at least two is different.
It is highly preferred that described liquid preparation comprises the first and second non-aqueous solvents, wherein the first solvent
Play a part solubilizing agent, and wherein the second solvent plays a part carrier solvent.
Such as, the inventor have discovered that the combination of NMP and propylene glycol provides particularly stable in the formulation
Active matter.The NMP, glycerol formal and/or the benzyl alcohol that comprise can be used as the solubilizing agent for active matter,
And solvent, such as propylene glycol can be used as carrier in the composition to provide the stability improved.
Preferably, minimal amount of solubilizing agent, such as NMP are only used.The amount of solubilizing agent can be according to combination
The type of activating agent and dissolubility in thing and change.
Preferably, in compositions, the amount of solubilizing agent is less than 40%w/v.
It is highly preferred that the amount of solubilizing agent is about 30%w/v in compositions.
In the present invention, it is preferred to NMP is only with minimum use, and it is only used as solubilizing agent.This with
Embodiment 1-4 in WO 02/41899 (WO ' 899) is contrary, and wherein main solvent is NMP, and group
Compound NMP add to volume (in major part situation in the final composition equal to about 60%w/v or
Bigger).NMP is simply served as main solvent and (is disclosed in the page 4 of WO ' 899, the most final combination
The 95%w/v of thing) embody used antibiotic, the most non-beta-lactam or macrolide antibiotics.
Preferably, in compositions, the amount of carrier solvent is at least 30%w/v.It is highly preferred that in preparation
The amount of carrier solvent is at least 40%w/v.
Preferably, the ratio of the first solvent and the second solvent is between 1:10-1:1.It is highly preferred that the
The ratio of one solvent and the second solvent is about between 1:2-1:1.
Carrier solvent such as propylene glycol more stimulates as solvent, and understands that it causes than NMP in injection
Time more position reaction.Based on be generally understood that in prior art, this may also be such as WO ' 899
Disclosure in do not instruct reader to use carrier solvent such as propylene glycol, and depend on a large amount of on the contrary
Another reason of NMP.
Think that this carrier solvent of the present invention contributes to providing beta-lactam/macrolide antibiosis in compositions
Element and the good stability of NSAID.WO ' 899 instructs the most by any way and uses carrier solvent
Feature, does not the most instruct the class of antibiotic used in the present invention.
Additionally, the solvent compositions disclosed in WO ' 899 will not provide the solvent compositions phase with the present invention
Same stabilizing effect, even if substituting example in WO ' 899 by macrolide/beta-Lactam antibiotic
More stable antibiotic/NSAID combination.
As known to the present inventor, know beta-lactam and macrolide antibiotic and flunixin
(paying close attention to NSAID in WO ' 899) is unstable.In the research that the present inventor is carried out, with WO ' 899
Disclosed in the similar compositions of those compositionss demonstrate the best stability.
Contrary, the present composition being limited to macrolide/beta-Lactam antibiotic demonstrates necessarily
Good stability (seeing the embodiment 6 of preferred forms part) under conditions of scope.
Preferably, non-aqueous solvent accounts for compositions more than 10%w/v.
It is furthermore preferred that non-aqueous solvent accounts for the 30%w/v-80%w/v of compositions.As previously discussed, this
The nonaqueous solvent content (and especially with respect to carrier solvent of solubilizing agent) that sample is high is providing more stable
Compositions and increase NSAID/ antibiotic concentration on be useful, and expect that it is relative to aqueous
Compositions produces the position reaction and pain significantly increased.But, this does not find.
Antioxidant
Preferably, liquid preparation comprises at least one antioxidant.
Preferably, antioxidant is selected from sodium formaldehyde sulfoxylate or butylated hydroxytoluene (BHT).But, this
Skilled person is it will be appreciated that substantially any antioxidant can be used for the present invention and it is not considered that super
Go out the scope of the invention.
Preferably, antioxidant is with 0.01-0.3%w/v, and most preferably dense with about 0.05%w/v
Degree is present in liquid preparation.
Particularly preferred formulation examples is specifically described in the optimum implementation part of this specification.
The preferred embodiment of Therapeutic Method
Throughout this specification, term " is administered " and should represent by from topically or systemically using (i.e. base
Throughout blood flow and the health of animal in basis) active matter in compositions is delivered to infection site.
Preferably, described compositions is used for treating compromised internal.Throughout this specification, term is " internal
Infect " internal position should be represented, it includes from external accessibility body cavity.Such as, this includes all
Such as body cavitys such as mouth, papillary duct, breast, vaginas.
Preferably, described compositions is to be systemically administered.The example of systemic applications can include passing through
Injection, bolus or perfusion, wherein active matter can be subsequently by animal blood flow distribution to infection and/or inflammation
Disease position.
Most preferably, described compositions passes through drug administration by injection.It should be noted that injection can be near infection site
Or local is carried out at infection site, but still produce good active matter systemic delivery.
Described compositions can subcutaneous injection or intramuscular injection.
Preferably, described compositions is in order to process clinical mastitis.But in some embodiments, may be used
It is used for compositions preventing mastitis in early days.Using NSAID treatment mastitis in the composition is new think of
Road, it has the remarkable advantage discussed throughout this specification.
But, inventors believe that described compositions may be used to treat substantially any type of inside micro-
Biological infection and/or relevant inflammation/pain.
Preferably, described compositions in order to treat inhuman animal, such as milch cow, sheep, goat
Or the animal commonly used in other dairy industries.
The preferred embodiment of dosage
Preferably, described compositions is with the antibiosis of 5-20mg/kg/ days (based on drug weight/animal weight)
The dosed administration of the plain NSAID with 0.2mg-4mg/kg/ days.
In preliminary test, this dosage demonstrates the MIC (2 μ g/ml) provided needed for tylosin, makes
The treatment content of antibiotic must be provided.But, due to the collaborative effect found between antibiotic and NSAID
Really, antibiotic can be more more effective than conventional so that has only to the antibiotic of lower loading, the most still has
Antibacterial infects the treatment of effect ground.
The inventors discovered that the amount of NSAID will depend upon which that type changes.Such as, each NSAID is excellent
The substantially dosage of choosing can be depending on its antiinflammatory drug effect and is securely distributed.
Preferably, the dosage of flunixin is between 1-3mg/kg/ days.Most preferably, flunixin
Dosage is about 2.2mg/kg/ days.
Preferably, the dosage of meloxicam is between 0.1-1mg/kg/ days.Most preferably, meloxicam
Dosage be about 0.5mg/kg/ days.
Preferably, the dosage of ketone ibuprofen is between 2-4mg/kg/ days.Most preferably, ketone group cloth Lip river
Fragrant dosage is about 3mg/kg/ days.
Preferably, the dosage of carprofen is between 0.5-2.5mg/kg/ days.Most preferably, carprofen
Dosage is about 1.4mg/kg/ days.
Described Therapeutic Method can use flexibly dosage can control according to type and the order of severity
Treat in disease and be adjusted.Such as, the present inventors have noted that packaging (flexipack) should for using flexibly
Dosage is particularly effective flexibly.Packaging is typically to be mixed by high and Low Density Polyethylene flexibly
The container that thing is made.This packaging can easily be buied from many manufacturers.
The preferred embodiment of preparation method
Discussing as in this specification, the major advantage using non-aqueous solvent is to increase compositions
In activity concentration.This has many advantages, including being administered bigger with relatively low volume to animal
The active matter of amount.This can help to reduce animal discomfort when administration time and injection.
Additionally, relatively low volume dose is favourable for depositing, owing to it accounts for less space.
Preferably, the NSAID in compositions is improved in corresponding waterborne compositions, in room temperature
Lower by the concentration that can not stably deposit (%w/v).
Preferably, NSAID is ketone ibuprofen, and the concentration of wherein ketone ibuprofen is higher than 4%
w/v。
The preferred aspect of preparation method described below.
Preferably, before adding NSAID or antibiotic, the first and second non-aqueous solvents are added
In mixing container.
The first and second selected nonaqueous solvents can be depending on the NSAID and antibiotic used in preparation
Type, quantity or concentration.The example of the first and second non-aqueous solvents is in optimum implementation part
There is provided.But, these examples are not intended to limit.
In some embodiments, extra non-aqueous solvent can be added.Alternatively, can the most only
Comprise a kind of non-aqueous solvent.
Preferably, before adding NSAID or antibiotic, non-aqueous solvent is heated to about
55-80℃.The temperature used can be depending on the particular actives used in compositions.
Preferably, before adding NSAID, antibiotic is added non-aqueous solvent and dissolves.Then
NSAID can be added and be dissolved in the mixture of the antibiotic through dissolving and non-aqueous solvent.This
A person of good sense find this substep add solvent, antibiotic and be eventually adding NSAID provide improve compositions molten
Xie Du and stability.
Preferably, NSAID and antibiotic are being added whole period to preparation substep, temperature is being maintained
At 55-80 DEG C.
Then the compositions containing NSAID and antibiotic is cooled to about room temperature (such as 20-30 DEG C), so
Add to final volume (in right amount) with non-aqueous solvent afterwards, and mix about 10-20 minute.
Then compositions can be saved in before administration at about 4 DEG C.
Some advantages of the present invention include:
-can make to have between NSAID and antibiotic the conspiracy relation effectiveness of antibiotic (NSAID improve).
-use non-aqueous solvent to contribute to overcoming between active matter incompatible, and particularly many anti-
The problem that raw element is unstable.
-use non-aqueous solvent that compositions can be made to provide as stable molten under some storage conditions
Compositions (non-suspensoid) in liquid.
-solution avoids caking, delivers the front problem relevant with injection for the demand of compositions suspendible again
(syringe needle blocking and the issuable ANIMAL PAIN of particulate matter).
-use non-aqueous solvent can improve the concentration of NSAID to exceeding in waterborne compositions and can obtain
Level.While it is contemplated that because of known non-aqueous solvent feature deliver time position reaction and pain
Increase, but do not find the raising of these side reactions.
The increase of-gained NSAID can also aid in and reduces not only by solvent, and (safe happy by antibiotic
Rhzomorph is known stimulus object) reaction of the position caused.Possibly, the concentration of the tylosin of compositions
Can increase because of position reaction less during injection.
-increased by the concentration making NSAID in compositions, two kinds of active matters at infection site it
Between find concertedness increase.By improving the effectiveness of antibiotic, can be potentially by lower concentration
Antibiotic is in order to provide identical result.
-avoid aqueous in compositions preventing the demand of compositions regulation to preferable pH, eliminate system
Additional step in Preparation Method.
-reduce pain and inflammation that compromised internal may be correlated with.
-improve operational efficiency (contrary with two kinds of compositionss, only by a kind of compositions).Such as, single
Antibiotic (such as tylosin) in product and the combination of NSAID eliminate the demand of multiple injection,
And will be easier to be administered and there is the therapeutic outcome of good compliance and improvement.
-deliver selection flexibly.
-preferably administration (injection) can improve drug distribution
-NSAID improves animal happiness, and antibiotic works simultaneously.
-except reducing pain and heating, NSAID can combine with endotoxin (gram negative bacteria),
Improve therapeutic outcome, and thus will become the important composition of the mastitis treatment scheme in future.
-preparation seems effective especially in treatment Gram-negative mastitis, and mastitis are it is contemplated that in the future
Within several years, will improve at Zelanian prevalence rate.
The preferred forms of the present invention
Embodiment 1
Table 1 below shows the multiple initial preparation tested by inventor according to the present invention.
The following is the evaluation of the suitability to test preparation.
Table 1: tylosin/flunixin combination
* adds 2% excess
* * pH regulator between (8-9.5)
The existing preparation of the tylosin alkali injection of F1 ACVM registration.
Showing of flunixin injection (trade (brand) name: Fluxamine injection) of F2 ACVM registration
There is preparation.
Under F3 room temperature, in 48 hours, product colour becomes burgundy.
F4 reaches pH regulator with the sodium hydroxide of 20%.Product colour keeps stable at 4-40 DEG C.
F5, in order to avoid pH problem, uses glycerol formal+propylene glycol preparation product.Product face
Color keeps stable at 4-40 DEG C.
F6 antioxidant is substituted from sodium formaldehyde sulfoxylate and becomes BHT.Product colour is at 4-40 DEG C
Keep stable.
F7 mixes through stable glycerol formal with stabilization formulations.Product colour is protected at 4-40 DEG C
Keep steady fixed.
F8 product colour keeps stable at 4-40 DEG C.
Sum up
Preparation F5 demonstrates more stable tylosin/flunixin preparation.The method preparing F5 preparation
There is provided as follows.
The preparation process of preparation F5
Prepare in container at clean and dry:
1. load the desired amount of through stable glycerol formal.
2. add and mix the propylene glycol of 25%.
3. heat the mixture to 70-80 DEG C.
4. add and dissolve tylosin alkali, and being sufficiently mixed and (be maintained at 70-80 DEG C
Temperature).
5. add and dissolve flunixin meglumine, and being sufficiently mixed and (be maintained at 70-80 DEG C
Temperature).
6. material is cooled to less than 30 DEG C.
7. add to final volume with propylene glycol, and be sufficiently mixed 10 minutes.
Embodiment 2
Testing two kinds of other preparations (F9 and F10), it comprises tylosin and carprofen or meloxicam.
These preparations presented below and preparation process.
Table 2: tylosin/carprofen and the combination of tylosin/meloxicam
* adds 5% excess
Preparation process for F9 and F10
1. prepare in container at clean and dry:
2. load the desired amount of NMP.
3. add and benzene mixed methanol.
4. add and mix (35%) propylene glycol.
5. heat the mixture to 70-80 DEG C.
6. add and dissolve tylosin alkali, and being sufficiently mixed (being maintained at the temperature of 70-80 DEG C).
7. add and dissolve meloxicam/carprofen, and being sufficiently mixed (being maintained at the temperature of 70-80 DEG C).
8. material is cooled to less than 30 DEG C.
9. add to final volume with propylene glycol, and be sufficiently mixed 10 minutes.
Embodiment 3
The present inventor tests the compositions comprising tylosin/ketone ibuprofen subsequently.
In this waterborne compositions, tylosin/ketone ibuprofen is stable.But, work as the present invention
When the concentration of ketone ibuprofen is risen above 4%w/v by people, compositions loses in waterborne compositions
Stability.
Preparation process for F11
1. in clean and dry preparing container loads the desired amount of propylene glycol, benzyl alcohol, and fully
Mixing.
2. heat the mixture to 60-70 DEG C.
3. add and dissolve tylosin alkali, and being sufficiently mixed (being maintained at the temperature of 60-70 DEG C).
Check the clarification of solution.
4. add ketone ibuprofen and dissolve, and being sufficiently mixed.Material is cooled to room temperature.
5. checking pH, it should be between 8.8-9.5.If desired, use the sodium hydroxide of 10%w/v
The hydrochloric acid of solution or 5%w/v is by between pH regulator to 8.8-9.5.
6. add to final volume with water, and be sufficiently mixed 10-15 minute.
7. check pH.It should be between 8.8-9.5.
Embodiment 4
The present inventor aims to provide the NSAID ketone group comprised than higher amount visible in embodiment 3
Ibuprofen and the compositions of tylosin.Ultimate principle is that concertedness is helped by the NSAID amount increased
Antibiotic effectiveness at infection site, and the pain relief improved is provided to animal simultaneously.
Being not intended to recover to suspensoid, the present invention needs to test higher (non-aqueous) solvent to load at height
Amount is lower stablizes NSAID.Successfully achieve compositions stable in solution.But, use non-aqueous
Pain when solvent expection causes compositions produce higher position reaction and inject.
Preparation process for F12
1. in clean and dry preparing, container loads the desired amount of METHYLPYRROLIDONE (NMP).
2. in container, load the desired amount of benzyl alcohol, and be sufficiently mixed.
3. in container, load propylene glycol (the 35% of still size), and be sufficiently mixed.
4. material is heated to 55-65 DEG C.
5. mixing adds butylated hydroxytoluene (BHT) and dissolves.
6. mixing adds tylosin alkali and dissolves (being maintained at the temperature of 55-65 DEG C).
7. mixing adds ketone ibuprofen and dissolves.
8. check the clarity of solution.
9. add to 98% volume of still size with propylene glycol, and be sufficiently mixed.
10. material is cooled to 25-30 DEG C and mixes.
11. add to final volume with propylene glycol, and are sufficiently mixed.
Embodiment 5: preliminary zooscopy reacts with position during test injection
Carry out studying comparing the test combination of ketone ibuprofen of the tylosin comprising 20% and 6%
Treatment equivalence between thing and industrial standard thing and side effect (side reaction during delivery and pain).
When in the muscle jointly using the milch cow that gives milk, industrial standard thing is Tylan (Elanco
Animal Health, Auckland, New Zealand) and Ketofen (Merial New Zealand, Auckland,
New Zealand).Tylan contains the tylosin of 20%w/v；Prescribed dose is 10mg/kg body weight.
Ketofen contains the ketone ibuprofen of 10%w/v, and prescribed dose is 3mg/kg.Tylan and Ketofen
It it is all waterborne compositions.
20 cattle of each nursery phase of 4 years old-6 years old are selected from the cows of about 1200 cattle.
Animal is drawn in pairs group, and random assortment in groups 1 or group 2.This research is dual crossing research, its
In each group each process with two inorganic agents during the animal section of research, thus provide treatment through respectively
20 animals for the treatment of period treatment.Dosage between two groups keeps constant, i.e. for tylosin
For 10mg/kg, it is 3mg/kg for ketone ibuprofen.
After milking at the 0th day, process cattle according to respective actual weight.Blood is collected at 11 time points
Sample, and real time record 24 hours.
Bioequivalence as follows, between research display test compositions and industrial standard material.
Solid line represents the tylosin plasma concentration of the test compositions of embodiment 4.Dotted line represents use
The tylosin plasma concentration of Tylan.
Solid line represents the ketone ibuprofen plasma concentration of the test compositions of embodiment 4.Dotted line represents to be made
By the ketone ibuprofen plasma concentration of Ketofen.
In a word, result of study shows the biology etc. similar between two compositionss when dosage keeps stablizing
Effect property level.This show combined compositions have compare individually dosed industrial standard thing for good
Good bioavailability.In itself, this is major advantage.
Another major advantage found from this research againsts one's expectation, relative to industrial standard thing
(Tylan and Ketofen), test compositions does not demonstrate the adverse effect (portion to animal of any increase
Position reaction or pain).
This be not it is contemplated that because embodiment 4 in test compositions in use non-aqueous solvent
It is considered when injection to cause disadvantageous side effect.Keep in view of the dosage organizing 1 and group 2 in research
Identical, it is contemplated that the increase of the NSAID (such as ketone ibuprofen) more than 3mg/kg may be realized
Dosage, simultaneously relative to current available compositions, it is to avoid increase (or even reduce) position reaction
/ pain.Can realize by improving the concentration of NSAID and increased dosage amount, this is because by non-aqueous molten
Agent is used for making active matter the most in the composition.
Embodiment 6: stability test
Three 4.5L batch of materials of example in embodiment 4 are carried out stability study.
Batch of material is inserted in 100ml glass amber vial, and 25 DEG C/60&RH,
Deposit under the setting condition of storage of 30 DEG C/65%RH and 40 DEG C/75%RH.
The physics of record product at predetermined intervals recommended such as ACVM and chemical property.
As shown in the table, compositions under 25 DEG C/60%RH and 30 DEG C/65%RH through at least 6
The moon is stable.
Storage condition: 25 DEG C/60%RH
Storage condition: 30 DEG C/65%RH
Storage condition: 40 DEG C/75%RH
Storage condition: 25 DEG C/60%RH
Storage condition: 30 DEG C/65%RH
Storage condition: 40 DEG C/75%RH
The aspect of the present invention is only described by way of example, and it should be understood that can modify it and add
Add without departing from its scope as limited in appended claims.
Claims (25)
1. for treating the nonaqueous compositions of injectable that in animal's mammary gland, microorganism is infected, wherein,
Described compositions comprises
A. nonsteroidal anti-inflammatory drug；
B. selected from beta-Lactam antibiotic and the antibiotic of macrolide antibiotic；
C. carrier,
It is characterized in that:
Described compositions comprises at least two non-aqueous solvent,
At least one of which non-aqueous solvent is solubilizing agent, and is glycerol formal or N-methyl-2-pyrroles
Alkanone；And
At least one non-aqueous solvent is carrier, and is propylene glycol,
In wherein said compositions, the amount of carrier is more than the amount of solubilizing agent in described compositions,
Wherein said solubilizing agent has and is easier to dissolve described nonsteroidal anti-inflammatory drug and/or anti-than carrier
The character of raw element；With
Wherein said nonsteroidal anti-inflammatory drug and antibiotic are dissolved in described at least two non-aqueous solvent
In.
2. the compositions of claim 1, wherein said non-aqueous solvent has one in following characteristics
Or multiple:
A) dielectric point more than 30 at 25 DEG C,
B) boiling point higher than 100 DEG C, and/or
C) it is dipolar aprotic solvent.
3. the compositions of claim 1, wherein said nonsteroidal anti-inflammatory drug is selected from carprofen, methoxy
Naphthalene propanoic acid, ibuprofen, ketone ibuprofen, than Luo Xikang, voltaren see diclofenac, etodolac, fluorine
Ni Kexin, Feracoxib, meloxicam, celecoxib, rofecoxib and combinations thereof.
4. the compositions of claim 1, wherein said nonsteroidal anti-inflammatory drug is selected from flunixin, U.S.
Luo Xikang, carprofen, ketone ibuprofen and combinations thereof.
5. the compositions of claim 1, dense with 1-15%w/v of wherein said nonsteroidal anti-inflammatory drug
Degree exists.
6. the compositions of claim 4, the concentration of wherein said flunixin is 7.3%w/v, Mei Luo
The concentration of former times health is 1.0%w/v, and the concentration of carprofen is the concentration of 3.0%w/v or ketone ibuprofen
For 4-10%w/v.
7. the compositions of claim 1, wherein said macrolide antibiotics selected from azithromycin,
Clarithromycin, dirithromycin, erythromycin, Roxithromycin, Ketek, carbomycinA, friendship sand are mould
Element, kitasamycin, midecamycin/midecamycin acetate, oleandomycin, spiramycin, triacetyl
Oleandomycin and tylosin and combinations thereof.
8. the compositions of claim 1, wherein said macrolide antibiotic is tylosin.
9. the compositions of claim 1, wherein said beta-Lactam antibiotic is penethacillin.
10. the compositions of claim 1, wherein said antibiotic exists with the concentration of 10-35%w/v.
The compositions of 11. claim 1, wherein said antibiotic exists with the concentration of 20.0%w/v.
The compositions of 12. claim 1, nonsteroidal anti-inflammatory drug and antibiotic in wherein said compositions
Ratio be 1:3w/v.
The compositions of 13. claim 1, wherein said compositions comprises at least one antioxidant.
The compositions of 14. claim 13, wherein said antioxidant is selected from sodium formaldehyde sulfoxylate or fourth
Base hydroxy-methylbenzene and combinations thereof.
The compositions of 15. claim 13, dense with 0.01-0.3%w/v of wherein said antioxidant
Degree is present in described compositions.
The compositions of 16. claim 1 is used for treating the medicine that in animal's mammary gland, microorganism is infected in preparation
Purposes in thing.
17. preparations are for treating the method for the nonaqueous compositions that microorganism is infected, institute in animal's mammary gland
State compositions and comprise nonsteroidal anti-inflammatory drug and selected from macrolide and the antibiosis of beta-Lactam antibiotic
Element,
It is characterized in that
A) adding at least two non-aqueous solvent to described compositions, at least one of which is non-aqueous molten
Agent is solubilizing agent, and at least one non-aqueous solvent is carrier, and wherein said solubilizing agent is glycerol acetonide
Formaldehyde or METHYLPYRROLIDONE, and described carrier is propylene glycol, carries in wherein said compositions
The amount of body is more than the amount of solubilizing agent in described compositions,
B) described nonsteroidal anti-inflammatory drug and antibiotic are dissolved in described at least two non-aqueous molten
In agent.
The method of 18. claim 17, the nonsteroidal anti-inflammatory drug in wherein said compositions increases to
Corresponding waterborne compositions will at room temperature deposit the concentration (%w/v) of instability.
The method of 19. claim 17, wherein said nonsteroidal anti-inflammatory drug is ketone ibuprofen, and
And the concentration of wherein ketone ibuprofen is more than 4%w/v.
The method of 20. claim 17, wherein before adding described nonsteroidal anti-inflammatory drug or antibiotic,
Described at least two non-aqueous solvent is added in mixing container.
The method of 21. claim 17, wherein before adding described nonsteroidal anti-inflammatory drug or antibiotic,
Described carrier is added in described solubilizing agent.
The method of 22. claim 17, is wherein maintained at 60 DEG C-80 DEG C by the temperature of described compositions,
Until described nonsteroidal anti-inflammatory drug and described antibiotic to be substantially dissolved in described at least two non-aqueous
In property solvent.
The method of 23. claim 17, wherein before adding described nonsteroidal anti-inflammatory drug, by described
Antibiotic adds described at least two non-aqueous solvent and dissolves.
The method of 24. claim 17, wherein described nonsteroidal anti-inflammatory drug is added and be dissolved in through
In the antibiotic dissolved and the mixture of at least two non-aqueous solvent.
The method of 25. claim 17, wherein will comprise the nonsteroidal anti-inflammatory drug through dissolving and antibiosis
The compositions of element is cooled to 30 DEG C, then adds to final volume with non-aqueous solvent, and mixes 10
Minute.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ588686A NZ588686A (en) | 2011-01-20 | 2011-01-20 | Injectable composition comprising an NSAID and an antibiotic in a non-aqueous solvent for treating a microbial infection in a mammary gland |
| NZ588686 | 2011-01-20 | ||
| PCT/NZ2012/000003 WO2012099479A1 (en) | 2011-01-20 | 2012-01-20 | Injectable compositions for mastitis comprising an nsaid and an antibiotic in a non-aqueous solvent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103327984A CN103327984A (en) | 2013-09-25 |
| CN103327984B true CN103327984B (en) | 2016-08-17 |
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ID=46515931
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|---|---|---|---|
| CN201280005989.4A Active CN103327984B (en) | 2011-01-20 | 2012-01-20 | Be included in NSAID and the antibiotic Injectable composition that is used for the treatment of mastitis in non-aqueous solvent |
Country Status (15)
| Country | Link |
|---|---|
| KR (1) | KR101905173B1 (en) |
| CN (1) | CN103327984B (en) |
| AU (1) | AU2012207698A1 (en) |
| BR (1) | BR112013018557B1 (en) |
| CL (1) | CL2013002086A1 (en) |
| CO (1) | CO6801732A2 (en) |
| CR (1) | CR20130401A (en) |
| GT (1) | GT201300182A (en) |
| IL (1) | IL227540A (en) |
| MX (1) | MX353876B (en) |
| NI (1) | NI201300063A (en) |
| NZ (1) | NZ588686A (en) |
| PE (1) | PE20140035A1 (en) |
| WO (1) | WO2012099479A1 (en) |
| ZA (1) | ZA201305780B (en) |
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| EP2995297A1 (en) * | 2014-09-09 | 2016-03-16 | Ceva Sante Animale | Parenteral compositions and uses thereof |
| AR102172A1 (en) * | 2015-10-05 | 2017-02-08 | Química Luar S R L | A BACTERICIDE AND VIRUCIDE PHARMACEUTICAL COMPOSITION |
| CN105663037A (en) * | 2016-01-27 | 2016-06-15 | 成都乾坤动物药业有限公司 | Amoxicillin solution as well as preparation method and application thereof |
| CN112472667B (en) * | 2019-08-23 | 2022-11-15 | 北京欧博方医药科技有限公司 | Retxib long-acting injection and preparation method and application thereof |
| CN111035614B (en) * | 2019-12-20 | 2024-02-02 | 北京喜禽药业有限公司 | High-content terramycin injection and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1600371A (en) * | 2003-09-22 | 2005-03-30 | 王玉万 | Preparing pharmaceutics of medication containing antimicrobials by using silicone oil as medium |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6787568B1 (en) * | 2000-11-27 | 2004-09-07 | Phoenix Scientific, Inc. | Antibiotic/analgesic formulation and a method of making this formulation |
| WO2005044254A1 (en) * | 2003-10-29 | 2005-05-19 | Idexx Laboratories, Inc. | Salts of pharmacologically active compounds |
| DE102004025324A1 (en) | 2004-05-19 | 2005-12-08 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation for veterinary medicine, process for their preparation and their use |
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2012
- 2012-01-20 CN CN201280005989.4A patent/CN103327984B/en active Active
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- 2012-01-20 BR BR112013018557-0A patent/BR112013018557B1/en active IP Right Grant
- 2012-01-20 PE PE2013001576A patent/PE20140035A1/en not_active Application Discontinuation
- 2012-01-20 MX MX2013008407A patent/MX353876B/en active IP Right Grant
- 2012-01-20 AU AU2012207698A patent/AU2012207698A1/en not_active Abandoned
- 2012-01-20 WO PCT/NZ2012/000003 patent/WO2012099479A1/en active Application Filing
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- 2013-07-19 CL CL2013002086A patent/CL2013002086A1/en unknown
- 2013-07-31 ZA ZA2013/05780A patent/ZA201305780B/en unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1600371A (en) * | 2003-09-22 | 2005-03-30 | 王玉万 | Preparing pharmaceutics of medication containing antimicrobials by using silicone oil as medium |
Also Published As
| Publication number | Publication date |
|---|---|
| IL227540A0 (en) | 2013-09-30 |
| IL227540A (en) | 2017-12-31 |
| MX2013008407A (en) | 2013-09-26 |
| AU2012207698A1 (en) | 2013-04-18 |
| KR101905173B1 (en) | 2018-11-28 |
| NI201300063A (en) | 2014-05-23 |
| NZ588686A (en) | 2013-07-26 |
| ZA201305780B (en) | 2014-04-30 |
| WO2012099479A1 (en) | 2012-07-26 |
| BR112013018557B1 (en) | 2021-11-03 |
| CR20130401A (en) | 2014-02-04 |
| CL2013002086A1 (en) | 2014-07-25 |
| MX353876B (en) | 2018-02-01 |
| PE20140035A1 (en) | 2014-02-16 |
| CN103327984A (en) | 2013-09-25 |
| GT201300182A (en) | 2014-07-28 |
| CO6801732A2 (en) | 2013-11-29 |
| KR20140012646A (en) | 2014-02-03 |
| BR112013018557A2 (en) | 2016-11-22 |
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