CN103327984A - Injectable compositions for mastitis comprising an NSAID and an antibiotic in a non-aqueous solvent - Google Patents

Abstract

An injectable composition when used for the treatment of a microbial infection in a mammary gland of an animal, wherein the composition includes a) a non-steroidal anti-inflammatory drug (NSAID); b) an antibiotic selected from the group consisting of a beta lactam antibiotic and macrolide antibiotic; characterised in that the composition includes a non-aqueous solvent, and the NSAID and antibiotic in the composition are dissolved in the non-aqueous solvent.

Description

Be included in NSAID and the antibiotic Injectable composition that is used for the treatment of mastitis in the non-aqueous solvent

Technical field

The present invention relates to the compositions for treatment of infection, although and nonspecific ground its most preferably be used for the treatment of mastitis.

Background technology

The present invention will discuss a kind of method, can treat infection in the animal by the method.

Should relate to domestic animal although spread all over this description, for example treatment of milk cattle it should be understood that the present invention's principle behind can be applicable to other animals, comprises the mankind.Spread all over this description, the instantiation relevant with 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 basically.

Spread all over this description and should refer to that at this character is bacteroidal infection, and be particularly related to the mastitis that produced by this bacterial infection.

Usually, antibiotic is introduced animal with the antagonism bacterial infection.This can be by various route of administration, comprises oral and local.A kind of preferably using is by (for example breast) surrounding injection in infected position.

The antibiotic demand of administration is expensive.

At first, medicine itself is expensive.

Secondly, in the situation of the mastitis that for example adversely affect the breast production of suckling, have dry up's phase (milk withholding time), wherein contaminated milk is newborn to be wasted the production of animal milk breast by throwing aside.In cows, this can cause the loss of annual several thousand dollars.Similarly, have such rules, its control will be introduced food chain (fowl egg or meat) from the animal product of the animal of having used antibiotic therapy in the recent period.

Therefore, if can provide for bacterial infection effectively and for the milk breast of throwing aside, have the antibiotic therapy of the shortest downtime, then will be desirable.

Mastitis are the high diseases of cost, it all affects the level of production of animal in short-term (Lac Bovis seu Bubali) and long-term (Production Life of shortening and superseded risk early), and lose the happiness of animal, and raising animal processor's (milker) pressure-particularly during the highest age of sucking.

Need to seek more easily administration, and be still effective new therapy.This can produce better compliance and better therapeutic outcome (cure rate).

If reach the active matter of enough high concentrations with the treatment malignant bacteria, with respect to the breast internal therapy of only treating a breast district, injectable antibiotic has advantages of whole four the breast districts for the treatment of (quarters of the udder).

Suppress the aimed concn that required antibiotic minimal inhibitory concentration (MIC) expression of specific bacteria is used for the mastitis treatment product.The product that can not reach desirable MIC may not be cured mastitis and be infected.

For example, staphylococcus aureus (Staphylococcus aureus) can be caused the mastitis that are difficult to cure, and to this and the conventional prescription of drawing up the product that contains tylosin.But, also do not set up for the work of tylosin to the MIC of staphylococcus aureus in the world.Most of MIC use erythromycin to set up, and it more seldom is used for the treatment of mastitis.

Reported that erythromycin is 0.5 μ g/ml to the MIC of staphylococcus aureus, and tylosin is 2 μ g/ml to the MIC of staphylococcus aureus.Basically, this shows that the concentration of the tylosin that need to effectively treat staphylococcus aureus is required approximately 4 times of erythromycin.

In fact, pharmacokinetic has been presented in the therapeutic process 20% tylosin injectable formulation and has only reached the approximately peak concentration of 1.4 μ g/ml, can not reach thus required treatment concentration (MIC).Thus, the active matter (〉 20% that needs the more heavy dose of and/or higher concentration of administration) to reach the milk breast concentration that is higher than MIC.

Therefore, need the improved antibiotic therapy of research and development (not only for tylosin, and for other antibiotic) to help to avoid the active matter (〉 20% to more heavy dose of or higher concentration) demand, reaching not only for staphylococcus aureus, but also the necessary MIC of reason that infects for other antibacterial.

In addition, needs research and development compositions wherein comprises excipient or extra active matter more effectively works when treating bacterial infection with the help antibiotic.

In the past, found that the co-administered of NSAID and antibiotic therapy is effective improving the antibiotic response.But, these active matters being combined in the stable compositions having any problem, this has caused usually two kinds of active matters being sent separately.This is normally inconvenient, and will preferably provide and comprise NSAID and antibiotic single compositions.

Also may be important for considering of animal happiness.For example the infection of mastitis is painful.Therefore, the not only use activating agent that has become routine operation and be, for example the NSAID treatment is infected, and treats associated pain.This therapeutic alliance is relatively new in industry.

US 2005/0277634 discloses NSAID (meloxicam) and antibiotic (penethacillin) is combined in the injection mixed suspension preparation with the treatment mastitis.They have discussed the concerted reaction between NSAID and the antibiotic, and it produce to need the antibiotic of low content more and reaches the effect of the content that is higher than MIC.Preferably, the concentration of NSAID is higher in the compositions, and the effect that antibiotic demonstrates is better.

But, have obvious shortcoming for mixed suspension preparation.These shortcomings comprise may lump, use front dispersion problem, send difficulty, inject rear reaction/pain and the not good absorption of active matter.Thus, will preferably provide NSAID and antibiotic combinations as stable liquid composite.In addition, providing load NSAID will be useful with the liquid composite that improves antibiotic effectiveness.But because those obvious problems as discussed above for example, this is also unrealized.

Usually, the obvious problem relevant with many injectable compositionss may be the reaction of appearance position and/or the pain that causes for animal when intramuscular or subcutaneous delivery.

Position reaction and pain during this injection are attributable to activating agent, for example tylosin antibiotic usually.But this problem other excipient in the thing that can be combined normally play the solvent of the carrier of activating agent or solubilizing agent effect and increase the weight of.This problem is recorded in the survey article in detail, the people such as Strickley, and Pharmaceutical Research, Vol., 21No.22004 February, exercise question is " Solubilizing Excipients in Oral and Injectable Formulations ".

Reason for this reason, veterinary chemist often is intended to exploitation as solution, and has the compositions of the solvent of alap concentration and/or volume in Injectable composition.Consequently, this can reduce the ability of the activating agent that reaches higher concentration, reduces compositions stability generally, and finally reduces the possible treatment successful of animal.

Therefore, veterinary chemist preferably uses position reaction and the pain of waterborne compositions when avoiding injecting.

Although this is reducing side effect, be that effectively waterborne compositions can cause the unstable of activating agent again, causes shorter the depositing the time limit of compositions (and final bioavailability) on the position reaction/pain when for example sending.It also can limit the ability of the higher surfactant concentration of maintenance.Then as discussing among the US 2005/0277634, may need it is reverted to suspensoid.

WO 02/41899 (WO ' 899) disclose comprise the antibiotic that all is dissolved in solvent and analgesics pour (pour-on) or Injectable composition.But, the compositions that the antibiotic of exemplary types (florfenicol, gentamycin and oxytetracycline) and the present invention pay close attention to, namely beta-lactam is different with macrolide.

In fact, known beta-lactam and macrolide antibiotic are unsettled especially, and are easy to and NSAID, for example flunixin reaction.Although be difficult to beta-lactam and macrolide antibiotic and NSAID combination, be very effective in the infected by microbes that this antibiotic is found in treating such as mastitis.

The such stability data that does not provide among the WO ' 899 namely hints many compositionss, and those compositionss (such as the compositions among the embodiment 4) that particularly have the greater activity agent concentration will not be stable storings.In fact, the research carried out of the inventor has shown that similar compositions is unsettled.

The objective of the invention is to overcome the above problems or provide effective selection to the public at least.

With all documents of addressing in this description, comprise that any patent or patent application are quoted and incorporate this paper into.Do not promise to undertake that any document consists of prior art.Documents shows what their author claimed, and the applicant keeps the accuracy of querying described document and the right of certainty.Can know to be, although this paper is open with reference to some prior aries, the document does not consist of in these documents any to consist of the promise of the part of common practise of the prior art in New Zealand or what other countries in office with understanding.

Spread all over this description, term " comprises/draw together " or its modification will be interpreted as that expression forgives the combination of described key element, integer or step or key element, integer or step, but does not forgive the combination of any other key element, integer or step or key element, integer or step.

Other aspects of the present invention and advantage will seem clear from the following description that only provides by way of example.

Summary of the invention

According to a first aspect of the invention, provide the Injectable composition when the infected by microbes in the mammary gland that is used for the treatment of animal,

Wherein, described compositions comprises

A. nonsteroidal anti-inflammatory drug (NSAID);

B. be selected from the antibiotic of beta-Lactam antibiotic and macrolide antibiotic;

It is characterized in that:

Described compositions comprises non-aqueous solvent, and

NSAID in the described compositions and antibiotic are dissolved in described non-aqueous solvent.

According to a further aspect in the invention, provide the method for the inside infected by microbes for the treatment of animal,

It is characterized in that

By drug administration by injection aforesaid compositions basically.

According to a further aspect in the invention, provide basically aforesaid compositions for the preparation of the purposes in the medicine for the treatment of infected by microbes.

Preparation is the method for aforesaid medicine basically, is characterised in that to described compositions to add at least a non-aqueous solvent.

The discussion of advantage provided by the invention

The inventor has found that infection site place and obvious inflammation on every side can hinder antibiotic effectiveness, because this has reduced the ability that reaches and act on antibacterial.

In the past, administration NSAID is with treatment inflammation and/or pain more.The inventor has found in single injectable compositions by with NSAID and the antibiotic together important synergy of administration.This synergy can make this antibiotic than this antibiotic is individually dosed more effective.Similarly, the inventor has found that in unitary agent NSAID and antibiotic combination have the synergy of enhancing, if in two independent preparations with NSAID and antibiotic therapy animal, then it does not exist.This may be partly owing to the ability that two kinds of active matters are provided in stable compositions together.

The inventor considers the binding mode that is not limited to propose, cooperative interaction can result from NSAID reduce the infection site place and around the inflammation of (in the situation of mastitis at the mammary gland place) so that NSAID can make antibiotic effectively be distributed in other inflammation parts.

In addition, synergy can be partly owing to NSAID in conjunction with endotoxin (endotoxemia), the inventor finds that in addition it hinders antibiotic effectiveness.

For example, produce endotoxic gram negative bacteria relevant with mastitis.This antibacterial can be caused the disease (heating and endotoxemia) of general.Although at present this is relatively uncommon (being lower than 1% sickness rate) in New Zealand, the use that feedstuff pad (feed-pads) and herd room (herd homes) increases may cause the sickness rate of the higher mastitis that caused by gram-negative pathogens.Thus, wish that preparation of the present invention will become infection in future, for example the important a member in the therapeutic scheme of mastitis.

In addition, owing to can acting on, NSAID reduces fever (heating) so that safety/comfortableness of antibiotic effectiveness and animal is better, so synergy can further strengthen.

In some NSAID and antibiotic process of the test, the inventor has put down in writing as discussed above synergy.Carrying out above experiment, and after definite advantageous effects, those skilled in the art will know that this synergy can expect antibiotic for common type, and be not only those particular instances of test.For example, all beta-lactams of expection will be demonstrated identical synergy with macrolide antibiotic when making up with NSAID.Known this antibiotic of two types has similar binding mode (cell protein is synthetic to be suppressed).

Another significant advantage of this combination that the inventor finds can be the happiness that NSAID can improve animal, and this may be infected by inside owing to reducing, for example pain and the inflammation of mastitis generation.

In addition, can provide in a combination preparation that two kinds of different active matters can help to overcome that a plurality of compositionss are sent, the demand of composition stores, cost, packing etc.The inventor can find to help the specific solvent type of two kinds of active matter combinations, and has found to be very difficult to make up in stable solution before these two kinds of active matters.Use in the past suspensoid that this active matter is combined in the single compositions.

As discussed below, the inventor finds because the concentration of NSAID increases the other synergy that can not expect between these two kinds of active matters that cause.

The purpose that improves NSAID concentration is to improve the initial synergy of finding of the inventor to assist to 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, this combination should provide the suitable dose of each activating agent.For example, (20% tylosin concentration is usually used in compositions for tylosin for example, recommended dose 10mg/kg) for a kind of certain antibiotics.The tylosin of this high concentration may be the limiting factor in the said composition usually, because it may cause the obvious stimulation when injecting.For the together dosage of NSAID (for example ketone ibuprofen), the concentration of preferred 6%w/v are provided.In fact, the compatibility of the dosage between the employed various active thing may be the importance that active compound successfully provides correct active matter amount when administration.

But when the inventor attempted providing the compositions that contains 6% ketone ibuprofen, the compositions with aqueous solvent was unstable.For the NSAID of other tests, if comprise NSAID under the desired concn with the reflection recommended dose, then in waterborne compositions, similarly find not good stability.

Do not wish to return to suspensoid, the inventor need to consider other approach.

The concentration that increases in order to remedy NSAID, the inventor uses non-aqueous solvent system to attempt being provided at stable compositions in the solution under the various conditions (for example being higher than 4 ℃ temperature).But as usually understanding in this area, expection returns to nonaqueous solvent and will cause reacting and/or pain with respect to the position of waterborne compositions increase when sending.

But unexpectedly be from the inventor's research, to find what this position reaction/pain did not increase to above discovery in commercial composite (waterborne compositions, for example Tylan and Ketofen).

Do not wish to be subject to specific binding mode, consider that the NSAID of increase helps to alleviate the inflammation/pain of part, injection site synergistically.Therefore, the additional quantity of NSAID may react on the position reaction that usually will increase when injection and more irritating solvent of pain.

Therefore, can not expectedly be, the inventor finds that antibiotic and NSAID can be included in the stable liquid composite together, has when making up with water-based system usually the NSAID concentration of accessible larger increase.Importantly, this can realize and not cause the position that increases when sending with respect to industrial standard thing (Tylan and Ketofen) to react or pain.

The downstream effect of this discovery is can increase NSAID or even antibiotic concentration (and final dose) and do not cause position reaction/pain extra when sending.With regard to infection, also can strengthen this synergy, improve overall therapeutic outcome.

The preferred embodiment of compositions

Provide compositions of the present invention as injectable liquid preparation.Spread all over this description, term " liquid preparation " is interpreted as any treatment preparation that expression has " injectable " denseness.This is many peasants and the preferred mode of administration of veterinary, and particularly when the treatment infection site, for example during mammary gland (mastitis), the local application of NSAID can have very large effect.Preferably, liquid preparation has injectable viscosity under lower temperature.

This liquid preparation is solution.This should represent that wherein all excipient and activating agent are dissolved in the solution basically and not in the compositions of suspensoid.As previously discussed, solvent provides many advantages that are better than suspensoid.For example, there are not caking, the problem of suspendible or injections difficult again.

This solution can have one or more phases.

Nonsteroidal anti-inflammatory drug

Spread all over this description, term " nonsteroidal anti-inflammatory drug " (NSAID) should represent not use any medicine or the reactive compound with antiinflammatory effect of steroidal compounds.

There are many dissimilar NSAID well known in the prior art.In scope of the present invention, should understand any or the combination of using known NSAID or find in the future those.

Preferably, NSAID be selected from carprofen, naproxen, ibuprofen, ketone ibuprofen, than Luo Xikang, voltaren see diclofenac, etodolac, flunixin, deracoxib, meloxicam, celecoxib, rofecoxib and their combination.

Most preferably, NSAID is selected from flunixin, carprofen, ketone ibuprofen and their combination.

The inventor finds that when with antibiotic combinations required for protection, these NSAID demonstrate maximum synergy.In addition, all to demonstrate from drug effect and safety perspective be effective antiinflammatory the cattle medicine to these NSAID.

Preferably, NSAID is present in the liquid preparation with the concentration of 1-15%w/v.As previously discussed, can preferably improve the concentration of NSAID to improve two kinds of synergies between the active matter.The advantage of even now will be expected very much, as long as still can't realize the combination of stable composition in such solution, say nothing of described compositions and will not demonstrate larger position reaction/pain than waterborne compositions when sending.

Preferably, NSAID flunixin meglumine is present in the compositions with the about concentration of 7.3%w/v.This can provide in the compositions approximately 4.4% flunixin.This be according to the close rate of tylosin combination.

The preferred roughly concentration of each NSAID also can be depending on the antibiotic concentration that uses in its antiinflammatory drug effect and safety overview and the compositions.

Preferably, the NSAID meloxicam is present in the compositions with the about concentration of 1%w/v.

Preferably, the NSAID carprofen is present in the compositions with the about concentration of 3%w/v.

Preferably, the NSAID ketone ibuprofen is present in the compositions with the about concentration of 4%-10%w/v.For example, when the concentration of tylosin antibiotic was 20%w/v in compositions, the concentration of corresponding ketone ibuprofen was preferably 6%w/v.If the concentration of tylosin increases to 30%w/v, the preferred concentration of ketone ibuprofen is 9%w/v.

Alternatively, NSAID is selected from the antiinflammatory of native form.For example, these can comprise Jadeite Mussel extract, ω 3 etc.

Antibiotic

Spread all over this description, the term antibiotic should represent (sterilization) of kill bacteria and/or (antibacterial) material or the chemical compound of bacteria growing inhibiting, no matter is natural, synthetic or semisynthetic.

Antibiotic in the compositions is selected from macrolide and beta-Lactam antibiotic.

Spread all over this description, term " macrolide " antibiotic should represent can to connect one or more desoxy sugars because existing, normally the macrolide ring of cladinose and desosamine and the activated any antibiotic of tool.Lactonic ring is 14,15 or 16 yuan of rings normally.

Macrolide antibiotics is generally used in the veterinary drug, and thinks to have identical binding mode.It is believed that, the binding mode of macrolide antibiotic comprises that for example interferencing protein synthesizes by hindering ribosomal translation.

Preferably, macrolide antibiotics is selected from azithromycin, clarithromycin, dirithromycin, erythromycin, 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, is used for veterinary drug treating the bacterial infection in the species on a large scale, and has the high margin of safety.Another advantage of tylosin is that it is licensed for the treatment of mastitis in New Zealand.

Tylosin has the activity for the resisting gram-positive antibacterial of wide spectrum, comprises staphylococcus (Staphylococci), streptococcus (Streptococci), corynebacterium (Corynebacteria) and Erysipelothrix (Erysipelothrix).It also has the activity for gram-negative large intestine Campylobacter (Campylobacter coli) and some spirillums (spirochaetes).It also has activity to mycoplasma (Mycoplasma) species.

Injectable tylosin preparation can cause pain, inflammation and the pruritus around the injection site.Therefore, the above side effect in the time of importantly can reducing the injection tylosin.Provide together antibiotic such as tylosin and NSAID to have advantages of extra, NSAID can help avoid the side effect of tylosin.Can help the reduction of this side effect by NSAID and the antibiotic synergy between during administration in a preparation.Spread all over this description, term " beta-lactam " antibiotic should represent to be included in any antibiotic of beta-lactam nucleus in its structure.For example, this can comprise penicillin derivative (penam), cephalosporin (cephem), monobactam and carbapenem.

The binding mode that it is believed that beta-Lactam antibiotic comprises the cell wall of attack bacteria.Beta-Lactam antibiotic can with beta-lactamase inhibitor, for example clavulanic acid provides together.

Preferably, beta-Lactam antibiotic is penethacillin.In recent research, find that penethacillin has the drug effect similar to tylosin (particularly preferred for class of antibiotic of the present invention).

The common advantage that beta-lactam and macrolide antibiotic are better than other class of antibiotic is that this antibiotic of two types all is weak base, and is lipophilic.This can be in body fluid produces than blood plasma such as the milk Ruzhong higher concentration.Thus, they are easier to reach the concentration that is higher than minimum inhibitory concentration (MIC) than alipotropic chemical compound.

Can not expectedly be that as if these class of antibiotic demonstrate synergy with NSAID.But other class of antibiotic are not observed this synergy.Preferably, antibiotic is with 10-35%w/v, and most preferably is present in the liquid preparation with the about concentration of 20.0-30.0%w/v.

Usually, higher antibiotic concentration will cause antibiotic volume that unit dose needs administration still less, and it can be more convenient for the peasant, and make meiofauna more comfortable.By improving the level of the NSAID in the compositions, also can improve the antibiotic concentration in the compositions, and do not improve position reaction when sending (effect of finding when returning to non-aqueous solvent to the present invention is similar, its yet expect the position reaction/pain that causes increase).

For example, if the inventor knows treatment for staphylococcus aureus, then the amount of antibiotic (for example tylosin) can be increased to 60%w/v to reach minimum inhibitory concentration (MIC).

Preferably, the ratio of NSAID and antibiotic (w/v) is respectively approximately 1:3 in the liquid preparation.If NSAID is flunixin, then this can be the ratio of particularly suitable.If but NSAID is dissimilar NSAID, for example meloxicam or carprofen, then this variable-scale.

Solvent

Spread all over this description, term " solvent " should represent to be present in any solvent in the compositions or the combination of different solvents.

Preferably, described solvent has one or more following character:

-non-aqueous;

Under-25 ℃ greater than 30 dielectric point (dielectric point);

-be higher than 100 ℃ boiling point; And/or

-classify as dipolar aprotic solvent.

Most preferably, described compositions is fully nonaqueous.The inventor has tested various waterborne compositions, finds them under high-temperature condition, and usually even at room temperature very unstable.It is unstable especially when for example, discovery tylosin and NSAID make up in aqueous formulation.If but NSAID and antibiotic combination coupling in the system based on non-aqueous solvent, then said composition keeps stable, and is special under lower temperature (for example 2-15 ℃).

Discovery becomes the compositions that only comprises non-aqueous solvent with waterborne compositions can provide compositions stable in the solution most effectively.In addition, complete nonaqueous solvent compositions so that the inventor concentration of NSAID is increased to above common possible concentration in the water-based system.Can not expect although increase the position reaction, this does not occur in the research that the inventor carries out.

Dielectric under 25 ℃ o'clock is favourable greater than the stability that 30 non-aqueous solvent also demonstrates for compositions.Non-aqueous solvent, for example ethanol (have 25 dielectric point) is not good solvent for the present invention, and does not provide and the dielectric o'clock dissolubility/stability greater than 30 solvent phase same level.The solvent of expection similar type will have similar beneficial effect.

Most preferably, non-aqueous solvent has the dielectric point of 30-50.Find that propylene glycol (32.1), NMP (32.2), DMSO (46.7) and DMA (38) improve the stability of active matter.Unexpectedly be to compare with waterborne compositions and find that not this solvent increases the position reaction/pain (may be because the second level discussed above synergy) when sending.The solvent of expection similar type will have similar beneficial effect.

Similarly, find that in addition boiling point is higher than 100 ℃ non-aqueous solvent the stability of improvement is provided, and do not increase the position reaction when sending.Moreover the second alcohol and water all is not good solvent.Otherwise the discovery solvent, for example propylene glycol (BP=188 ℃), glycerol formal (BP=190-195 ℃), NMP (BP=202-204 ℃), DMSO (BP=189 ℃), DMA (BP=164-166 ℃) have advantage discussed above.The solvent of expection similar type will have similar beneficial effect.

In addition, it is particularly advantageous finding to comprise at least a non-aqueous solvent that broad sense is categorized as dipolar aprotic solvent.For example, it is very effective solvent that discovery NMP does not increase the position reaction for improvement stability, although it is considered to the zest solvent, and causes the position when injecting to react.Preferably, non-aqueous solvent is selected from METHYLPYRROLIDONE (NMP), glycerol formal, propylene glycol and benzyl alcohol.

At stable composition with NSAID concentration is increased be found for example NMP and propylene glycol known high stimulus object when being injection too of especially effective solvent.Therefore, especially unexpectedly be to find when injectable composition, these solvents do not cause the position reaction of increase.

Preferably, liquid preparation comprises at least two kinds of different non-aqueous solvents.

More preferably, described liquid preparation comprises the first and second non-aqueous solvents, and wherein the first solvent plays a part solubilizing agent, and wherein the second solvent plays a part carrier solvent.

For example, the inventor has found the active matter that provides stable especially in the preparation that is combined in of NMP and propylene glycol.The NMP that comprises, glycerol formal and/or benzyl alcohol can be used as the solubilizing agent for active matter, and solvent, for example propylene glycol can be used as carrier so that the stability of improvement to be provided in compositions.

Preferably, only use minimum solubilizing agent, for example NMP.The amount of solubilizing agent can change according to type and the dissolubility of activating agent in the compositions.

Preferably, the amount of solubilizing agent is lower than 40%w/v in the compositions.

More preferably, the amount of solubilizing agent is about 30%w/v in the compositions.

In the present invention, preferred NMP is only with minimum use, and only as solubilizing agent.This is opposite with embodiment 1-4 among the WO 02/41899 (WO ' 899), and wherein main solvent is NMP, and compositions adds to volume (equaling approximately 60%w/v or larger in most of situation in final composition) with NMP.NMP is simply embodied employed antibiotic, i.e. non-beta-lactam or macrolide antibiotics as main solvent (being disclosed in the page 4 of WO ' 899, up to the 95%w/v of final composition).

Preferably, the amount of carrier solvent is 30%w/v at least in the compositions.More preferably, the amount of carrier solvent is 40%w/v at least in the preparation.

Preferably, the ratio of the first solvent and the second solvent is between 1:10-1:1.More preferably, the ratio of the first solvent and the second solvent is between 1:2-1:1.

Carrier solvent such as propylene glycol more stimulate as solvent, and understand it and cause the more position reaction when injecting than NMP.Based on what usually understand in the prior art, this may also be not instruct the reader to use carrier solvent such as propylene glycol in for example WO ' 899 open, and mainly depends on the contrary another reason of a large amount of NMP.

Think that this carrier solvent of the present invention helps to provide the good stability of beta-lactam/macrolide antibiotic and NSAID in the compositions.WO ' 899 does not instruct the feature of using carrier solvent by any way, does not instruct the class of antibiotic of using among the present invention yet.

In addition, disclosed solvent compositions can not provide the stabilizing effect identical with solvent compositions of the present invention among the WO ' 899, even macrolide/beta-Lactam antibiotic is substituted the more stable antibiotic of example among the WO ' 899/NSAID combination.

Known such as the inventor, know beta-lactam and macrolide antibiotic and flunixin (WO pays close attention to NSAID in ' 899) unstable.In the research that the inventor carries out, the compositions display similar to those disclosed compositions among the WO ' 899 goes out not good stability.

Opposite, the present composition that is limited to macrolide/beta-Lactam antibiotic demonstrates good stability under the condition of certain limit (referring to the embodiment 6 of preferred forms part).

Preferably, non-aqueous solvent accounts for compositions above 10%w/v.

Preferred, non-aqueous solvent accounts for the 30%w/v-80%w/v of compositions.As previously discussed, high like this nonaqueous solvent content (and particularly with respect to carrier solvent of solubilizing agent) is useful more stable compositions and the NSAID/ antibiotic concentration of increase are provided, and expects position reaction and the pain that it enlarges markedly with respect to the aqueous combination deposits yields.But this does not find.

Antioxidant

Preferably, liquid preparation comprises at least a antioxidant.

Preferably, antioxidant is selected from sulphoxylic acid formaldehyde sodium or butylated hydroxytoluene (BHT).But, it will be appreciated by those skilled in the art that any antioxidant can be used for the present invention basically, and should not think and exceed the scope of the invention.

Preferably, antioxidant is with 0.01-0.3%w/v, and most preferably is present in the liquid preparation with the about concentration of 0.05%w/v.

Particularly preferred formulation examples specifically describes the optimum implementation part in this description.

The preferred embodiment of Therapeutic Method

Spread all over this description, term " administration " should represent by use (blood flow and the health that namely basically spread all over animal) from part or general the active matter in the compositions to be delivered to infection site.

Preferably, described compositions is used for the treatment of inner the infection.Spread all over this description, term " the inner infection " should represent the position in the body, and it comprises from external accessibility body cavity.For example, this comprises body cavitys such as mouth, papillary duct, breast, vagina.

Preferably, described compositions is with general ground administration.The example of general administration can comprise by injection, bolus or perfusion, wherein active matter can be subsequently by the animal blood distribution to infecting and/or inflammation part.

Most preferably, described compositions is passed through drug administration by injection.Should note injecting and to carry out near infection site or in part, infection site place, but still produce good active matter systemic delivery.

But described compositions subcutaneous injection or intramuscular injection.

Preferably, described compositions is in order to process clinical mastitis.But in some embodiments, compositions can be used for preventing early stage mastitis.Using NSAID treatment mastitis in compositions is new approaches, and it has the remarkable advantage that spreads all over the discussion of this description.

But the inventor thinks that described compositions can be in order to treatment basically the inside infected by microbes of any type and/or relevant inflammation/pain.

Preferably, described compositions is in order to treat inhuman animal, for example animal commonly used in milch cow, sheep, goat or other dairy industries.

The preferred embodiment of dosage

Preferably, described compositions is with the dosed administration of the NSAID of the antibiotic of 5-20mg/kg/ days (based on drug weight/animal weight) and 0.2mg-4mg/kg/ days.

In preliminary test, the MIC (2 μ g/ml) that provides tylosin required is provided this dosage, so that antibiotic treatment content is provided.But because the synergy of finding between antibiotic and the NSAID, what antibiotic can be than routine is more effective, so that only need the more antibiotic of low content, but still effectively treats antibacterial and infects.

The inventor finds that the amount of NSAID will depend on type and changes.For example, each NSAID preferably roughly dosage can be depending on its antiinflammatory drug effect and safety distributes.

Preferably, the dosage of flunixin is between 1-3mg/kg/ days.Most preferably, the dosage of flunixin is approximately 2.2mg/kg/ days.

Preferably, the dosage of meloxicam is between 0.1-1mg/kg/ days.Most preferably, the dosage of meloxicam is approximately 0.5mg/kg/ days.

Preferably, the dosage of ketone ibuprofen is between 2-4mg/kg/ days.Most preferably, the dosage of ketone ibuprofen is approximately 3mg/kg/ days.

Preferably, the dosage of carprofen is between 0.5-2.5mg/kg/ days.Most preferably, the dosage of carprofen is approximately 1.4mg/kg/ days.

Described Therapeutic Method can use flexibly dosage adjusting in the treatment disease according to type and the order of severity.For example, the inventor notice flexible packing (flexipack) for use this flexibly dosage be effective especially.Pack flexibly the container of normally being made by high and Low Density Polyethylene mixture.This packing can easily be buied from many manufacturers.

The preferred embodiment of preparation method

As discussing in this description, using the major advantage of non-aqueous solvent is the activity concentration that can increase in the compositions.This has many advantages, and comprising can be to animal with the low relatively large active matter of volume administration.Animal when this can help to reduce administration time and injection is uncomfortable.

In addition, lower volume dose is favourable for depositing, because it accounts for less space.

Preferably, the NSAID in the compositions is increased in the waterborne compositions of correspondence, at room temperature can not stablizes the concentration (%w/v) of depositing.

Preferably, NSAID is ketone ibuprofen, and wherein the concentration of ketone ibuprofen is higher than 4%w/v.

The preferred aspect of preparation method below will be discussed.

Preferably, before adding NSAID or antibiotic, the first and second non-aqueous solvents are added in the mixer.

Selected the first and second nonaqueous solvents can be depending on NSAID and antibiotic type, quantity or the concentration of using in the preparation.The example of the first and second non-aqueous solvents partly provides in optimum implementation.But these examples are not intended to limit.

In some embodiments, can add extra non-aqueous solvent.Alternatively, can only comprise suitably a kind of non-aqueous solvent.

Preferably, before adding NSAID or antibiotic, non-aqueous solvent is heated to approximately 55-80 ℃.Employed temperature can be depending on the particular actives of using in the compositions.

Preferably, before adding NSAID, antibiotic is added non-aqueous solvent and dissolving.Then NSAID can be added and be dissolved in the mixture of the antibiotic of dissolving and non-aqueous solvent.The inventor finds that this adds step by step solvent, antibiotic and adds at last NSAID provides improved composition dissolves degree and stability.

Preferably, NSAID and antibiotic are added step by step to preparation whole during, temperature is maintained 55-80 ℃.

Then will contain extremely approximately room temperature (for example 20-30 ℃) of NSAID and antibiotic composition cools, and then add to final volume (in right amount) with non-aqueous solvent, and mixed approximately 10-20 minute.

Then compositions can be kept at approximately 4 ℃ before administration under.

Advantages more of the present invention comprise:

-can make conspiracy relation (NSAID improves antibiotic effectiveness) is arranged between NSAID and antibiotic.

-use non-aqueous solvent help to overcome between the active matter incompatible, and the unsettled problem of many antibiotic particularly.

-use non-aqueous solvent can make compositions be provided as compositions (non-suspensoid) in the solution stable under some storage conditions.

-solution is avoided caking, before sending for compositions again demand and the relevant problem of injection (syringe needle obstruction and the issuable animal pain of particulate matter) of suspendible.

-use non-aqueous solvent the concentration of NSAID can be increased to above available level in the waterborne compositions.Although expection is reacted because of the position of feature when sending of known non-aqueous solvent and the increase of pain, do not find the raising of these side reactions.

The increase of-gained NSAID also can help to reduce not only by solvent, and is reacted by the position that antibiotic (tylosin is known stimulus object) causes.Possibly, the concentration of the tylosin of compositions can increase because of the position reaction still less of when injection.

-increasing by the concentration that makes NSAID in the compositions, the concertedness of finding between two kinds of active matters at infection site place increases.By improving antibiotic effectiveness, can be potentially with the antibiotic of lower concentration in order to identical result to be provided.

-avoid the moisture demand that has prevented from compositions is adjusted to desirable pH in the compositions, eliminate the additional step in the preparation method.

Pain and inflammation that the inner infection of-minimizing may be correlated with.

-improve operational efficiency (opposite with two kinds of compositionss, as only to use a kind of compositions).For example, the demand of multiple injection has been eliminated in the combination of the antibiotic in single product (for example tylosin) and NSAID, and will be easier to administration and have good compliance and the therapeutic outcome of improvement.

-send flexibly selection.

-preferred administration (injection) can improve drug distribution

-NSAID improves the animal happiness, and antibiotic works simultaneously.

-except reducing pain and heating, NSAID can with endotoxin (gram negative bacteria) combination, improve therapeutic outcome, and will become thus the important composition of following mastitis treatment scheme.

As if-preparation is effective especially in treatment Gram-negative mastitis, and mastitis are expected at several years in the future and will improve at Zelanian prevalence rate.

Preferred forms of the present invention

Embodiment 1

Following table 1 has shown according to a plurality of initial preparation by inventor's test of the present invention.

It below is the evaluation to the suitability of test preparation.

Table 1: tylosin/flunixin combination

It is 2% excessive that * adds

* * is used for the pH regulator between (8-9.5)

The existing preparation of the tylosin alkali injection of F1 ACVM registration.

Flunixin injection (the trade (brand) name: the existing preparation Fluxamine injection) of F2 ACVM registration.

Under the F3 room temperature in 48 hours product colour become burgundy.

F4 reaches pH regulator with 20% sodium hydroxide.Product colour was stablized 4-40 ℃ of lower the maintenance.

F5 uses glycerol formal+propylene glycol formulated product for fear of the pH problem.Product colour was stablized 4-40 ℃ of lower the maintenance.

The F6 antioxidant is substituted by the sulphoxylic acid formaldehyde sodium and becomes BHT.Product colour was stablized 4-40 ℃ of lower the maintenance.

F7 mixes through stable glycerol formal with stabilization formulations.Product colour was stablized 4-40 ℃ of lower the maintenance.

The F8 product colour was stablized 4-40 ℃ of lower the maintenance.

Sum up

Preparation F5 demonstrates more stable tylosin/flunixin preparation.The method for preparing the F5 preparation provides as follows.

The preparation process of preparation F5

In clean and dry preparation container:

1. load aequum through stable glycerol formal.

2. add and mix 25% propylene glycol.

With mixture heated to 70-80 ℃.

4. add and dissolving tylosin alkali, and fully mixing (remaining on 70-80 ℃ temperature).

5. add and dissolving flunixin meglumine, and fully mixing (remaining on 70-80 ℃ temperature).

6. material is cooled to and is lower than 30 ℃.

7. add to final volume with propylene glycol, and fully mixed 10 minutes.

Embodiment 2

Test two kinds of other preparations (F9 and F10), it comprises tylosin and carprofen or meloxicam.These preparations and preparation process below are provided.

Table 2: the combination of tylosin/carprofen and tylosin/meloxicam

It is 5% excessive that * adds

The preparation process that is used for F9 and F10

1. in clean and dry preparation container:

2. load the NMP of aequum.

3. add and benzene mixed methanol.

4. add and mix (35%) propylene glycol.

With mixture heated to 70-80 ℃.

6. add and dissolving tylosin alkali, and fully mixing (remaining on 70-80 ℃ temperature).

7. add and dissolving meloxicam/carprofen, and fully mixing (remaining on 70-80 ℃ temperature).

8. material is cooled to and is lower than 30 ℃.

9. add to final volume with propylene glycol, and fully mixed 10 minutes.

Embodiment 3

The inventor tests the compositions that comprises tylosin/ketone ibuprofen subsequently.

In this waterborne compositions, tylosin/ketone ibuprofen is stable.But when the inventor was increased to the concentration of ketone ibuprofen greater than 4%w/v, compositions lost the stability in waterborne compositions.

The preparation process that is used for F11

1. in clean and dry preparation container, load propylene glycol, the benzyl alcohol of aequum, and fully mix.

With mixture heated to 60-70 ℃.

3. add and dissolving tylosin alkali, and fully mixing (remaining on 60-70 ℃ temperature).

Check the clarification of solution.

4. add ketone ibuprofen and dissolving, and fully mix.Material is cooled to room temperature.

5. check pH, it should be between 8.8-9.5.Such as needs, the hydrochloric acid that uses the sodium hydroxide solution of 10%w/v or 5%w/v with pH regulator between the 8.8-9.5.

6. water adds to final volume, and fully mixes 10-15 minute.

7. check pH.It should be between 8.8-9.5.

Embodiment 4

The inventor aims to provide and comprises than the NSAID ketone ibuprofen of visible more high-load among the embodiment 3 and the compositions of tylosin.Ultimate principle is that the NSAID that increases measures the antibiotic effectiveness that concertedness ground is helped the infection site place, and the pain relief of raising is provided to animal simultaneously.

Do not wish to return to suspensoid, the present invention need to test stronger (non-aqueous) solvent to stablize NSAID under high heap(ed) capacity.Successfully realized compositions stable in the solution.But, the pain when using the non-aqueous solvent expection to cause compositions to produce stronger position reaction and injection.

The preparation process that is used for F12

1. in clean and dry preparation container, load the METHYLPYRROLIDONE (NMP) of aequum.

2. in container, load the benzyl alcohol of aequum, and fully mix.

3. load propylene glycol (still size 35%) in the container, and fully mix.

With heating material to 55-65 ℃.

5. mix and add butylated hydroxytoluene (BHT) and dissolving.

6. mix and add tylosin alkali and dissolving (remaining on 55-65 ℃ temperature).

7. mix and add ketone ibuprofen and dissolving.

8. check the clarity of solution.

9. add to 98% volume of still size with propylene glycol, and fully mix.

10. material is cooled to 25-30 ℃ and mixing.

11. add to final volume with propylene glycol, and fully mix.

Embodiment 5: the position reaction when tentatively zooscopy is with test injection

Study relatively to comprise test composition and the treatment equivalence between the industrial standard thing and the side effect (side reaction when sending and pain) of the ketone ibuprofen of 20% tylosin and 6%.

When in the muscle of jointly using the milch cow that gives milk, the 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 the 10mg/kg body weight.Ketofen contains the ketone ibuprofen of 10%w/v, and prescribed dose is 3mg/kg.Tylan and Ketofen are waterborne compositions.

From the cows of about 1200 cattle, select 20 cattle of each nursery phase of 4 years old-6 years old.

Animal is drawn group in pairs, and random assortment in groups 1 or organize 2.This research is dual crossing research, and wherein each group is processed separately with two inorganic agents in the animal section process of research, and 20 animals for the treatment of through each treatment period treatment are provided thus.It is constant that dosage between two groups keeps, and is 10mg/kg for tylosin namely, is 3mg/kg for ketone ibuprofen.

After milking in the 0th day, process cattle according to actual weight separately.Collect blood samples at 11 time points, and real time record 24 hours.

As follows, studies show that the bioequivalence between test composition and industrial standard material.

Solid line represents the tylosin plasma concentration of the test composition of embodiment 4.Dotted line represents to use the tylosin plasma concentration of Tylan.

Solid line represents the ketone ibuprofen plasma concentration of the test composition of embodiment 4.Dotted line represents to use the ketone ibuprofen plasma concentration of Ketofen.

In a word, result of study shows when dosage keeps stablizing similar bioequivalence level between two compositionss.This shows that the compositions through combination has and compares the individually dosed good bioavailability of industrial standard thing.In itself, this is major advantage.

Another major advantage of finding from this research againsts one's expectation, and with respect to industrial standard thing (Tylan and Ketofen), test composition does not demonstrate the adverse effect (to position reaction or the pain of animal) of any increase.

This can not expect, because the non-aqueous solvent that uses in the test composition among the embodiment 4 is considered to cause disadvantageous side effect when injection.The dosage maintenance of considering in the research group 1 and group 2 is identical, can expect the increased dosage amount that may realize the NSAID (for example ketone ibuprofen) greater than 3mg/kg, simultaneously with respect to present available compositions, (or even reduce) position reaction/pain of avoiding increasing.Can realize the increased dosage amount by the concentration that improves NSAID, this is because non-aqueous solvent is used for making active matter be stabilized in compositions.

Embodiment 6: stability test

Three 4.5L batch of materials to example among the embodiment 4 carry out stability study.

Batch of material is inserted in the 100ml glass amber vial, and at 25 ℃/60﹠amp; Deposit under the setting condition of storage of RH, 30 ℃/65%RH and 40 ℃/75%RH.

The physics and chemistry character with the predetermined distance record product such as the ACVM recommendation.

As shown in the table, compositions was stable through at least 6 months under 25 ℃/60%RH and 30 ℃/65%RH.

Storage condition: 25 ℃/60%RH

Storage condition: 30 ℃/65%RH

Storage condition: 40 ℃/75%RH

Storage condition: 25 ℃/60%RH

Storage condition: 30 ℃/65%RH

Storage condition: 40 ℃/75%RH

Aspect of the present invention is only described by way of example, and should understand and can make amendment and add and do not deviate from its scope as limiting in the claims of enclosing it.

Claims (35)

1. the Injectable composition that is used for the treatment of infected by microbes in the animal's mammary gland, wherein, described compositions comprises

A. nonsteroidal anti-inflammatory drug (NSAID);

B. be selected from the antibiotic of beta-Lactam antibiotic and macrolide antibiotic;

It is characterized in that:

Described compositions comprises non-aqueous solvent, and the NSAID in the described compositions and antibiotic are dissolved in the described non-aqueous solvent.

2. the compositions of claim 1, wherein said compositions is nonaqueous.

3. claim 1 or 2 compositions, wherein said non-aqueous solvent have one or more in the following characteristics:

A) under 25 ℃ greater than 30 dielectric point,

B) be higher than 100 ℃ boiling point, and/or

C) be dipolar aprotic solvent.

4. each compositions in the aforementioned claim, wherein said non-aqueous solvent is selected from following group: METHYLPYRROLIDONE (NMP), dimethyl sulfoxide (DMSO), dimethyl acetylamide (DMA), glycerol formal, propylene glycol, benzyl alcohol and their combination.

5. each compositions in the aforementioned claim, wherein said compositions comprises the first and second non-aqueous solvents.The compositions of claim 4, wherein said the first non-aqueous solvent is glycerol formal or NMP, and described the second non-aqueous solvent is propylene glycol.

6. each compositions in the aforementioned claim, wherein said NSAID is selected from carprofen, naproxen, ibuprofen, ketone ibuprofen, than Luo Xikang, voltaren see diclofenac, etodolac, flunixin, Feracoxib, meloxicam, celecoxib, rofecoxib and their combination.

7. each compositions in the aforementioned claim, wherein said NSAID is selected from flunixin, meloxicam, carprofen, ketone ibuprofen and their combination.

8. each compositions in the aforementioned claim, wherein said NSAID exists with the concentration of 1-15%w/v.

9. the compositions of claim 7, the concentration of wherein said flunixin are about 7.3%w/v, and the concentration of meloxicam is about 1.0%w/v, and the concentration of carprofen is that the concentration of approximately 3.0%w/v or ketone ibuprofen is about 4-10%w/v.

10. each compositions in the aforementioned claim, wherein said macrolide antibiotics is selected from azithromycin, clarithromycin, dirithromycin, erythromycin, Roxithromycin, Ketek, carbomycinA, josamycin, kitasamycin, midecamycin/midecamycin acetate, oleandomycin, spiramycin, triacetyloleandomycin and tylosin and their combination.

11. each compositions in the aforementioned claim, wherein said macrolide antibiotic is tylosin.

12. each compositions in the aforementioned claim, wherein said beta-Lactam antibiotic is penethacillin.

13. each compositions in the aforementioned claim, wherein said antibiotic exists with the concentration of 10-35%w/v.

14. each compositions in the aforementioned claim, wherein said antibiotic exists with the about concentration of 20.0%w/v.

15. each compositions among the claim 1-14, NSAID and antibiotic ratio are about 1:3w/v in the wherein said compositions.

16. each compositions in the aforementioned claim, wherein said compositions comprises at least a antioxidant.

17. the compositions of claim 16, wherein said antioxidant are selected from sulphoxylic acid formaldehyde sodium or butylated hydroxytoluene (BHT) and their combination.

18. the compositions of claim 16 or 17, wherein said antioxidant is present in the described compositions with the concentration of 0.01-0.3%w/v.

19. be used for the treatment of the method for non-human animal's inside infected by microbes,

Wherein be provided for treating the method for non-human animal's inside infected by microbes,

It is characterized in that its step is

By use among the claim 1-20 each compositions to the injection of described animal.

20. the method for claim 19, wherein said compositions is through subcutaneous injection.

21. the method for claim 19 or 20, wherein using dosage is that the antibiotic of every kg non-human animal 5-10mg every day (mg/kg/ days) and 0.2-4mg/kg/ days NSAID treat inhuman animal.

22. each method among the claim 19-21, wherein use 5-10mg/kg/ days antibiotic and following each roughly the NSAID of dosage treat inhuman animal:

A.2.2mg/kg/ day flunixin,

B.0.5mg/kg/ day meloxicam,

C.3mg/kg/ day ketone ibuprofen,

D.1.4mg/kg/ day carprofen.

23. each method among the claim 19-22 is wherein used the clinical mastitis of described combination treatment and/or early stage mastitis.

24. among the claim 1-18 each compositions for the preparation of the treatment infected by microbes medicine in purposes.

25. for the preparation of the method for the compositions of infected by microbes in the treatment mammary gland, described compositions comprises NSAID and is selected from the antibiotic of macrolide and beta-Lactam antibiotic,

It is characterized in that

Add at least a non-aqueous solvent to guarantee the dissolving of described NSAID and described antibiotic to described compositions.

26. the method for claim 25, the NSAID in the wherein said compositions increases to corresponding waterborne compositions will at room temperature deposit unsettled concentration (%w/v).

27. the method for claim 25 or 26, wherein said NSAID is ketone ibuprofen, and wherein the concentration of ketone ibuprofen greater than 4%w/v.

28. each method among the claim 25-27 wherein before adding described NSAID or antibiotic, adds described non-aqueous solvent in the mixer.

29. each method among the claim 25-28 wherein before adding described NSAID or antibiotic, adds the second non-aqueous solvent in described the first non-aqueous solvent.

30. each method among the claim 25-29, wherein the temperature with described compositions remains on 60 ℃-80 ℃, until described NSAID and described antibiotic are dissolved in the described non-aqueous solvent basically.

31. each method among the claim 25-30 wherein before adding described NSAID, adds described non-aqueous solvent and dissolving with described antibiotic.

32. each method among the claim 25-31 wherein adds described NSAID and is dissolved in the mixture of the antibiotic of dissolving and non-aqueous solvent.

33. each method among the claim 25-31 wherein will comprise through the NSAID of dissolving and antibiotic composition cools to approximately 30 ℃, then add to final volume (in right amount) with non-aqueous solvent, and mix approximately 10 minutes.

34. compositions, its basically as described herein, and the preparation F3-F10 that shows among the embodiment 1-3 with reference to preferred forms part.

35. preparation comprises the method for NSAID and antibiotic compositions, its basically as described herein, and the preparation process that shows among the embodiment 1-3 with reference to the preferred forms part.