CN1812814A - Dispersible pharmaceutical composition for treatment of mastitis and otic disorders - Google Patents

Abstract

A method is provided for treatment and/or prevention of an infective condition in a fluid-containing organ having a natural exterior orifice, such as the udder of a milk-producing animal or an ear of a subject. The invention also relates to a dispersible pharmaceutical composition suitable for infusion into the organ according to the method of the invention, and to a process for preparing such a composition.

Description

The dispersible pharmaceutical composition that is used for the treatment of mastitis and ear disease

Technical field

The present invention relates to treat and/or prevent the method for the infectious conditions of the organ that contains liquid with natural outer hole, described organ is the breast of milcher or the ear of object for example.The present invention also relates to dispersible pharmaceutical composition, it is applicable to that the method according to this invention inculcates in the described organ, and relates to the such method for compositions of preparation.

Background technology

Mastitis are inflammation of the mammary gland of milcher (for example milch cow), are modally caused by bacterial infection.Antibacterial enters by the papillary duct of animal, and can cause acute, clinical or subclinical mastitis.Will turn out to be the origin cause of formation pathogen of bovine mastitis above 135 kinds of biologies.3 groups of main pathogen are gram-positive coccus, gram-negative bacillus and gram-positive bacillus.Health, environmental factors and the metabolism disorder that is derived from high milk production combine, and cause the condition that helps the mastitis outbreak.The somatic cell of the increase relevant with mastitis counting and infects positive correlation, and with milk production negative correlation.Frequently, the cow that infects need be separated from drove, and it is not given milk.Mastitis often influence cow throughout one's life, unless this disease has obtained suitable treatment.In typical drove, average infection rate is the 10%-30% of cow, loss Shi $185-$250/ cow/year of every cow.For milk products industry, bovine mastitis is the disease of economic cost maximum, and only in the U.S., that estimates every year is lost in 2,000,000,000 dollars.Main loss is because the Milk Production that reduces.

It is well-known using for the milcher breast to comprise antibiotic compositions to be used for the treatment of mastitis interiorly.Several compositionss that are applicable to this administration can be made oil-based formulation.

The U.S. Patent number 3 of Parizeau, 636,194 disclose a kind of being used for by inculcating the compositions of treatment mastitis in the breast, it comprises antibiotic, vegetable oil, is used for promoting the pure molten part of oil at the dispersive natural phosphatidyl choline phospholipid material of milk, described phospholipid is selected from: phosphatidylcholine and PHOSPHATIDYL ETHANOLAMINE and its mixture, and be present in the described oil with at least 0.25% amount.It is said that such compositions can be distributed to the milk neutralization fast short wean (milkout) time is provided.

GB Patent Application No. 1,181,527 disclose a kind of compositions that is used for the treatment of mastitis, and it comprises active substance and pharmaceutically acceptable oil base, and described compositions contains to be useful on and promotes compositions dispersive phospholipid material of all being made up of pure soluble substance basically in milk.

European Patent Application No. 0 222 712 discloses a kind of compositions, it contains one or more antimicrobials, they are dispersed in the oil of being made up of the mixture of the spermol of Palmic acid and stearic triglyceride and polyoxyethyleneization and stearyl alcohol, and maintain in the oil medium of mineral, plant, synthetic or blended extraction.It is said that such compositions can quicken the release of antimicrobial in breast, strengthen its potentiality and reduce weaning time biology.

Isakson ﹠amp; The U.S. Patent number 5,756,529 of Talley discloses the method for the inflammation of using pyrazolyl benzenesulfonamide compounds treatment companion animals.It is said that such chemical compound can be used for the treatment of pain, heating, arthrosis, traumatic injury, arthritis, myositis, tendinitis, equine colic, mastitis, peritonitis, dermatosis, scald, gingivitis, allergy, conjunctivitis, ophthalmia disease, swelling and myocardial ischemia.

International Patent Publication No. WO 02/22107 discloses the compositions that comprises one or more bioactivators in liquid-carrier, described carrier has been modified to has the oxidation product that increases level, wherein said bioactivator comprises anti-infective, antineoplastic agent, immunomodulator, antipyretic, analgesic and antiinflammatory (for example, cyclo-oxygenase-2 (COX-2) inhibitor).Can use such compositions by the approach of parenteral (for example, subcutaneous, intramammary, intravenous, endoperitoneal or intramuscular), partial, intravaginal, per os or rectum.

International Patent Publication No. WO 02/06865 discloses the compositions that comprises one or more bioactive substances in non-aqueous carrier, and wherein said compositions has been adjusted to has about 0.2 to about 0.5 water activity.Recommend parenteral, partial, per os, intravaginal, rectum and intramammary route of administration.Anti-infective, antineoplastic agent, immunomodulator, antipyretic, analgesic and antiinflammatory (for example, cox 2 inhibitor) are arranged in the bioactivator of listing.

International Patent Publication No. WO 99/20259 discloses the combination of thiamphenicol and diclofenac, and it is used in the veterinary drug of treatment with the infection of inflammatory disease.

International Patent Publication No. WO 01/60409 discloses a kind of paste composition, and it comprises therapeutic agent, fumed silica, viscosity modifier and hydrophilic support; Wherein said therapeutic agent is selected from insecticide, acaricide, parasiticide, antibiotic, the growth reinforcing agent, oil-soluble NSAID, avermectins, milbemycin, nordulisporic acid, estrogen, Progesterone, Phenylpyrazole, the pyridyl methyl derivatives of replacement and cox 2 inhibitor.Per os, partial, corium be applicable to this paste composition with subepidermal route of administration.It is said that such compositions has purposes in the veterinary practice of the following disease of treatment: for example pneumonia, mastitis, metritis, rhinitis and bronchitis.

U.S. Patent Application Publication No. 2002/0032228 discloses and has contained the application of heterocyclic chemical compound (for example diphenyl heterocycle derivatives) in the following disease of treatment: diarrheal disease, pertussis, anthrax, smooth muscle contraction disease and mastitis.As preferred diphenyl heterocycle derivatives, celecoxib and rofecoxib have been listed.

Contain the summary of the paper of Valette (1957) from the Labrafil product pamphlet of Gattefoss é Corporation (bulletin OL0050/ the 5th edition), this paper has been discussed Labrafil ^TMThe feature of M-1944CS in auditory meatus.This paper has also been described an experiment, relate to with the blended Labrafil of Gentian Violet ^TMM-1944CS is injected into cow teat.Confirmed Labrafil ^TMThe whole surface of energy moistening mammary gland substantial portion, and reach retromammary neuroganglion.

Gao etc. (1995) are at Pharmaceutical Research 12 (6), 2 pieces of articles among the 857-868, " Controlled release of a contraceptive steroid frombiodegradable and injectable gel formulations:in vitroevaluation " and " Controlled release of a contraceptive steroidfrom biodegradable and injectable gel formulations:in vivoevaluation " described and contained levonorgestrel, Labrafil ^TMThe preparation of the gel of M-1944CS and palmityl stearoyl glyceride.

In the modal child's disease of the U.S., ear disease comes second after only coming flu.Most of ear disease is the result of the painful inflammatory reaction that causes of ear infection, allergy or wound.Ear infection can be antibacterial, fungus or viral source, and is difficult in the practice determine nosetiology accurately, because often be difficult to separate and cultivate cause of disease biology.External otitis (external ear infection), otitis media (middle ear infection) and otorrhea (causing the otitis media of the ear drum membrane with perforation that overflows) are most popular ear diseases.

External otitis relates to the auditory meatus part of external ear, and it is the common otology problem that mainly occurs in the hot wet weather, and the frequency ratio in the swimmer is high 5 times in non-swimmer.In the early stage, symptom comprises itching of auditory meatus and pain, and when compressing external auditory meatus, tenderness when pullling ear-lobe or movable jaw.In the later stage, auditory meatus is suppurated, and audition may reduce.Cases of otitis externa above 90% is because antibacterial and fungal infection.

Pathological condition can be derived from, and can cause, the variation of the gas/liquid interfacial surface tension of tissue surface, especially epithelial surface tissue.External auditory meatus is lined with epithelium.The exudate of earwaxing generally is secreted on the epithelial tissue of external auditory meatus liner, and it can give its extra high surface tension.The inflammation by-product can further increase such surface tension.The surface tension that increases is the symptom of otitis and the key factor of treatment aspect.In addition, even when pipe is not closed, is present in the surface tension that increases on the external auditory meatus epithelium liner and trends towards stoping therapeutic agent evenly and/or effectively to use.

In the past, shown the therapeutic agent of antimicrobial acivity and antiinflammatory action, treated external otitis by topical application.Used the local effectively antibiotic ear suspension of broad-spectrum to destroy pathogenetic bacteria, it contains antibacterial, bykomycin for example, and colistin sulfate, polymyxin B, or its combination, their effect all is a broad-spectrum.Used antifungal local action medicament to destroy basic mycosis, for example nystatin and clotrimazole.In addition, use the antiviral agent acyclovir to treat viral external otitis, comprised herpes zoster.

Used antiinflammatory in the suspension that is often included in above-mentioned local action to control the inflammatory process of external otitis, described antiinflammatory comprises, for example, and hydrocortisone, hydrocortisone acetate and dexamethasone sodium phosphate.The most common ground is used in combination antimicrobial and antiinflammatory and treats the disease cause of disease, that trigger, for example bacterial infection, and inflammatory process self.They also use for the suspension of the drop form of suffering from ear as local application the most commonly.In order to strengthen and the more uniform conveying of this medicine to external auditory meatus epithelium lining to be provided, use the core of making by absorbent material (for example Cotton Gossypii) that suspension is drawn into auditory meatus.But, because exudate is present in the external otitis of suppuration form, and earwaxes and be present in in fact all inflammation, high surface tension can hinder the uniform distribution of this medicine in whole external auditory meatus.

In the U.S., modal ear disease otitis media is the main cause of hearing disability, and is representing the important deformity of learning process childhood period of the obstruction.See Estrada (1997), Infect.Med.14 (3), 239-244.In every year, otitis media accounts for all children more than 35% of pediatrician of going to a doctor, and represent in the annual U.S. health expenditure more than 3,500,000,000 dollars.

In the otitis media episode process, be present in and be positioned at the higher relatively surface tension at the interface of the gas/liquid on the leather sheet on the tube cavity, can increase and open the required opening pressure of this pipeline.

Typically, with the antibiotherapy treatment ear infection disease of a course of treatment, for example otitis media.See The Merck Manual, the 17th edition (1999), Section 7, and Chapter 84.The systemic administration antibiotic needs high predose and tangible lag time usually, to reach the treatment level in the ear.Approach whole body drug application by parenteral or per os, though finally reach Eustachian tube and middle ear, may have bad general action, and the more important thing is, the suitable medicine that concentrates dosage can not be transported to especially effectively their place of real needs, be delivered directly to target tissue.Simultaneously, the closed chamber dissection of middle ear that directly medicinal application is concurrent.

In many pieces of patents and open source literature, those that quote respectively below comprising, proposed will be in pharmaceutically acceptable excipient the antibacterial of preparation and the combination of antiinflammatory are applied to ear partly together.

The U.S. Patent number 6,395,746 of Cagle etc.

The U.S. Patent number 6,440,964 of Cagle etc.

The U.S. Patent number 6,509,327 of Cagle etc.

The U.S. Patent number 5,679,665 of Bergamini etc.

Purwar ﹠amp; The U.S. Patent number 5,965,549 of Goldman

U.S. Patent Application Publication No. 2001/0049366.

U.S. Patent Application Publication No. 2002/0142999.

U.S. Patent Application Publication No. 2002/0044920 discloses by (for example using TNF antagonist and pyrimidine synthesis inhibitors and steroid, anti-inflammatory compound, be also referred to as the NSAID (non-steroidal anti-inflammatory drug) of NSAID, or cox 2 inhibitor), cytotoxic compound, antitumor metabolite or secondary antirheumatic, the ear disease of treatment immunity-mediation.

U.S. Patent Application Publication No. 2002/0076383 discloses by external auditory meatus and has used compositions as aerosol, said composition comprises capillary lipid surfactant, diffusant and the propellant that its amount can be reduced in the gas/liquid interface on the epithelial tissue liner effectively, wherein said diffusant is selected from lipid, sterol, fatty acid, cholesteryl ester, phospholipid, carbohydrate and albumen all are powder types.It is open to it is said that said composition can increase external auditory meatus, provides simultaneously the protection of external otitis takes place.

U.S. Patent Application Publication No. 2002/0064503 discloses by exterior air drain and has used compositions as aerosol, wherein said compositions comprises its amount and can be reduced in the capillary lipid surfactant at the gas/liquid interface on the epithelial tissue liner effectively and be selected from following diffusant: sterol, lipid, fatty acid, cholesteryl ester, phospholipid, carbohydrate and albumen all are powder types.It is said that said composition can increase the opening and the pressure equalization performance of Eustachian tube inner chamber.

Expected that ear drop is as the preparation type of selective COX-2-inhibitor 2, in the patent of for example quoting respectively below and open source literature.

The U.S. Patent number 6,307,047 of Black etc.

The U.S. Patent number 6,329,526 of Adams etc.

Application No. 2001/0041726.

Application No. 2001/0053764.

Application No. 2002/0010146.

Application No. 2002/0013318.

Above-cited all patents and open source literature are all incorporated by reference here.

Although recently obtained progress aspect the cause of disease of ear disease understanding, they still can not prevent to a great extent, and are difficult to treat effectively.Therefore, provide effectively be used to prevent and treat ear disease and with the method and composition of its complications associated with arterial system be useful.

Except its antibacterial activity, considerably less antibacterial also has antiinflammatory, anesthesia, analgesic or analgesia character.Therefore, separately with antibacterial treatment infectious conditions typically can not reduce inflammation, pain, swelling, heating and often be accompanied by other complication of this infectious conditions.Before reducing to the inferior quantity of causing a disease, can not address these problems fully usually with the causal organism of antibacterial removing infectious conditions or with it.

Infectious conditions with the treatment of independent antiinflammatory has inflammatory components can reduce inflammation, swelling, pain, heating and other complication, but can not treat the infectious conditions on basis.

Be intended to be used for administration in the breast treat or prevent milcher mastitis compositions and be used for the most frequently used packing container and the conveyer device that the compositions of ear disease is treated in ear's administration, but be to make by the plastics of oxygen flow, for example polyethylene, polypropylene etc. and its mixture.If said composition comprises the composition that is easy to oxidative degradation, for example active medicine or excipient, then but the packing container of oxygen flow and conveyer device have proposed to be loaded on the long-term chemistry of compositions wherein and/or the serious problems of physical stability for the compositions of mastitis-resisting be used for the treatment of or prevent the application of the compositions of ear disease.

Although above-cited document discloses many compositionss that are used for the treatment of mastitis or are used for the treatment of ear disease, they all do not have to solve for but the compositions in the container that is packaged in oxygen flow provides the chemistry of prolongation and/or the problem of physical stability, and wherein said compositions comprises forms of pharmacologically active agents and/or the excipient that is easy to oxidative degradation.Although top instruction is arranged; this area still needs to compare the pharmaceutical composition with one or more following advantages with the prior art compositions that is used for the treatment of mastitis or ear disease: (a) chemistry of Yan Changing and/or physical stability; but even when in container that is packaged in oxygen flow and the conveyer device; particularly when wherein said compositions comprises the forms of pharmacologically active agents that is easy to oxidative degradation or excipient; (b) effect of the infectious biological of anti-broad variety; (c) can treat the inflammatory components of mastitis or ear disease and infect component effectively; (d) can treat the pain of mastitis or ear disease effectively; inflammation; heating; edema and infection component; (e) use compositions after; minimum stimulation or not stimulation; (f) can be with the activating agent targeted to infection site; (g) fast dispersibility of the compositions of mastitis-resisting in milk and udder fluids, as compared; to reach effective levels of drugs rapidly at infection site; (h) to lactating cow weaning time than weak point behind the treatment mastitis; (i) 0 day massacre meat is withdrawn the phase (withdrawl period) behind the mastitis treatment; (j) treat the mastitis of cow of not galactopoiesis after; short pressing down breast (milk withholding) time after the calving; (k) fast dispersibility of ear compositions in the wax sample wet environment of ear; to reach effective levels of drugs rapidly at infection site; (l) the capillary reduction at epithelial tissue gas/liquid interface; it is open to increase auditory meatus; (m) to the protective layer of the ear mucosa of inflammation; (n) raising of the therapeutic index of activating agent; reduced its general toxicity simultaneously; and the danger of systemic effect is minimized; (o) reduced and alleviated the required time of infectious conditions with inflammatory components; (p) reduced side effect; (q) can use the more activating agent of low dosage; effect still is provided simultaneously; (r) can use the more antibacterial of high dose, and not have the side effect of increase.

Summary of the invention

Now, developed new Therapeutic Method and pharmaceutical composition with some or all above-mentioned favourable character.More specifically, provide the method for the infectious conditions of the organ that contains liquid that new treating and/or preventing have natural outer hole, described organ is the breast of milcher or the ear of human or animal's object for example.This method comprises, by outer hole to this organ use antibacterial and with the conjoint therapy of antibacterial in use second kind of medicament, the latter is antiinflammatory, anesthetis, sodium channel inhibitor, analgesics and/or antipyretic.Antibacterial is used as pharmaceutical composition, and it also comprises excipient (vehicle) except antibacterial, and the latter comprises dispersible and insoluble two oleophylics of ethanol of (a) water, (b) microwax and (c) pharmaceutically-acceptable non-aqueous carrier.

When it was contacted with aqueous medium, such compositions had low interfacial tension.Without being limited by theory, think that this low interfacial tension can make compositions easily be distributed in the udder fluids, as compared (for example milk) in the wet environment with the more wax sample of gill.Therefore, in a preferred method of the present invention, be administered to the organ that contains liquid after, compositions can be distributed in the liquid.

This method can, for example, comprise breast and inculcate this compositions interiorly and inculcate this compositions with being used for the treatment of the mastitis of milcher or other cystic hyperplasia of breast or ear and be used for the treatment of and/or prevent ear disease, and in the infectious conditions of the broad variety of the infection biological that relates to broad variety, be effective.Term " is inculcated " and is comprised any operation here, wherein makes fluid composition advance to contain in the organ of liquid by outer orifice flow, under the situation about for example inculcating in breast, is papillary duct, or under the situation that ear is inculcated, is external auditory meatus, regardless of the markers that relates to.In context, " inculcating " and " injection " is synonym basically.For example, insert in the outer hole of papillary duct, and compositions is injected in the breast, can use compositions by breast interiorly by nozzle by intubate nozzle with the mastitis syringe.

The approach of the route of administration by being different from antibacterial can be used second kind of medicament.Perhaps, can use 2 kinds of reagent by identical approach, that is, and by the outer hole of organ, for example, the papillary duct under the situation of breast, or the external auditory meatus under the situation of ear.When using by identical approach, preferably with the form of the fluid composition that comprises above-mentioned excipient, by in the breast or ear inculcate and use second kind of medicament and antibacterial.Particularly preferably, use antibacterial and second kind of medicament with the single compositions that contains 2 kinds of medicaments.

Therefore, provide the pharmaceutical composition that comprises excipient in addition, described excipient comprises dispersible and insoluble two oleophylics of ethanol of (a) water, (b) microwax and (c) pharmaceutically-acceptable non-aqueous carrier.Described excipient contains antibacterial that stably is dispersed in antimicrobial effective amount wherein and second kind of medicament for the treatment of effective dose, and the latter is antiinflammatory, anesthetis, sodium channel inhibitor, analgesics, edema agent and/or antipyretic.

In one embodiment, antibacterial in the compositions, second kind of medicament and/or excipient (excipient) are easy to oxidative degradation, and but when in container that is packaged in the wall with oxygen flow or the conveyer device, said composition can show the chemistry and/or the physical stability of prolongation.

New compositions has low interfacial tension in waterborne liquid, compare with the oil-based formulation of routine thus and improved the dispersibility of compositions in milk and udder fluids, as compared.The quick distribution that this has caused compositions to spread all over breast makes antibacterial and/or second kind of medicament arrive the tissue of infection rapidly thus, and the medicine of effect level is provided at infection site.The interfacial tension of compositions in waterborne liquid determined to make compositions to disperse in liquid and spread required energy, and makes in the compositions particles suspended pass oil/milk or oil/essential energy of udder fluids, as compared interface boundary.

Compare with conventional composition, the low interfacial tension of compositions has also improved the dispersibility of compositions in the wax sample wet environment of ear.Resultant composition spreads all over the mucosa of auditory meatus and contains the quick distribution of the wax of liquid, makes antibacterial and/or second kind of medicament arrive the tissue of infection rapidly, and the medicine of effect level is provided at infection site.Such compositions can also generate the protective layer to the ear mucosa of inflammation.

Conjoint therapy according to the present invention provides the effective treatment to the infection component and the inflammatory components of infectious conditions, and can reduce the solution infectious conditions time required with relevant inflammation.Preferably, this method or compositions provide effectively treating and/or preventing the forfeiture of pain, inflammation, heating, swelling, edema, rubescent, hot, the mucosa that increases or mucosa/Catarrhal secretion, anorexia, insensitive, organ or systemic-function and the infection component relevant with mastitis or ear infection.

The inflammation relevant with infectious conditions can suppress antibacterial and reach infection site effectively.With the conjoint therapy of antibacterial in use selective COX-2-inhibitor 2, can alleviate the inflammation relevant, and can improve the ability that antibacterial reaches infection site effectively with infectious conditions.

Although some antibacterial can resist infectious bacteria very effectively, with the danger of adverse side effect, for example rubescent in short-term, swelling and inflammation.In practice, the acceptable dosage of some antibacterial can be subjected to making the restriction of so minimized requirement of side effect.Conjoint therapy method of the present invention can make these danger minimize, and improves the treatment of mastitis and ear disease thus.

Without being limited by theory, think that some antibacterial when being administered to some object, can promote endotoxic release, this has caused the reaction of TNF α (tumor necrosis factor) mediation again, think that also such reaction can be blocked or alleviate to selective COX-2-inhibitor 2.

Can use the more therapeutic agent of low dosage according to conjoint therapy of the present invention, effect still is provided simultaneously.In addition, local application antibacterial and second kind of optional medicament can provide the targeted to infection and/or inflammation part according to the present invention.

Can improve the therapeutic index of activating agent by reducing its general toxicity and the danger of systemic side effects being minimized as conjoint therapy provided herein.Therapeutic index is the tolerance on the border between effective dosage and the deleterious dosage in the treatment of medicine, and typical earth surface is shown LD ₅₀(making the lethal dosage of 50% colony) and ED ₅₀The ratio of (the effective dosage of treatment in 50% colony).

When by in the breast during infusion administration, for example when the treatment mastitis, preferable methods and compositions can have additional advantage.For example, preferable methods can realize short weaning time suitably.The weaning time of lactating cow is from using the time period of mastitis treatment to the salable milk that resumes production.After such using, before thinking that this milk is suitable for the human consumption, the concentration of activating agent in milk must be reduced to the acceptable level of appropriate managerial mechanism.Suitably short weaning time can reduce the dairy farmer's who is caused by the mastitis outburst monetary loss.

Alternatively or additionally, behind the cow mastitis treatment of not galactopoiesis, after calving, preferable methods can realize lowly pressing down the breast time, and does not have activating agent to remain among the offspring.

Alternatively or additionally, behind the mastitis treatment, preferable methods can realize that massacring meat in zero day withdraws the phase.This character is particular importance, because it allows the farmer to dispose cow through treatment at any time, it financially is favourable being made in like this, and need after treatment cow not kept and feed the specific time.

Term " treatment " comprises that here described animal does not show the clinical sign of mastitis as yet to non-lactogenic animal (for example cow of not galactopoiesis) administering therapeutic agent, but is in the danger that clinical mastitis take place.Therefore, the invention provides and reduce the method that the danger of clinical mastitis takes place following lactogenic animal on the line, this method comprises, with the conjoint therapy of second kind of medicament as described herein in, use antibacterial for animal mamma as raw material, every kind all is the treatment effective dose interiorly.

In a preferred embodiment, still, conjoint therapy according to the present invention is administered to the milcher with mastitis clinical sign.Therefore, the invention provides the method for clinical mastitis of treatment milcher, this method comprises, with the conjoint therapy of second kind of medicament as described herein in, use antibacterial for animal mamma as raw material interiorly, every kind all is to treat effective dose.

When by the ear infusion administration, for example when treatment ear infection disease, preferable methods and compositions can have other advantage.For example, preferable methods can increase the opening of auditory meatus, reduces the resistance to sound conduction thus, improves the definition and the sensitivity of audition.

Alternatively or additionally, preferable methods provides the bag tegillum on leather sheet on the ear, it can be protected from the illeffects of water and water ballast toxin, stimulus object and antigen thing, and helps the prevention ear disease.

Another advantage of method and composition of the present invention is, no matter is in the breast or ear is used, and they can allow antibacterial at least to infecting and/or the targeted of inflammation part.When using the compositions that comprises antibacterial and second kind of medicament as described herein of the present invention, provide 2 kinds of medicaments to infecting and/or the targeted of inflammation part.

Another advantage of preferred compositions is, no matter is in the breast or ear's administration, and they all only cause minimum stimulation or non-stimulated after administration.

When comparing with waterborne compositions with the oil of routine, another advantage of compositions of the present invention is the physical stability that improves, for example because the compositions resuspending that improves.Verified, compositions of the present invention can cause the flocculation of some drugs, improves resuspending thus, and eliminates the conveying of the problem and the possible inferior effective or non-effective dose of suspension caking.

The method for preparing pharmaceutical composition of the present invention is provided.This method comprises, order with any appropriate, mixing water dispersible and insoluble two oleophylics of ethanol, microwax, pharmaceutically-acceptable non-aqueous carrier, antibacterial and second kind of medicament as described herein, compositions is provided, and such compositions preferably has the chemistry and/or the physical stability of prolongation as described herein.

Thereby the present invention provides solution for the several long-standing problem of this area, and has one or more advantages that surpass the method and composition of prior art.From the following description, can understand further feature of the present invention, advantage and benefit.

Detailed Description Of The Invention

The invention provides the method for infectious conditions that treatment has the organ that contains liquid in natural outer hole, this method comprises, by outer hole with antibacterial be administered to organ and with its conjoint therapy in use second kind of medicament as described herein; Wherein said antibacterial is used as the pharmaceutical composition that comprises antibacterial and excipient, and this excipient comprises dispersible and insoluble two oleophylics of ethanol of (a) water, (b) microwax and (c) pharmaceutically-acceptable non-aqueous carrier.The present invention also provide compositions of the present invention production be used for the treatment of or prevent to have natural outside application in the medicine of infectious conditions of the organ that contains liquid in hole.The present invention also provides in treatment or prevention has the compositions of using in the method for infectious conditions of the organ that contains liquid in hole outside natural.

Should be understood that method of mentioning that relates to " antibacterial " and the compositions that comprises " antibacterial " comprise such method and composition here, wherein used to surpass a kind of antibacterial.In addition, surpass " the second kind of medicament " that a kind of antiinflammatory, anesthetis, antipyretic, sodium channel inhibitor, edema agent and/or analgesics can randomly form this paper.

" infectious conditions " comprises any disease, obstacle or the situation by malignant bacteria mediation here, perhaps it otherwise to antibacterial for example the antibiotic medicine treatment respond, no matter whether with pain, heating, swelling or inflammation.But the present invention concentrates on such disease with pain, heating, swelling or inflammatory components especially.

Desired as this paper, the organ that contains liquid comprises the suckling organ, for example the breast of milcher (for example cow, goat or sheep)." milcher " can be female any mammalian species, but preferably for the purpose domesticated animal of milk is provided, for example cow, goat or sheep, and comprise such animal, no matter they are in whether lactogenic during the infectious conditions or during the treatment.The natural outer hole of suckling organ is the hole of papillary duct.The organ that contains liquid also comprises the ear of human or animal's object.The natural outer hole of ear is the hole of external auditory meatus.

As used herein, term " antimicrobial effective amount " refers to, when by method administration of the present invention, be enough to the outbreak of one or more symptoms of the infectious conditions that alleviates, alleviate, prevent or postpone to be treated, or be enough to reduce the amount of cause of disease biomass and/or active antibacterial.

Term " conjoint therapy " refers to therapeutic scheme here, wherein individually or together uses antibacterial and second kind of medicament, and its mode can provide the coefficient beneficial effect from these therapeutic agents.Such beneficial effect can include but not limited to the pharmacokinetics or the pharmacodynamics combined effect of therapeutic agent.Conjoint therapy can, for example, can use, thereby reduce the danger or the incidence rate of the ill effect relevant with high dose more than the dosage of in monotherapy, normally using a kind of or 2 kinds of medicaments of low dosage more.Perhaps, conjoint therapy can produce the therapeutic effect that improves with the normal dose of every kind in monotherapy medicament." conjoint therapy " here is not intended to comprise and uses 2 kinds or the multiple therapeutic agent part as the monotherapy scheme of separating, described scheme produce by accident and at random successively or treatment simultaneously.

Typically, experience certain period of time (according to the combination of selecting, normally several minutes, a few hours, a couple of days or several weeks) is used antibacterial and second kind of medicament.Can that is to say in mode successively,, typically at interval be no more than about 24 hours, perhaps, use these therapeutic agents in simultaneously mode basically in the different time.

When using simultaneously, can use antibacterial and second kind of medicament in the dosage form of separating or in common preparation (that is, with single dosage form).When sequentially or when using 2 kinds of medicaments in the dosage form of separating, can and in any pharmaceutically acceptable dosage form, use second kind of medicament by the approach of any appropriate, for example by being different from approach and/or the dosage form that antibacterial uses.Perhaps, be similar to antibacterial, second kind of medicament can be dispersed in the excipient, it comprises dispersible and insoluble two oleophylics of ethanol of (a) water, (b) microwax and (c) pharmaceutically-acceptable non-aqueous carrier, and use in the natural outer hole of the organ by containing liquid.In a preferred embodiment, 2 kinds of medicaments are dispersed in the identical excipient jointly, and in single operation, use.

As used herein, term " treatment effective dose " refers to, when by method administration of the present invention, be enough to the outbreak of one or more symptoms of the disease that alleviates, alleviate, prevent or postpone to be treated, or be enough to reduce the amount of cause of disease biomass and/or active activating agent.Phrase " treatment effective dose every kind " refers to, when the method according to this invention in conjoint therapy during administration, the amount of the amount of antibacterial and second kind of medicament is enough to provide antibacterial action and is selected from following effect: antiinflammatory, anesthesia, sodium channel inhibitor, edema, analgesia and/or refrigeration function.Such amount can equal, be greater than or less than in monotherapy when using in the treatment effectively the amount of antibacterial or the amount of second kind of medicament.

" second kind of medicament " here is the active medicine that has antiinflammatory, anesthesia, edema, analgesia, sodium channel inhibitor and/or separate thermal property.Preferably, when according to the present invention during administration, such medicament shows antiinflammatory action at least.

The pharmaceutical composition that comprises antibacterial and comprise second kind of medicament in certain embodiments is the injectable compositions that maybe can inculcate of liquid, for example be applicable to the compositions that breast is interior or ear is inculcated, have the medicament that is dispersed in the excipient as described herein.Term in context " dispersion " refers to that dissolving (that is, molecularity is disperseed) or colloidality disperse, for example as emulsion or suspension.Typically, at least a therapeutic agent is to be suspended in the excipient with solid particulate form.

Excipient comprises 3 kinds of bases, randomly with other composition.

First kind of basis is dispersible and insoluble two oleophylics of ethanol of water." two oleophylics " is defined as the material with the molecular structure that contains obvious polarity zone and obvious apolar regions.Two lipophilic these 2 zones structurally sufficiently away from, make 2 zones peculiar property obviously separate.Term " ethanol is insoluble " refers to that two oleophylics are insoluble to ethanol basically at 20 ℃.

Second kind of basis of excipient is microwax.

The third basis of excipient is the pharmaceutically-acceptable non-aqueous carrier.Carrier is oil typically, as hereinafter more completely describing.

When the compositions that can be distributed to after being administered to the organ that contains liquid in the liquid was provided, the selection of excipient component was important.Without being limited by theory, think that this branch breaking up in intraorganic liquid is with antibacterial and the infection site of second kind of medicament targeted choosing wantonly to organ.

When method of the present invention comprises by papillary duct with compositions injection or when inculcating into breast, be that this paper is described as the process of " inculcating in the breast ", regardless of the markers that relates to, it can treat mastitis, other cystic hyperplasia of breast and/or the situation relevant with cystic hyperplasia of breast effectively.

When method of the present invention comprises by external auditory meatus with compositions injection or when inculcating into ear, promptly this paper is described as the process of " ear is inculcated ", regardless of the markers that relates to, it can treat and/or prevent effectively ear disease and/or with its complications associated with arterial system.Suffer from such ear disease or with the object of its complications associated with arterial system can be people, companion animals, horse, domestic animal etc.

The example of this ear disease includes but not limited to: external otitis (external ear infection), and otitis media (middle ear infection) comprises acute, secreted, the otitis media of serosity and chronic form, otorrhea (causing the otitis media of the ear drum membrane that overflows) with perforation, acute mastoiditis is with the relevant infection of ear operation process (for example tympanostomy etc.), otosclerosis, otalgia, ear pain, otitis disease, otorrhagia, Lermoyez syndrome, Menetrier's disease, vestibular neuronitis, optimum paroxysmal position is dizzy, zoster oticus, the Ramsay HH, viral nervous unit is scorching, neuroganglitis, geniculate herpes, labyrinthitis, comprise suppurative labyrinthitis and viral endolymphatic labyrinth inflammation, perilymphatic fistula, presbyacusis, drug-induced ototoxicity, acoustic neuroma, aerotitis, infectious myringitis, bullous myringitis, the ear tumor, squamous cell carcinoma, basal cell carcinoma, other ear cancer, the cancer otic condition, nonchromaffin paraganglioma, chemodectoma, the tympanic body tumor, glomus tympanicum tumor, perichondritis, ear eczema-like dermatitis, pernicious external otitis, hematoma under the perichondrium, ceruminal adenoma, impacted cerumen, sebaceous cyst, osteoma, keloid, tinnitus, dizzy, tympanum infects, otitis media, furuncle of ear, petrositis, conductivity and sensorineural hearing loss, epidural abscess, lateral sinus thrombosis, subdural empyema, otitic hydrocephalus, Dandy syndrome, bullous myringitis, otitis externa diffusa, foreign body, keratosis obturans, otomycosis, wound, acute aero-otitis media, acute Eustachian tube blocks, with any above-mentioned infection complications associated with arterial system (hearing disability for example, brain abscess, heating, cholesteatoma, the calcification of middle ear and internal ear, the ear drum membrane of perforation, meningitis, facial paralysis etc.), postoperative otalgia etc.

Method of the present invention is specially adapted to treat external otitis, otitis media, and otorrhea is with the infection with inflammatory components relevant with the ear operation process.

In one embodiment, ear disease is neoplasia.Neoplastic example like this includes but not limited to: ear neoplasia, squamous cell carcinoma, basal cell carcinoma, pernicious external otitis, pernicious nonchromaffin paraganglioma, malignant jugulare phlebangioma, pernicious glomus tympanicum tumor, cancer otic condition etc.

Antibacterial and second kind of medicament conjoint therapy together provide and have used antibacterial separately or second kind of medicament compared enhanced treatment option.As mentioned above, antibacterial is dispersed in the excipient, it comprises dispersible and insoluble two oleophylics of ethanol of (a) water, (b) microwax, (c) pharmaceutically-acceptable non-aqueous carrier, and use by for example intramammary or inculcating of ear, and second kind of medicament is the pharmaceutical dosage form that is mixed with acceptable arbitrarily rapid release or continues to discharge.The suitable dosage form of second kind of medicament includes but not limited to: suspension, solution, emulsion, tablet, capsule, pill, powder, granule, elixir, tincture, syrup, lozenge, dragee, gel, ointment, the paste that can be coated with out, slurry agent, aerosol, ear drop, nasal drop, eye drop, suppository, implant etc., and can use by any approach, include but not limited to: per os, comprise oral administration with mouth in, for example, the Sublingual, suck etc.; Parenteral, for example intramuscular, subcutaneous, intravenous, endoperitoneal, IA, intradermal, intravertebral, intrathoracic, in the marrow, intrasynovial, in the sheath, intracardiac, ICV, in the capsule, intracranial, etc.; Intramammary, partial, transdermal, intranasal, ear, mucosa, rectum, intravaginal, lung etc.

Preferably, second kind of medicament is formulated in the pharmaceutically acceptable excipient, and with antibacterial and second kind of pharmacy application in the same organ that contains liquid, inculcating for example by intramammary or ear.When using as composition component with the required amount of this paper, pharmaceutically acceptable carrier or medium are to not unacceptably deleterious or deleterious effect of animal.The excipient composition of such carrier or medium can be with another kind of excipient in deleterious mode and the compositions or therapeutic agent reaction.

Randomly, can be in addition and other bioactivator and non-drug therapy combination, use above-mentioned therapeutic agent.For example, be used for the treatment of cancer or cancer before (for example ear neoplasia of ear situation, squamous cell carcinoma, basal cell carcinoma, pernicious external otitis, pernicious nonchromaffin paraganglioma, malignant jugulare phlebangioma, pernicious glomus tympanicum tumor, cancer otic condition etc.), antineoplastic agent can be added in the conjoint therapy of the present invention.This antineoplastic agent includes but not limited to: Anastrozole, calcium carbonate, capecitabine, NSC-241240, cisplatin, docetaxel, eflornithine, etoposide, exemestane, fluoxymestrine, gemcitabine, goserelin, irinotecan, ketoconazole, letrozole, folinic acid, levamisole, megsetrol, paclitaxel, raloxifene, tretinoin, selenium (Selenomethionine), Sulindac sulfone, tamoxifen, plug is for group, topotecan, toremifene, vinblastine, vincristine, vinorelbine etc. and its combination.

In all embodiments of the present invention, antibacterial is to use partly at least.An indispensable requirement of the successful treatment of local infection sexually transmitted disease (STD) disease (for example mastitis) is that antibacterial must arrive infection site with the concentration that is close to or higher than minimum inhibitory concentration, and such concentration must be kept specific minimum time.Antibacterial arrives infection site, and (for example, in breast there is significant difference in) ability, and these are greater than the difference of their inherent antibacterial activities.An advantage according to local application of the present invention is, antibacterial and preferably second kind of medicament can preferentially point to their site of action, thereby compare with other route of administration (for example intramuscular, subcutaneous with approach per os), produce therapeutical effect quickly and be transported to infection site more completely.Local application can allow to reduce for total therapeutic dose of certain effects, and avoids first pass effect of hepar.In addition, the local application meeting reduces or eliminates the secondary effect at the position beyond infection site, particularly with a kind of or 2 kinds of activating agents related those.The local application activating agent also can improve its therapeutic index by reducing its general toxicity and the danger of the systemic effect of not expecting being minimized.

In another embodiment, the invention provides the pharmaceutical composition that comprises excipient that is suitable for inculcating in the breast, described excipient comprises dispersible and insoluble two oleophylics of ethanol of (a) water, (b) microwax and (c) pharmaceutically-acceptable non-aqueous carrier; Stably be dispersed with the antibacterial of antimicrobial effective amount and second kind of medicament as described herein of treatment effective dose in the described excipient.Such compositions is applicable to single administration, and the conjoint therapy of the method according to this invention is provided.

Preferably, such compositions can reduce the high surface tension at the epithelial tissue gas/liquid interface relevant with ear disease, thereby increases the opening of auditory meatus.The capillary reduction at last leather sheet gas/liquid interface, fluid accumulation is minimized, and in some cases, the liquid that retains owing to the surface tension that raises in the energy emptying auditory meatus, and/or can separate relative epithelial wall (because the surface tension of rising of tissue of auditory meatus near-end, often near arriving together), improve sound conduction thus.As used herein term " increases and opens " obstruction that refers to open auditory meatus and reduce or eliminate auditory meatus, thereby forms open pipeline.To the resistance of sound conduction from the dwindling of volume, partial blockage or stop up auditory meatus fully, this be because the epithelial wall swelling that causes of inflammation, the superincumbent recruitment of secretion earwax gather and/or the productive set of liquid wherein, comprise the waste product that contains immunne response or the liquid of outer unboiled water.

In a specific embodiment of the present invention, composition components (antibacterial and/or second kind of medicament and/or excipient composition) is easy to oxidative degradation.Such compositions can show the chemistry and/or the physical stability of prolongation, even but when in container that is packaged in oxygen flow or the conveyer device.Term " chemistry and/or the physical stability that prolong " refers to that here the compositions of the present embodiment has chemistry and/or the physical stability bigger than the reference group compound of the same medicine that comprises same concentrations.In context, " reference group compound " refers to not have a kind of in two oleophylics and the microwax or 2 kinds but is similar to the compositions of the present composition in others.

But the container of oxygen flow or conveyer device can be made by the thermoplastic of any appropriate.The example of this material includes but not limited to the polymer and the copolymer of following material: polystyrene, polyacrylonitrile, polrvinyl chloride and particularly polyolefin.Polyolefin comprises, for example, and polyethylene, polypropylene, polybutene, polyisoprene, polypenthylene, its copolymer and its mixture.

The compositions that is used for using in the breast generally is to be packaged in syringe, and this instrument used for injection is useful on the intubate nozzle that inserts nipple, so that by papillary duct compositions is directly squeezed in the mammary gland.Breast inner suspension preparation normally prepares in the excipient of thickening, is deposited in the intubate nozzle to prevent drug particles, otherwise can causes spray nozzle clogging, fully extruding composition.

Cephalosporin is a class antibiotic substance, many activity with broad-spectrum antagonism gram-positive bacterium and gram negative bacteria wherein.

Develop in the early stage work of breast inner suspension liquid of cephalosporin ceftiofur the applicant, the 12.5mg/ml ceftiofur hydrochloride is suspended in the excipient of thickening, the latter comprises the glyceryl monostearate of 20mg/ml in Oleum Arachidis hypogaeae semen.Although be that effectively in the time of in being packaged in polyethylene syringes, after room temperature storage was less than 18 months, the effectiveness of said composition was brought down below 90% of label value clinically.The oxidative degradation of having determined ceftiofur hydrochloride is the main cause that this effectiveness reduces.Breast inner suspension liquid needs and at least 90% label can be renderd a service the room temperature preservation time limit that keeps minimum 24 months.

Then, many ceftiofur hydrochloride suspension compositions are prepared in the excipient of multiple thickening, but and be packaged in the polyethylene syringes of oxygen flow.Having produced concentration is the ceftiofur hydrochloride formulations of 12.5mg/ml.All excipient all are based on Oleum Gossypii semen, and it has following annexing ingredient:

1) 50mg/ml microwax.

2) 70mg/ml microwax+1.0mg/ml propyl gallate.

3) 100mg/ml microwax+50mg/ml Labrafil ^TMM-1944CS.

4)40mg/ml?Gelucire ^TM?62/05+10mg/ml?Gelucire ^TM?33/01。

5)70mg/ml?Lexemul ^TM?AR。

6)2.5mg/ml?Coagulan ^TM?GP-1。

7) 10mg/ml microwax+5mg/ml Hydrofol Glycerides ^TMT 57L.

8)30mg/ml?Drewpol ^TM?10-10-S。

9) 15mg/ml beeswax mixture.

10)60mg/ml?Drewpol ^TM?10-10-S。

11) 10mg/ml beeswax mixture+50mg/ml Labrafil ^TMM-1944CS.

12) 100mg/ml microwax+1.0mg/ml propyl gallate.

13) 70mg/ml microwax+100mg/ml Labrafil ^TMM-1944CS.

14) 70mg/ml microwax+100mg/ml Labrafil ^TMThe M-1944CS+0.2mg/ml Yoshinox BHT.

15) 70mg/ml microwax+50mg/ml Labrafil ^TMThe M-1944CS+1.0mg/ml propyl gallate.

16) 70mg/ml microwax+50mg/ml Labrafil ^TMThe M-1944CS+0.2mg/ml Yoshinox BHT.

17) 50mg/ml microwax+1.0mg/ml propyl gallate.

18) 100mg/ml microwax+100mg/ml Labrafil ^TMThe M-1944CS+1.0mg/ml propyl gallate.

19) 100mg/ml microwax+100mg/ml Labrafil ^TMThe M-1944CS+0.2mg/ml Yoshinox BHT.

20) 100mg/ml microwax+50mg/ml Labrafil ^TMThe M-1944CS+1.0mg/ml propyl gallate.

21) 100mg/ml microwax+50mg/ml Labrafil ^TMThe M-1944CS+0.2mg/ml Yoshinox BHT.

22) 50mg/ml microwax+100mg/ml Labrafil ^TMThe M-1944CS+0.2mg/ml Yoshinox BHT.

Labrafil ^TMM-1944CS can be dispersed in the water, and at 20 ℃ of two oleophylics that are insoluble to basically in the ethanol.Gelucire ^TM62/05 and Gelucire ^TMThe 33/01st, inert excipients basically, it is derived from natural hydrogenant food grade fat and oily.Lexemul ^TMAR is the glyceryl monostearate of the stable cationic self emulsifying of acid." beeswax mixture " refers to contain the mixture of white beeswax, Brazil wax and candelilla wax.Coagulan ^TMGP-1 is a N-acyl glutamic acid diamides, and it is the aminoacid gellant of oil.Drewpol ^TMBe the glyceride of modifying.

The most surprisingly, but find that room temperature storage only contained Labrafil after 24 months in the polyethylene syringes of oxygen flow ^TMThose ceftiofur hydrochloride compositionss of M-1944CS and microwax provide can keep the preparation that at least 90% label is renderd a service.With do not contain Labrafil ^TMThe estimation room temperature preservation time limit of the comparable preparation of M-1944CS is compared, and is included in the Labrafil in the Oleum Gossypii semen ^TMThe high 2.4-3.7 of estimation room temperature preservation time limit of the ceftiofur hydrochloride formulations of M-1944CS and microwax doubly.In addition, although but in the polyethylene syringes of oxygen flow, after 24 months, be included in the Labrafil in the Oleum Gossypii semen in room temperature storage ^TMThe ceftiofur hydrochloride compositions of M-1944CS and beeswax mixture has the effectiveness less than 90%, after storing 24 months under the identical condition, is included in the Labrafil in the Oleum Gossypii semen ^TMThe ceftiofur hydrochloride formulations that can compare viscosity that has of M-1944CS and microwax has shown effectiveness greater than 90% label value.

Comprise cephalosporin, water is dispersible and the compositions of insoluble two oleophylics of ethanol, microwax and non-aqueous carrier, except chemistry and/or physical stability that prolongation can be provided, the effect of the infection biological of antagonism broad variety can also be provided, compositions is dispersed in rapidly in milk and the udder fluids, as compared, to reach effective levels of drugs at infection site rapidly, the weaning time short to lactating cow, massacre meat in zero day and withdraw the phase, short pressing down the breast time and use the minimum stimulation in back after the cow treatment back calving of not galactopoiesis to non-stimulated.

Go for antibacterial according to purposes of the present invention comprise any can treat and/or prevent effectively cystic hyperplasia of breast and/or ear disease and/or with the medicament of its complications associated with arterial system.Suitable antibacterial includes but not limited to: the beta-lactam antibacterial for example natural with synthetic penicillins medicament, comprise penam penicillin (benzylpcnicillin for example, phenoxy group penicillin; coxacillin, NAFCILLIN, methicillin; oxazacillin, amoxicillin, temocillin; ticarcillin etc.), penicillinase-stable penicillin, acylamino-and penicillin carboxy (piperacillin for example; the azlocillin, mezlocillin, Carbenicillin; temocillin, ticarcillin etc.) and more broad-spectrum penicillin (streptomycin for example; neomycin, framycetin, gentamycin; apramycin, amikacin, spectinomycin; the amoxicillin, ampicillin etc.), cephalosporins; Macrolide (tylosin for example, tilmicosin, aivlosin; erythromycin, azithromycin, spiramycin; josamycin, kitasamycin etc.), but woods amine (cillimycin for example; clindamycin, pirlimycin etc.), pleuromutilin (tiamulin for example; valnemulin etc.), polypeptide, glycopeptide (for example vancomycin etc.); polymyxin (for example polymyxin B, polymyxin E etc.), sulfonamides (sulfamethazine for example; sulfadiazine, silver sulfadiazine, sulfatroxazole; sulfamethoxypyridazine, sulphanilamide, sulfamethoxazole; sulfafurazole, sulfamethizole, mafenide etc.; make up individually or with trimethoprim), chloromycetin, thiamphenicol; florfenicol, Tetracyclines medicine (tetracycline for example, chlortetracycline; oxytetracycline, meclocycline, doxycycline; minocycline etc.), quinolinones and fluoroquinolone (ciprofloxacin for example, enoxacin; grepafloxacin, levofloxacin, lomefloxacin; norfloxacin, ofloxacin, Sparfloxacin; trovafloxacin, cinocacin, nalidixan etc.); tiamulin, colistin, meropenem; sulbactam, tazobactam, metacycline; pyrimethamine, sulfacetamide ， oxazolidone; for example, eperezolid, Linezolid; N-((5S)-3-(3-fluoro-4-(4-(2-fluoro ethyl)-3-oxygen-1-piperazinyl) phenyl-2-oxygen-5-oxazolidinyl) methyl) acetamide, (S)-N-((3-(5-(3-pyridine radicals) thiophene-2-yl)-2-oxygen-5-oxazolidinyl) methyl) acetamide, 2; 2-two fluoro-N ((5S-3-[3-fluoro-4-(4-glycolyl piperazine-1-yl) phenyl]-2-oxo-1,3-oxazolidine-5-yl) methyl } thioacetamide, (S)-N-((3-(5-(4-pyridine radicals) pyridine-2-yl)-2-oxygen-5-oxazolidinyl) methyl) acetamide hydrochloride etc.; aminoglycoside (kanamycin, tobramycin, netilmicin etc.); aminocyclitol; amphenicol, Ansamycin, carbapenem; cephamycin; rifampicin, monobactam, oxacephems; streptogramin (quinupristin for example; dalfopristin etc.), cycloserine, mupirocin; the urea hydroxamate; folacin (for example trimethoprim etc.), antibiotics antineoplastic agent (aclarubicin for example, actinomycin D; actinoplanone; the aeroplysinin derivant, Nippon Soda anisomycin, anthracycline; Azino-micyin-A; busucaberin, bleomycin sulfate, bryostatin-1; calicheamycin; chromoximycin, dactinomycin, daunorubicin; ditrisarubicin B; amycin, amycin-Fibrinogen, elsamicin-A; epirubicin; erbstatin, esorubicin, esperamicin-Alb; fostriecin; glidobactin, gregatin-A, grincamycin; herbimycin; the jaundice element, illudin, shell pine; kesarirhodins; menogaril, mitomycin, mitoxantorone; mutamycin; mycophenolate, neoenactin ， oxalysine; oxaunomycin; peplomycin, pilatin, pirarubicin; porothramycin; pyrindamycin A, rapamycin, rhizomycin; rodorubicin; sibanomicin, siwenmycin, sorangicin-A; sparsomycin; Steffimycin B, talisomycin, terpentecin; thrazine; tricrozarin A, zorubicin, general antibacterial (for example 2; the 4-di-amino-pyrimidine); nitrofuran sulfone, Marbofloxacin etc. and its combination.

Should be appreciated that any concrete medical compounds of mentioning comprises tautomer, stereoisomer, enantiomer, salt, hydrate and the prodrug of this chemical compound herein, and do not refer in particular to any solid state form of this medicine, unless context requires like this.

Preferred antibacterial is a cephalosporin; include but not limited to: ceftiofur hydrochloride; ceftiofur free acid; for example; the acid of ceftiofur crystal detachment; ceftiofur sodium; other ceftiofur salt; cefalexin; cefradine; cefquinome; cefacetrile; cefalonium; cefuroxime; cefazidime; cefoperazone; sodium cephemethcarboxylate; the cephem heptahydrate, cephalosporin dihydrate or trihydrate, cefadroxil monohydrate; the cefazolin sodium sodium-hydrate; cefiximine, ceftaxime, ceftizoxime; ceftriaxone; adjacent formyl cefadole, the salt of 3-acetate methyl-7-(imino group acetylamino)-cephalosporin acid derivative, the monohydrate of 7-(D-alpha-amido-α-(to hydroxyphenyl) acetylamino)-3-methyl-3-cephem-1-formic acid; cis-7-((2-amino-1-thiazolyl) (methoxyimino) acetyl group) amino)-hydrochlorate of 3-methyl-3-cephem-4-formic acid; the cephemcarboxylic acid addition salts, (pivaloyl oxygen) methyl 7-β-(2-(2-amino-4-thiazolyl) acetylamino)-3-(((1-(2-(dimethylamino) ethyl)-1H-tetrazolium-5-yl) sulfo-) methyl)-3-cephem-4-formates, cefalexin; Biocef, 7-(D-2-naphthyl glycyl amino)-3-methyl-3-cephem-4-formic acid tetrahydrate etc.The most preferred cephalosporin that is used for according to purposes of the present invention is ceftiofur and its pharmaceutically acceptable salt.Particularly preferably be ceftiofur free acid, the most in particular with crystal form, and ceftiofur hydrochloride.

When antibiotic substance was ceftiofur or its salt, other form, preferred concentration range in compositions of the present invention was about 1 to about 1000mg/ml, and more preferably about 5 to about 750mg/ml, and more preferably about 10 to about 100mg/ml.For the antibiotic substance except that ceftiofur, on the basis of disclosed data, those skilled in the art can determine the proper concentration of antibiosis equivalence.

Second kind of medicament can have antiinflammatory, anesthesia, sodium channel inhibitor, edema, analgesia and conciliate in the thermal property one or more. has anti-inflammatory; The example of the medicament of analgesia and/or solution thermal property includes but not limited to: Aceclofenac; Acemetacin; E-acetylamino caproic acid; Acetaminophen; Acetaminosalol; Antifebrin; Acetylsalicylic acid (aspirin); S-adenosylmethionine; Alclofenac; Alclometasone; Alfentanil; Algestone; Allylprodine; Alminoprofen; Aloxiprin; Alphaprodine; Two (acetylsalicylate) aluminium; Amcinonide; The fragrant acid of ammonia; Amino Chlorthenoxazine; 3-amino-4-hydroxybutyric acid; 2-AMINO-4-PICOLINE; Aminopropylon; Aminopyrin; Amixetrine; Ammonium salicylate; Ampiroxicam; Amtolmetin Guacil; Anileridine, antipyrine, antrafenine; Apazone; Beclomethasone, Bendazac, benorylate; Benoxaprofen; Burgodin, Benzpiperylone, benzydamine; Benzylmorphine; Bermoprofen, betamethasone, Bezitramide; α-bisabolol; The fragrant acid of bromine, antisepsin, 5 bromosalicylic acid acetate; Bromosaligenin; Bucetin, bucloxic acid, bucolome; Budesonide; Bufexamac, bumadizone, buprenorphine; Butacetin; Butibufen, butorphanol, carbamazepine; Carbifene; Carprofen, carsalam, Sai-Mi-Xi-Bu; Anesin; Chloroprednisone, Chlorthenoxazine, choline magnesium trisalicylate; Choline Salicylate; Quinophan, cinmetacin, cinnoxicam; Ciramadol; Clidanac, clobetasol, clocortolone; Clometacin; Clonitazene, Clonixin, Clopirac; Cloprednol; Cloves, codeine, codeine MB; Codeine phosphate; Codeine sulfate, cortisone, cortivazol; Cropropamide; Crotetamide, cyclazocine, deflazacort; Boldenone; Deracoxib, Desomorphine, desonide; Desoximetasone; Dexamethasone, Dexoxadrol, dextromoramide; Dextropropoxyphene; Dezocine, diamorphone, diampromide; Diclofenac; Difenamizole, Difenpiramide, diflorasone; Diflucortolone; Diflunisal, Difluprednate, paracodin; Dihydrocodeinone enol acetate; Paracodin phosphate, paramorphane, acetylsalicylic acid dihydroxy aluminium; Dimenoxadol; Dimepheptanol, dimethylthiambutene, amidalgon; Diphenhydramine hydrochloride; Dipipanone, diprocetyl, analgin; Ditazole; Dl-chloropheniramine ， drogelor, Emorfazone; Enfenamic acid; Enoxolone, epirizole, Eptazocine; Etersalate; Ethenzamide, Ethoheptazine, Etodolac; Etoxazene; Ethoheptazine, Ethylmethylthiambutene, dionin; Etodolac; Etofenamate, Etonitazene, etoricoxib; Eugenol; Felbinac, fenbufen, fenclofenac; Fenclozic acid; Fendosal, fenoprofen, fentanyl; Fentiazac; Fepradinol, feprazone, floctafenine; Fluazacort; Flucloronide, flufenamic acid, aniprime; Flunisolide; Flunixin, Flunoxaprofen, FA; Fluocinonide; FA, fluocortin butyl, fluocortolone; Fluoresone; Fluorometholone, fluperolone, Flupirtine; Fluprednidene; Fluprednisolone, Fluprofen, Fluproquazone; Fludroxycortide; The fluorine allodihydrotestosterone, Flurbiprofen, fluticasone; Formocortal; Fosfosal, Furofenac, gentianic acid; Glafenine; Glucametacin, ethylene glycol salicylate, guaiazulene; Halcinonide; Halobetasol, Halometasone, Halopredone; Heroin; Hydrocodone, Hydrocortamate, hydrocortisone; Hydromorphone; Hydroxypethidine, ibufenac, brufen; Ibuproxam; Imidazole salicylate, Indomethacin, indoprofen; Isofezolac; The isoflupredone acetate, isoladol, Isomethadone; Isonixin; Isoxepac, isoxicam, Ketobemidone; Ketoprofen; Ketorolac, p-Lactylphenetidine, Li Feitaming; Levallorphan; Levorphan, levophenacylmorphan, lofentanil; Lonazolac; Lornoxicam, loxoprofen, lysine acetylsalicylic acid salt; Lysozyme chloride; Mazipredone, meclofenamic acid, Medroxyprogesterone; Mefenamic acid; Meloxicam, pethidine, meprednisone; Meptazinol; Mesalazine, metazocine, methadone; Levomepromazine; The methyl ephedrine hydrochloride, medrat, gaultherolin; Metiazinic acid; Methopholine, metopon, miroprofen; Mofebutazone; Mofezolac, Mometasone, morazone; Morphine; Morphine hydrochloride, morphine sulfate, morpholine salicylate; Myrophine; Nabumetone, Nalbuphine, lethidrone; 1-naphthyl salicylate; Naproxen, narceine, nefopam; Nicomorphine; Nifenazone, Niflumic Acid, aulin; 5 '-nitro-2 '-the propoxyl group antifebrin; Norlevorphanol, Normethadone, normorphine; Norpipanone; Coscopin, Olsalazine, opium; Oxaceprol; Oxametacine, olsapozine, Oxepinac; Oxycodone; Oxymorphone, Oxyphenbutazone, narsco; Paramethasone; Paranyline, parecoxib, Parsalmide; Pentazocine; Perisoxal, phenacetin, phenadoxone; Phenomorphan; Phenazocine, phenazopyridine hydrochloride, phenocoll; Phenoperidine; Phenopyrazone, phenyl acetyl salicylate, bute; The phenyl propanol amine hydrochlorate; Phenyl salicytate, fenyramidol, piketoprofen; Piminodine; Pipebuzone, piperylone, piprofen; Pirazolac; Pirinitramide, piroxicam, pranoprofen; Prednicarbate; Prednisolone, metacortandracin, prednisolone valerate; Prednylidene; Pirprofen, piroxicam, proglumetacin; Proheptazine; Promedol, Propacetamol, properidine; Propiram; Propoxyl group benzene, propyphenazone, proquazone; Protizinic acid; Proxazole, ramifenazone, Remifentanil; Rimazolium Metilsulfate; Rofecoxib, salacetamide, salicin; Salicylamide; The adjacent acetic acid of salicylamide, salicylic acid, salicylsulfuric acid; Salsalate; Salverine, serratiopeptidase, simetride; Sudoxicam; Sufentanil, SASP, sulindac; Superoxide dismutase; Suprofen, Suxibuzone, Talniflumate; Tenidap; Tenoxicam, Terofenamate, Tet; Thiazolinobutazone; Tiaprofenic Acid, Tiaprofenic Acid, tiaramide; Tilidine; Tinoridine, tiopinac ， tioxaprofen; Tixocortol; Tolfenamic acid, tolmetin, C16H25NO2; Fluoxyprednisolone; Tropesin, valdecoxib, viminol; Xenbucine; Ximoprofen, Zaltoprofen, zidometacin; Help U.S. acid etc. and its combination.

In one embodiment, second kind of medicament is steroidal anti-inflammatory agents.Suitable steroid includes but not limited to: alclometasone, amcinonide, betamethasone, betamethasone 17-valerate, clobetasol, clobetasol propionate, clocortolone, cortisone, boldenone, deoxycorticosterone, desonide, desoximetasone, dexamethasone, dexamethasone 21-.gamma.-pyridinecarboxylic acid salt, diflorasone, fluocinonide, fluocinolone acetonide, fluorometholone, flurandrenolide, fluticasone, halcinonide, halobetasol, hydrocortisone, the hydrocortisone acetate, hydrocortisone cipionate, hydrocortisone hemisuccinic acid ester, hydrocortisone 21-lysine ester, the hydrocortisone succinate, isoflupredone, isoflupredone acetate, medrat, the medrat acetate, medrat sodium succinate, medrat suleptnate, mometasone, prednicarbate, andrographolide, andrographolide acetate, andrographolide hemisuccinic acid ester, prednisolone sodium phosphate, Meticortene Soluble, andrographolide valerate-acetate, prednisone, triamcinolone, triamcinolone acetonide etc. and its combination.

In another embodiment, the second medicament is antalgesic, and it is selected from for example alfentanil, Allylprodine; Alphaprodine, anileridine, benzylmorphine, Bezitramide; Buprenorphine, butorphanol, Clonitazene, codeine; Cyclazocine, Desomorphine, dextromoramide, dextropropoxyphene; Dezocine, diampromide, diamorphone, paracodin; Paramorphane, dimenoxadol, dimepheptanol, dimethylthiambutene; Amidalgon, dipipanone, Eptazocine, Ethoheptazine; Ethylmethylthiambutene, dionin, Etonitazene, fentanyl; Heroin, hydrocodone, Hydromorphone, hydroxypethidine; Isomethadone, Ketobemidone, levallorphan, levorphan; Levophenacylmorphan, lofentanil, pethidine, meptazinol; Metazocine, methadone, metopon, morphine; Myrophine, Nalbuphine, lethidrone, narceine; Nicomorphine, Norlevorphanol, Normethadone, normorphine; Norpipanone, opium, Oxycodone, Oxymorphone; Narsco, pentazocine, phenadoxone, phenazocine; Phenomorphan, phenoperidine, piminodine, pirinitramide; Proheptazine, promedol, properidine; Propiram, propoxyl group benzene, sufentanil; Tilidine, C16H25NO2 etc. and its combination.

In another embodiment, second kind of medicament is NSAID, and it for example is selected from salicyclic acid derivatives (salicylic acid for example; acetylsalicylic acid, methyl salicylate, diflunisal; olsalazine, salsalate, sulfasalazine etc.); indole and indenes acetic acid (for example indomethacin, etodolac, sulindac etc.); fragrant that ester (etofenamicacid for example, meclofenamic acid, mefenamic acid; flufenamic acid, niflumic acid and tolfenamic acid etc.), heteroaryl acetic acid (acemetacin for example; alclofenac, clidanac, diclofenac; fenclofenac, fentiazac, furofenac; ibufenac, Isoxepac, ketorolac; oxipinac, tiopinac, tolmetin; zidometacin, zomepirac etc.), aryl acetic acid and propanoic derivatives (alminoprofen benoxaprofen for example, bucloxic acid, carprofen; fenbufen, fenoprofen, fluprofen; flurbiprofen, ibuprofen, indoprofen; ketoprofen, miroprofen, naproxen; naproxen sodium, oxaprozin, pirprofen; pranoprofen, suprofen, tiaprofenic acid tioxaprofen etc.), bmap acid (for example former times health derivant ampiroxicam, cinnoxicam drogelor; lornoxicam, meloxicam, piroxicam; sudoxicam and tenoxicam; with pyrazolone derivant aminophenazone, phenazone, azapropazone; dipyrone; oxyphenbutazone, bute etc.), p-aminophenyl amphyl (for example acetaminophen etc.); alkane ketone (for example nabumetone etc.); nimesulide, proquazone etc. and its combination.

In preferred embodiments, second kind of antiinflammatory that medicament is selective COX-2-inhibitor 2 class.Selective COX-2-inhibitor 2 is optionally to suppress the active chemical compound of cyclo-oxygenase-2 (COX-2).The therapeutic compound that term " selective COX-2-inhibitor 2 " and " selective cyclooxygenase-2 inhibitor " refer to optionally to suppress the COX-2 isoform of cyclo-oxygenase interchangeably and significantly do not suppress cyclo-oxygenase-1 (COX-1).As used herein, term " selective COX-2-inhibitor 2 " also refers to prodrug or salt, and it can change into the chemical compound that can optionally suppress COX-2 with respect to COX-1 in vivo.The selectivity factor that preferred selective COX-2-inhibitor 2 shows is at least about 10, and more preferably, at least about 50, and more preferably, at least about 100, wherein " selectivity factor " is defined as IC ₅₀(COX-1)/IC ₅₀(COX-2), IC ₅₀Be in external or body, in the experiment, to produce 50% compound concentration that suppresses of enzymatic activity.

Can be used for selective COX-2-inhibitor 2 of the present invention and include but not limited to following chemical compound, and comprise its tautomer, stereoisomer, enantiomer, salt, hydrate, prodrug and its combination.Can use any such selective COX-2-2 suppressive drug known in the art or prodrug.

The spendable preferred selective COX-2-2 of this paper suppressive drug is the chemical compound of formula (I):

Or its prodrug or pharmaceutically acceptable salt, wherein:

A is selected from following substituent group: undersaturated or undersaturated heterocyclic radical of part and the undersaturated or undersaturated carbocyclic ring of part are preferably selected from following heterocyclic radical: pyrazolyl, furanonyl, isoxazolyl, pyridine radicals, cyclopentenes ketone group and pyridazine ketone group;

X is O, S or CH ₂

N is 0 or 1;

R ¹Be that at least one is selected from following substituent group: heterocyclic radical, cycloalkyl, cycloalkenyl group and aryl, and randomly be selected from following group and replace by one or more in commutable position: alkyl, haloalkyl, cyano group, carboxyl, alkoxy carbonyl group, hydroxyl, hydroxyalkyl, halogenated alkoxy, amino, alkyl amino, arylamino, nitro, alkoxyalkyl, alkyl sulphinyl, halogen, alkoxyl and alkylthio group;

R ²Be methyl, amino or amino carbonyl alkyl;

R ³Be one or more following groups that are selected from: hydrogen, halogen, alkyl; alkenyl, alkynyl, oxo; cyano group, carboxyl, cyano group alkyl; heterocyclyloxy, alkyl oxygen, alkylthio group; alkyl-carbonyl, cycloalkyl, aryl; haloalkyl, heterocyclic radical, cycloalkenyl group; aralkyl, heterocyclic radical alkyl, acyl group; alkylthio alkyl, hydroxyalkyl, alkoxy carbonyl group; aryl carbonyl, aromatic alkyl carbonyl, arylalkenyl; alkoxyalkyl, aryl alkylthio, aryl oxide alkyl; aralkyl sulfane base, sweet-smelling alkoxy alkyl, alkoxy aromatic alkoxyalkyl; alkoxycarbonyl alkyl, amino carbonyl, amino carbonyl alkyl; alkyl amino-carbonyl, N-aromatic yl aminocarbonyl, N-alkyl-N-aromatic yl aminocarbonyl; alkyl amino alkyl carbonyl, carboxyalkyl, alkyl amino; the N-arylamino, N-aryl alkyl amino, N-alkyl-N-aryl alkyl amino; N-alkyl-N-arylamino; aminoalkyl, alkyl amino alkyl, N-arylamino alkyl; the N-alkyl amino alkyl aryl; N-alkyl-N-alkyl amino alkyl aryl, N-alkyl-N-arylamino alkyl, aryl oxide; aralkoxy; arylthio, aromatic alkylthio, alkyl sulphinyl; alkyl sulphonyl; amino-sulfonyl, alkyl amino sulfonyl, N-n-aryl sulfonyl; aryl sulfonyl and N-alkyl-N-n-aryl sulfonyl, R ³Randomly be selected from following group and replace by one or more: alkyl, haloalkyl, cyano group in commutable position, carboxyl, alkoxy carbonyl group, hydroxyl, hydroxyalkyl, halogenated alkoxy, amino, alkyl amino, arylamino, nitro, alkoxyalkyl, alkyl sulphinyl, halogen, alkoxyl and alkylthio group; And

R ⁴Be selected from hydrogen and halogen.

One group of particularly preferred selective COX-2-2 suppressive drug is the chemical compound with formula (II):

R wherein ⁵Be methyl or amino, R ⁶Be hydrogen or C _1-4Alkyl or alkoxyl, X ' are N or CR ⁷, R wherein ⁷Be hydrogen or halogen, and Y and Z be carbon or nitrogen-atoms independently, they have defined 5 yuan of contiguous atoms to 6 yuan of rings, described ring is randomly replaced by oxygen, halogen, methyl or halogenated methyl in one or more positions, or its isomer, tautomer, pharmaceutically acceptable salt or prodrug.Preferred this 5 yuan to 6 yuan rings are to be no more than a substituted cyclopentenone in position, furanone, methylpyrazole ， isoxazole and pyridine ring.

Another organizes particularly preferred selective COX-2-2 suppressive drug is the chemical compound with formula (III):

X wherein " be O, S or N-low alkyl group; R ⁸It is low-grade halogenated alkyl; R ⁹It is hydrogen or halogen; R ¹⁰Be hydrogen, halogen, low alkyl group, lower alkoxy or halogenated alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, low-grade alkyl amino sulfonyl, rudimentary aryl alkyl amino sulfonyl, rudimentary heteroarylalkyl amino-sulfonyl, or 5 yuan or 6 member heterocyclic ring containing nitrogen sulfonyls; And R ¹¹And R ¹²Be hydrogen independently, halogen, low alkyl group, lower alkoxy, or aryl; With its pharmaceutically acceptable salt.

Useful especially formula (III) chemical compound is (S)-6,8-two chloro-2-(trifluoromethyl)-2H-1-.alpha.-5:6-benzopyran-3-formic acid.

In addition-to organize particularly preferred selective COX-2-2 suppressive drug be 5-alkyl-2-arylamino phenyl acetic acid and its derivant.The useful especially chemical compound of this class is lumiracoxib and its pharmaceutically acceptable salt.

Illustrative ground; in method and composition of the present invention, can use: celecoxib; deracoxib; valdecoxib; parecoxib; rofecoxib; etoricoxib; lumiracoxib; 2-(3; the 5-difluorophenyl)-3-[4-(methyl sulphonyl) phenyl]-2-cyclopentenes-1-ketone; (S)-6; 8-two chloro-2-(trifluoromethyl)-2H-1-.alpha.-5:6-benzopyran-3-formic acid; 2-(3; the 4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3-(2H)-2H-Pyridazin-3-one; 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide (being also referred to as abelacoxib); 1-benzyl-4-[(4-oxo-piperidine-1-yl) sulfonyl] piperidines-4-t-butyl formate; 4-[5-(phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide and their salt; celecoxib more especially; deracoxib; valdecoxib; parecoxib and its salt; rofecoxib; etoricoxib, lumiracoxib, 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide; 1-benzyl-4-[(4-oxo-piperidine-1-yl) sulfonyl] piperidines-4-t-butyl formate, and 4-[5-(phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide.

By any known method, for example, can prepare the valdecoxib that is used in the compositions of the present invention in U.S. Patent number 5,633, the 272 described modes of Talley etc.By any known method,, can prepare parecoxib and its salt of being used in the compositions of the present invention for example in U.S. Patent number 5,932, the 598 described modes of Talley etc.By any known method, for example, can prepare the rofecoxib that is used in the compositions of the present invention in U.S. Patent number 5,474, the 995 described modes of Ducharme etc.By any known method, for example, can prepare the etoricoxib that is used in the compositions of the present invention in International Patent Publication No. WO 98/03484 described mode.By any known method,, can prepare 2-(3, the 5-difluorophenyl)-3-[4-(methyl sulphonyl) phenyl that is used in the compositions of the present invention for example in european patent number 0,863 134 described mode]-2-cyclopentenes-1-ketone.By any known method, for example, can prepare the deracoxib that is used in the compositions of the present invention in U.S. Patent number 5,466, the 823 described modes of Talley etc.By any known method; for example in International Patent Publication No. WO 00/24719 described mode; can prepare 2-(3, the 4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl sulphonyl) phenyl that is used in the compositions of the present invention]-3-(2H)-2H-Pyridazin-3-one.By any known method, be included in the method described in the patent disclosure text that discloses these medicines, for example under the situation of celecoxib, the U.S. Patent number of quoting in the above 5,466,823 or at the U.S. Patent number 5,892 of Zhi etc., method described in 053 can prepare with other selective COX-2-2 suppressive drug.Above-cited all patents and open source literature are all incorporated by reference here.

When second kind of medicament was selective COX-2-inhibitor 2, preferred concentration range in compositions of the present invention was about 0.01 to about 1000mg/ml, and more preferably about 0.1 to about 750mg/ml, and more preferably about 5 to about 250mg/ml.For second kind of medicament except selective COX-2-inhibitor 2, on the basis of disclosed data, those skilled in the art can determine proper concentration.

In another embodiment, second kind of medicament is anesthetis.Anesthetis includes but not limited to: ambucaine, amolanone, amylocaine, oxybuprocaine, benzocaine, betoxycaine, xenysalate, bupivacaine, butacaine, butamben, butamben picrate, butanilicaine, butethamine, 2-diethylaminoethyl p-butoxybenzoate., carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, quinisocaine, dimethocaine, diperodon, biphenyl hydroxylamine, dyclonine, ecgonidine, ecgonine, ethyl chloride, etidocaine, betaeucaine, fomocaine, hexylcaine hydrochloride, the hydrogen procaine, Oxyprocaine, hydroxytetracaine, isobucaine, cycloform, ketocaine, leucinocaine, levoxadrol, lignocaine, mepivacaine, meprylcaine, metabutoxycaine, metabutethamine, Myrtecaine, octacaine, orthocaine, Mucaine, parethoxycaine, Holocaine, phenol, piperocaine, piridocaine, Polidocanol, pramocaine, prilocaine, procaine, primacaine, proparacaine, propipocaine, propoxycaine, pseudo-cocaine, pyrrocaine, replivicane, ropivacaine, saligenin, tetracaine, tolycaine, mesocainum, lignocaine etc. and its combination.

Preferred anesthetis comprises lignocaine, bupivacaine, prilocaine, ropivacaine and its tautomer, stereoisomer, enantiomer, salt, hydrate, prodrug and its combination.

In another embodiment, second kind of medicament is sodium channel inhibitor.Be used for sodium channel inhibitor of the present invention and comprise those that can pass through the additional antiinflammatory effect of mechanism arbitrarily, include but not limited to ease the pain, reduce edema etc.

Sodium channel inhibitor used according to the invention can be selected from following non-limiting tabulation: NaV1.8 (PN3) hypotype sodium channel inhibitor, NaV1.3 (III type) hypotype sodium channel inhibitor, carbamyl, fragrant that ester, former times the health class, propionic acid amide., pyrazine acyl guanidine semicarbazones, semicarbazides, etc.

Perhaps, sodium channel inhibitor that can be used according to the invention can be selected from following non-limiting tabulation: amiloride, 4-amino-2-(4-methyl piperazine-1-yl)-5-(2; 3, the 5-trichlorophenyl) pyrimidine, amitryptiline; the dehydration and deoxidation tetrodotoxin, aprindine, reddish black A; benzamil, benzothiazole, benzoxazinate; carvedilol, deoxidation tetrodotoxin, norpace (disopyramide); encainide, ethyoxyl deoxidation tetrodotoxin, euprocin; fenalcomine, fluarizine, gabapentin; isoflurane, lifarizine, lorcainide; 1-mesyl-3-(4-phenoxy group) phenyl-1H-pyrazoles, methoxiflurane lignocaine, methoxyl group Fugu ocellatus toxin; chloromethane, 2-methyl isophthalic acid-[3-(4-Phenoxyphenyl)-1H-pyrazoles] acetone, mexiletine; N-acenaphthene-5-base-N '-4-methoxyl group naphthyl guanidine; naepaine, N-(2-chloro-6-aminomethyl phenyl)-N-4-pyridine radicals urea, N-[3-(2; 6-dimethyl-piperidino)]-α-Ben Jibenyixian amine; N-methyl strychnine, 1-[3-[4-(4-nitrophenoxy) phenyl]-the 1H-pyrazoles] ethyl ketone, oxcarbazepine; oxesazeine; oxyburocaine, oxythazaine, handkerchief oolong; phenamil; the phenyl benzothiazole, phenytoin, pregabalin; procainamide; Propafenone, propanocaine, ralitoline; riluzole; saxitoxin, tekacaine, tetrodiaminotoxin; tetrodonic acid; Fugu ocellatus toxin, topiramate, 5-(2; 3; the 5-trichlorophenyl)-2,4-diaminourea-pyrimidine, 6-(2; 3; the 5-trichlorophenyl)-1,2,4 triazines-5-base amine; verapamil; zolamine, zonisamide etc. and its combination.

Be applicable to that two oleophylics of the present invention comprise dispersible and insoluble two oleophylics of ethanol of all water.

Preferred this two oleophylics are the glyceride by the Pegylation of the alcoholysis reaction preparation of natural glycerin three esters and Polyethylene Glycol, and example includes but not limited to that following Gattefoss é is oily or from other manufacturer's the oil that is equal to basically: Labrafil ^TMM-1944CS, Labrafil ^TMM-1966CS, Labrafil ^TMM-1969CS, Labrafil ^TMM-1980CS, Labrafil ^TMM-2125CS, Labrafil ^TMWL-2609BS, Labrafil ^TMISO and its combination.

Preferred two oleophylics are the glyceride of the Pegylation that as above prepares, and it comprises oleic acid or linoleic main fatty acid component, and example includes but not limited to following Gattefoss é oil or from other manufacturer's the oil that is equal to basically: Labrafil ^TMM-1944CS, Labrafil ^TMM-1966CS, Labrafil ^TMM-1969CS, Labrafil ^TMM-1980CS, Labrafil ^TMM-2125CS, Labrafil ^TMWL-2609BS and its combination.

Preferred two oleophylics are the glyceride of the Pegylation that as above prepares, and it comprises oleic main fatty acid component, and example includes but not limited to following Gattefoss é oil or from other manufacturer's the oil that is equal to basically: Labrafil ^TMM-1944CS, Labrafil ^TMM-1966CS, Labrafil ^TMM-1980CS and its combination.

Most preferred two oleophylics are pegicol 5-oleate, for example Labrafil of Gattefoss é Corporation ^TMM-1944CS.

The preferred concentration range for of two oleophylics in compositions of the present invention is about 0.01% to about 99% weight/volume, and more preferably about 1% to about 80% weight/volume, and more preferably about 3% to about 25% weight/volume.

Microwax is as at for example Handbook of Pharmaceutical Excipients, and the 3rd edition or at National Formulary, defined in the 19th edition (NF 19), and can obtain from many manufacturers, comprise Witco Corporation.

The preferred concentration range for of microwax in compositions of the present invention is about 0.001% to about 50% weight/volume, and more preferably about 0.1% to about 40% weight/volume, and more preferably about 1% to about 15% weight/volume.

Pharmaceutically-acceptable non-aqueous carrier of the present invention can be fully saturated, or partially or completely undersaturated.The example of non-aqueous carrier includes but not limited to: vegetable oil, mineral oil, artificial oil and its combination.The example of fully saturated non-aqueous carrier includes but not limited to medium chain, and (for example chain is about C to the ester of long-chain fatty acid ₆To about C ₂₄Fatty acid triglycercide).The mixture of fatty acid be from natural oil (Oleum Cocois for example, palm-kernel oil, babassu oil, etc.) in separate and purified.In some embodiments, medium chain (about C ₈To about C ₁₂) triglyceride is useful.The indicative saturated non-aqueous carrier of illustration comprises capric acid (about 20% to about 45%) and sad (about 45% to about 80%).Other complete saturated non-aqueous carrier includes but not limited to saturated Oleum Cocois (it typically comprises the mixture of lauric acid, myristic acid, Palmic acid, capric acid and caproic acid), comprises that Huls is with trade (brand) name Miglyol ^TMThe article number of selling is those of 810,812,829 and 840).Be pointed out that the NeoBee that Drew Chemicals sells in addition ^TMProduct.Isopropyl myristate is another example of the non-aqueous carrier that uses in compositions of the present invention.The example of artificial oil comprises the triglyceride and the propylene glycol diesters of the saturated or unsaturated fatty acid with 6-24 carbon atom, and described fatty acid is caproic acid for example, sad (caprylic acid), pelargonic acid (n-nonanoic acid), capric acid (capric acid), undecanoic acid, lauric acid, tridecanoic acid, tetradecylic acid (myristic acid), pentadecanoic acid, hexadecylic acid (Palmic acid), heptadecanoic acid, stearic acid (stearic acid), nonadecanoic acid, heptadecanoic acid, arachidic acid, heneicosoic acid, behenic acid and tetracosanoic acid, etc.The example of unsaturated carboxylic acid comprises oleic acid, linoleic acid plus linolenic acid, etc.Should be understood that non-aqueous carrier can comprise the glycerol list of fatty acid, two and three esters, or blended glyceride and/or propylene glycol diesters, wherein at least one glycerol molecule has been used the fatty acid esterification of different carbon atom length.The limiting examples that is used as " the non-oil " of carrier in compositions of the present invention is a Polyethylene Glycol.

Preferred non-aqueous carrier is a for example Oleum Gossypii semen of vegetable oil, Semen Maydis oil, Oleum sesami, soybean oil, olive oil, fractionated Oleum Cocois, Oleum Arachidis hypogaeae semen, sunflower oil, safflower oil, almond oil, American Avocado Tree oil, Petiolus Trachycarpi oil, palm-kernel oil, babassu oil, beech nut oil, Semen Lini oil, colza wet goods.Most preferred non-aqueous carrier is an Oleum Gossypii semen.As an example, can obtain the Oleum Gossypii semen of 70% unsaturated fatty acid goods form from SigmaChemical Co.

The preferred concentration range for of non-aqueous carrier in compositions of the present invention is about 0.5% to about 99% weight/volume, and more preferably about 10% to about 95% weight/volume, and more preferably about 40% to about 90% weight/volume.

Compositions of the present invention can randomly comprise arbitrarily conventional drug excipient (excipient) in addition, its not can with the basis generation adverse reaction of compositions.Such excipient includes but not limited to: antioxidant, and antiseptic, suspending agent, stabilizing agent, lytic agent, wetting agent, lubricant, emulsifying agent is regulated salt, coloring agent, alcohols, isotonic agent, penetrating agent, counter-stimulus, buffer agent and its combination of osmotic pressure.

By the intubate nozzle of mastitis syringe being inserted the outer hole of papillary duct of milcher breast, and compositions irritated in the breast, can use the compositions that comprises antibacterial and optional second kind of medicament, treat or prevent mastitis.

By the nozzle of aural syringe, [allotter or other suitable ear conveyer device being inserted the external auditory meatus of object ear, and compositions irritated in the ear, can use the compositions that comprises antibacterial and optional second kind of medicament, treat or prevent ear disease.

The preferred amounts that should be understood that the compositions that will use under specific circumstances changes with the particular location of the concrete compositions of using, application mode, treatment and biology and other factors.Use conventional Consideration, for example, the activity difference by routine contrast theme composition and known pharmaceutical agents for example, by suitable conventional pharmaceutical scheme, can be identified for the dosage of specific purpose.

The suspension composition that contains antibacterial (for example, ceftiofur hydrochloride) and second kind of medicament (for example, selective COX-2-inhibitor 2 deracoxib) of the present invention of illustrative has following composition:

Antibacterial 1-150mg/ml

Second kind of medicament 1-350mg/ml

Labrafil ^TM?M-1944CS 1-75％

Microwax 0.1-25%

Oleum Gossypii semen is in right amount to 100%

(all percentage ratios are weight/volume).

Embodiment

The following examples have illustrated aspects more of the present invention, but not should be understood to restriction.

Embodiment 1

Prepared have following composition pass through inculcate the suspension of using in the breast:

Ceftiofur hydrochloride (micronized) 12.5mg/ml

Labrafil ^TM?M-1944CS 50mg/ml

Microwax NF 70mg/ml

Oleum Gossypii semen NF is an amount of

Under mixing, the Oleum Gossypii semen with microwax and about 27% total amount in pot is heated to 85-98 ℃.Under mixing, in producing jar, remaining Oleum Gossypii semen is heated to 85-98 ℃.After microwax melts fully, the microcrystalline wax/cottonseed oil mixture in the pot is transferred in the production jar that Oleum Gossypii semen is housed, and thoroughly mixed.The mixture that obtains is cooled to 38-45 ℃, under mixing, in producing jar, adds Labrafil ^TMM-1944CS forms excipient.Then, ceftiofur hydrochloride is added in the excipient, and mix the compositions that obtains, form uniform suspension.Suspension is sieved, and the 12ml high density polyethylene (HDPE) mastitis syringe of packing into.By dosage is the gamma-radiation of 25-40kGy, the final sterilization packaged products.

At 39 ℃, use the droplet size technology of deionized water, the 70mg/ml microwax that is used in the Oleum Gossypii semen by contrast does not still have Labrafil ^TMM-1944CS preparation with reference to suspension, determined the interfacial tension of top suspension.

Contain the Labrafil in Oleum Gossypii semen ^TMThe interfacial tension of the suspension of M-1944CS and microwax is 6.5 dyne/cm, and this is than reference suspension (22.5 dyne/cm) low about 3.4 times.

With conjoint therapy with the 100mg/ml parecoxib sodium in the phosphate buffered saline (PBS) medium of the dosage parenteral injection of 4mg/kg body weight/day in, by inculcating in the breast, above-mentioned suspension is administered to lactating cow with 125mg/quarter/ days dosage (2-8 days).This conjoint therapy can be treated the lactating cow mastitis effectively.

Embodiment 2

Prepared have following composition pass through inculcate the suspension of using in the breast:

Ceftiofur hydrochloride (micronized) 12.5mg/ml

Labrafil ^TM?M-1944CS 50mg/ml

Microwax NF 100mg/ml

Oleum Gossypii semen NF is an amount of

Under mixing, in producing jar, microwax and Oleum Gossypii semen are heated to 85-98 ℃.After microwax melts fully, mixture is cooled to 38-45 ℃, under mixing, in producing jar, adds Labrafil ^TMM-1944CS forms excipient.Then, ceftiofur hydrochloride is added in the excipient that obtains, and mix, form uniform suspension.Suspension is sieved, and the 12ml high density polyethylene (HDPE) mastitis syringe of packing into.By dosage is the gamma-radiation of 25-40kGy, the final sterilization packaged products.

At 39 ℃, use the droplet size technology of deionized water, the 100mg/ml microwax that is used in the Oleum Gossypii semen by contrast does not still have Labrafil ^TMM-1944CS preparation with reference to suspension, determined the interfacial tension of top suspension.

Contain the Labrafil in Oleum Gossypii semen ^TMThe interfacial tension of the suspension of M-1944CS and microwax is 7.1 dyne/cm, and this is than reference suspension (28.1 dyne/cm) low about 4.0 times.

With conjoint therapy with the 200mg/ml parecoxib sodium in the phosphate buffered saline (PBS) medium of the dosage parenteral injection of 4mg/kg body weight/day in, by inculcating in the breast, 125mg/quarter/ days dosage (2-8 days) is administered to lactating cow with above-mentioned suspension.This conjoint therapy can be treated the lactating cow mastitis effectively.

Embodiment 3

Prepared have following composition pass through inculcate the suspension of using in the breast:

Ceftiofur hydrochloride (micronized) 12.5mg/ml

Labrafil ^TM?M-1944CS 200mg/ml

Microwax NF 100mg/ml

Oleum Gossypii semen NF is an amount of

Under mixing, in producing jar, microwax and Oleum Gossypii semen are heated to 85-98 ℃.After microwax melts fully, mixture is cooled to 38-45 ℃, under mixing, in producing jar, adds Labrafil ^TMM-1944CS forms excipient.Then, ceftiofur hydrochloride is added in the excipient that obtains, and mix, form uniform suspension.Suspension is sieved, and the 12ml high density polyethylene (HDPE) mastitis syringe of packing into.By dosage is the gamma-radiation of 25-40kGy, the final sterilization packaged products.

At 39 ℃, use the droplet size technology of deionized water, the 100mg/ml microwax that is used in the Oleum Gossypii semen by contrast does not still have Labrafil ^TMM-1944CS preparation with reference to suspension, determined the interfacial tension of top suspension.

Contain the Labrafil in Oleum Gossypii semen ^TMThe interfacial tension of the suspension of M-1944CS and microwax＜1 dyne/cm, this than reference suspension (28.1 dyne/cm) low above 28 times.

With conjoint therapy with the 100mg/ml parecoxib sodium in 15% Polyethylene Glycol phosphate buffered saline (PBS) medium of the dosage parenteral injection of 4mg/kg body weight/day in, by inculcating in the breast, above-mentioned suspension is administered to lactating cow with 125mg/quarter/ days dosage (2-8 days).This conjoint therapy can be treated the lactating cow mastitis effectively.

Embodiment 4

Prepared have following composition pass through inculcate the suspension of using in the breast:

Ceftiofur crystal detachment acid (micronized) 25mg/ml

Deracoxib 170mg/ml

Labrafil ^TM?M-1966CS 100mg/ml

Microwax NF 50mg/ml

Semen Maydis oil NF is an amount of

Under mixing, in producing jar, microwax and Semen Maydis oil are heated to 85-98 ℃.After microwax melts fully, mixture is cooled to 30-45 ℃, under mixing, in producing jar, adds Labrafil ^TMM-1966CS forms excipient.Then, acid of ceftiofur crystal detachment and deracoxib are added in the excipient that obtains, and mix, form uniform suspension.Suspension is sieved, and the 12ml high density polyethylene (HDPE) mastitis syringe of packing into.By dosage is the gamma-radiation of 25-40kGy, the final sterilization packaged products.

With 500mg ceftiofur crystal detachment acid/quarter and 3, the dosage of 400mg deracoxib/quarter by inculcating in the breast, is administered to above-mentioned suspension all four quarter of not galactopoiesis cow.This suspension can be treated the mastitis of not galactopoiesis cow effectively.

Embodiment 5

Prepared the ear that passes through and inculcated the suspension of using with following composition:

Pirlimycin 25mg/ml

Rofecoxib 25mg/ml

Labrafil ^TM?M-1980CS 500mg/ml

Microwax NF 0.10mg/ml

Propyl gallate 1.0mg/ml

Mineral oil is an amount of

Under mixing, the mineral oil with microwax and about 27% total amount in pot is heated to 85-98 ℃.Under mixing, in producing jar, remaining Oleum Gossypii semen is heated to 85-98 ℃.After microwax melts fully, the microwax/mineral oil mixture in the pot is transferred in the production jar that mineral oil is housed, and thoroughly mixed.The mixture that obtains is cooled to 38-45 ℃, under mixing, in producing jar, adds Labrafil ^TMM-1980CS.Under mixing, in producing jar, add propyl gallate, form excipient.Then, pirlimycin and rofecoxib are added in the excipient that obtains, and mix, form uniform suspension.Suspension is sieved, and the 20ml polypropylene containers of packing into.

With the dosage of 2.5mg pirlimycin/kg body weight and 2.5mg rofecoxib/kg body weight, use above-mentioned suspension by inculcating into the Canis familiaris L. ear.This suspension can be treated the Canis familiaris L. external otitis effectively.

Embodiment 6

Prepared have following composition pass through inculcate the suspension of using in the breast:

Ceftiofur hydrochloride (micronized) 50mg/ml

Deracoxib 300mg/ml

Labrafil ^TM?M-1944CS 50mg/ml

Microwax NF 70mg/ml

Oleum Gossypii semen NF is an amount of

Under mixing, the Oleum Gossypii semen with microwax and about 27% total amount in pot is heated to 85-98 ℃.Under mixing, in producing jar, remaining Oleum Gossypii semen is heated to 85-98 ℃.After microwax melts fully, the microcrystalline wax/cottonseed oil mixture in the pot is transferred in the production jar that Oleum Gossypii semen is housed, and thoroughly mixed.The mixture that obtains is cooled to 38-45 ℃, under mixing, in producing jar, adds Labrafil ^TMM-1944CS forms excipient.Then, ceftiofur hydrochloride and deracoxib are added in the excipient that obtains, and mix, form uniform suspension.Suspension is sieved, and the 12ml high density polyethylene (HDPE) mastitis syringe of packing into.By dosage is the gamma-radiation of 25-40kGy, the final sterilization packaged products.

With 500mg ceftiofur hydrochloride/quarter and 12, the dosage of 000mg deracoxib/quarter by inculcating in the breast, is administered to above-mentioned suspension all four quarter of not galactopoiesis cow.This suspension can be treated the mastitis of not galactopoiesis cow effectively.

Embodiment 7

Prepared have following composition pass through inculcate the suspension of using in the breast:

Ceftiofur sodium (micronized) 25mg/ml

Valdecoxib 1.5mg/ml

Labrafil ^TM?WL-2609BS 75mg/ml

Microwax NF 100mg/ml

Miglyol ^TM812 is an amount of

Under mixing, in pot with the Miglyol of microwax and about 30% total amount ^TM812 are heated to 85-98 ℃.Under mixing, in producing jar with remaining Miglyol ^TM812 are heated to 85-98 ℃.After microwax melts fully, with the microwax/Miglyol in the pot ^TM812 mixture are transferred to Miglyol are housed ^TMIn 812 the production jar, and thoroughly mix.The mixture that obtains is cooled to 38-45 ℃, under mixing, in producing jar, adds Labrafil ^TMWL-2609BS forms excipient.Then, ceftiofur sodium and valdecoxib are added in the excipient that obtains, and mix, form uniform suspension.Suspension is sieved, and the 12ml high density polyethylene (HDPE) mastitis syringe of packing into.By dosage is the gamma-radiation of 25-40kGy, the final sterilization packaged products.

With the dosage of 500mg ceftiofur sodium/quarter and 30mg valdecoxib/quarter,, above-mentioned suspension is administered to all four quarter of not galactopoiesis cow by inculcating in the breast.This suspension can be treated the mastitis of not galactopoiesis cow effectively.

Embodiment 8

Prepared the ear that passes through and inculcated the suspension of using with following composition:

Ceftiofur hydrochloride (micronized) 100mg/ml

Deracoxib 100mg/ml

Labrafil ^TM?M-1944CS 700mg/ml

Microwax NF 0.05mg/ml

Mineral oil is an amount of

Under mixing, the mineral oil with microwax and about 27% total amount in pot is heated to 85-98 ℃.Under mixing, in producing jar, remaining mineral oil is heated to 85-98 ℃.After microwax melts fully, the microwax/mineral oil mixture in the pot is transferred in the production jar that mineral oil is housed, and thoroughly mixed.The mixture that obtains is cooled to 38-45 ℃, under mixing, in producing jar, adds Labrafil ^TMM-1944CS forms excipient.Then, ceftiofur hydrochloride and deracoxib are added in the excipient that obtains, and mix, form uniform suspension.Suspension is sieved, and the 50ml polypropylene containers of packing into.

With the dosage of 4mg ceftiofur hydrochloride/kg body weight and 4mg deracoxib/kg body weight, use above-mentioned suspension by the ear that beats into object.This suspension can treat and/or prevent otitis media effectively.

Embodiment 9

Prepared the ear that passes through and inculcated the suspension of using with following composition:

Ceftiofur hydrochloride (micronized) 100mg/ml

Labrafil ^TM?M-1944CS 700mg/ml

Microwax NF 0.1mg/ml

Oleum Gossypii semen NF is an amount of

Under mixing, in producing jar, microwax and Oleum Gossypii semen are heated to 85-98 ℃.After microwax melts fully, mixture is cooled to 38-45 ℃, under mixing, in producing jar, adds Labrafil ^TMM-1944CS forms excipient.Then, ceftiofur hydrochloride is added in the excipient that obtains, and mix, form uniform suspension.Suspension is sieved, and the 60ml polypropylene containers of packing into.

With the capsular conjoint therapy of 2 dosage forms for oral administration 200mg Celebrex  every day (celecoxib) in, with the dosage of 4mg ceftiofur hydrochloride/kg body weight, use above-mentioned suspension by inculcating into the ear of object.This conjoint therapy can treat and/or prevent external otitis effectively.

Embodiment 10

Prepared the ear that passes through and inculcated the suspension of using with following composition:

Ceftiofur hydrochloride (micronized) 75mg/ml

Labrafil ^TM?M-1944CS 750mg/ml

Microwax NF 0.05mg/ml

Mineral oil is an amount of

Under mixing, in producing jar, microwax and mineral oil are heated to 85-98 ℃.After microwax melts fully, mixture is cooled to 38-45 ℃, under mixing, in producing jar, adds Labrafil ^TMM-1944CS forms excipient.Then, ceftiofur hydrochloride is added in the excipient that obtains, and mix, form uniform suspension.Suspension is sieved, and the 20ml polypropylene conveyer device of packing into.

With the conjoint therapy of 1 dosage forms for oral administration 10mg Bextra  every day (valdecoxib) tablet in, with the dosage of 2mg ceftiofur hydrochloride/kg body weight, use above-mentioned suspension by inculcating into the ear of object.This conjoint therapy can be treated infectious myringitis effectively.

Embodiment 11

Prepared the ear that passes through and inculcated the suspension of using with following composition:

Ceftiofur hydrochloride (micronized) 100mg/ml

Parecoxib free acid 100mg/ml

Labrafil ^TM?M-1944CS 700mg/ml

Microwax NF 0.1mg/ml

Oleum Gossypii semen NF is an amount of

Under mixing, in producing jar, microwax and Oleum Gossypii semen are heated to 85-98 ℃.After microwax melts fully, mixture is cooled to 38-45 ℃, under mixing, in producing jar, adds Labrafil ^TMM-1944CS forms excipient.Then, ceftiofur hydrochloride and parecoxib are added in the excipient that obtains, and mix, form uniform suspension.Suspension is sieved, and the 60ml polypropylene containers of packing into.

With the dosage of 4mg ceftiofur hydrochloride/kg body weight and 4mg parecoxib/kg body weight, use above-mentioned suspension by inculcating into the ear of object.This conjoint therapy can treat and/or prevent external otitis effectively.

Embodiment 12

Prepared the ear that passes through and inculcated the suspension of using with following composition:

Lignocaine 100mg/ml

Linezolid 100mg/ml

Parecoxib free acid 100mg/ml

Labrafil ^TM?M-1944CS 700mg/ml

Microwax NF 0.1mg/ml

Oleum Gossypii semen NF is an amount of

Under mixing, in producing jar, microwax and Oleum Gossypii semen are heated to 85-98 ℃.After microwax melts fully, mixture is cooled to 38-45 ℃, under mixing, in producing jar, adds Labrafil ^TMM-1944CS forms excipient.Then, Linezolid, lignocaine and parecoxib are added in the excipient that obtains, and mix, form uniform suspension.Suspension is sieved, and the 60ml polypropylene containers of packing into.

With the dosage of 4mg Linezolid/kg body weight, 4mg lignocaine/kg body weight and 4mg parecoxib/kg body weight, use above-mentioned suspension by inculcating into the ear of object.This conjoint therapy can treat and/or prevent external otitis effectively.

Described the present invention in detail, and, obviously can modify and change, and do not departed from the scope of appended claims with reference to its preferred embodiment.

Claims (63)

1. treat and/or prevent the method for the infectious conditions of the organ that contains liquid with natural outer hole, this method comprises, by outer hole with antibacterial be administered to organ and with the conjoint therapy of described antibacterial in use the second kind of medicament that is selected from anesthetis, sodium channel inhibitor and edema agent; Wherein said antibacterial is used as the pharmaceutical composition that comprises described antibacterial and excipient, and described excipient comprises dispersible and insoluble two oleophylics of ethanol of (a) water, (b) microwax and (c) pharmaceutically-acceptable non-aqueous carrier.

2. the process of claim 1 wherein that described infectious conditions is the cystic hyperplasia of breast of milcher, and wherein use the compositions that comprises antibacterial by inculcating in the breast.

3. the method for claim 2, wherein said disease is mastitis.

4. the process of claim 1 wherein that described infectious conditions is the ear disease of object or the complication relevant with this disease and wherein inculcates by ear and use the compositions that comprises antibacterial.

5. the method for claim 4, wherein said disease is selected from: external otitis, otitis media, otorrhea, acute mastoiditis, otosclerosis, ear pain, otorrhagia, otitis disease, Lermoyez syndrome, Menetrier's disease, vestibular neuronitis, optimum paroxysmal position is dizzy, zoster oticus, the Ramsay HH, viral nervous unit is scorching, neuroganglitis, geniculate herpes, labyrinthitis, suppurative labyrinthitis, perilymphatic fistula, presbyacusis, drug-induced ototoxicity, acoustic neuroma, aerotitis, infectious myringitis, bullous myringitis, squamous cell carcinoma, basal cell carcinoma, the cancer otic condition, nonchromaffin paraganglioma, chemodectoma, the tympanic body tumor, glomus tympanicum tumor, perichondritis, the ear eczema-like dermatitis, pernicious external otitis, hematoma under the perichondrium, ceruminal adenoma, impacted cerumen, sebaceous cyst, osteoma, keloid, otalgia, tinnitus, dizzy, tympanum infects, otitis media, furuncle of ear, petrositis, conductivity and sensorineural hearing loss, epidural abscess, lateral sinus thrombosis, subdural empyema, otitic hydrocephalus, Dandy syndrome, bullous myringitis, otitis externa diffusa, foreign body, keratosis obturans, the ear tumor, otomycosis, wound, acute aero-otitis media, acute Eustachian tube blocks, postoperative otalgia, cholesteatoma, the infection relevant with the ear operation process and with the complication of any described disease association.

6. the method for claim 4, wherein said disease is selected from: external otitis, otitis media, otorrhea and the infection relevant with the ear operation process.

7. the method for claim 4, wherein said disease is neoplasia.

8. the method for claim 7 also comprises the conjoint therapy with antineoplastic agent and antiinflammatory.

9. the process of claim 1 wherein and use described second kind of medicament by the approach different with the route of administration of antibacterial.

10. the process of claim 1 wherein and use described second kind of medicament by the approach identical with antibacterial.

11. the method for claim 1, wherein second kind of medicament is to use as the pharmaceutical composition that comprises described second kind of medicament and excipient, described excipient comprises dispersible and insoluble two oleophylics of ethanol of (a) water, (b) microwax and (c) pharmaceutically-acceptable non-aqueous carrier.

12. the process of claim 1 wherein that described pharmaceutical composition also comprises second kind of medicament.

13. the process of claim 1 wherein that described antibacterial is selected from: natural and synthetic Penicillin antibiotics, cephalosporin, macrolide, but the woods amine, pleuromutilin, polypeptide, polymyxin, sulfonamides, chloromycetin, thiamphenicol, florfenicol, tetracycline antibiotics, quinolinones, fluoroquinolone, tiamulin, ciprofloxacin, colistin, meclocycline, mafenide, metacycline, norfloxacin, ofloxacin, pyrimethamine, silver sulfadiazine, sulfacetamide, sulfafurazole, tobramycin, vanemulin oxazolidone, glycopeptide, aminoglycoside and aminocyclitol, amphenicol, Ansamycin, carbapenem, cephamycin, vancomycin, monobactam, oxacephems, general antibacterial, antibiotic type antineoplastic agent, the nitrofuran sulfone, Marbofloxacin and its tautomer, stereoisomer, enantiomer, salt, hydrate and prodrug.

14. the method for claim 13; wherein said cephalosporin is selected from: ceftiofur; cefalexin; cefradine; cefquinome; cefacetrile; cefpodoxime; cefovecin; cefalonium; cefuroxime; cefazidime; cefoperazone; sodiumcephemethcarboxylate; cephem; cefadroxil; cefazolin sodium; cefiximine; ceftaxime; ceftizoxime; ceftriaxone, adjacent formyl cefadole, the salt of following material: 3-acetate methyl-7-(imino group acetylamino)-cephalosporin acid derivative; 7-(D-alpha-amido-α-(to hydroxyphenyl) acetylamino)-3-methyl-3-cephem-1-formic acid; cis-7-((2-amino-1-thiazolyl) (methoxyimino) acetyl group) amino)-and the hydrochlorate of 3-methyl-3-cephem-4-formic acid, cephemcarboxylic acid, (pivaloyl oxygen) methyl-7-β-(2-(2-amino-4-thiazolyl) acetylamino)-3-(((1-(2-(dimethylamino) ethyl)-1H-tetrazolium-5-yl) sulfo-) methyl)-3-cephem-4-formates; cefalexin; 7-(D-2-naphthyl glycyl amino)-3-methyl-3-cephem-4-formic acid and its tautomer; stereoisomer; enantiomer; salt; hydrate and prodrug and its combination.

15. the method for claim 13, wherein said antibacterial comprise ceftiofur or its pharmaceutically acceptable salt or form.

16. the method for claim 15, wherein said antibacterial comprises ceftiofur hydrochloride.

17. the method for claim 15, wherein said antibacterial comprise the acid of ceftiofur crystal detachment.

18. the method for claim 1, wherein said antibacterial comprises and is selected from Xia Shu De oxazolidone: eperezolid, Linezolid, N-((5S)-3-(3-fluoro-4-(4-(2-fluoro ethyl)-3-oxygen-1-piperazinyl) phenyl-2-oxygen-5-oxazolidinyl) methyl) acetamide, (S)-N-((3-(5-(3-pyridine radicals) thiophene-2-yl)-2-oxygen-5-oxazolidinyl) methyl) acetamide and (S)-N-((3-(5-(4-pyridine radicals) pyridine-2-yl)-2-oxygen-5-oxazolidinyl) methyl) acetamide hydrochloride and its combination.

19. the process of claim 1 wherein that described second kind of medicament comprises anesthetis.

20. the process of claim 1 wherein that described second kind of medicament comprises sodium channel inhibitor.

21. the process of claim 1 wherein that described second kind of medicament comprises the edema agent.

22. treat and/or prevent the method for the infectious conditions of the organ that contains liquid with natural outer hole, this method comprises, by outer hole with antibacterial be administered to organ and with the conjoint therapy of described antibacterial in use and comprise antiinflammatory and narcotic second kind of medicament; Wherein said antibacterial is used as the pharmaceutical composition that comprises described antibacterial and excipient, and described excipient comprises dispersible and insoluble two oleophylics of ethanol of (a) water, (b) microwax and (c) pharmaceutically-acceptable non-aqueous carrier.

23. the method for claim 22, wherein said second kind of medicament comprises selective COX-2-inhibitor 2 and anesthetis.

24. the method for claim 22, wherein said antibacterial are ceftiofur or its pharmaceutically acceptable salt or form; Antiinflammatory is selected from deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, lumiracoxib, 2-(3, the 5-difluorophenyl)-3-[4-(methyl sulphonyl) phenyl]-2-cyclopentenes-1-ketone, (S)-6,8-two chloro-2-(trifluoromethyl)-2H-1-.alpha.-5:6-benzopyran-3-formic acid, 2-(3, the 4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3-(2H)-2H-Pyridazin-3-one, 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide, 1-benzyl-4-[(4-oxo-piperidine-1-yl) sulfonyl] piperidines-4-t-butyl formate, 4-[5-(phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide, its salt and prodrug; And anesthetis is lignocaine.

25. the method for claim 22, wherein said antibacterial is a Linezolid, and second kind of medicament comprises selective COX-2-inhibitor 2 and lignocaine.

26. the method for claim 22, wherein said medicine also comprise second kind of medicament.

27. comprise the pharmaceutical composition of excipient, described excipient comprises dispersible and insoluble two oleophylics of ethanol of (a) water, (b) microwax and (c) pharmaceutically-acceptable non-aqueous carrier; Described excipient has antibacterial that stably is dispersed in antimicrobial effective amount wherein and the second kind of medicament that is selected from anesthetis, sodium channel inhibitor and edema agent for the treatment of effective dose.

28. the compositions of claim 27, it is applicable to the breast that is administered to milcher by inculcating in the breast, to treat and/or prevent the bacterial disease of breast.

29. the compositions of claim 28, wherein said bacterial disease is mastitis.

30. the compositions of claim 27, it is applicable to ear's administration, to treat and/or prevent ear infection.

31. the compositions of claim 27; wherein said antibacterial is selected from: ceftiofur; cefalexin; cefradine; cefquinome; cefacetrile; cefpodoxime; cefovecin; cefalonium; cefuroxime; cefazidime; cefoperazone; sodiumcephemethcarboxylate; cephem; cefadroxil; cefazolin sodium; cefiximine; ceftaxime; ceftizoxime; ceftriaxone, adjacent formyl cefadole, the salt of following material: 3-acetate methyl-7-(imino group acetylamino)-cephalosporin acid derivative; 7-(D-alpha-amido-α-(to hydroxyphenyl) acetylamino)-3-methyl-3-cephem-1-formic acid; cis-7-((2-amino-1-thiazolyl) (methoxyimino) acetyl group) amino)-and the hydrochlorate of 3-methyl-3-cephem-4-formic acid, cephemcarboxylic acid, (pivaloyl oxygen) methyl-7-β-(2-(2-amino-4-thiazolyl) acetylamino)-3-(((1-(2-(dimethylamino) ethyl)-1H-tetrazolium-5-yl) sulfo-) methyl)-3-cephem-4-formates; cefalexin; 7-(D-2-naphthyl glycyl amino)-3-methyl-3-cephem-4-formic acid, its tautomer; stereoisomer; enantiomer; salt; hydrate and prodrug and its combination.

32. the compositions of claim 27, wherein said antibacterial comprise ceftiofur or its pharmaceutically acceptable salt or form.

33. the compositions of claim 27, wherein said antibacterial comprises ceftiofur hydrochloride.

34. the compositions of claim 27, wherein said antibacterial comprise the acid of ceftiofur crystal detachment.

35. the compositions of claim 32, the concentration of wherein said antibacterial is 1-1000mg/ml.

36. the compositions of claim 32, the concentration of wherein said antibacterial is 5-750mg/ml.

37. the compositions of claim 32, the concentration of wherein said antibacterial is 10-100mg/ml.

38. the compositions of claim 27, wherein said antibacterial comprises and is selected from Xia Shu De oxazolidone: eperezolid, Linezolid, N-((5S)-3-(3-fluoro-4-(4-(2-fluoro ethyl)-3-oxygen-1-piperazinyl) phenyl-2-oxygen-5-oxazolidinyl) methyl) acetamide, (S)-N-((3-(5-(3-pyridine radicals) thiophene-2-yl)-2-oxygen-5-oxazolidinyl) methyl) acetamide and (S)-N-((3-(5-(4-pyridine radicals) pyridine-2-yl)-2-oxygen-5-oxazolidinyl) methyl) acetamide hydrochloride.

39. each compositions among the claim 27-38, wherein said two oleophylics are the glyceride by the Pegylation of the alcoholysis reaction preparation of natural glycerin three esters and Polyethylene Glycol.

40. the compositions of claim 39, the glyceride of wherein said Pegylation comprise oleic acid or linoleic main fatty acid component.

41. the compositions of claim 39, the glyceride of wherein said Pegylation comprise oleic main fatty acid component.

42. the compositions of claim 39, the glyceride of wherein said Pegylation are pegicol 5-oleates.

43. the compositions of claim 39, wherein said two oleophylics account for the 0.01%-99% weight/volume of compositions.

44. the compositions of claim 39, wherein said two oleophylics account for the 1%-80% weight/volume of compositions.

45. the compositions of claim 39, wherein said two oleophylics account for the 3%-25% weight/volume of compositions.

46. each compositions among the claim 27-38, wherein said microwax account for the 0.001%-50% weight/volume of compositions.

47. each compositions among the claim 27-38, wherein said microwax account for the 0.1%-40% weight/volume of compositions.

48. each compositions among the claim 27-38, wherein said microwax account for the 1%-15% weight/volume of compositions.

49. each compositions among the claim 27-38, wherein said non-aqueous carrier is selected from: vegetable oil, mineral oil, medium chain is to long-chain fatty acid and its Arrcostab, and medium chain is to the propylene glycol diesters of long-chain fatty acid, fatty acid single, two and triglyceride, Polyethylene Glycol and its combination.

50. the compositions of claim 49, wherein said non-aqueous carrier are to be selected from following vegetable oil: Oleum Gossypii semen, Semen Maydis oil, Oleum sesami, soybean oil, olive oil, Oleum Cocois, fractionated Oleum Cocois, Oleum Arachidis hypogaeae semen, sunflower oil, safflower oil, almond oil, American Avocado Tree oil, Petiolus Trachycarpi oil, palm-kernel oil, babassu oil, beech nut oil, Semen Lini oil, rapeseed oil and its combination.

51. the compositions of claim 49, wherein said non-aqueous carrier is an Oleum Gossypii semen.

52. sad for 45%-80% of the compositions of claim 49, capric acid that wherein said non-aqueous carrier packet content is 20%-45% and amount is radix with the weight of non-aqueous carrier.

53. the compositions of claim 49, wherein said non-aqueous carrier account for the 0.5%-99% weight/volume of compositions.

54. the compositions of claim 49, wherein said non-aqueous carrier account for the 10%-95% weight/volume of compositions.

55. the compositions of claim 49, wherein said non-aqueous carrier account for the 40%-90% weight/volume of compositions.

56. the compositions of claim 27, wherein said second kind of medicament is anesthetis.

57. the compositions of claim 27, wherein said second kind of medicament is sodium channel inhibitor.

58. each compositions among the claim 25-36, it also comprises at least a following excipient that is selected from: antioxidant, antiseptic, stabilizing agent, wetting agent, lubricant, emulsifying agent, salt, coloring agent, alcohols and the buffer agent of adjusting osmotic pressure.

59. comprise the pharmaceutical composition of excipient, described excipient comprises dispersible and insoluble two oleophylics of ethanol of (a) water, (b) microwax and (c) pharmaceutically-acceptable non-aqueous carrier; What described excipient had the antibacterial that stably is dispersed in antimicrobial effective amount wherein and a treatment effective dose comprises antiinflammatory and narcotic second kind of medicament.

60. the compositions of claim 59, wherein said two oleophylics are pegicol 5-oleates; Non-aqueous carrier is an Oleum Gossypii semen; Antibacterial comprises ceftiofur or its pharmaceutically acceptable salt or form; Antiinflammatory is selected from: deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, lumiracoxib, 2-(3, the 5-difluorophenyl)-3-[4-(methyl sulphonyl) phenyl]-2-cyclopentenes-1-ketone, (S)-6,8-two chloro-2-(trifluoromethyl)-2H-1-.alpha.-5:6-benzopyran-3-formic acid, 2-(3, the 4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methyl sulphonyl) phenyl]-3-(2H)-2H-Pyridazin-3-one, 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide, 1-benzyl-4-[(4-oxo-piperidine-1-yl) sulfonyl] piperidines-4-t-butyl formate, 4-[5-(phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide, its salt and prodrug; And anesthetis is lignocaine.

61. goods, but it comprises the container or the conveyer device of the wall with oxygen flow, and have the compositions of the claim 27 that is mounted in it.

62. the goods of claim 61, but wherein said wall is to be made by the material that comprises poly oxygen flow.

63. the goods of claim 61, wherein said compositions table reveal the chemistry and/or the physical stability of prolongation.