KR100780983B1 - Dispersible formulation of an anti-inflammatory agent - Google Patents

Abstract

The present invention relates to a method for treating and / or preventing inflammation in a body fluid-containing organ having natural outer spheres, such as the breast of a milk-producing animal or the ear of a subject. The present invention further relates to dispersible pharmaceutical compositions suitable for infusion into said organs according to the methods of the present invention, and methods of making such compositions.

Anti-inflammatory agents, vehicles, body fluid-containing organs, amphiphilic oils, microcrystalline waxes, non-aqueous carriers

Description

Dispersible formulation of an anti-inflammatory agent

The present invention relates to a method for treating and / or preventing inflammation in a body fluid-containing organ having natural outer spheres, such as the breast of a milk-producing animal or the ear of a subject. The present invention further relates to dispersible pharmaceutical compositions suitable for infusion into said organs according to the methods of the present invention, and methods of making such compositions.

Mastitis is an inflammation of the mammary gland of a milk-producing animal, for example a dairy cow, most often caused by a bacterial infection. Bacteria enter the animal's papillary ducts and can cause acute, clinical or subclinical mastitis. More than 135 organisms have been recorded as causative pathogens for bovine mastitis. Three of the main groups of pathogens are Gram-positive Cocous, Gram-negative Bacillus and Gram-positive Bacillus. Metabolic disturbances resulting from hygiene, environmental factors and high milk production combine to create a condition favorable for the development of mastitis. An increase in the number of somatic cells associated with mastitis is positively associated with infection and negatively associated with milk production. Frequently, infected cows should be removed from the herd to prevent milking. Mastitis often affects cows throughout their lives if the disease is not treated properly. The infection rate is on average 10-30% of the cattle in the herd, with losses ranging from $ 185 to $ 250 per cow per year. Bovine mastitis is the most economically damaging disease in dairy farming, with losses estimated at $ 2 billion annually in the United States alone. Most of these losses are due to reduced milk production.

Since inflammation and leukocytosis resulting from intestinal bacterial mastitis often persist after further bacteria cannot be separated from the gland, long-term anti-inflammatory drug therapy may be useful for the treatment of mastitis.

Intramammary administration of dispersible compositions comprising antibacterial agents for the treatment of mastitis in milk-producing animals is well known. Several compositions suitable for such administration are formulated as oil-based formulations.

US Pat. No. 3,636,194 (Parizeau) describes a composition for treating mastitis by intramammary injection, comprising an alcohol-soluble fraction of antibiotics, vegetable oils, natural lecithin phospholipids for promoting the dispersion of oils in milk. Wherein the phospholipid is selected from the group consisting of phosphatidyl choline and phosphatidyl ethanolamine and mixtures thereof and is present in an amount of at least 0.25% in the oil. Such compositions are described to provide fast dispersion and short milkout time into milk.

British Patent Application No. 1,181,527 describes a composition for treating mastitis comprising an active ingredient and a pharmaceutically acceptable oil base, wherein the composition is substantially completely alcohol-soluble to promote dispersion of the composition in milk. It includes a phospholipid substance consisting of.

European Patent Application No. 0 222 712 is dispersed in an oil consisting of a mixture of triglycerides of palmitic acid and stearic acid with polyoxyethylenated cetyl alcohol and stearyl alcohol and retained in an oily medium of an inorganic, plant, synthetic or mixed extract A composition comprising at least one antimicrobial agent is described. Such compositions are said to accelerate the release of antimicrobial agents in the breast to enhance their biological potential and reduce milk downtime.

The use of anti-inflammatory agents to treat mastitis has also been suggested.

Isakson & Talley, US Pat. No. 5,756,529, describes how to use pyrazolyl benzenesulfonamide compounds to treat inflammation in companion animals. These compounds are said to be useful for the treatment of pain, fever, joint disease, trauma, arthritis, myositis, tendinitis, horse abdominal pain, mastitis, peritonitis, dermatitis, burns, gingivitis, irritability, conjunctivitis, eye inflammation, boils and myocardial ischemia Lose.

International Patent Publication No. WO 02/22107 is one comprising anti-infective agents, anti-neoplastic agents, immunomodulators, antipyretics, analgesics and anti-inflammatory agents (eg COX-2 inhibitors) in liquid carriers modified to have increased levels of oxidation products. The composition containing the above bioactive agent is described. Such compositions may be administered parenterally (eg, subcutaneously, intramammary, intravenously, intraperitoneally or intramuscularly), topically, vaginally, orally or rectally.

International Patent Publication No. WO 02/006865 describes one or more bioactive materials in a non-aqueous carrier, wherein the composition is adjusted to have a water activity of about 0.2 to about 0.5. Parenteral, topical, oral, vaginal, rectal and intramammary routes of administration are shown. Bioactive agents include anti-infective agents, anti-neoplastic agents, immunomodulators, antipyretics, analgesics and anti-inflammatory agents (eg COX-2 inhibitors).

International Patent Publication No. WO 99/20259 describes a combination of thiamphenicol and diclofenac for use in veterinary medicine to treat infections with associated inflammatory diseases.

International Patent Publication No. WO 01/60409 describes a paste composition comprising a therapeutic agent, a fumed silica, a viscosity modifier and a hydrophilic carrier, wherein the therapeutic agent is an insecticide, acaricide, insect repellent, antibiotic, growth promoter, fat soluble NSAID, avermectin, Milbemycin, nordulisporic acid, estrogen, progestin, phenylpyrazole, substituted pyridyl methyl derivatives and COX-2 inhibitors. Oral, topical, dermal and subcutaneous routes of administration are contemplated for paste compositions. Such compositions are said to have applications in veterinary practice in the treatment of diseases such as pneumonia, mastitis, uteritis, rhinitis and bronchitis.

US Patent Application Publication No. 2002/0032228 describes the use of heterocycle containing compounds, such as diphenyl heterocycle derivatives, for the treatment of diarrhea disease, whooping cough, anthrax, smooth muscle hydrocephalus and mastitis. Celecoxib and rofecoxib are listed as preferred diphenyl heterocycle derivatives.

The Labrafil Product Brochure (Notice OL 0050 / 5th edition) from Gattefosse Corporation includes excerpts from the dissertation by Vallette (1957) that describe the characteristics of the Labrafil ^™ M-1944CS in the ear canal. . The same dissertation describes an experiment involving the injection of Labrafil ^™ M-1944CS mixed with Gentian violet into bovine papilla. Labrafil ^™ has been found to wet the entire surface of the parenchyma of the breast and reach the posterior mammary ganglion.

Two publications (Gao et al. (1995) in Pharmaceutical Research 12 (6), 857-868, "Controlled release of a contraceptive steroid from biodegradable and injectable gel formulations: in vitro evaluation" and "Controlled release of a contraceptive steroid from biodegradable and injectable gel formulations: in vivo evaluation ") describe the preparation of gels comprising levonorgestrel, Labrafil ^™ M-1944CS and glyceryl palmitostearate.

Ear disorders are the most frequent among children in the United States, and are classified as follows after the common cold. Most ear disorders are the result of painful inflammatory reactions to infections, allergic reactions or trauma to the ear. Ear infections may be of bacterial, fungal or viral origin and the determination of the exact etiology is often not feasible because it is often difficult to isolate and culture the causative organism. Otitis (ear infection), otitis media (inflammation of the middle ear) and ear (otitis media due to rupture of the tympanic membrane) are among the most prevalent ear disorders.

Otitis media associated with the ear canal section of the ear canal is a common ophthalmologic problem that occurs mainly during hot and humid climates and is five times more frequent in swimmers than non-swimmers. In the early stages, symptoms include itching and pain in the ear canal and are alleviated by applying pressure around the ear canal, pulling the earlobe, or moving the jaw. In the final stage, pus develops in the ear canal and hearing can be reduced. More than 90% of otitis externa are due to bacterial and fungal infections.

Pathological symptoms may arise from and cause changes in the surface tension of the tissue surface, especially the air / liquid interface of epithelial surface tissue. The outer ear canal is lined with epithelium. Earwax exudates commonly secreted into epithelial tissue lining the ear canal confer an especially high surface tension. Inflammatory by-products can further increase this surface tension. Increased surface tension is an important factor in both the symptoms and treatment of otitis. In addition, even if the conduit is not closed, the increased surface tension imparted to the epithelial lining of the outer ear canal tends to inhibit uniform and / or effective application of the therapeutic agent.

In the past, otitis externa has been treated with topical application of therapeutic agents that exhibit antimicrobial activity and anti-inflammatory activity. It is caused by a broad spectrum of topically effective antibiotic ear suspensions, including antibacterial agents such as neomycin sulfate, colistin sulfate, polymyxin B, or combinations thereof, all of which have a broad spectrum effect. It has been used to destroy bacteria. Antimycotic topical agents such as nistatin and clotrimazole have been used to destroy underlying fungal diseases. In addition, antiviral acyclovirs have been used to treat viral otitis externa, including shingles.

Anti-inflammatory agents, including, for example, hydrocortisone, hydrocortisone acetate and dexamethasone sodium phosphate, which are often included in the topical action suspensions described above, have been used to modulate the inflammatory process of otitis externa. Often antimicrobial and anti-inflammatory agents are used in combination to treat not only the inflammatory process itself, but also the causative triggers that cause it, such as bacterial infections. In addition, they are often administered in suspension in the form of drops for topical administration to the infected ear. This medicament is used to draw the suspension into the ear canal to deliver more evenly to and enhance the epithelial lining of the ear canal. However, due to the exudates present in the purulent form of otitis externa and the earwax present in virtually all inflammatory symptoms, high surface tension interferes with the uniform distribution of these drugs throughout the outer ear canal.

The most common otitis media with ear impairment is the leading cause of hearing loss in the United States, and represents an important deficiency that interferes with childhood learning processes (Estrada (1997), Infect. Med. 14 (3), 239-244). Otitis media accounts for more than 35 percent of all children who visit a pediatrician each year, and make up more than $ 3.5 billion of US health care annually.

During an episode of otitis media, the relatively high surface tension present at the air / liquid interface located in the epithelial lining of the lumen increases the opening pressure required to open these channels.

Typical ear infection disorders, such as otitis media, are treated as a course of antibiotic therapy (The Merck Maraual, 17th edition (1999), Section 7, Chapter 84). Systemic administration of antibiotics generally requires high initial doses and significant delays to achieve therapeutic levels in the ear. Systemic application of drugs via the parenteral or oral route eventually reaches the Yusut Tachio tube and middle ear, but may have deleterious systemic effects and, more importantly, where concentrated concentrations of applicable drugs are actually needed Is not particularly effective at delivering directly to the target tissue. At the same time, direct drug application is complicated by the sealed chamber structure of the middle ear.

Combinations of antibacterial and anti-inflammatory agents formulated together in pharmaceutically acceptable vehicles have been proposed for topical application to the ear in various patents and publications, including those cited below.

US Patent No. 6,395,746 to Cagle et al.

U.S. Patent No. 6,440,964 to Cagle et al.

US Patent No. 6,509,327 (Cagle et al.).

U.S. Patent No. 5,679,665 (Bergamini et al.).

US patent number. 5,965,549 (Purwar & Goldman).

US Patent Application Publication No. 2001/0049366.

US Patent Application Publication No. 2002/0142999.

US Patent Application Publication No. 2002/0044920 describes TNF antagonists and pyrimidine synthesis inhibitors for steroids, anti-inflammatory compounds (such as non-steroidal anti-inflammatory drugs (also known as NSAIDs) or COX-2 inhibitors), cytotoxic compounds, anti-neoplastic It has been described to treat immune-mediated ear disorders by administration with metabolites or secondary antirheumatic agents.

US Patent Application Publication No. 2002/0076383 describes the administration of an aerosol via the ear canal via a composition comprising an amount of lipid surfactant, dispersant and propellant effective to lower the surface tension of the air / liquid interface to epithelial tissue lining. Wherein the dispersant is selected from the group consisting of lipids, sterols, fatty acids, cholesterol esters, phospholipids, carbohydrates and proteins, all in powder form. This composition is said to increase the ear canal patency and prevent the occurrence of otitis externa.

U.S. Patent Application Publication No. 2002/0064503 discloses lipid surfactants in an amount effective to lower the surface tension of the air / liquid interface to epithelial tissue lining, and all of the powdered lipids, sterols, fatty acids, cholesterol esters, phospholipids, carbohydrates and proteins. It describes the administration of an aerosol via an external airway to a composition comprising a dispersant selected from the group consisting of: This composition is said to increase the openness and pressure equalization performance of the Yusutachio tube lumen.

Ear drops have been considered, for example, as the type of agent for selective COX-2 inhibitors in the patents and publications cited separately below.

US Patent Application Publication No. 2001 / 004J726.

U.S. Patent Application Publication No. 2001/0053764.

US Patent Application Publication No. 2002/0010146.

US Patent Application Publication No. 2002/0013318.

US Patent No. 6,307, 047 (Black et al.).

US Patent No. 6,329, 526 (Adams et al.).

All patents and publications cited above are hereby incorporated by reference.

Despite recent progress made in understanding the cause of ear disorders, it is largely unpredictable and difficult to treat effectively. Thus, it is useful to provide effective methods and compositions for preventing and treating ear disorders and related complications.

The most commonly used containers and delivery means for compositions for intramammary administration to treat or prevent mastitis in milk-producing animals or compositions for ear administration for treating ear disorders are oxygen-permeable plastic materials, for example Polyethylene, polypropylene, and the like and mixtures thereof. The use of oxygen-permeable packaging containers and delivery means for anti-breast infection compositions and compositions for the treatment or prevention of otic disorders, where the composition comprises, for example, oxidative degradation components, such as active drugs or excipients, It causes serious problems with the long term chemical and / or physical stability of the compositions contained therein.

The references cited above describe many compositions for the treatment of mastitis or the treatment of ear disorders, but none of the literature focuses on the problem of providing extended chemical and / or physical stability of compositions packaged in oxygen-permeable containers. Not matched, the composition comprises a pharmaceutically active agent and / or excipient which is susceptible to oxidative degradation. Notwithstanding the above teachings, there is a need in the art for pharmaceutical compositions having one or more of the following advantages over compositions of the prior art used in the treatment of mastitis or compositions of the prior art used for the treatment or prevention of ear disorders. Still present in: (a) expanded chemical and / or physical stability when packaged in oxygen-permeable containers and delivery devices, especially even when the composition contains a pharmaceutical active agent or excipient that is susceptible to oxidative degradation, (b) Safe and effective treatment of inflammatory-components of mastitis or ear disorders, (c) safe and effective treatment of pain, inflammation, edema, fever and boil associated with mastitis or ear disorders, (d) minimal or no irritation after administration of the composition, ( e) rapid dispersibility of the anti-mammalitis composition in milk and in mammary fluids to rapidly achieve effective drug levels at the site of inflammation, (f) salts Rapid dispersibility of the ear composition in a wet environment of ear viscous to rapidly achieve effective drug levels at the site, (g) lowering the surface tension of the air / liquid interface of epithelial tissue, increased openness of the ear canal, and (h) Protective coating on the swollen mucous membrane of the ear.

Summary of the Invention

In accordance with the present invention novel treatment methods and pharmaceutical compositions have been developed that have some or all of the advantageous properties described above. In particular, new methods are provided for treating and / or preventing inflammation in body fluid-containing organs having natural outer spheres, such as the breast of a milk-producing animal or in the ears of a human or animal. The method of the present invention comprises administering an anti-inflammatory agent to the trachea via an external sphere and concurrently administering a second drug described herein. Anti-inflammatory agents, in addition to the aforementioned drugs, include a vehicle comprising (a) an amphipathic oil that is water dispersible and ethanol insoluble, (b) microcrystalline wax, and (c) a pharmaceutically acceptable non-aqueous carrier. It is administered as a composition comprising.

Such compositions have low interfacial tension when placed in contact with an aqueous medium. Without wishing to be bound by theory, it is believed that such low interfacial tensions result in compositions that disperse immediately in a humid environment of mammary fluids such as milk and mucus in the ears. In a preferred embodiment of the invention, the composition is dispersed in bodily fluid when administered to a bodily fluid-containing organ.

Preferred anti-inflammatory agents for use in the methods of the invention are selective COX-2 inhibitors.

The methods of the invention may include intramammary infusion of the composition for the treatment of mastitis or other diseases of the breast, or infusion of the composition for the treatment and / or prevention of ear disorders, for example in milk-producing animals. It is effective in various inflammatory disorders that may be associated with various organisms. The term “injection” herein includes all operations in which the liquid composition flows to the body fluid-containing organ through an external orifice, such as a teat canal in the case of an inflammatory infusion or an ear canal in the case of an ear infusion. In the present invention, "infusion" and "injection" are substantially synonymous. For example, the compositions of the present invention can be administered intramammary by inserting the cannula nozzle of a mastitis syringe into the outer opening of the teat canal and injecting it through the nozzle into the breast.

In another embodiment of the anti-inflammatory agent, for example, the COX-2 inhibitor is administered in parallel treatment with the second drug. The second drug may be a therapeutically active agent useful for the treatment of mastitis or ear disorders. Such second drugs include, but are not limited to, antibacterial agents, anti-neoplastic agents, anesthetics, sodium channel blockers, antipyretics, analgesics, anti-edema agents, and combinations thereof.

The second drug may be administered by a route other than that of the anti-inflammatory agent. Alternatively, both drugs can be administered via the same route, i.e. through the external sphere of the organ, for example the papillary conduit for the breast or the external ear canal for the ear. When administered by the same route, both drugs are preferably administered by intramammary or ear infusion in the form of a liquid composition comprising the vehicle described above. In particular, it is preferred that the anti-inflammatory agent and the second drug be administered in a single composition comprising both drugs.

Accordingly, there is further provided a pharmaceutical composition comprising a vehicle comprising (a) an amphiphilic oil that is water dispersible and ethanol insoluble, (b) microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier. . The vehicle has an anti-inflammatory effective amount of anti-inflammatory agent, for example a selected COX-2 inhibitor, which is stably dispersed therein.

In one embodiment, the anti-inflammatory and / or excipients in the composition are susceptible to oxidative degradation and such compositions exhibit extended chemical and / or physical stability when packaged in containers or delivery devices having oxygen-permeable walls.

Since the composition of the present invention has a low interfacial tension in aqueous body fluids, the dispersibility of the composition in milk and breast fluid is increased compared to conventional oil based formulations. This allows for rapid dispensing of the composition through the breast so that the anti-inflammatory and / or second drug quickly reaches the swollen tissue, providing an effective level of drug at the site of inflammation. The interfacial tension of the composition in aqueous body fluids determines the energy required for dispersion and scattering of the composition in body fluids and the energy required for suspended particles in the composition across the oil / milk or oil / breast interface boundaries.

In addition, the low interfacial tension of the composition of the present invention increases the dispersibility of the composition in a humid environment of the viscous ear of the ear as compared to conventional compositions. Rapid distribution through the wax-containing lipid and mucous membranes of the ear canal allows the anti-inflammatory agent and / or the second drug to quickly reach swollen tissue, providing an effective level of drug at the site of inflammation. Such compositions may also provide a protective coating against swollen mucous membranes of the ear.

Preferably, the methods or compositions of the present invention provide effective treatment of inflammatory components of breast or ear disorders. Preferably, the methods or compositions of the present invention provide effective treatment and / or prevention of pain, inflammation, boils, edema and / or fever associated with this disorder.

When administered by intramammary infusion, for example in the treatment of mastitis, preferred methods and compositions may have additional advantages. For example, preferred methods enable suitably short milk break times. The milk stop time of the lactating cow is the time from the administration of mastitis treatment to the resumption of sellable milk production. Following this administration, the concentration of active agent (s) in the milk must be lowered to a level acceptable to the appropriate regulator before the milk is considered suitable for human consumption. Suitably short milk break times reduce monetary losses for dairy farmers caused by mastitis outbreaks.

Alternatively or in addition, preferred methods of the present invention allow for a short milk retention time after calfing after treating mastitis of dry cow, with no activity remaining in the offspring.

Alternatively or in addition, the preferred method of the present invention allows for a zero slaughter meat dead period after treatment of mastitis. This property is particularly important because it allows the farmer to dispose of the treated cow at any time, which is more financially advantageous than having to keep and breed the cow for a certain time after treatment.

When administered by ear infusion, for example in the treatment of an infectious disorder of the ear with an inflammatory component, preferred methods and compositions of the present invention may have additional advantages. For example, the preferred method increases the openness of the ear canal, thereby reducing the resistance to sound transmission, and improving the clarity and sensitivity of hearing.

Alternatively or in addition, preferred methods of the present invention provide a coating that protects the epithelial lining of the ear against the deleterious effects of water and aqueous toxins, irritants and antigenic substances to help prevent ear disorders.

A further advantage of the methods and compositions of the present invention in intramammary or ear use is to enable targeted delivery of one or more anti-inflammatory agents to the site of inflammation. When a composition of the invention comprising both an anti-inflammatory agent and a second drug as defined herein is used, targeted delivery of both agents to the site of infection and / or inflammation is provided.

A further advantage of the preferred compositions of the present invention for intramammary or ear administration is that there is minimal to no irritation after administration.

A further advantage of the compositions of the present invention is improved physical stability, for example by improved composition resuspension, as compared to conventional oils and aqueous compositions. The compositions of the present invention have been found to agglomerate certain drugs to improve resuspension and to eliminate the problem of suspending cake formation and the possibility of delivering weaker or non-effective doses than normal effects.

Methods of preparing the pharmaceutical compositions of the present invention are provided. The process of the present invention comprises mixing the water dispersible and ethanol insoluble amphiphilic oil, microcrystalline wax, pharmaceutically acceptable non-aqueous carrier and anti-inflammatory agent, for example a COX-2 inhibitor, in a suitable order For example, preferably with a composition having extended chemical and / or physical stability as described herein.

Accordingly, the present invention provides an answer to long lasting problems in the art and has one or more advantages over the prior art methods and compositions. Other features, advantages and advantages of the invention will be apparent from the following description.

The present invention provides an anti-inflammatory effective amount of an anti-inflammatory agent; And an anti-inflammatory agent in the form of a pharmaceutical composition comprising (a) a water-dispersible and ethanol-insoluble amphiphilic oil, (b) a microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier. It provides treatment and / or prophylaxis of inflammation in a fluid-containing organ having natural external spheres, including administration via external spheres to a fluid-containing organ having spheres. The present invention also provides the use of a composition of the invention in the manufacture of a medicament for treating or preventing inflammation in a body fluid-containing organ having a natural outer sphere. In addition, the present invention provides the use of the composition of the present invention in a method of treating or preventing inflammation in a body fluid-containing organ having natural outer spheres.

The methods of the invention are particularly useful for the treatment and / or prevention of inflammation accompanying symptoms of infection. An “infection symptom” herein includes a disease, disorder or symptom mediated by a pathogenic bacterium, or is in response to treatment with an antibacterial agent, for example an antibiotic drug.

Reference to a accompanying method and to a composition comprising a “anti-inflammatory agent” will be understood to include methods and compositions in which one or more anti-inflammatory agents are used. In addition, one or more therapeutically active agents other than anti-inflammatory agents may optionally form a “second drug” herein.

As used herein, the term “anti-inflammatory amount” refers to an amount of anti-inflammatory agent sufficient to reduce, alleviate, prevent or delay the onset of one or more symptoms of an inflammatory condition to be treated when administered by the methods of the present invention. As used herein, the term “therapeutically effective amount”, when administered by a method of the invention, reduces, alleviates, prevents or delays the onset of one or more symptoms of a condition to be treated, or reduces the number and / or activity of the causative organism. It refers to the amount of active agent sufficient to make. The phrase "in each therapeutically effective amount" means that the amount of anti-inflammatory agent and the amount of the second drug, when administered in combination therapy in accordance with the present invention, have anti-inflammatory effects and antibacterial, analgesic, sodium channel blockade, anti-edema, analgesic, anti-neoplastic and (Or) sufficient to provide all of the selected effects among the antipyretic effects. This amount may be the same, more or less than the amount of therapeutically effective anti-inflammatory agent or the second drug when used as monotherapy.

Fluid-containing organs contemplated herein include breast organs, such as breast-producing animals, such as cattle, goats or sheep. A "milk-producing animal" may be a female of any mammalian species, but is preferably an animal, for example a cow, a goat or a sheep, raised for the purpose of providing milk, and at or in the condition of inflammation and / or infection Includes animals that secrete or do not secrete milk at the time. The natural outer sphere of the breast organ is the cavity of the papillary conduit. In addition, fluid-containing organs include the ears of a human or animal subject. The natural outer sphere of the ear is the hole in the outer ear canal.

The present invention also provides a pharmaceutical composition comprising an anti-inflammatory agent in combination with a vehicle comprising (a) an amphiphilic oil that is water dispersible and ethanol insoluble, (b) microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier. As a composition, a therapeutically effective amount is administered via the external sphere to a body-containing organ having natural external spheres; Provided is a method of treating inflammation in a body fluid-containing organ having natural outer spheres comprising administering a therapeutically effective amount of a second drug as defined herein as a combination treatment with the anti-inflammatory agent.

The term “combination treatment” herein means a treatment regimen in which the anti-inflammatory agent and the second drug are administered separately or together in a manner that provides a beneficial effect by the co-action of these therapeutic agents. Such beneficial effects may include, but are not limited to, pharmacokinetic or pharmacodynamic co-action of the therapeutic agent. Concomitant treatment may, for example, enable the administration of smaller doses of one or both agents than the amount normally administered during single treatment, thereby reducing the risk associated with high doses or reducing the occurrence of side effects. Alternatively, the combination treatment may exhibit an increased therapeutic effect at normal doses of each agent when treated alone. “Concomitant treatment” herein is not intended to include the administration of two or more therapeutic agents as part of a separate monotherapy that inadvertently and optionally represents continuous or simultaneous treatment.

Administration of the anti-inflammatory agent and the second drug is usually carried out over a limited time period (usually minutes, hours, days or weeks depending on the combination selected). These therapeutic agents can be administered in a sequence, ie at different times, separated by a time difference of typically up to about 24 hours, or in a substantially simultaneous manner.

When administered simultaneously, the anti-inflammatory agent and the second drug may be administered in separate or co-formulations, ie in a single dosage form. If the two agents are administered in sequence or in separate dosage forms, the second drug may be in any suitable route and in any pharmaceutically acceptable dosage form, e.g., in a route different from that used for anti-inflammatory agents and ( Or) in dosage form. Alternatively, the second drug, such as an anti-inflammatory agent, is dispersed in a body fluid containing a (a) amphiphilic oil that is water dispersible and ethanol insoluble, (b) microcrystalline wax, and (c) a pharmaceutically acceptable non-aqueous carrier. It can be administered via the natural outer sphere of the organ containing it. In a preferred embodiment, both drugs are co-dispersed in the same vehicle and administered in a single operation.

Preferably, the second drug is formulated in a pharmaceutically acceptable vehicle, and both the anti-inflammatory agent and the second drug are administered to the same body fluid-containing organ, for example by intramammary or ear injection. Pharmaceutically acceptable carriers or vehicles are those which do not have any unacceptable damaging or toxic effects when administered in the required amount as a component of the composition. No excipient component of such a carrier or vehicle reacts in a deleterious manner with the therapeutic agent in another excipient or composition.

Pharmaceutical compositions comprising an anti-inflammatory agent are liquid injectable or injectable compositions having the formulation dispersed in a vehicle as described herein. The term "dispersed" herein means to be dissolved (ie, molecularly dispersed) or colloidally dispersed, for example as an emulsion or suspending agent. Typically, the anti-inflammatory agent is suspended in solid particulate form in the vehicle.

The vehicle includes three essential ingredients, optionally with additional ingredients.

The first of these essential ingredients is an amphiphilic oil that is water dispersible and ethanol insoluble. "Amphiphilic oil" is defined as a material having a molecular structure having a distinct polar region and a distinct non-polar region. Structurally, these two regions of the amphiphilic oil are far enough apart that the unique properties of the two regions are clearly distinguished. The term "ethanol insoluble" means that the amphiphilic oil is essentially insoluble in ethanol at 20 ° C.

The second essential component of the vehicle is microcrystalline wax.

The third essential component of the vehicle is a pharmaceutically acceptable non-aqueous carrier. Such carriers are typically oils more fully described below.

The choice of vehicle component is important for providing a composition that is dispersed in the body fluid when administered to a body fluid-containing organ. Without being bound by theory, it is believed that targeted delivery of anti-inflammatory agents and any second drugs to intratracheal inflammatory sites is achieved by dispersion in intratracheal fluids.

When the method of the present invention comprises injecting or injecting the composition into the breast via the papillary conduit, it may provide effective treatment of mastitis, other diseases of the breast and / or symptoms associated with breast disease. "Intramammary infusion" is the act of flowing a liquid composition through the teat canal to the breast, regardless of the time it takes. "Injection" and "injection" herein are substantially synonymous.

When the method of the present invention involves injecting or injecting a composition into the ear through the ear canal, the process described as "ear infusion", regardless of the view taken, provides for effective treatment and / or treatment of an ear disorder and / or complications associated therewith. ) Can provide a room. Subjects suffering from such ear disorders or related complications can be humans, pets, horses, farm livestock and the like.

Examples of such ear disorders include otitis externa (ear infection), otitis media (middle ear infection) (including acute, secretory, serous and chronic forms of otitis media); Iritis (otitis media caused by rupture of the tympanic membrane), acute mastoiditis, infections related to ear surgery (e.g., tympanic incision), scleroderma, earache, ear pain, ear infections, ear bleeding, lermuwai Lermoyez syndrome, Meniere syndrome, vestibular neuritis, benign paroxysmal positional dizziness, heterogeneous shingles, Ramsay Hunt syndrome, viral neuritis, ganglionitis, thyroid herpes, purulent otitis and viral endolamps Otitis, including otitis, perilymph fistula, senile hearing loss, drug-induced ear toxicity, auditory neuroma, otitis media, infectious tympitis, bullous tymitis, ear neoplasm, squamous cell carcinoma, basal cell carcinoma, other ear cancers, pre- Cancerous ear disease, non-chrome-friendly paraganglion tumor, chemosensitive tumor, glomerular jugular tumor, glomerular tympanic tumor, chondritis, ear myocardial dermatitis, malignant otitis, subchondral hematoma, ear canal, mesothelioma, blood Cystoma, osteomas, keloids, tinnitus, dizziness, tympanic infection, tympanic infection, earlobe, vertebral infection, prenegative and sensorineural hearing loss, epidural abscess, lateral venous thrombosis, subdural sinusitis, ear hydrocephalus, Dandy syndrome , Bullous tyrositis, diffuse otitis externa, foreign body, obstructive keratosis, binary fungus, trauma, acute atmospheric otitis media, acute ear canal occlusion, postoperative ear pain, complications associated with these infections (e.g., deafness, brain abscess, fever, pearloma, middle and inner ear) Calcification, ruptured eardrum, meningitis, facial paralysis, etc.), but is not limited thereto.

The methods of the present invention are particularly suitable for the treatment of infections with otitis externa, otitis media, ir and inflammatory components associated with surgical treatment of the ear.

In one embodiment, the ear disorder is neoplasia. Examples of such neoplasia include ear neoplasia, squamous cell carcinoma, basal cell carcinoma, malignant otitis media, malignant nonchrome-friendly paraganglia, malignant jugular tumor, malignant glomerular tympanic cancer, and pre-cancerous ear disease. It is not limited to this.

Treatment with anti-inflammatory agents in combination with a second drug improves treatment options compared to monotherapy. As noted above, the anti-inflammatory agent is dispersed in a vehicle comprising (a) an amphiphilic oil that is water dispersible and ethanol insoluble, (b) microcrystalline wax, and (c) a pharmaceutically acceptable non-aqueous carrier, eg For example, by intramammary or ear infusion, the second drug may be formulated in any acceptable immediate or sustained release pharmaceutical dosage form, but is administered, for example, by intramammary or ear injection. Suitable dosage forms of the second drug include suspensions, solutions, emulsions, tablets, capsules, pills, powders, granules, elixirs, tinctures, syrups, lozenges, dragees, gels, ointments, dispersible pastes, Slurries, aerosols, nebulizers, ear adjuvants, nasal drops, eye drops, suppositories, implants, and the like, but are not limited to, all routes, such as around the mouth and mouth, eg sublingual, Oral, including cheeks; Parenteral, eg, intramuscular, subcutaneous, intravenous, intraperitoneal, intraarticular, intradermal, intramedullary, sternum, intramedullary, synovial, intraluminal, intracardiac, intraventricular, capsule, intracranial, and the like; Intramammary, topical, transdermal, intranasal, ear, mucosal, rectal, vaginal, lung, and the like can be administered, but is not limited thereto.

Optionally, administration of the therapeutic agents described above may be performed in further combination with other biologically active agents and non-drug therapeutics.

In all embodiments of the invention, the one or more anti-inflammatory agents are administered locally. The advantage of this local administration is that the anti-inflammatory agent is preferentially drawn to its site of action, allowing for a faster therapeutic action and more complete delivery to the site of inflammation compared to other routes of administration, such as intramuscular, subcutaneous and oral routes. Local administration can reduce the total therapeutic dose for the indicated effects, thus avoiding the first pass effect of the liver. Local administration also reduces or eliminates collateral effects, particularly those associated with the active agent at sites other than the site of infection. In addition, local administration of the active agent can improve the therapeutic index by reducing its general toxicity and minimizing the risk of undesirable systemic effects. The therapeutic index is a measure of the limit between a therapeutically effective dose and a toxic dose of a drug, typically expressed as the ratio of LD ₅₀ (fatal dose to 50% of the population) to ED ₅₀ (therapeutically effective dose at 50% of the population). .

In a further aspect, the invention includes a vehicle comprising (a) an amphiphilic oil that is water dispersible and ethanol insoluble, (b) microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier, This provides pharmaceutical compositions for intramammary and / or ear infusions having anti-inflammatory effective amounts of anti-inflammatory agents, such as COX-2 inhibitors, stably dispersed therein.

Preferably, such compositions lower the high surface tension of the air / liquid interface of epithelial tissue associated with ear disorders to increase the ear canal patency. Reducing the surface tension of the air / liquid interface of the epithelial lining minimizes fluid accumulation, in some cases enabling the drainage of fluid retained in the conduit due to increased surface tension and / or (often elevated surface of tissue It allows separation of the adjacent epithelial wall and the opposite epithelial wall of the ear conduit (due to be close together with each other due to tension) to improve sound conduction. As used herein, the term "increased open negative" refers to the opening of the ear conduit to form an open conduit, and the reduction or removal of obstruction. Resistance to sound conduction is associated with the collection of bodily fluids, including swelling of the epithelial wall as a result of inflammation, accumulation of increased secretion of earwax secreted into the ear, and / or body fluids or exogenous water, including waste products of immune responses. Thereby resulting in volume reduction, partial obstruction or complete occlusion of the conduit.

In certain embodiments of the invention, the components of the composition (anti-inflammatory and / or second drug and / or excipient components) are susceptible to oxidative degradation. The compositions exhibit extended chemical and / or physical stability even when packaged in oxygen permeable containers or delivery devices. The term "extended chemical and / or physical stability" herein means that the composition of the invention has higher chemical and / or physical stability than the reference composition comprising the same drug in the same concentration. "Reference composition" in the present invention means a composition similar to the composition of the present invention but without one or both of amphiphilic oil and microcrystalline wax.

The oxygen permeable container or delivery device may be made of a suitable plastic material. Examples of such materials include, but are not limited to, polystyrene, polyacrylonitrile, polyvinyl chloride, and especially polymers and copolymers of polyolefins. Examples of the polyolefins include polyethylene, polypropylene, polybutene, polyisoprene, polypentene, copolymers thereof and mixtures thereof.

Compositions for intramammary administration are generally packaged in a syringe provided with a cannula nozzle for insertion into the teat to enable the composition to be pushed directly into the mammary gland directly through the teat canal. Intramammary suspension formulations are generally prepared in thickened vehicles to prevent debris of drug particles in the cannula nozzles, which can cause nozzle clogging that results in incomplete rejection of the composition.

Anti-inflammatory agents herein may have one or both of analgesic and antipyretic properties in addition to anti-inflammatory activity. The term “anti-inflammatory” herein includes compounds that are primarily analgesic or antipyretic and have an incidental anti-inflammatory effect. Examples of anti-inflammatory agents useful herein include, but are not limited to, aceclofenac, acemethasin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid (aspirin), S-adenosylmethionine, Alclofenac, Alclomethasone, Alfentanil, Algestone, Allylprodine, Alminopropene, Aloxyprin, Alphaprodine, Aluminum Bis (acetylsalicylate), Amcinond, Amfenac, Aminochlor Tenoxazine, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylone, aminopyrin, amicsetlin, ammonium salicylate, ampicoxycam, amtolmethin guacyl, anileridine, Antipyrine, Anthraphenin, Apazone, Beclomethasone, Bendazac, Benolylate, Benoxapropene, Benzpiperilone, Benzidamine, Benzylmorphine, Vermopropene, Betamethasone, Vezitramide, α-bisabolol , Bromfenac, p-bromo Acetanilide, 5-bromosalicylic acid acetate, bromosalginine, butetine, bucloxane, butcolom, budesonide, bupecsa film, butadizone, buprenorphine, butetacetin, butybufen, buttorpanol, carbamaze Pin, carbiphene, caprophene, casalam, celecoxib, chlorobutanol, chloroprednisone, chlortenoxazine, choline salicylate, cincopene, synmethasin, cinnaxicam, siramadol, clidanac, clobeta Sol, clocortolone, clomethasine, clonitogen, clonicin, clopilac, cloprednol, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate, cortisone, cortibazole, cropropamide, Crotetamide, Cyclozosin, Deplazacort, Dehydrotestosterone, Delacoxib, Desomorphine, Desonide, Desoxymethasone, Dexamethasone, Dexoxadrol, Dextromoramide, Dextropropoxyphene,Chosin, Diampramide, Diamorphone, Diclofenac, Difenamizole, Difenpyramid, Diclorasone, Diflucortolone, Diflunisal, Difluprenate, Dihydrocodeine, Dihydrocodeinone enol acetate, Di Hydrocodein phosphate, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxaldol, dimeptanol, dimethyl thiambutene, dioxapetyl butyrate, diphenhydramine hydrochloride, dipipanone, diprocetyl, Dipyrone, Ditazole, Dichlorpheniramine Maleate, Doxycam, Emorphazon, Ephenamic Acid, Enoxolone, Epyrizole, Eptazosin, Ethersate, Etenzamide, Etoheptazine, Etodolac, Ethoxazene, etoheptazine, ethylmethyl thiabutene, ethyl morphine, etodolak, etophenamate, etonitogen, etoricoxib, eugenol, felbinac, fenbufen, fenclofenac, fenclocic acid, fen Butchery, Feno Propene, fentanyl, pentiazac, pepradinol, peprazone, flocfenin, fluazacort, fluchloronide, flufenamic acid, flumethasone, flunisolide, flunicin, flunoxapropene, fluorine Sinolone acetonide, fluorinide, fluorinone acetonide, flucortin butyl, fluorocortolone, fluoresone, fluorometholone, fluperolone, flupyrithin, fluprednide, fluprednisolone, flupropene , Fluprocuazone, fluandrenolide, flubiprofen, fluticasone, formocortal, phosphosal, furofenac, gentisic acid, glafenin, glucametacin, glycol salicylate, Iazulene, hacinononide, halobetasol, halomethasone, halofredone, heroin, hydrocodone, hydrocortamate, hydrocortisone, hydromorphone, hydroxypettidine, ibufenac, ibuprofen, ibuproc 3, imidazole salicylate Yit, indomethacin, indopropene, isofezolac, isoflupredone acetate, isoladol, isometadon, isonicsin, isoxepac, isoxiccam, ketobemidone, ketoprofen, ketorolac, p- Lactophenetide, Lefetamine, Levalorphan, Levorpanol, Levofenacyl-Morpan, Lofentanil, Ronazolac, Lornoxicam, Roxoprofen, Lysine Acetylsalicylate, Lysozyme Chloride, Marge Predon, meclofenamic acid, medridone, mefenamic acid, meloxycamp, meperidine, meprednisone, meftazinol, mesalamine, metazosin, methadone, metrotrimeprazine, methyllephedrine hydrochloride, Methylprednisolone, methylsalicylate, methiazine acid, metopoline, metopon, miroprofen, mofebutazone, mopezolac, mometasone, Morazone, morphine, morphine hydrochloride, morphine sulfate, morpholine salicylate Silates, miropine, nabumetone, nalbuphine, nallopine, 1-naphthyl salicylate, naproxen, narcein, nepofam, nicomorphine, nifenazone, niflumonic acid, nimesulide, 5'-nitro-2'-propoxyacetanilide, norreborpanol, normetathone , Normorphine, norpipanone, noscapine, olsalazine, opaum, oxaceprole, oxametacin, oxaprozin, oxypinac, oxycodone, oxymorphone, oxyphenbutazone, papaveretum, paramethasone, Paraniline, parecoxib, parsalmid, pentazosin, peroxalk, phenacetin, phenadoxone, phenomorphan, phenazosin, phenazopyridine hydrochloride, phenocol, fenoferidine, fenofirazone, phenyl acetyl Salicylate, phenylbutazone, phenylpropanolamine hydrochloride, phenyl salicylate, penamimidol, piketoprofen, piminodine, pipebuzone, piperilon, pyrazolac, pyritramide, pyroxam, Pirprofen, pranoprofen, prednicarbate, predni Solon, prednisone, prednisbal, prednilidene, proglumetacin, propheptazine, promethol, propacetamol, propridine, propiram, propoxyphene, propifenazone, proquazone, protizinic acid , Proxazole, ramipenazone, remifentanil, limazolium methylsulfate, rofecoxib, salaceamide, salicylic acid, salicylate, salicylate o-acetic acid, salicylic acid, salicysulfuric acid, salsalate, salberine , Cerathiopeptidase, Simetride, Sudoxicam, Sufentanil, Sulfasalazine, Sulpindak, Superoxide Dismutase, Supropene, Succibuzone, Talniflumate, Tenipap, Tenoxycam, Terro Phenamate, tetrandrine, thiazolinobutazone, thiapropenoic acid, tiaramid, tilidine, tinoridine, thiopinac, thioxapropene, thixocortol, tolpenamic acid, tolmethine, tramadol, triamcinolone, tro Fexin, Valdecoxib, Biminol, Xsenbucin, Xsy Propene, include jalto propene, map meth sour crude mepi lock or the like, and combinations thereof.

In one embodiment the anti-inflammatory agent is a steroid. Suitable steroids include aclomethasone, amcinolone, betamethasone, betamethasone 17-valerate, clobetasol, clobetasol propionate, clocortolone, cortisone, dehydrotestosterone, deoxycorticosterone, desony De, desoxymethasone, dexamethasone, dexamethasone 21-isonicotinate, diflorasone, fluorinide, fluorocinolone, fluorometholone, flulandrenoid, fluticasone, hacinonoid, halobetasol , Hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone hemisuccinate, hydrocortisone 21-lysinate, hydrocortisone sodium succinate, isoflupredone, isoflupredone acetate, methylprednisolone, methylprednisolone Acetate, methylprednisolone sodium succinate, methylprednisolone sulphate, Metason, prednicabate, prednisolone, prednisolone acetate, prednisolone hemisuccinate, prednisolone sodium phosphate, prednisolone sodium succinate, prednisolone valerate-acetate, prednisolone, triamcinolone, triamcinolone acetonide, and the like, and combinations thereof. It is not limited.

In another embodiment, the anti-inflammatory agent is, for example, alfentanil, allylprodine, alphaprodinin, anileridine, benzylmorphine, benzitramide, buprenorphine, butopanol, clonitogen, codeine, cyclazin, Desormorphone, dextromemoramide, dextropropoxyphene, dezosin, dimpromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepetanol, dimethylthiambutene, dioxapetyl Butyrate, Dipipanone, Eptazosin, Etoheptazine, Ethylmethylthiambutene, Ethylmorphine, Etonitagen, Fentanyl, Heroin, Hydrocodone, Hydromorphone, Hydroxypettidine, Isometadon, Ketobemidone, Levalorphan, levorpanol, levofenacyl-morphan, lofentanil, meperidine, meptazinol, metazosin, methadone, methopone, morphine, myropin, nalbuphine, nallopine, narcein, nicomorphine , Norreborpanol, normethadone, normorphine, no Lepiphanone, opaum, oxycodone, oxymorphone, papameretium, pentazosin, phenadoxone, phenazosine, phenomorphan, phenoferidine, pyminodine, pyritramide, proheptazine, promethol, properi Analgesics selected from dine, propiram, propoxyphene, sufentanil, tilidine, tramadol and the like, and combinations thereof.

In another embodiment, the anti-inflammatory agent is an NSAID, for example salicylic acid derivatives (e.g. salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, olsalazine, salsalate, sulfasalazine, etc.), indole and indene acetic acid ( Examples: indomethacin, etodolak, sulindac, etc.), phenamate (e.g. etophenamic acid, meclofenamic acid, mefenamic acid, flufenamic acid, niflumic acid, and tolenic acid), heteroaryl acetic acid (e.g. Methacin, Alclofenac, Clidanac, Diclofenac, Penclofenac, Pentiazac, Furofenac, Ibufenac, Isoxepac, Ketorolac, Oxypinac, Thiopinac, Tolmetin, Zidomethacin, Zomepilac, etc. ), Aryl acetic acid and propionic acid derivatives (e.g. aminopropene, benoxapropene, bucloxane, carpropene, fenbufen, phenopropene, flupropene, flubiprofen, ibuprofen, indopropene , Ketoprofen, miroprofen, naproxen, naproxen sodium, Oxaprozin, pirporphene, pranopropene, suprofen, thiapropene acid, thioxapropene, etc., enolic acid (e.g., oxycam derivatives ampyroxicam, cynoxycam, doxycampa, lornoxi Cham, meloxycham, pyroxamc, sulfoxamc and tenoxamc, and pyrazolone derivatives aminopyrin, antipyrin, apazone, dipyrone, oxyfenbutazone, phenylbutadon, etc., para-aminophenol derivatives (eg : Acetaminophen, etc.), alkanones (e.g., nabumethone, etc.), nimesulide, proquazone and the like and combinations thereof.

In a preferred embodiment, the anti-inflammatory agent is a selective COX-2 inhibitor. Selective COX-2 inhibitors are compounds that selectively inhibit cyclooxygenase-2 (COX-2) activity. The terms "selective COX-2 inhibitor" and "selective cyclooxygenase-2 inhibitor" interchangeably inhibit the COX-2 isoform of the enzyme cyclooxygenase and cyclooxygenase-1 (COX-1 ) Refers to a therapeutic compound that less significantly inhibits. As used herein, the term “selective COX-2 inhibitor” also refers to prodrugs or salts that are converted in vivo to compounds that exhibit selective inhibition of COX-2 over COX-1. Preferred COX-2 inhibitors exhibit a selectivity of at least about 10, more preferably at least about 50, even more preferably at least about 100, wherein the "selectivity" is IC ₅₀ (COX-1) / IC ₅₀ (COX-2) Is defined as IC50 is the concentration of compound that shows 50% inhibition of enzyme activity in vitro or in vivo.

Selective COX-2 inhibitors applicable to the present invention include, but are not limited to, the compounds described below, tautomers, stereoisomers, enantiomers, salts, hydrates, prodrugs, and combinations thereof. Any selective COX-2 inhibitory drug or prodrug known in the art can be used.

Preferred selective COX-2 inhibitory drugs useful herein are compounds of Formula (I), or prodrugs or pharmaceutically acceptable salts thereof:

Where

A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings, preferably pyrazolyl, furanyl, isoxazolyl, pyridinyl, cyclopentenonyl and pyridazino A heterocyclyl group selected from a niyl group;

X is O, S or CH ₂ ;

n is O or 1;

R ¹ is one or more substituents selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, optionally substituted at alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxylalkyl, halo Substituted with one or more radicals selected from alkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;

R ² is methyl, amino or aminocarbonylalkyl;

R ³ is hydrido, halo, alkyl, alkenyl, alkynyl, oxo, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocycle Aryl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxy Alkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylamino Carbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylamino Alkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-al Kyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, At least one radical selected from N-arylaminosulfonyl, arylsulfonyl and N-alkyl-N-arylaminosulfonyl, R ³ is alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl Is substituted with one or more radicals selected from hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;

R ⁴ is selected from hydrido and halo.

Particularly preferred groups of selective COX-2 inhibitory drugs are compounds of formula (II), or isomers, tautomers, pharmaceutically acceptable salts or prodrugs thereof:

Wherein, R ⁵ is a methyl or amino group, R ⁶ is a hydrogen or C _{1 -4} alkyl or alkoxy group, X 'is N or CR ^7, R ⁷ is hydrogen or halogen, Y and Z are optionally independently A carbon or nitrogen atom defining adjacent atoms of a 5-6 membered ring substituted at one or more positions with an oxo, halo, methyl or halomethyl group. Preferred such 5- to 6-membered rings are cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted at one or less positions.

Another particularly preferred group of selective COX-2 inhibitory drugs is a compound of Formula III and pharmaceutically acceptable salts thereof:

Wherein X "is O, S or N-lower alkyl; R ⁸ is lower haloalkyl; R9 is hydrogen or halogen; R ¹⁰ is hydrogen, halogen, lower alkyl, lower alkoxy or haloalkoxy, lower aralkyl Carbonyl lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, or 5- or 6-membered nitrogen-containing heterocyclosulfonyl; R ¹¹ and R ¹² is independently hydrogen, halogen, lower alkyl, lower alkoxy or aryl.

Particularly useful compounds of formula III are (S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid.

Another particularly preferred group of selective COX-2 is 5-alkyl-2-arylaminophenylacetic acid and derivatives thereof. Particularly preferred compounds of this class are lumiracoxib and pharmaceutically acceptable salts thereof.

By way of example, celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib, 2- (3,5-difluorophenyl) -3- [4 -(Methylsulfonyl) phenyl] -2-cyclopenten-l-one, (S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid, 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methyl-1-butoxy) -5- [4- (methylsulfonyl) phenyl] -3- (2H) -pyrida Xenon, 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide (also known as avelaxoxyb), tert-butyl 1-benzyl-4-[(4-oxopiperidin-1-yl} sulfonyl] pyreridine-4-carboxylate, 4- [5- (phenyl) -3- (trifluoromethyl) -1H -Pyrazol-1-yl] benzenesulfonamide and salts thereof, more preferably celecoxib, deracoxib, valdecoxib, parecoxib and salts thereof, rofecoxib, etoricoxib, lumiracoxib , 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H -Pyrazol-1-yl] benzosulfonamide, tert-butyl 1-benzyl-4-[(4-oxopiperidin-1-yl} sulfonyl] pyriridine-4-carboxylate, and 4- [5- (phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide is useful in the methods and compositions of the present invention.

Valdecoxib for use in the compositions of the present invention can be prepared by known methods, for example as described in US Pat. No. 5,633,272 to Taley et al. Parecoxib for use in the compositions of the present invention can be prepared by known methods, for example as described in US Pat. No. 5,932,598 (Talley et al.). Lo pecoxib used in the compositions of the present invention may be prepared by known methods, for example, as described in US Pat. No. 5,474,995 to Ducharme et. Etholicoxib used in the compositions of the present invention may be prepared by known methods, for example by the method described in International Patent Publication No. 98/03484. 2- (3,5-difluorophenyl) -3- [4- (methylsulfonyl) phenyl] -2-cyclopenten-l-one used in the composition of the present invention is a known method, for example in Europe It may be prepared by the method described in Patent No. 0 863 134. Delacoxib used in the compositions of the present invention can be prepared by known methods, for example, as described in US Pat. No. 5,466,823 (Talley et al.). 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methyl-1-butoxy) -5- [4- (methylsulfonyl) phenyl] used in the compositions of the present invention 3- (2H) -pyridazinone can be prepared by known methods, for example by the method described in International Patent Publication No. WO 00/24719. Other selective COX-2 inhibitory drugs can be prepared by known methods, including those described in the patent literature describing such drugs: for example, for celecoxib, US Pat. Nos. 5,466,823 or 5,466,823 (Zhi, cited above). Etc.). All patents and publications cited above are hereby incorporated by reference.

When the anti-inflammatory agent is a selective COX-2 inhibitor, the preferred concentration range in the compositions of the present invention is about 0.01 to about 1000 mg / ml, more preferably about 0.1 to about 750 mg / ml, even more preferably about 5 to about 250 mg / ml. For second drugs other than selective COX-2 inhibitors, suitable concentration ranges can be determined by one skilled in the art based on known data.

Reference to a particular drug compound includes tautomers, stereoisomers, enantiomers, salts, hydrates, and prodrugs of the compound, and are not specified in any solid state form of the drug, unless otherwise noted.

In a preferred embodiment, the second drug administered in combination therapy with a selective COX-2 inhibitor is an antibacterial agent. Antibacterial agents suitable for use in accordance with the present invention include agents effective for the treatment and / or prevention of breast disorders and / or ear disorders and / or complications associated therewith. Suitable antibacterial agents include beta-lactam antibacterial agents, for example drugs of the natural and synthetic penicillin type (penam penicillin (e.g. benzyl penicillin, penoxymethyl penicillin, coxacillin, napcillin, methicillin, oxacillin, amoxicillin ), Penicillinase-stable penicillins, asyloamino and carboxypenicillin (e.g. piperacillin, azlocillin, mezlocillin, carbenicillin, temocillin, ticarcillin And more broad spectrum penicillins (e.g. streptomycin, neomycin, pramicetin, gentamicin, apramycin, amikacin, spectinomycin, amoxicillin, ampicillin, etc.), cephalosporins, macrolides (such as Examples: tylosin, tilmicocin, iblocin, erythromycin, azithromycin, spiramycin, probemycin, chitasamycin, etc., lincosamide (e.g., lincomycin, clindamycin, pyrilima ), Pleuromutinine (e.g., thiamuline, balnemuline, etc.), polypeptides, glycopeptides (e.g., vancomycin, etc.), polymyxins (e.g., polymyxin B, polymyxin E, etc.), sulfonamides (e.g., Sulfamethazine, sulfadiazine, silver sulfadiazine, sulfatroxazole, sulfamethoxypyridazine, sulfanamide, sulfamethoxazole, sulfisoxazole, sulfamethiazole, mefenide, etc., alone or trimetoprim ), Chloramphenicol, thiamphenicol, florfenicol, drugs of the tetracycline type (e.g. tetracycline, chlortetracycline, oxytetracycline, domeclocycline, doxycycline, minocycline, etc.), quinolones and fluoroquinolones ( Examples: Ciprofloxacin, Enoxacin, Grepafloxacin, Levofloxacin, Lomefloxacin, Norfloxacin, Ofloxacin, Sparfloxacin, Trobafloxacin, Sinocacine, Nalidixic Acid), Tiamoline, Collis , Mefenenem, sulbactam, tazobactam, metacycline, pyrimethamine, sulfacetamide, oxazolidinone, e.g. eperezolide linezolid, N-((5S) -3- (3-fluoro -4- (4- (2-fluoroethyl) -3-oxy-1-piperazinyl) phenyl-2-oxy-5-oxazolidinyl) methyl) acetamide, (S) -N-((3 -(5- (3-pyridyl) thiophen-2-yl) -2-oxy-5-oxazolidinyl) methyl) acetamide, 2,2-difluoro-N-({(5S) -3 -[3-fluoro-4- (4-glycloylpiperazin-1-yl) phenyl] -2-oxo-1,3-oxazolidin-5-yl} methyl) ethanethioamide, (S) Aminoglycosides (kanamycin, toe), such as -N-((3- (5- (4-pyridyl) pyrid-2-yl) -2-oxy-5-oxazolidinyl) methyl) acetamide hydrochloride Bramycin, netylmycin, and the like), aminocyclitol, amphenicol, ansamycin, carbapenem, cephamycin, rifampicin, monobactam, oxacefem, streptogramine (e.g. quinupristine, dalpopristin, etc.), cycles Serine, murphyrosine, urea hydroxamate, folic acid homologues (e.g. trimethoprim), antibiotic-type antineoplastic agents (e.g. aclarubicin, actinomycin D, actinoplanone, aero Plysinine derivatives, nipon soda anisomycin, anthracycline, azinomycin-A, busukaberine, bleomycin sulfate, bryostatin-1, calichemycin, cromoximacin, dactinomycin, daunorubicin, Ditrisarrubicin B, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-A1b, postriecin, glydobactin, gregatin-A, green Carmycin, Herbimycin, Idarubicin, Illudin, Kazusamycin, Kesariridine, Menogaryl, Mitomycin, Mitoxantone, Mutamycin, Mycophenolate Mofetil, Neoenactin, Oxalicin, Oxauno Mycin, peplomycin, pilate, pyrarubi , Portramycin, pyriindamycin A, rapamycin, lioxin, rhorubicin, sibanomycin, siwenmycin, sorangicin-A, spartosomycin, stepymycin B, thalisomycin, terpenthecin, tragin , Triclozarine A, zolevicin, systemic antibacterial agents (eg 2,4-diaminopyrimidine), nitrofuran sulfone, marbofloxacin, and the like, and combinations thereof, may be, but is not limited to.

Preferred antibacterial agents include cephalosporins such as ceftiofur hydrochloride, ceftiofur free acid such as ceftiofur crystalline free acid, ceftiour sodium, other ceftiofur salts, cephalexin, cefe Pradines, cefquinom, cephacetyl, cephalonium, cefuroxime, cefazidim, cepharazone, sodium cefemethcarboxylate, cefeheptahydrate, cephalosporin di- or tri-hydrate, cepharoxyl Monohydrate, Sephazoline Sodium Monohydrate, Sepikcimine, Ceftaxime, Ceftisimsim, Ceftriaxone, o-formylsephamandol, 3-acetoxymethyl-7- (iminocetamido) -cephalo Salts of sporanic acid derivatives, monohydrate of 7- (D-alpha-amino-alpha- (p-hydroxyphenyl) acetamino) -3-methyl-3-cepem-1-carboxylic acid, syn-7- ( (2-amino-1-thiazolyl) (methoxyimino) acetyl) amino) -3-methyl-3-cepem-4-carboxylic acid Hydrochloride salts, cefem acid addition salts, (pivaloyloxy) methyl 7-beta- (2- (2-amino-4-thiazolyl) acetamido) -3-(((1- (2- (dimethyl Amino) ethyl) -1H-tetrazol-5-yl) thio) methyl) -3-cepem-4-carboxylate, cephalexin, cephalexin monohydrate, 7- (D-2-naphtiglyciloamino)- 3-methyl-3-cepem-4-carboxylic acid tetrahydrate and the like, but are not limited thereto. Most preferred cephalosporins for use according to the invention are ceftiofur and pharmaceutically acceptable salts thereof. Ceftiofur free acid is particularly preferred, crystalline form and ceftiofur hydrochloride are most preferred.

When the antibacterial material is in the form of ceftiofur or salts thereof, the preferred concentration range in the composition of the present invention is about 1 to about 1000 mg / ml, more preferably about 5 to about 750 mg / ml, even more preferably About 10 to about 100 mg / ml. For antibacterial materials other than ceftiofur, suitable concentration ranges which may be antibacterial equivalent may be determined by one skilled in the art based on known data.

In another embodiment, the second drug is an anti-neoplastic agent. Suitable antineoplastic agents include, but are not limited to, anastrozole, calcium carbonate, capecitabine, carboplatin, cyplatin, docetaxel, eplomitin, etoposide, exemestane, fluoxymethrin , Gemcitabine, goserelin, irinotecan, ketoconazole, letrozole, leucovorin, levamisol, megestrol, paclitaxel, raloxifene, retinoic acid, selenium (selenomethionine), sulindac sulfone, tamoxifen, thiotepa, topotecan, Toremifene, vinvastin, vincristine, vinorelbine, and the like, and combinations thereof.

In another embodiment, the second drug comprises an anesthetic. Anesthetics include ambucaine, amolanone, amylocaine, benosinate, benzocaine, bethoxycaine, bifenamine, bupivacaine, butacaine, butambene, butambene peakrate, butanilicaine, butetamine, Butoxycaine, Cartikaine, Chloroprocaine, Cocaethylene, Cocaine, Cyclomethicain, Dibucaine, Dimethisoquine, Dimethokine, Diferodon, Diphenylhydramine, Diclonin, Exgonidine, Exgonin , Ethyl chloride, ethidocaine, β-eucaine, pomocaine, hexylcaine, hydroprocaine, hydroxyprocaine, hydroxytetracaine, isobutane, isobutyl p-aminobenzoate, ketocaine, Sinocine, Reboxadrol, Lidocaine, Mepivacaine, Meprylcaine, Metabutoxycaine, Metabutetamine, Myrtecaine, Octacaine, Orthocaine, Oxetazaine, Oxyprocaine, Paretoxine, Penacane Phenol, piperocaine, pyridocaine, polydocanol, Pramokine, Prilocaine, Procaine, Primacaine, Proparacaine, Propicocaine, Propoxycaine, Pseudococaine, Pyrocaine, Replibican, Ropivacaine Salicylic Alcohol, Tetracaine, Tolucaine, Tree Mecaine, xylocaine, and the like and combinations thereof, but are not limited thereto.

Preferred analgesics include lidocaine, bupivacaine, prilocaine, ropivacaine and tautomers, stereoisomers, enantiomers, salts, hydrates, prodrugs and combinations thereof.

In another embodiment, the second drug is a sodium channel blocker. Sodium channel blockers useful in the present invention include supplementing the effects of anti-inflammatory agents by all mechanisms, such as, but not limited to, reducing pain, reducing edema, and the like.

Sodium channel blockers useful according to the invention may be selected from the following non-limiting list: NaV1.8 (PN3) subtype sodium channel blocker, NaVl.3 (type III) subtype sodium channel blocker, carboxamide, phenamate, Oxycam, propanamide, pyrazinoylguanidine semicarbazone, semicarbazide and the like.

Alternatively, sodium channel blockers suitable for use according to the present invention may be selected from the following non-limiting list: amylolide, 4-amino-2- (4-methylpiperazin-1-yl) -5- (2 , 3,5-trichlorophenyl) pyrimidine, amitriptyline, anhydrotetrodotoxin, apridine, azure A, benzyl, benzoxazinate, carvedilol, deoxytetrodotoxin, disopyramid, encainide, e Oxytetrodotoxin, Euprosin, Lenalcomin, Fluarizine, Gabapentin, Isoflurane, Liparizine, Lorcainide, 1-methylsulfonyl-3- (4-pentoxy) phenyl-1H-pyrazole, Methoxyflu Lan xylocaine, methoxytetrodotoxin, methyl chloride, 2-methyl-1- [3- (4-phenoxyphenyl) -1H-pyrazole] propanone, mexyletine, N-acenaft-5-yl -N'-4-methoxynaphthyl guanidine, naepine, N- (2-chloro-6-methylphenyl) -N-4-pyridinyl urea, N- [3- (2,6-dimethyl-1- Piperidinyl)]-α-phenylbenzeneacene Amide, N-methylstrikinin, 1- [3- [4- (4-nitrophenoxy) phenyl] -1H-pyrazole] ethanone, oxabazepine, oxasezein, oxybrorocaine, oxytazaine, panku Rhonium, phenamyl, phenyl benzothiazole, phenytoin, pregabalin, procaineamide, propaphenone, propanocaine, ralitololin, rilusol, saxitoxin, tecacaine, tetradiaminotoxin, tetrodonic acid , Tetrodotoxin, topiramate, 5- (2,3,5-trichlorophenyl) -2,4-diamino-pyrimidine, 6- (2,3,5-trichlorophenyl) -1,2,4- Triazine-5-ylamine, verapamil, zolamine, zonisamide and the like, and combinations thereof.

Amphiphilic oils suitable for the present invention include all amphiphilic oils that are water dispersible and ethanol insoluble.

More preferred amphiphilic oils are polyglycolated glycerides prepared by the polyalcoholization reaction of natural triglycerides with polyethylene glycols, including but not limited to the following Gattefosse oils or substantially equivalents from other manufacturers. NO: Labrafil ^™ M-1944CS, Labrafil ^™ M-1966CS, Labrafil ^™ M-1969CS, Labrafil ^™ M-1980CS, Labrafil ^™ M-2125CS, Labrafil ^™ WL-2609BS, Labrafil ^™ ISO and combinations thereof.

More preferred amphiphilic oils are polyglycolated glycerides prepared as described above, comprising the major fatty acid components of oleic or linoleic acid, including but not limited to the following Gattefosse oils or substantially equivalents from other manufacturers. But not: Labrafil ^™ M-1944CS, Labrafil ^™ M-1966CS, Labrafil ^™ M-1969CS, Labrafil ^™ M-1980CS, Labrafil ^™ M-2125CS, Labrafil ^™ WL-2609BS and combinations thereof.

More preferred amphiphilic oils are polyglycolated glycerides prepared as described above, comprising the major fatty acid components of oleic acid, including but not limited to the following Gattefosse oils or substantially equivalents from other manufacturers. NO: Labrafil ^™ M-1944CS, Labrafil ^™ M-1966CS, Labrafil ^™ M-1980CS, and combinations thereof.

The most preferred amphiphilic oil is Pecolol 5-Olate, for example Labrafil ^™ M-1944CS (Gattfosse Corporation).

Preferred concentrations for the amphiphilic oil in the compositions of the present invention are about 0.01 to about 99% weight / volume, more preferably about 1 to about 80% weight / volume, even more preferably about 3 to about 25% weight / Volume.

Microcrystalline waxes are, for example, as defined in Handbook of Pharnzaceutical Excipients, 3rd ed. Or National Formulary, l9th ed. (NF 19), and can be obtained from many manufacturers, including Eitco Corporation.

Preferred concentrations for the microcrystalline wax in the compositions of the invention are about 0.001 to about 50% weight / volume, more preferably about 0.1 to about 40% weight / volume, even more preferably about 1 to about 15% weight. Volume.

Pharmaceutically acceptable non-aqueous carriers of the invention may be fully saturated or partially or fully unsaturated. Examples of non-aqueous carriers include, but are not limited to, vegetable oils, inorganic oils, synthetic oils, and combinations thereof. Examples of fully saturated non-aqueous carriers include esters of medium to long chain fatty acids (eg, about C ₆ To aliphatic triglycerides having a chain length of about C ₂₄ ), but is not limited thereto. The mixture of fatty acids is separated from natural oils (eg coconut oil, palm oil, babassu oil, etc.). In some embodiments, heavy chain (about C ₈ to about C ₁₂ ) triglycerides are useful. Exemplary saturated non-aqueous carriers include capric acid (about 20% to about 45%) and caprylic acid (about 45% to about 80%). Other fully saturated non-aqueous carriers include saturated coconut oil (typically lauric acid, myristic acid, palmitic), including those sold under the trade name 810, 812, 829, and 840 under the trade name Miglyol ^™ and the production trade mark from Huls. Acids, capric acid and mixtures of caproic acid), but is not limited thereto. There is also a NeoBee ^™ product available from Drew Chemicals. Isopropyl myristate is another example of a non-aqueous carrier useful in the compositions of the present invention. Examples of synthetic oils include saturated or unsaturated fatty acids having 6 to 24 carbon atoms, for example hexanoic acid, octanoic acid (caprylic acid), nonanoic acid (fellargonic acid), decanoic acid (capric acid), undecanoic acid, Lauric acid, tridecanoic acid, tetradecanoic acid (mylistic acid), pentadecanoic acid; Triglycerides such as hexadecanoic acid (palmitic acid), heptadecanoic acid, octadecanoic acid (stearic acid), nonadecanoic acid, heptadecanoic acid, eicosanoic acid, henecosanoic acid, docosanoic acid and lignoseric acid, and Propylene glycol diesters. Examples of unsaturated carboxylic acids include oleic acid, linoleic acid, linolenic acid, and the like. Non-aqueous carriers may include mono-, di- and triglyceryl esters or mixed glycerides and / or propylene glycol diesters of fatty acids, wherein one or more molecules of glycerol are esterified with fatty acids of varying carbon lengths. It is understood that. A non-limiting example of a "non-oil" useful as a carrier in the compositions of the present invention is polyethylene glycol.

Preferred non-aqueous carriers are vegetable oils such as cottonseed oil, corn oil, sesame oil, soybean oil, olive oil, fractionated coconut oil, peanut oil, sunflower oil, safflower seed oil, almond oil, avocado oil, palm oil, palm oil, baba Lactation, beechnut oil, linseed oil, rapeseed oil. Most preferred non-aqueous carrier is cottonseed oil. By way of example, cottonseed oil is available in the formulation of 70% unsaturated fatty acids from Sigma Chemical Co.

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

The compositions of the present invention may optionally further comprise all conventional pharmaceutical excipients which do not adversely react with the essential ingredients of the composition. Such excipients include antioxidants, preservatives, suspending agents, stabilizers, solubilizers, wetting agents, lubricants, emulsifiers, salts for controlling osmotic pressure, colorants, alcohols, isotonic agents, buffers, penetrants, anti-irritants, and combinations thereof. It is not limited.

The composition of the present invention can be administered by inserting the cannula nozzle of a mastitis syringe into the outer orifice of the nipple conduit of the breast of a milk-producing animal and injecting the composition into the breast for the treatment of mastitis.

The compositions of the present invention can be administered by inserting a nozzle of an ear syringe, ear drop dispenser or other suitable ear delivery device into the ear canal of the subject's ear and injecting the composition into the ear for the treatment or prevention of an ear disorder.

It will be appreciated that in certain cases the preferred amount of composition to be administered may vary depending upon the particular composition employed, the mode of application, the particular situation and organism to be treated, and other factors. Dosages for a given purpose can be determined by conventional considerations, for example by conventional comparison of the differential activity of the subject composition and known drugs, for example by suitable conventional pharmaceutical protocols.

Although the present invention primarily relates to local delivery of the anti-inflammatory agent to the site of inflammation in the organ where it is administered, the compositions of the present invention are also useful for systemic delivery of the anti-inflammatory agent via intramammary injection to milk-producing animals. For example, it is more effective and convenient to administer the therapeutic agent to a milk-producing animal, eg a cow, by intramammary infusion rather than by other routes, such as oral or parenteral. Thus, in the treatment of inflammatory diseases other than the breast, including, for example, arthritis, the compositions described herein may be administered by intramammary infusion.

An illustrative suspending agent composition of the present invention comprising an anti-inflammatory agent, for example a COX-2 inhibitor deracoxib, has the following composition:

Selective COX-2 Inhibitor 1-350 mg / ml Labrafil ^TM M-1944CS 1-75% Microcrystalline wax 0.1-25% Cottonseed oil Appropriate amount to be 100%

The following examples are intended to illustrate aspects of the invention and should not be considered as limiting.

Example  One

Suspending agents have been prepared having the following composition administered by intramammary infusion:

Parecoxib Free Acid 100 mg / ml Labrafil ^TM M-1944CS 50 mg / ml Microcrystalline Wax NF 70 mg / ml Cottonseed oil NF Quantity

Microcrystalline wax, and about 27% of the total amount of cottonseed oil, were heated to 85-98 ° C. while mixing in a kettle. The remaining cottonseed oil was heated to 85-98 ° C. while mixing in the production tank. The microcrystalline wax was completely melted and the microcrystalline wax / cotton oil mixture in the kettle was transferred to a production tank containing cottonseed oil and mixed thoroughly. The resulting mixture was cooled to 38-45 ° C. and added to the preparation tank while mixing Labrafil ^™ M-1944CS to form a vehicle. Parecoxib was then added to the vehicle and the resulting composition was mixed to form a uniform suspending agent. Suspensions were screened and filled with a 12 ml high density polyethylene mastitis injector. Finally the packaged product was sterilized with a gamma ray of 25-40 kGy dose.

The suspending agent was injected intramammary at a dose of 1,200 mg into each infected quarter of the breast of the lactating cow. Suspensions were effective in the treatment of mastitis in lactating cows.

Suspending agents have been prepared having the following composition administered by intramammary infusion:

Deracoxib 170 mg / ml Labrafil ^TM M-1966CS 100 mg / ml Microcrystalline Wax NF 50 mg / ml Corn oil NF Quantity

Microcrystalline wax, and corn oil, were heated to 85-98 ° C. while mixing in the production tank. After the microcrystalline wax was completely melted, the mixture was cooled to 30-45 ° C. and Labrafil ^™ M-1966CS was added to the preparation tank with mixing to form a vehicle. Deracoxib was then added to the vehicle and mixed to form a uniform suspending agent. Suspensions were screened and filled with a 12 ml high density polyethylene mastitis injector. Finally the packaged product was sterilized with a gamma ray of 25-40 kGy dose.

The suspending agent was injected intramammary into dry cows at a dose of 3,400 mg deracoxib / gut. Suspensions were effective in the treatment of mastitis in dry cows.

Example  3

Suspending agents have been prepared having the following composition administered by ear infusion:

Lopecoxib 25 mg / ml Labrafil ^TM M-1980CS 500 mg / ml Microcrystalline Wax NF 0.10 mg / ml Profile gallate 1.0 mg / ml Mineral oil Quantity

About 27% of the total amount of microcrystalline wax and mineral oil was heated to 85-98 ° C. while mixing in the kettle. The remaining mineral oil was heated to 85-98 ° C. while mixing in the production tank. The microcrystalline wax was completely melted and the microcrystalline wax / mineral oil mixture in the kettle was transferred to a production tank containing mineral oil and mixed thoroughly. The resulting mixture was cooled to 38-45 ° C. and added to the preparation tank with Labrafil ^™ M-1980CS mixing. The propyl gallate was then added to the preparation tank with mixing to form a vehicle. Rofecoxib was added to the resulting vehicle and mixed to form a uniform suspending agent. Suspensions were screened and filled into 20 ml polyethylene containers.

The suspending agent was injected into dog ears at a dose of 2.5 mg rofecoxib / kg body weight. Suspensions were effective in the treatment of otitis externa in dogs.

Example  4

Suspending agents have been prepared having the following composition administered by intramammary infusion:

Deracoxib 300 mg / ml Labrafil ^TM M-1944CS 50 mg / ml Microcrystalline Wax NF 70 mg / ml Cottonseed oil NF Quantity

About 27% of the total amount of microcrystalline wax and cottonseed oil was heated to 85-98 ° C. while mixing in the kettle. The remaining cottonseed oil was heated to 85-98 ° C. while mixing in the production tank. The microcrystalline wax was completely melted and the microcrystalline wax / cotton oil mixture in the kettle was transferred to a production tank containing cottonseed oil and mixed thoroughly. The resulting mixture was cooled to 38-45 ° C. and added to the preparation tank while mixing Labrafil ^™ M-1944CS to form a vehicle. Delacoxib was then added to the resulting vehicle and mixed to form a uniform suspending agent. Suspensions were screened and filled with a 12 ml high density polyethylene mastitis injector. Finally the packaged product was sterilized with a gamma ray of 25-40 kGy dose.

The suspending agent was injected intramammary in a dose of 1,200 mg deracoxib / gut in all four quarters of dry cow. Suspensions were effective in the treatment of mastitis in dry cows.

Example  5

Suspending agents have been prepared having the following composition administered by intramammary infusion:

Valdecoxib 1.5 mg / ml Labrafil ^TM WL-2609BS 75 mg / ml Microcrystalline Wax NF 100 mg / ml Miglyol ^TM 812 Quantity

About 30% of the total amount of microcrystalline wax and Miglyol ^™ 812 were heated to 85-98 ° C. while mixing in the kettle. The remaining Miglyol ^™ 812 was heated to 85-98 ° C. while mixing in the production tank. The microcrystalline wax was completely melted and the microcrystalline wax / Miglyol ^™ 812 mixture in the kettle was transferred to a production tank containing Miglyol ^™ 812 and then thoroughly mixed. The resulting mixture was cooled to 38-45 ° C. and added to the preparation tank while mixing Labrafil ^™ WL-2609BS to form a vehicle. Valdecoxib was then added to the resulting vehicle and mixed to form a uniform suspending agent. Suspensions were screened and filled with a 12 ml high density polyethylene mastitis injector. Finally the packaged product was sterilized with a gamma ray of 25-40 kGy dose.

The suspending agent was injected intramammary into all four quarters of dry cows at a dose of 30 mg valdecoxib / morrows. Suspensions were effective in the treatment of mastitis in dry cows.

Example  6

Suspending agents have been prepared having the following composition administered by ear infusion:

Ceftiofur Hydrochloride (Undifferentiated) 100 mg / ml Deracoxib 100 mg / ml Labrafil ^TM M-1944CS 700 mg / ml Microcrystalline Wax NF 0.05 mg / ml Mineral oil Quantity

Microcrystalline wax, and about 27% of the total amount of mineral oil, were heated to 85-98 ° C. while mixing in the kettle. The remaining mineral oil was heated to 85-98 ° C. while mixing in the production tank. The microcrystalline wax was completely melted and the microcrystalline wax / mineral oil mixture in the kettle was transferred to a production tank containing mineral oil and mixed thoroughly. The resulting mixture was cooled to 38-45 ° C. and Labrafil ^™ M-1944CS was added to the preparation tank with mixing to form a vehicle. Ceftiofur hydrochloride and delacoxib were added to the resulting vehicle and mixed to form a uniform suspending agent. Suspensions were screened and filled into 50 ml polypropylene containers.

The suspending agent was injected into the subject's ears at doses of 4 mg ceftiofur hydrochloride / kg body weight and 4 mg deracoxib / kg body weight. Suspensions have been effective in treating and / or preventing otitis externa.

Example  7

Suspending agents have been prepared having the following composition administered by ear infusion:

Ceftiofur Hydrochloride (Undifferentiated) 100 mg / ml Parecoxib Free Acid 100 mg / ml Labrafil ^TM M-1944CS 700 mg / ml Microcrystalline Wax NF 0.1 mg / ml Cottonseed oil NF Quantity

Microcrystalline wax and cottonseed oil were heated to 85-98 ° C. while mixing in the production tank. The microcrystalline wax was melted completely and the mixture was cooled to 38-45 ° C. and Labrafil ^™ M-1944CS was added to the preparation tank with mixing to form a vehicle. Ceftiofur hydrochloride and parecoxib were added to the resulting vehicle and mixed to form a uniform suspending agent. Suspensions were screened and filled into 60 ml polypropylene containers.

The suspending agent was injected into the subject's ears at doses of 4 mg ceftiofur hydrochloride / kg body weight and 4 mg parecoxib / kg body weight. Suspensions have been effective in treating and / or preventing otitis externa.

Example  8

Suspending agents have been prepared having the following composition administered by ear infusion:

Lidocaine 100 mg / ml Parecoxib Free Acid 100 mg / ml Labrafil ^TM M-1944CS 700 mg / ml Microcrystalline Wax NF 0.1 mg / ml Cottonseed oil NF Quantity

Microcrystalline wax and cottonseed oil were heated to 85-98 ° C. while mixing in the production tank. The microcrystalline wax was melted completely and the mixture was cooled to 38-45 ° C. and Labrafil ^™ M-1944CS was added to the preparation tank with mixing to form a vehicle. Lidocaine and parecoxib were added to the resulting vehicle and mixed to form a uniform suspending agent. Suspensions were screened and filled into 60 ml polypropylene containers.

The suspending agent was injected into the subject's ears at doses of 4 mg lidocaine / kg body weight and 4 mg parecoxib / kg body weight. Suspensions have been effective in treating and / or preventing otitis externa.

Although the present invention has been described in detail with reference to its preferred embodiments, it is apparent that modifications and variations are possible without departing from the scope of the appended claims.

Claims (65)

Celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib, 2- (3,5-difluorophenyl) -3- [4- (methylsul Ponyl) phenyl] -2-cyclopenten-l-one, (S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid, 2- (3,4 -Difluorophenyl) -4- (3-hydroxy-3-methyl-1-butoxy) -5- [4- (methylsulfonyl) phenyl] -3- (2H) -pyridazinone, 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide and salts thereof, and an anti-inflammatory agent selected from the group consisting of a compound of formula II; And (a) amphiphilic oils, which are polyglycolyzed glycerides prepared by the hydroalcolytic reaction of natural triglycerides using polyethylene glycols, which are water dispersible and ethanol, (b) microcrystalline waxes and (c) pharmaceutical A pharmaceutical composition comprising a vehicle comprising an acceptable non-aqueous carrier is administered via the external sphere to a body fluid-containing organ having natural external spheres; In combination with the anti-inflammatory agent, a second drug selected from the group consisting of antibacterial, analgesic, antipyretic, anesthetic, sodium channel blocker, anti-neoplastic and anti-edema agents may be administered by a route different from the route of administration of the anti-inflammatory agent. A method of treating, preventing, or treating and preventing inflammatory symptoms in a body fluid-containing organ having a natural outer sphere in animals other than humans. <Formula II>

Wherein R ⁵ is a methyl or amino group, R ⁶ is hydrogen or a C _1-4 alkyl or alkoxy group, X 'is N or CR ⁷ , R ⁷ is hydrogen or halogen, and Y and Z are independently provided Carbon or nitrogen atoms which define adjacent atoms of a 5-6 membered ring which is cyclic or substituted at one or more positions with an oxo, halo, methyl or halomethyl group. The method of claim 1, wherein the body fluid-containing organ is the breast of a milk producing animal and the composition is administered by intramammary infusion. The method of claim 2, wherein the inflammatory symptoms are associated with mastitis. The method of claim 1, wherein the body fluid-containing organ is the subject's ear and the composition is administered by infusion into the ear. The method according to claim 4, wherein the inflammatory symptoms are otitis externa, otitis media, ir, acute mastoiditis, infection associated with ear surgery, ear sclerosis, ear aches, ear pain, ear infection, ear bleeding, Lermoyez syndrome, menisci Otitis, including Meniere syndrome, vestibular neuritis, benign paroxysmal positional dizziness, heterogeneous shingles, Ramsay Hunt syndrome, viral neuritis, ganglionitis, sputum herpes, purulent otitis and viral endocarditis Perilymph fistula, senile deafness, drug-induced ear toxicity, auditory neuroma, otitis media, infectious tympitis, bullous tymitis, ear neoplasm, squamous cell carcinoma, basal cell carcinoma, other ear cancers, pre-cancerous ear disease, bichrome Affinity adrenal ganglion tumor, chemosensitive tumor, glomerular jugular vein tumor, glomerular tympanic tumor, chondritis, ear rash dermatitis, malignant otitis media, subchondral hematoma, ear canal adenoma, mesothelioma, sebaceous cyst, osteoma, Droid, tinnitus, dizziness, tympanic infection, typhus, ear boil, condysitis, prenegative and sensorineural hearing loss, epidural abscess, lateral venous sinus thrombosis, subdural sinusitis, ear hydrocephalus, Dandy's syndrome, bullous tymitis, A method comprising the ear disorder selected from the group consisting of diffuse otitis externa, foreign body, obstructive keratosis, binary fungus, trauma, acute atmospheric otitis media, acute ear canal obstruction, postoperative ear pain and related complications. The method of claim 4, wherein the inflammatory condition is associated with an ear disorder selected from the group consisting of otitis externa, otitis media, irritation, and infection with an inflammatory component associated with surgical treatment of the ear. delete The method of claim 1, wherein the second drug comprises an antibacterial agent. The method of claim 8, wherein the antibacterial agent is a natural or synthetic phenylsilin-type antibiotic, cephalosporin, macrolide, lincosamide, flauromutillin, polypeptide, polymyxin, sulfonamide, chloramphenicol, thiamphenicol, Florfenicol, tetracycline-type antibiotics, quinolone, fluoroquinolone, thiamulin, ciprofloxacin, colistin, domeclocycline, mafenide, metacycline, norfloxacin, oploxacin, pyrimethamine, silver sulphate Padiazine, sulfacetamide, sulfisoxazole, tobramycin, vaneulin, oxazolidinone, glycopeptide, amino glycosides and aminocyclitol, amphenicol, ansamycin, carbapenem, sefamycin, vancomycin, monobactam , Oxacefem, systemic antibacterial agents, antibiotic-type antineoplastic agents, nitrofuran sulfones, marbofloxacin and tautomers, stereoisomers, enantiomers thereof, Method selected from the group consisting of hydrate. The method of claim 8, wherein the antibacterial agent comprises oxazolidinone. The method of claim 10, wherein the oxazolidinone is eperazole, lineazole, N-((5S) -3- (3-fluoro-4- (4- (2-fluoroethyl) -3-oxy -1-pyrerazinyl) phenyl-2-oxy-5-oxazolidinyl) methyl) acetamide, (S) -N-((3- (5- (3-pyridyl) thiophen-2-yl ) -2-oxy-5-oxazolidinyl) methyl) acetamide, 2,2-difluoro-N-({(5S) -3- [3-fluoro-4- (4-glyloylpipepe) Razin-1-yl) phenyl] -2-oxo-1,3-oxazolidin-5-yl} methyl) ethanethioamide and (S) -N-((3- (5- (4-pyridyl)) Pyrid-2-yl) -2-oxy-5-oxazolidinyl) methyl) acetamide hydrochloride. The method of claim 8, wherein the antibacterial agent comprises cephalosporin. The method of claim 12, wherein the cephalosporin is ceftiofur, cephalexin, cepradine, cefquinom, cephacetyl, cephalonium, cepuroxime, cefazidim, cepharazone, sodium cefemethcarboxylate, cefem , Cephadoxyl, cefazoline sodium, sepiccimine, ceftaxime, ceftizone, ceftriaxone, o-formylsephamandol, 3-acetoxymethyl-7- (iminocetamido) -cephalosporane Salts of acid derivatives, 7- (D-α-amino-α- (p-hydroxyphenyl) acetamino) -3-methyl-3-cepem-1-carboxylic acid, syn-7-((2-amino-1 Hydrochloride salts of -thiazolyl) (methoxyimino) acetyl) amino) -3-methyl-3-cepem-4-carboxylic acid, cefeic acid, (pivaloyloxy) methyl-7-beta- (2- ( 2-amino-4-thiazolyl) acetamido) -3-(((1- (2- (dimethylamino) ethyl) -1H-tetrazol-5-yl) thio) methyl) -3-cepem-4 Carboxylates, cephalexin, 7- (D-2-naphtiglysylamino) -3-methyl-3-cepem-4-carboxylic acids, and their arcs It is selected from the group consisting of isomers, stereoisomers, enantiomers, salts and hydrates. The method of claim 13, wherein the cephalosporin is in the form of ceftiofur or a pharmaceutically acceptable salt thereof. Celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib, 2- (3,5-difluorophenyl) -3- [4- (methylsul Ponyl) phenyl] -2-cyclopenten-l-one, (S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid, 2- (3,4 -Difluorophenyl) -4- (3-hydroxy-3-methyl-1-butoxy) -5- [4- (methylsulfonyl) phenyl] -3- (2H) -pyridazinone, 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, 4- [5- (phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide and salts thereof, and an anti-inflammatory agent selected from the group consisting of a compound of formula II; (a) amphiphilic oils, which are polyglycolyzed glycerides prepared by the hydroalcolytic reaction of natural triglycerides with polyethylene glycol, (b) water soluble, ethanol insoluble, (b) microcrystalline wax and (c) pharmaceutically acceptable A vehicle comprising a non-aqueous carrier; And administering a pharmaceutical composition comprising a second drug selected from the group consisting of analgesics, antipyretics, anesthetics, sodium channel blockers, anti-neoplastic agents, and anti-edema agents, via external spheres to body fluid-containing organs having natural external spheres. A method of treating, preventing, or treating and preventing inflammatory symptoms in a fluid-containing organ having a natural outer sphere in an animal other than human. <Formula II>

Wherein R ⁵ is a methyl or amino group, R ⁶ is hydrogen or a C _1-4 alkyl or alkoxy group, X 'is N or CR ⁷ , R ⁷ is hydrogen or halogen, and Y and Z are independently provided Carbon or nitrogen atoms which define adjacent atoms of a 5-6 membered ring which is cyclic or substituted at one or more positions with an oxo, halo, methyl or halomethyl group. delete delete delete delete delete delete delete The method of claim 1 or 15, wherein the anti-inflammatory agent is deracoxib. The method according to claim 1 or 15, wherein the anti-inflammatory agent is parecoxib or a salt thereof. The method of claim 1 or 15, wherein the anti-inflammatory agent is celecoxib. The method of claim 1 or 15, wherein the anti-inflammatory agent is valdecoxib. (a) amphiphilic oils, which are polyglycolyzed glycerides prepared by the hydroalcolytic reaction of natural triglycerides with polyethylene glycol, (b) water soluble, ethanol insoluble, (b) microcrystalline wax and (c) pharmaceutically acceptable A vehicle comprising a non-aqueous carrier, wherein said vehicle is an anti-inflammatory effective amount of anti-inflammatory agent stably dispersed therein as celecoxib, deracoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib , Lumiracoxib, 2- (3,5-difluorophenyl) -3- [4- (methylsulfonyl) phenyl] -2-cyclopenten-l-one, (S) -6,8-dichloro- 2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid, 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methyl-1-butoxy) -5- [4- (methylsulfonyl) phenyl] -3- (2H) -pyridazinone, 4- [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazole -1-yl] benzenesulfonamide, 4- [5- (phenyl) -3- (trifluoro Til) -1H-pyrazol-1-yl] benzenesulfonamide and salts thereof, and an anti-inflammatory agent selected from the group consisting of compounds of formula II, further comprising a second drug selected from the group consisting of anesthetics and antibacterial agents. Pharmaceutical compositions comprising. <Formula II>

Wherein R ⁵ is a methyl or amino group, R ⁶ is hydrogen or a C _1-4 alkyl or alkoxy group, X 'is N or CR ⁷ , R ⁷ is hydrogen or halogen, and Y and Z are independently provided Carbon or nitrogen atoms which define adjacent atoms of a 5-6 membered ring which is cyclic or substituted at one or more positions with an oxo, halo, methyl or halomethyl group. delete delete delete delete delete delete The composition of claim 27 wherein the anti-inflammatory agent is deracoxib. The composition of claim 27 wherein the anti-inflammatory agent is parecoxib or a salt thereof. The composition of claim 27 wherein the anti-inflammatory agent is celecoxib. The composition of claim 27 wherein the anti-inflammatory agent is valdecoxib. The composition of claim 27 wherein the anti-inflammatory agent is present at a concentration of 0.01 to 1000 mg / ml. The composition of claim 27 wherein the anti-inflammatory agent is present at a concentration of 0.1 to 750 mg / ml. The composition of claim 27 wherein the anti-inflammatory agent is present at a concentration of 5 to 250 mg / ml. delete The composition of claim 27 wherein the polyglycolyzed glycerides comprise a major fatty acid component of oleic acid or linoleic acid. The composition of claim 27 wherein the polyglycolated glycerides comprise the major fatty acid component of oleic acid. The composition of claim 27 wherein the polyglycolyzed glyceride is PEGol 5-oleate. The composition of claim 27, wherein the amphipathic oil comprises 1 to 80% weight / volume of the composition. The composition of claim 27, wherein the amphiphilic oil comprises 3-25% weight / volume of the composition. The composition of claim 27 wherein the amphipathic oil comprises from 0.01 to 99% weight / volume of the composition. The composition of claim 27, wherein the microcrystalline wax comprises 0.001 to 50% weight / volume of the composition. The composition of claim 27, wherein the microcrystalline wax comprises 0.1 to 40% weight / volume of the composition. The composition of claim 27, wherein the microcrystalline wax comprises 1 to 15% weight / volume of the composition. 41. The non-aqueous carrier according to any one of claims 27 and 34 to 40, wherein the non-aqueous carrier is a vegetable oil, mineral oil, medium to long chain fatty acids and alkyl esters thereof, propylene glycol diesters of medium to long chain fatty acids, mono of fatty acids. A composition selected from the group consisting of di- and triglyceryl esters and polyethylene glycols. The composition of claim 51, wherein the non-aqueous carrier is a vegetable oil. 53. The vegetable oil of claim 52, wherein the vegetable oils are cottonseed oil, corn oil, sesame oil, soybean oil, olive oil, fractionated coconut oil, peanut oil, sunflower oil, safflower seed oil, almond oil, avocado oil, palm oil, palm oil, babasu oil, beach The composition selected from the group consisting of nut oil, linseed oil and rapeseed oil. 54. The composition of claim 53, wherein the vegetable oil is cottonseed oil. The composition of claim 27, wherein the non-aqueous carrier constitutes 0.5-99% weight / volume of the composition. The composition of claim 27, wherein the non-aqueous carrier comprises 10 to 95% weight / volume of the composition. The composition of claim 27, wherein the non-aqueous carrier comprises 40 to 90% weight / volume of the composition. 28. The method according to claim 27, which is selected from the group consisting of antioxidants, preservatives, stabilizers, wetting agents, suspending agents, lubricants, solubilizers, emulsifiers, salts for controlling osmotic pressure, colorants, alcohols, penetrants, anti-irritants, isotonic agents and buffers. A composition further comprising the above excipients. The composition of claim 27 wherein the second drug comprises an anesthetic. The composition of claim 27, wherein the second drug comprises an antibacterial agent. delete 28. The method of claim 27 wherein the polyglycolyzed glyceride is PEGol 5-oleate, the non-aqueous carrier is cottonseed oil, the anti-inflammatory agent is deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, Etoricoxib, lumiracoxib, 2- (3,5-difluorophenyl) -3- [4- (methylsulfonyl) phenyl] -2-cyclopenten-l-one, (S) -6, 8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid, 2- (3,4-difluorophenyl) -4- (3-hydroxy-3-methyl-1 -Butoxy) -5- [4- (methylsulfonyl) phenyl] -3- (2H) -pyridazinone, 4- [5- (4-fluorophenyl) -3- (trifluoromethyl)- 1H-pyrazol-1-yl] benzenesulfonamide, tert-butyl 1-benzyl-4-[(4-oxopiperidin-1-yl} sulfonyl] piperidine-4-carboxylate, 4- [5- (phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide and salts thereof, wherein the second drug comprises lidocaine. An article of manufacture comprising a container or delivery tool having an oxygen permeable wall, wherein the composition of claim 27 is contained therein. 64. The article of claim 63, wherein the oxygen permeable wall is made of an oxygen permeable material comprising polyethylene. The article of claim 63, wherein the composition exhibits extended chemical, physical, or chemical and physical stability.