RU2319508C2 - Dispersible preparation of antiinflammation agent - Google Patents

Abstract

FIELD: medicine, in particular composition for treatment and/or prevention of inflammation condition.

SUBSTANCE: claimed composition contains anti-inflammation agent and optionally other active agents, water dispersible and ethanol insoluble amphipathic oil, microcrystalline wax and pharmaceutically acceptable non-aqueous carrier. Method for treatment includes administering of said composition in organ.

EFFECT: agent with increased oxidative stability, low interface tensile and reduced side effects.

65 cl, 9 ex

Description

Field of Invention

The present invention relates to a method for treating and / or preventing an inflammatory condition in an organ containing a liquid and having a natural external opening, such as an udder of an animal producing milk, or an ear of a subject. The invention also relates to a dispersible pharmaceutical composition suitable for infusion into an organ according to the method of the invention, and to a method for producing such a composition.

BACKGROUND OF THE INVENTION

Mastitis is an inflammation of the mammary gland of animals producing milk, such as dairy cows, most often caused by a bacterial infection. Bacteria penetrate the nipple of the animal and can cause acute, clinical, or subclinical mastitis. It has been confirmed that more than 135 organisms are pathogens that cause mastitis in cows. The three main groups of pathogens are gram-positive cocci, gram-negative bacilli and gram-positive bacilli. Hygiene, environmental factors and metabolic disorders resulting from high milk production combine to create conditions favorable for the onset of mastitis. The increased content of somatic cells associated with mastitis positively correlates with infection and negatively correlates with milk production. Often infected cows have to be removed from the herd and milking stopped. If the disease is not treated properly, mastitis often affects the cow throughout its life. The percentage of infection averages from 10% to 30% of cows per ordinary herd, with losses ranging from $ 185 to $ 250 per cow per year. Cow mastitis is the most costly disease for the dairy industry, and losses in the United States alone are estimated at two billion dollars annually. Most of these losses are due to reduced milk production.

Since inflammation and leukocytosis caused by coliform mastitis often persist even after the bacteria can no longer be excreted from the gland, the use of long-term anti-inflammatory drug therapy can be useful in the treatment of mastitis.

The intramammary administration of dispersible compositions containing an antibacterial agent for the treatment of mastitis in animals producing milk is well known. Some compositions suitable for such administration are formulated as oil-based preparations.

US Pat. No. 3,636,194 to Parizeau discloses a composition for treating mastitis by intramammary infusion containing an antibiotic, vegetable oil, an alcohol-soluble fraction of the natural phospholipid substance lecithin, which disperses the oil in milk, and the phospholipid is selected from the group consisting of phosphatidylcholine and phosphatidylethyleneamine , and is present in the specified oil in an amount of at least 0.25%. It is indicated that such compositions provide rapid dispersion in milk and a short elimination time with milk (miikout times).

UK patent application No. 1181527 discloses a composition for treating mastitis containing an active substance and a pharmaceutically acceptable oil base containing a phospholipid substance consisting essentially of an alcohol-soluble substance that disperses the composition in milk.

European patent application No. 0222712 discloses a composition that contains one or more antimicrobial agents dispersed in an oil consisting of a mixture of triglycerides of palmitic and stearic acids together with polyoxyethylene cetyl alcohol and stearyl alcohol, and is placed in an oil medium of mineral, vegetable, synthetic or mixed origin. It is indicated that such compositions accelerate the release of the antimicrobial agent in the udder, enhancing its biological potential and reducing the elimination time with milk.

The use of anti-inflammatory agents for the treatment of mastitis has also been proposed.

US Pat. No. 5756529, Isakson & Talley, discloses a method of using pyrazolyl-benzenesulfonamide compounds for treating inflammation in a pet. Such compounds are indicated to be useful in the treatment of pain, fever, joint disease, traumatic injury, arthritis, myositis, tendonitis, colic in horses, mastitis, peritonitis, skin conditions, burns, gingivitis, hypersensitivity, conjunctivitis, eye inflammation, swelling and ischemia myocardium.

International Patent Publication No. WO 02/22107 discloses compositions containing one or more bioactive agents in a liquid carrier, which is modified to contain increased levels of oxidation products, where bioactive agents include anti-infective agents, anti-tumor agents, immunomodulators, antipyretics , analgesics and anti-inflammatory agents (e.g., COX-2 (cyclooxygenase-2) inhibitors). Such compositions may be administered parenterally (e.g., subcutaneously, intramammally, intravenously, intraperitoneally or intramuscularly), topically, intravaginally, orally or rectally.

International Patent Publication No. WO 02/06865 discloses one or more bioactive substances in a non-aqueous carrier, the composition being adjusted to a water activity of from about 0.2 to about 0.5. Parenteral, local, oral, intravaginal, rectal and intramammary routes of administration are suggested. Among the bioactive agents are anti-infective agents, anti-tumor agents, immunomodulators, antipyretic drugs, analgesics and anti-inflammatory agents (for example, COX-2 inhibitors).

International Patent Publication No. WO 99/20259 discloses a combination of thiamphenicol and diclofenac for use in veterinary medicine for the treatment of infections with associated inflammatory conditions.

International Patent Publication No. WO 01/60409 discloses a pasty composition comprising a therapeutic agent, carbon black, a viscosity modifier and a hydrophilic carrier; where the therapeutic agent is selected from insecticides, acaricides, parasiticides, antibiotics, growth enhancers, oil-soluble NSAIDs (non-steroidal anti-inflammatory drugs), avermectins, milbemycins, nordulisporic acid, estrogens, progestins, phenylpyridazole phenylpyrazides. Oral, local, cutaneous and subcutaneous routes of administration of a pasty composition are considered. It is indicated that such compositions are used in veterinary practice in the treatment of diseases such as pneumonia, mastitis, metritis, rhinitis and bronchitis.

US Patent Application Publication No. 2002/0032228 discloses the use of a heterocycle-containing compound, for example a diphenyl heterocyclic derivative, for the treatment of diarrheal diseases, whooping cough, anthrax, smooth muscle contraction conditions and mastitis. Celecobsib and rofecoxib are listed as preferred diphenyl heterocyclic derivatives.

The Gattefossé Corporation Labrafil Product Brochure (Review OL 0050 / 5th Edition) contains an extract from Valette's dissertation (1957) discussing Labrafil ™ M-1944CS features in the ear canal. The same dissertation describes an experiment involving the injection of Labrafil ™ M-1944CS mixed with gentian violet into a cow's nipple. Labrafil ™ was shown to moisturize the entire surface of the cut of the mammary parenchyma and reach the retromammary ganglion.

In two articles, Gao et al. (1995) in Pharmaceutical Research 12 (6), 857-868, "Controlled release of a contraceptive steroid from biodegradable and injectable gel formulations: in vivo evaluation ", describes the preparation of gels containing levonorgestrel, Labrafil ™ M-1944CS and glyceryl palmitostearate.

Ear disorders are the second most common illness in children in the United States, second only to the common cold. Most ear disorders are the result of a painful inflammatory reaction to infections, allergies, or ear trauma. Ear infection can be of bacterial, fungal or viral origin, and determining the exact etiology is impractical, since the pathogen is often difficult to isolate and cultivate. The most common ear disorders include otitis media (infections of the outer ear), otitis media (infections of the middle ear) and otorrhea (otitis media with a torn eardrum and effusion).

Otitis externa, affecting parts of the ear canal of the outer ear, is a common otological problem that occurs mainly during hot, humid weather, and is five times more common in swimmers compared to non-swimmers. At the initial stage, symptoms include itching and pain in the ear canal, as well as pain when pressing around the external auditory canal, stretching the earlobe, or moving the jaw. At the last stage, suppuration occurs in the ear canal and hearing may decrease. More than 90% of cases of external otitis media are caused by bacterial and fungal infections.

Pathological conditions can occur due to changes and can cause changes in surface tension at the air / liquid phase interfaces of tissue surfaces, especially epithelial tissue surfaces. The external auditory canal is lined with epithelium. Sulfur exudate, usually secreted onto the epithelial tissue lining the external auditory canal, giving it a particularly high surface tension. Inflammatory by-products may further increase such surface tension. Increased surface tension is an important factor in both the symptoms and treatment of otitis media. In addition, and even in the absence of a canal closure, increased surface tension constantly present on the epithelial lining of the external ear canal tends to impede the uniform and / or effective application of therapeutic agents.

In the past, otitis externa was treated by topical application of therapeutic agents demonstrating both antimicrobial and anti-inflammatory effects. For the destruction of pathogenic bacteria we used ear suspensions of broad-spectrum antibiotics that are effective when applied topically, containing antibacterial agents, such as neomycin sulfate, colistin sulfate, polymyxin B, or combinations thereof, all of which have a wide spectrum of action. Local antifungal agents, such as nystatin and clotrimazole, were used to eradicate the underlying fungal disease. In addition, the antiviral agent acyclovir was used to treat viral otitis externa, including herpes zoster.

To control the inflammatory process with external otitis media, anti-inflammatory agents were used, including, for example, hydrocortisone, hydrocortisone acetate and dexamethasone sodium phosphate, which are often included in the local suspension above. Most often, antimicrobial and anti-inflammatory agents are used in combination to treat the underlying cause, an initiating disorder, such as a bacterial infection, as well as the inflammatory process itself. Most often, they are also administered in the form of suspensions in the form of drops for topical administration into the affected ear. In order to increase and ensure a more uniform delivery of such drugs to the epithelial lining of the external ear canal, tampons made of absorbent material, such as cotton, are used to draw the suspension into the ear canal. However, due to exudate present in the purulent forms of otitis externa and earwax present in virtually all inflammatory conditions, high surface tension prevents the uniform distribution of such drugs throughout the external auditory canal.

The most common ear disorder, otitis media, in the United States is a major cause of hearing loss and is a significant disadvantage that interferes with childhood learning. See Estrada (1997), infect. Med. 14 (3), 239-244. Otitis media accounts for more than 35 percent of pediatrician's annual visits to pediatricians and means more than $ 3.5 billion annually for US health care.

During attacks of otitis media, relatively high surface tensions present at the air / liquid interface located on the epithelial lining of the lumen of the tube increase the opening pressure required to open this channel.

Usually infectious ear disorders, such as otitis media, are treated with a course of antibiotic therapy. See The Merck Manual, 17th edition (1999), Section 7, Chapter 84. Systemic administration of antibiotics usually requires high starting doses and a palpable lag period to achieve therapeutic levels in the ear. The systemic use of drugs through the parenteral or oral route, when ultimately reaching the Eustachian tube and middle ear, may be accompanied by adverse systemic effects and, more importantly, not particularly effective in delivering a concentrated dose of applied drugs to where they are really needed directly target tissue. At the same time, the direct application of the drug is complicated by the anatomy of the clogged cavities of the middle ear.

Various patents and publications, including the patents and publications listed below, for topical administration to the ear have proposed combinations of antibacterial and anti-inflammatory drugs, together formulated in a pharmaceutically acceptable excipient.

US Patent No. 6395746, Cagle et al.

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

U.S. Patent No. 6,009,327, Cagle et al.

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

U.S. Patent No. 5,965,549 to Purwar & Goldman.

US Patent Application Publication No. 2001/0049366.

US Patent Application Publication No. 2002/0142999.

US Patent Application Publication No. 2002/0044920 discloses the treatment of immune-mediated ear disorders by administering a TNF antagonist (tumor necrosis factor) and a pyrimidine synthesis inhibitor with a steroid, an anti-inflammatory compound (e.g., a non-steroidal anti-inflammatory drug, also known as an NSAID, or a COX- inhibitor 2), a cytotoxic compound, an antitumor metabolite, or a secondary antirheumatic agent.

US Patent Application Publication No. 2002/0076383 discloses the administration of an aerosol composition through the external auditory canal, the composition containing a lipid surfactant in an amount effective to reduce surface tension at the air / liquid interface on the epithelial tissue lining, a spreading agent and a propellant, where the spreading agent is selected from the group consisting of lipids, sterols, fatty acids, cholesterol esters, phospholipids, carbohydrates and proteins, all from toryh are in powder form. It is indicated that the composition increases the patency of the external auditory canal, while providing protection against the occurrence of external otitis media.

US Patent Application Publication No. 2002/0064503 discloses the administration of a composition in the form of an aerosol through the external respiratory tract, the composition containing a lipid surfactant in an amount effective to reduce surface tension at the air / liquid interface on the epithelial tissue lining, and the spreading agent is selected from the group consisting of sterols, lipids, fatty acids, cholesterol esters, phospholipids, carbohydrates and proteins, all of which are in powder form. It is indicated that this composition increases the permeability and efficiency of equalizing the pressure in the lumen of the Eustachian tube.

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

U.S. Patent Application No. 2001/0041726.

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

US Patent Application No. 2002/0010146.

U.S. Patent Application No. 2002/0013318.

US patent No. 6307047, Black et al.

U.S. Patent No. 6,329,526, Adams et al.

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

Despite recent successes in understanding the causes of ear disorders, they remain largely unavoidable and difficult to treat effectively. Therefore, it would be useful to propose effective methods and compositions for the prevention and treatment of ear disorders and related complications.

The most commonly used packaging containers and delivery vehicles for compositions intended for intramammary administration for the treatment or prevention of mastitis in animals producing milk, as well as compositions for introduction into the ears for the treatment of ear disorders, are created from oxygen-permeable plastics, for example polyethylene, polypropylene, etc. .d., and mixtures thereof. The use of oxygen-permeable packaging containers and delivery devices for anti-mastitis compositions and for compositions for treating or preventing ear disorders poses serious problems regarding the long-term chemical and / or physical stability of the compositions contained therein if the composition includes an ingredient, for example, an active drug or an excipient, which are subject to oxidative decomposition.

Although the documents listed above disclose a number of compositions for treating mastitis or for treating ear disorders, none of them address the problem of ensuring long-term chemical and / or physical stability of a composition packaged in an oxygen-permeable container, where this composition contains a pharmaceutically active agent and / or an excipient that is susceptible to oxidative degradation. Despite the above guidelines, there is still a need in the art for pharmaceutical compositions having one or more of the following advantages over prior art compositions used in the treatment of mastitis, or over prior art compositions used in the treatment or prevention of earplugs disorders:

(a) long-term chemical and / or physical stability, even when packaged in oxygen-permeable containers and delivery vehicles, especially when the composition contains a pharmaceutically active agent or an excipient susceptible to oxidative degradation, (b) a safe, effective treatment of the inflammatory component of mastitis or ear disorder, ( c) safe, effective treatment of pain, inflammation, swelling, fever and swelling associated with mastitis or ear disorder, (d) minimal irritation or absence of irritation after e administration of the composition, (d) rapid dispersibility protivomastitnoy composition in milk and in udder fluids to quickly achieve effective levels of drug in the sites of inflammation; (f) rapid dispersibility of the ear composition in a waxy moist environment of the ear to quickly achieve effective levels of medication in places of inflammation, (g) a decrease in surface tension at the air / liquid interface of the epithelial tissue, increasing the permeability of the auditory canal, and (h) a protective coating for inflamed mucous membranes of the ear.

SUMMARY OF THE INVENTION

New methods of treatment and pharmaceutical compositions have been developed that have some or all of the beneficial properties described above. In particular, a new method is proposed for treating and / or preventing an inflammatory condition in an organ containing a liquid having a natural external opening, for example, in the udder of an animal producing milk, or in the ear of a human or animal. This method involves administering an anti-inflammatory agent to an organ through an external opening and administering it in combination therapy with a second agent as defined herein. The anti-inflammatory agent is administered in the form of a pharmaceutical composition containing, in addition to the specified agent, an excipient that contains (a) amphipathic oil, which is dispersible in water and insoluble in ethanol, (b) microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier.

Such a composition has a low interfacial tension upon bringing contact with an aqueous medium. Without being bound by theory, it appears that this low interfacial tension results in a composition that is readily dispersible in udder fluids such as milk, as well as in a more waxy, moist ear environment. Therefore, in a preferred method according to the invention, when introduced into an organ containing a liquid, the composition is dispersed in this liquid.

A preferred anti-inflammatory agent for use in the method of the invention is a selective COX-2 inhibitor.

The method may, for example, include an intramammary infusion of such a composition for treating mastitis or other udder diseases in an animal producing milk, or infusion into the ear of such a composition for treating and / or preventing ear disorders, and is effective in a wide range of inflammatory disorders that can be associated with a wide range of infectious organisms. The term “infusion” as used herein encompasses any procedure in which a liquid composition is forced to flow into an organ containing a fluid through an external opening, for example, a nipple channel in the case of an intramammary infusion, or an external auditory channel in the case of an infusion in the ear, regardless of the time required. In the present context, “infusion” and “injection” are essentially synonyms. For example, the composition can be administered intramammary by introducing a catheter nozzle of a mastitis syringe into the external opening of the nipple channel and injecting the composition through the nozzle into the udder.

In another embodiment, in combination therapy, an anti-inflammatory agent, for example a selective COX-2 inhibitor, is administered with a second agent. The second agent may be any therapeutically active agent useful in the treatment of mastitis or ear disorders. Such second agents include, but are not limited to, antibacterial agents, antitumor agents, anesthetics, sodium channel blockers, antipyretics, analgesics, decongestants, and the like, as well as combinations thereof.

The second agent may be administered by a route other than the route of administration of the anti-inflammatory agent. Alternatively, both agents can be administered in the same way, i.e. through the external opening of the organ, for example, through the nipple channel in the case of an udder, or through the external auditory canal in the case of an ear. When the administration is carried out in the same way, it is preferable to administer both agents by intramammary infusion or infusion into the ear in the form of a liquid composition containing an excipient as described above. It is especially preferred to administer the anti-inflammatory agent and the second agent in a single composition containing both agents.

Accordingly, there is further provided a pharmaceutical composition comprising an excipient that contains (a) an amphipathic oil that is water dispersible and insoluble in ethanol, (b) microcrystalline wax, and (c) a pharmaceutically acceptable non-aqueous carrier. The excipient contains an anti-inflammatory agent stably dispersed in it, for example, a selective COX-2 inhibitor, in an amount effective against inflammation.

In one embodiment, the anti-inflammatory agent and / or excipient in the composition is susceptible to oxidative degradation, and the composition has long chemical and / or physical stability when packaged in a container or delivery device having an oxygen permeable wall.

The new composition has a low interfacial tension in aqueous fluids, whereby the dispersibility of this composition in milk and udder fluids is increased compared to a traditional oil-based preparation. This leads to a quick distribution of the composition along the udder and, thus, allows the anti-inflammatory agent and / or the second agent to quickly reach the inflamed tissue, providing an effective level of drug at the site of inflammation. The interfacial tension of the composition in an aqueous liquid determines the energy required for dispersion and distribution of the composition in the liquid, as well as the energy necessary for the suspended particle in the composition to cross the oil / milk or oil / liquid interface in the udder.

The low interfacial tension of the composition also increases the dispersibility of the composition in a waxy, moist ear environment compared to a conventional composition. The resulting rapid distribution of the composition across the mucous membranes and lipid wax of the ear canal allows the anti-inflammatory agent and / or second agent to quickly reach the inflamed tissue, providing an effective level of drug at the site of inflammation. Such a composition may also form a protective coating for inflamed mucous membranes of the ear.

Preferably, the method or composition provides an effective treatment for the inflammatory component of a breast or ear disorder. Preferably, the method or composition provides effective treatment and / or prevention of pain, inflammation, swelling, edema and / or fever associated with such a disorder.

When administered by intramammary infusion, for example in the treatment of mastitis, preferred methods and compositions may have additional advantages. For example, a preferred method provides a suitable short excretion time with milk. Breeding time with milk for a milk-producing cow is a period of time from the administration of a mastitis treatment agent to the resumption of production suitable for the sale of milk. After such an introduction, before milk is considered suitable for human consumption, the concentration of the active agent (s) in the milk should drop to a level permitted by the relevant regulatory body. An appropriate short elimination time with milk reduces the material losses of dairy farmers from an outbreak of mastitis.

An alternative or additionally preferred method provides a short delay in milk production after calving after treatment of dry bovine mastitis, with no residual active agent in the offspring.

Alternative or additionally, the preferred method provides a zero period of rejection of slaughter for meat after treatment of mastitis. This property is especially important because it allows the farmer to dispose of the healed cow at any time when it is financially advantageous, instead of having to keep and feed the cow for a certain time after its treatment.

When administered by infusion into the ear, for example in the treatment of infectious ear disorders having an inflammatory component, preferred methods and compositions may have additional advantages. For example, the preferred method increases the permeability of the auditory canal and thereby reduces the resistance to the passage of sound, improving the purity and sensitivity of hearing.

An alternative or additionally preferred method is to cover the epithelial ear lining, which protects against the harmful effects of water and water-borne toxins, irritants and allergens, and helps prevent ear disorders.

An additional benefit of the methods and compositions of the invention for both inflammatory and ear applications is that they provide targeted delivery of at least an anti-inflammatory agent to the site of inflammation. When a composition of the invention is used containing both an anti-inflammatory agent and a second agent, as defined herein, targeted delivery of both agents to the site of infection and / or inflammation is provided.

Another advantage of the preferred compositions for both inflammatory and aural administration is that, after administration, they cause minimal or no irritation.

Another advantage of the composition according to the invention is improved physical stability when compared with traditional oil or water compositions, for example due to the improved resuspendability of the composition. It is shown that the composition according to the invention causes the flocculation of certain drugs, thereby improving resuspendability and eliminating the problem of the formation of a suspension in the suspension and the possible delivery of an insufficiently strong or ineffective dose.

A method of obtaining a pharmaceutical composition according to the invention. The method comprises mixing, in any suitable order, an amphipathic oil that is water dispersible and insoluble in ethanol, microcrystalline wax, a pharmaceutically acceptable non-aqueous carrier and an anti-inflammatory agent, for example a COX-2 selective inhibitor, to obtain a composition, which composition preferably has long-term chemical and / or physical stability, as defined herein.

Thus, the present invention provides a solution to several longstanding problems in this field and has one or more advantages over the methods and compositions of the prior art. Other features, advantages, and benefits of the invention will be apparent from the description that follows.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a method of treating and / or preventing an inflammatory condition in an organ containing a liquid having a natural external opening, comprising administering an anti-inflammatory agent to the body through the external opening, in the form of a pharmaceutical composition containing an anti-inflammatory agent in an amount effective against inflammation, and an excipient, which contains (a) an amphipathic oil that is water dispersible and insoluble in ethanol, (b) microcrystalline wax and (c) a pharmacist an acceptable non-aqueous carrier. The invention also provides the use of a composition of the present invention in the manufacture of a medicament for treating or preventing an inflammatory condition in an organ containing a liquid having a natural external opening. The invention further provides a composition for use in a method of treating or preventing an inflammatory condition in an organ containing a liquid having a natural external opening.

This method is particularly useful in the treatment and / or prevention of inflammation accompanying an infectious condition. An “infectious condition” as used herein includes any disease, disorder, or condition mediated by pathogenic bacteria, or that it is treatable with an antibacterial agent, such as an antibiotic drug.

It should be understood that the reference in this description to methods, including compositions containing an “anti-inflammatory agent”, encompasses such methods and compositions that use more than one anti-inflammatory agent. Also, more than one therapeutically active agent other than an anti-inflammatory agent may possibly form a “second agent” in this case.

The term “anti-inflammatory amount” as used herein refers to an amount of an anti-inflammatory agent that, when administered by the method of the invention, is sufficient to reduce, alleviate, prevent, or delay the onset of one or more symptoms of an inflammatory condition that is being treated. The term “therapeutically effective amount”, as used herein, refers to the amount of active agent that, when administered by the method of the invention, is sufficient to reduce, alleviate, prevent or delay the onset of one or more symptoms of the condition that is being treated, or to reduce the amount and / or pathogen activity. The expression “in therapeutically effective amounts of each” means that when administered in combination therapy according to the method of the invention, the amount of anti-inflammatory agent and the amount of the second agent are sufficient to provide both an anti-inflammatory effect and an effect selected from an antibacterial, anesthetic, sodium channel blocking agent, decongestant, analgesic, antitumor and / or antipyretic effects. Such amounts may be the same, as well as more or less than the amount of anti-inflammatory agent or the amount of the second agent, which are therapeutically effective when used in monotherapy.

An organ containing a liquid as intended herein includes an organ related to the mammary gland, for example, an udder of an animal producing milk, such as a cow, goat or sheep. An “animal producing milk” can be a female of any mammalian species, but preferably an animal raised to produce milk, such as a cow, goat or sheep, and this term includes such animals, whether they produce milk or not. during an inflammatory and / or infectious condition or at the time of treatment. The natural external opening of the organ related to the mammary gland is the opening of the nipple channel. The fluid-containing organ also includes the ear of a human or animal. The natural external opening of the ear is the opening of the external auditory canal.

The invention further provides a method for treating an inflammatory condition in an organ containing a liquid having a natural external opening, comprising administering an anti-inflammatory agent to the organ through the external opening and administering, when combined with the second agent, as defined herein, in a therapeutically effective amount of each of them; where the anti-inflammatory agent is administered in the form of a pharmaceutical composition containing said agent and an excipient that contains (a) an amphipathic oil that is water dispersible and insoluble in ethanol, (b) microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier.

The term “combination therapy” as used herein refers to a treatment regimen in which the anti-inflammatory agent and the second agent are administered individually or together in such a way as to provide a beneficial effect of the combined action of these therapeutic agents. Such a beneficial effect may include, but is not limited to, the pharmacokinetic or pharmacodynamic joint action of therapeutic agents. Combination therapy, for example, may make it possible to administer a lower dose of one or both agents compared to the dose that would normally be administered during monotherapy, thereby reducing the risk or prevalence of side effects associated with higher doses. Alternatively, combination therapy can lead to an increased therapeutic effect with a normal dose of each agent in monotherapy. In this description, it is assumed that "combination therapy" does not cover the introduction of two or more therapeutic agents, as part of separate monotherapy regimens that randomly and arbitrarily lead to sequential or simultaneous treatment.

The administration of the anti-inflammatory agent and the second agent is usually carried out over a period of time (usually minutes, hours, days or weeks, depending on the combination selected). These therapeutic agents can be administered sequentially, that is, at different points in time, usually separated from each other by no more than approximately 24 hours, or essentially simultaneously.

When administered simultaneously, the anti-inflammatory agent and the second agent can be administered in separate dosage forms or together with the drug, i.e. in one dosage form. When two agents are administered sequentially or in separate dosage forms, the second agent can be administered in any suitable way and in any pharmaceutically acceptable dosage form, for example by and / or in a dosage form that is different from that used for the anti-inflammatory agent. Alternatively, the second agent, like an anti-inflammatory agent, can be dispersed in an excipient that contains (a) an amphipathic oil that is water dispersible and insoluble in ethanol, (b) microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier, and administered via a natural the outer opening of an organ containing fluid. In a preferred embodiment, both agents are dispersed together in the same vehicle and administered in one go.

Preferably, the second agent is formulated in a pharmaceutically acceptable excipient, and both the anti-inflammatory agent and the second agent are administered into the same organ containing the liquid, for example by intramammary or ear infusion. A pharmaceutically acceptable carrier or excipient is a carrier or excipient that does not have an unacceptably harmful or toxic effect on the subject when administered as a component of the composition in an amount required in this case. None of the excipient ingredient of such a carrier or excipient reacts undesirably with another excipient or with the therapeutic agent (s) in the composition.

A pharmaceutical composition containing an anti-inflammatory agent is a liquid injection or infusion composition containing said agent dispersed in an excipient as described herein. The term “dispersed” as used herein means dissolved (ie, molecularly dispersed) or colloidally dispersed, for example, as an emulsion or suspension. Typically, an anti-inflammatory agent is suspended in a particulate excipient.

The filler contains three main ingredients, possibly together with additional ingredients.

The first of these main ingredients is amphipathic oil, which is dispersible in water and insoluble in ethanol. "Amphipathic oil" is defined as a substance having a molecular structure with a distinctly polar region and a distinctly non-polar region. Structurally, these two sections of amphipathic oil are quite far from each other, so that the unique properties of the two sections are clearly separated. The term "insoluble in ethanol" means that the amphipathic oil is essentially insoluble in ethanol at 20 ° C.

The second main ingredient of the filler is microcrystalline wax.

The third main ingredient of the excipient is a pharmaceutically acceptable non-aqueous carrier. Such a carrier is usually an oil, as described more fully in this description below.

The choice of filler components is important in obtaining a composition that, when introduced into an organ containing a liquid, is dispersed in the liquid. It seems, without regard to theory, that such a dispersion in a fluid in an organ leads to targeted delivery of an anti-inflammatory agent and, possibly, a second agent to the site of inflammation in the organ.

When the method of the invention involves injecting or infusing the composition into the udder through the nipple channel, it can provide effective treatment for mastitis, other diseases of the udder and / or condition associated with breast disease. "Intramammary infusion" is a procedure in which a liquid composition is forced to flow into the udder through the nipple channel, regardless of the time required. In this context, “infusion” and “injection” are essentially synonyms.

When the method of the invention involves injecting or infusing the composition into the ear through the external auditory canal, the process described herein as “infusion into the ear”, regardless of the time required, can provide effective treatment and / or prevention of an ear disorder and / or complication associated with with him. A subject suffering from such an ear disorder or complication associated with it may be a person, a pet, a horse, farm animals and the like.

Examples of such ear disorders include otitis media (infections of the outer ear), otitis media (middle ear infections), including acute, secretory, serous and chronic forms of otitis media, otorrhea (otitis media with torn eardrum and effusion), acute mastoiditis, infections, associated with surgical operations on the ear (such as tympanostomy and the like), otosclerosis, earache, ear pain, ear inflammation, ear bleeding, Lermuaye syndrome, Meunier's disease, vestibular neuronitis, benign paroxysmal position dizziness, auricular herpes zoster, Ramsay Hunt syndrome, viral neuronitis, ganglionitis, herpes of the cranked node, labyrinthitis, including purulent labyrinthitis and viral endolymphatic labyrinthitis, perilymph fistula, presbyakusis, induced neurotransmittance, secondary neurotransmittinosis, myringitis, ear neoplasm, squamous cell carcinoma, basal cell carcinoma, other ear cancers, ear precancerous conditions, nonchromaffin paragangliomas, hemodectomas, jugular glomus tumors, glomus tympanicum tumors, perichondritis, auricular eczematoid dermatitis, malignant external otitis media, subperichondrial hematoma, ceruminomas, sulfur plugs, sebaceous cysts, osteomas, keloids, ear noise, dizziness, tympanic membrane infection, tympanic membranes, tympanic membranes, tympanum conductive and sensorineural hearing loss, epidural abscess, lateral sinus thrombosis, subdural empyema, otitic hydrocephalus, Dandy syndrome, bullous myringitis, diffuse external otitis media, foreign bodies, obstructive Ker toz (keratosis obturans), otomycosis, trauma, acute barotitis, acute obstruction of the Eustachian tube, a complication associated with any of the above infections (such as hearing loss, brain abscess, fever, cholesteatoma, calcification of the middle and inner ear, rupture of the eardrum, meningitis, facial paralysis and the like), post-surgical otalgia and the like, but are not limited to them.

The method according to the invention is particularly suitable for the treatment of otitis externa, otitis media, otorrhea, and infections having an inflammatory component that is associated with ear surgery.

In one embodiment, the ear disorder is neoplasia. Examples of such neoplasia include ear neoplasia, squamous cell carcinoma, basal cell carcinoma, malignant otitis externa, nonchromaffin paraganglioma malignant, jugular glomus malignant, glomus tympanicum malignant, ear precancer and the like, but are not limited to them.

Combined therapy with an anti-inflammatory agent together with a second agent provides enhanced treatment options compared to the administration of each agent alone. As indicated above, the anti-inflammatory agent is dispersed in an excipient that contains (a) amphipathic oil, which is water dispersible and insoluble in ethanol, (b) microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier, and is administered, for example, by intramammary or an ear infusion, while the second agent is formulated in any suitable pharmaceutical dosage form with immediate or delayed release. Suitable dosage forms for the second agent include suspension, solution, emulsion, tablet, capsule, pill, powder, granules, elixir, tincture, syrup, lozenges, dragees, gel, ointment, spreading paste, suspension, aerosol spray, ear drops, drops for the nose, eye drops, suppositories, implants and the like, but are not limited to, and can be administered by any route, including oral, including oral and intraoral, for example, sublingual, buccal, etc .; parenteral e.g. intramammary, local, transdermal, intranasal, auricular, through the mucous membrane, rectal, intravaginal, pulmonary and the like, but not limited to.

Perhaps the introduction of therapeutic agents described above may occur in additional combination with other biologically active agents and non-drug therapies.

In all embodiments of the invention, at least the anti-inflammatory agent is administered topically. An advantage of such topical administration is that the anti-inflammatory agent is preferably directed to its site of action, which leads to a more rapid onset of therapeutic action and more complete delivery to the site of inflammation compared to other routes of administration such as the intramuscular, subcutaneous and oral routes. Local administration may allow the total therapeutic dose for a given effect to be reduced, and to avoid the effect of the first passage through the liver. In addition, topical administration reduces or eliminates secondary effects, especially effects associated with the active agent in places other than the site of infection. Topical administration of the active agent can also improve its therapeutic index by reducing its general toxicity and minimizing the risk of unwanted systemic effects. The therapeutic index is an indicator of the difference between a therapeutically effective dose and a toxic dose of a drug and is usually expressed as the ratio of LD ₅₀ (dose lethal for 50% of the population) to ED ₅₀ (dose therapeutically effective in 50% of the population).

In a further embodiment of the invention, there is provided a pharmaceutical composition adapted for intramammary and / or ear infusion, comprising an excipient that includes (a) amphipathic oil that is water dispersible and insoluble in ethanol, (b) microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier; an excipient containing an anti-inflammatory agent stably dispersed therein, for example, a COX-2 selective inhibitor in an amount effective against inflammation.

Preferably, such a composition reduces the high surface tension of the water / liquid epithelial tissue interface associated with an ear disorder so as to increase the patency of the auditory canal. Reducing the surface tension of the water / liquid phase boundary of the epithelial lining can minimize fluid accumulation and in some cases makes it possible to remove the fluid held in the canal due to increased surface tension in it and / or allows separation of the proximal and opposite epithelial walls of the auditory canal (often moved closer to each other due to increased surface tension of the tissues), whereby the transmission of sound is improved. The term "increased patency", as used herein, refers to the opening, and reduction, or removal of blockage of the auditory canal so as to form a passable canal. Resistance to sound transmission occurs due to a decrease in volume, partial congestion or complete blockage of the auditory canal due to swelling of the epithelial walls as a result of inflammation, the accumulation of increased amounts of sulfur secreted on them, and / or accumulation of liquids in it, including liquids containing by-products immune response or exogenous water.

In a particular embodiment of the invention, the ingredient of the composition (anti-inflammatory agent and / or second agent and / or excipient ingredient) is oxidatively degraded. Such a composition has long chemical and / or physical stability even when packaged in an oxygen-permeable container or delivery device. The term "long-term chemical and / or physical stability" as used herein means that the composition of the present embodiment has greater chemical and / or physical stability compared to a comparative composition containing the same drug in the same concentration. "Comparative composition" in the present context means a composition in which one or both of amphipathic oil and microcrystalline wax are missing, but in other respects it is similar to the composition of the invention.

The oxygen permeable containers or delivery agent may be made of any suitable thermoplastic material. Examples of such materials include, but are not limited to, polymers and copolymers of polystyrene, polyacrylonitrile, polyvinyl chloride, and especially polyolefins. Polyolefins include, for example, polyethylene, polypropylene, polybutenes, polyisoprenes, polypentenes, their copolymers and mixtures thereof.

The composition for intramammary administration is usually packaged in syringes that are provided with a catheter nozzle for insertion into the nipple to allow the composition to be expelled directly into the mammary gland through the nipple channel. Intramammary suspension formulations are usually prepared in thickened excipients to prevent sedimentation of drug particles in the catheter nozzle, which may cause blockage of the nozzle, resulting in incomplete expulsion of the composition.

The anti-inflammatory agent in this description may have one or both analgesic or antipyretic properties in addition to its anti-inflammatory activity. The term “anti-inflammatory agent” as used herein encompasses compounds that are primarily analgesics or antipyretics that have a secondary anti-inflammatory effect. Examples of anti-inflammatory agents useful herein include aceclofenac, acemetacin, e-atsetamidokapronovuyu acid, acetaminophen, atsetaminosalol, acetanilide, acetylsalicylic acid (aspirin), S-adenosylmethionine, alclofenac, alclometasone, alfentanil, algeston, allylprodine, alminoprofen, aloksiprin, alphaprodine , bis (acetylsalicylate) aluminum, amcinonide, amfenac, aminochlorothenoxazine, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylone, aminopyrine, amixetrine, ammonium salicylate, ampiroxicam, amtolmetining , anileridine, antipyrine, anthraphenin, apazone, beclomethasone, bendazac, benorilate, benoxaprofen, benzitramide, benzpiperilone, benzidamine, benzylmorphine, bermoprofen, betamethasone, bezitramide, α-bisabolol, bromfenacanoyl bromoacetal, bromoacetal bromide, bromide bromide, bromide bromide , buccloic acid, bucol, budesonide, bufexamak, bozdizon, buprenorphine, butacetin, butibufen, butofanol, carbamazepine, carbifen, carprofen, karsalam, celecoxib, chlorobutanol, chlorprednisone, chlortenoxazine choline, choline, choline, choline, , cinchofen, cinmetacin, cinnoxicam, ciramadol, clidanac, clobetasol, clocortolone, clomethacin, clonitazen, clonixin, clopirac, cloprednol, clove, codeine, codeine methyl bromide, codeine phosphate, codeine sulfate cortisolate, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisolamine, cortisoltamide , dehydrotestosterone, deracoxib, desomorphine, desonide, deoxymethasone, dexamethasone, dexoxadrol, dextromoradine, dextropropoxyphene, deocin, diamorphon, diampromide, diclofenac, diphenamisole, diphenpyramide, diflouflonone, difloflodolon, okodein, dihydrocodeinone-enol acetate, dihydrocodeine phosphate, dihydromorphine, dihydroxyaluminum acetylsalicylate, dimenoxadol, dimefeptanol, dimetiltiambuten, dioksafetila butyrate, diphenhydramine hydrochloride, dipipanone, diprotsetil, dipyrone, ditazol, DL-chlorpheniramine maleate, droxicam, emorfazone, enfenamovuyu acid enoksolon, epirizole , eptazocin, etersalate, ethenzamide, ethoheptazine, ethodolac, ethoxazene, ethoheptazine, ethyl methyl thiambutene, ethyl morphine, etodolac, etofenamate, ethonitazene, etoricoxib, eugenol, felbinak, fenbufen, fenchlofen , Fenklozovuyu acid, fendosal, fenoprofen, fentanyl, fentiazac, fepradinol, feprazone, floctafenine, fluazakort, flucloronide, flufenamic acid, flumethasone, flunisolide, flunixin, flunoksaprofen, fluocinolone acetonide, fluocinonide, fluocinolone acetonide, fluokortinbutil, fluocortolone, fluorezon, fluorometholone, fluperolon , flupirtine, flupredniden, fluprednisolone, fluprofen, fluproquasone, flurandrenolide, flurbiprofen, fluticasone, formocortal, phosphosal, furofenac, gentisic acid, glafenin, glucamethacin, glycol salicylate, guaia halcinonide, halobetazole, halomethasone, haloprednone, heroin, hydrocodone, hydrocortamate, hydrocortisone, hydromorphone, hydroxypetidine, ibufenac, ibuprofen, ibuproxam, imidazolsalicylate, indomethacin, isophexonecofenone isofadone isofadone isofadone isofadone isofladone , ketorolac, para-lactophenetide, lefetamine, levallorfan, levorphanol, levofenacylmorphan, lofentanil, lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate, lysozyme chloride, mazipredone, meclofenamic acid, medrizone , mefenamic acid, meloxicam, meperidine, meprednisone, meptazinol, mesalamine, metazocin, methadone, metotrimeprazine, methephedrine hydrochloride, methylprednisolone, methyl salicylate, methiazinic acid, metofolin, metopon, morafinofrine, morofofenoframofene, morofonefin morfofenofene, morofonefinofone, morofonefinoformone sulfate, morpholine salicylate, myrofin, nabumetone, nalbuphine, nalorfin, 1-naphthylsalicylate, naproxen, narcein, nefopam, nicomorphine, nifenazone, niflumic acid, nimesulide, 5′-nitro-2′-propoxyacetanilanide, norlevad NORMORPHINE, norpipanon, noscapine, olsalazine, opium, oksatseprol, oksametatsin, oxaprozin, oksipinak, oxycodone, oxymorphone, oxyphenbutazone, papaveretum, paramethasone, paranilin, parecoxib, parsalmid, pentazocine, perizoksal, phenacetin, fenadokson, fenomorfan, phenazocine, phenazopyridine hydrochloride, fenokoll phenoperidine, phenopyrazone, phenylacetylsalicylate, phenylbutazone, phenylpropanolamine hydrochloride, phenylsalicylate, pheniramidol, picketoprofen, piminodine, pipebuzon, piperilone, pyrazolac, pyritramide, piroxicam, pirprofen, pirprofen, pirprofen, Arbat, prednisolone, prednisone, prednisone, prednilidene, proglumethacin, proheptazine, promedol, propacetamol, properidine, propiram, propoxyphene, propiphenazone, proquazone, protisinic acid, proxazole, ramifenazylamofalicamide, rismazalicamide, azimazalicamide, azimazalicamide, azimazalicamide acetic acid, salicylic acid, salicylic acid, salsalate, salverin, serratiopeptidase, simetrid, sudoxicam, sufentanil, sulfasalazine, sulindac, superoxide dismutase, suprofen, suksibuzon, taliflumat, tenidap, te oksikam, terofenamate, tetrandrin, thiazolinobutazone, thiaprofenic acid, thiaprofenic acid, thiaramide, tilidine, tinoridine, thiopinac, thioxaprofen, thixocortol, tolfenamic acid, tolmetin, tramadol, triamcinolinopinolimenopinolenecenefinolimenecenefinolinopenemenecolinefinolinopolenecenefinolimenecenefinolinopolenecenefinolimenecenefinolinopenefinolinopenemenecolinefinolinopenefinolamine benzopinenecenefinolinopenemene benzene and the like, and combinations thereof, but are not limited to.

In one embodiment, the anti-inflammatory agent is a steroid. Suitable steroids include alklomethasone, amcinonide, betamethasone, betamethasone-17-valerate, clobetasol, clobetasol propionate, clocortolone, cortisone, dehydrotestosterone, deoxycorticosterone, desonide, deoxymethasone, dexamethasone-delucidonefenlozone-deloquinone-deloquinone-delucidone-diaclozencide-diaclozenflucene-deloquinone-deloquinone-deloquinone-deloquinone-deloquinone-delucidone-fluoride , galcinonide, halobetazole, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone hemisuccinate, hydrocortisone 21-lysinate, sodium hydrocortisone succinate, isoflupredone, isoflupred on acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone suleptanate, mometasone, predicarbate, prednisolone, prednisolone acetate, prednisolone hemisuccinate, prednisolone sodium phosphate, prednisolone sodium succinate, trisolone acetone, prednisolone, trisolone acetone, trisolone combinations thereof, but not limited to.

In another embodiment, the anti-inflammatory agent is an analgesic selected, for example, from alfentanil, allylprodin, alfaprodin, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromodamide, dixtromodamide, diformromide diamide, diformromide amide, dixtromidefamide, diformromide diamide, diformromide diamide, diformromide diamine, diformromide amide, diformromide amide, diformromide amide, diformromide amide, diformromide amide, diformromide amide, diformromide amide, diformromide amide dihydromorphine, dimenoxadol, dimeheptanol, dimethylthiambutene, dioxafetil butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, ethonitazene, fentanyl, hero on, hydrocodone, hydromorphone, gidroksipetidina, isomethadone, ketobemidone, levallorphan, levorphanol, levofenatsilmorfana, lofentanil, meperidine, meptazinola, metazocine, methadone, metopon, morphine, mirofina, nalbuphine, nalorphine, nartseina, nicomorphine, norlevorfanola, normetadona, NORMORPHINE, norpipanona, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenazocine, phenomorphine, phenoperidine, piminodine, pyritramide, proheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol and the like, and combinations thereof.

In yet another embodiment, the anti-inflammatory agent is an NSAID selected, for example, from salicylic acid derivatives (such as salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, olsalazine, salsalate, sulfasalazine and the like), indole and indenoacetic acids (such as indomethacol , sulindac and the like), phenamates (such as etofenamic, meclofenamic, mefenamic, flufenamic, niflumic and tolfenamic acids and the like), heteroaryl acetic acids (such as acemetacin, alklofenac, clida nak, diclofenac, fenchlofenac, fentiazac, furofenac, ibufenac, isoxepac, ketorolac, oxypinac, thiopinac, tolmetin, zidomethacin, zomepirac and the like), aryl acetic acid and propionic acid derivatives (such as alminoprofen, fenfenfenpenofenpensen , fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, naproxen sodium, oxaprozin, pyrprofen, pranoprofen, suprofen, thiaprofen acid, thioxaprofen and the like), enolic acids (such as oxime derivatives: mpiroxicam, cinnoxicam, droxikam, lornoxicam, meloxicam, piroxicam, sudoxicam and tenoxicam, and pyrazolone derivatives: aminopyrine, antipyrine, apazone, dipyrone, oxyphenbutazone, phenylbutazone and the like), such as parafenomethane, and the like), nimesulide, proquasone and the like, and combinations thereof.

In a preferred embodiment, the anti-inflammatory agent is a selective COX-2 inhibitor. A COX-2 selective inhibitor is a compound that selectively inhibits cyclooxygenase-2 (COX-2) activity. The terms “COX-2 selective inhibitor” and “cyclooxygenase-2 selective inhibitor” interchangeably refer to a therapeutic compound that selectively inhibits the COX-2 isoform of the cyclooxygenase enzyme with less significant inhibition of cyclooxygenase-1 (COX-1). As used herein, the term “selective COX-2 inhibitor” also refers to a salt or prodrug that is converted in vivo to a compound that exhibits selective inhibition of COX-2 compared to COX-1. Preferred COX-2 selective inhibitors exhibit a selectivity of at least about 10, more preferably at least about 50, and even more preferably at least about 100, where the “selectivity factor” is defined as IR ₅₀ (SOX-1) / IR ₅₀ (COX-2), wherein the IC ₅₀ is the concentration of the compound providing 50% inhibition of enzyme activity in an in vitro or in vivo test.

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

A preferred selective COX-2 inhibitory drug useful here is a compound of formula (I):

or a prodrug thereof, or a pharmaceutically acceptable salt, wherein:

A is a substituent selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings, preferably the heterocyclyl group is selected from the groups pyrazolyl, furanonyl, isoxazolyl, pyridinyl, cyclopentenonyl and pyridazinonyl;

X represents O, S or CH ₂ ;

n is 0 or 1;

R ₁ represents at least one substituent selected from heterocyclyl, cycloalkyl, cycloalkenyl and aryl, and is optionally substituted at the position at which substitution is possible with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;

R ₂ represents methyl, amino or aminocarbonylalkyl;

R ₃ represents one or more than one radical selected from hydrido, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl , heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxy aralkoxyalkyl, onyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N alkylaminoalkyl; N-arylaminoalkyl; N-aralkylaminoalkyl; N-alkyl-N-aralkylaminoalkyl; N-alkyl-N-arylaminoalkyl; alkyl-N-arylaminosulfonyl, exc R ³ is optionally substituted at the position at which possible substitution, with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; and

R ⁴ selected from hydrido and halogen.

A particularly preferred group of selective COX-2 inhibitory drugs are compounds of formula (II):

where R ⁵ represents a methyl or amino group, R ⁶ represents hydrogen, or a C _1-4 alkyl or alkoxy group, X ′ represents N or CR ⁷ , where R ⁷ represents hydrogen or halogen, and Y and Z independently represent carbon or nitrogen atoms defining adjacent atoms of a five to six membered ring which is optionally substituted at one or more positions by oxo, halo, methyl or halogenomethyl groups, or an isomer, tautomer, pharmaceutically acceptable salt or prodrug thereof. Preferably, such five to six membered rings are cyclopentenone, furanone, methylpyrazole, isoxazole and pyridine rings substituted at most in one position.

Another particularly preferred group of selective COX-2 inhibitory drugs are compounds having the formula (III):

where X ″ represents O, S or N-lower alkyl; R ⁸ represents lower haloalkyl; R ⁹ represents hydrogen or halogen; R ¹⁰ represents hydrogen, halogen, lower alkyl, lower alkoxy or haloalkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroalkylaminosulfonyl or 5- or 6-membered nitrogen-containing heterocycle; and R ¹¹ and R ¹² independently represent hydrogen, halogen, lower alkyl, lower alkoxy or aryl; and their pharmaceutically acceptable salts.

A particularly useful compound of formula (III) is (S) -6,8-dichloro-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid.

Another particularly preferred group of selective COX-2 inhibitory drugs are 5-alkyl-2-arylaminophenylacetic acids and their derivatives. Particularly useful compounds of this class are lumiracoxib and its pharmaceutically acceptable salts.

By way of illustration, celecoxib deracoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, lumiracoxib, 2- (3,5-difluorophenyl) -3- [4- (methylsulphonyl) phenyl] -2-cyclopentene- are useful in the method and composition of the invention. 1-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 (also known as abelacoxib), tert-butyl-1-benzyl-4 - [(4-oxopiperidin-1-yl) sulfonyl] piperidin-4-k rboxylate, 4- [5- (phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide and their salts, more specifically celecoxib, deracoxib, valdecoxib, parecoxib and its salts, rofecoxib, etoricoxib, lumiracoxib, 4 - [5- (4-fluorophenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, tert-butyl-1-benzyl-4 - [(4-oxopiperidin-1-yl) sulfonyl] piperidin- 4-carboxylate and 4- [5- (phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide.

Valdecoxib used in the compositions of the invention can be obtained by any known method, for example, the method described in US patent No. 5633272, Talley et al. Parecoxib and its salts used in the compositions of the invention can be obtained by any known method, for example, the method described in US patent No. 5932598, Talley et al. Rofecoxib used in the compositions of the invention can be obtained by any known method, for example, the method described in US patent No. 5474995, Ducharme et al. Etoricoxib used in the compositions of the invention can be obtained by any known method, for example, the method described in international publication application No. WO 98/03484. 2- (3,5-Difluorophenyl) -3- [4- (methylsulfonyl) phenyl] -2-cyclopenten-1-one used in the compositions of the invention can be obtained by any known method, for example, the method described in European patent No. 0863134 Deracoxib used in the compositions of the invention can be prepared by any known method, for example, the method set forth in US Pat. No. 5,466,823 to Talley et al. 2- (3,4-Difluorophenyl) -4- (3-hydroxy-3-methyl-1-butoxy) -5- [4- (methylsulfonyl) phenyl] -3- (2H) -pyridazinone used in the compositions of the invention can be obtained by any known method, for example, the method set forth in the international publication of application No. WO 00/24719. Other selective COX-2 inhibitory drugs can be obtained by any known method, including the methods described in patent publications disclosing such drugs; for example, in the case of celecoxib, in the aforementioned US patent No. 5466823 or in US patent No. 5892053, Zhi et al. All patents and publications cited above are hereby incorporated by reference.

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

It should be understood that any reference in this description to a specific drug compound includes tautomers, stereoisomers, enantiomers, salts, hydrates and prodrugs of this compound, and does not specify any one form of solid state of the drug, if not required by context.

In one embodiment, the second agent administered in combination therapy with a COX-2 selective inhibitor is an antibacterial agent. Antibacterial agents suitable for use according to the invention include any such agent that is effective in the treatment and / or prevention of breast disorders and / or ear disorders and / or related complications. Suitable antibacterial agents include betalactam antibacterial agents, such as natural and synthetic penicillin group agents, including penam (4-thia-1-azabicyclo- [3.2.0] heptane) -7-one) penicillins (such as benzylpenicillin, phenoxymethylpenicillin , nafcillin, methicillin, oxacillin, amoxicillin, temocillin, ticarcillin and the like), penicillins, acylamino and carboxypenicillins resistant to penicillinase (such as piperacillin, azlocillin, meslocillin, carbenicillin tomocillin tomocillin wider) and wider penicillins (such as streptomycin, neomycin, framycetin, gentamicin, apramycin, amikacin, spectinomycin, amoxicillin, ampicillin and the like), cephalosporins, macrolides (such as tylosin, tylmicosin, aivromycin, spiritsin, erythromycin, erythromycin, erythromycin, erythromycin, erythromycin, yosamycin, kitazamycin and the like), lincosamides (such as lincomycin, clindamycin, pirlimycin and the like), pleuromutilins (such as tiamulin, valnemulin and the like), polypeptides, glycopeptides (such as vancomycin and the like), polymyxins (t such as polymyxin B, polymyxin E and the like), sulfonamides (such as sulfamethazine, sulfadiazine, silver sulfadiazine, sulfatroxazole, sulfamethoxypyridazine ,. sulfanilamide, sulfamethoxazole, sulfisoxazole, sulfamethizole, mafenide and the like, individually or in combination with trimethoprim), chloramphenicol, thiamphenicol, florfenicol, tetracycline agents (such as tetracycline, chlortetracycline, oxytetracycline, like, doxin) quinolones and fluoroquinolones (such as ciprofloxacin, enoxacin, grefafloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, cinocacin, nalidixic acid and the like), ty mulin, colistin, meropenem, sulbactam, tazobactam, metacyclin, pyrimethamine, sulfacetamide, oxazolidinone, for example eperezolid, linezolid, N - ((5S) -3- (3-fluoro-4- (4- (2-fluoroethyl) -3- hydroxy-1-piperazinyl) phenyl-2-hydroxy-5-oxazolidinyl) methyl) acetamide, (S) -N - ((3- (5- (3-pyridyl) thiophen-2-yl) -2-hydroxy-5 -oxazolidinyl) methyl) acetamide, 2,2-difluoro-N - ({(5S) -3- [3-fluoro-4- (4-glycoloylpiperazin-1-yl) phenyl] -2-oxo-1,3- oxazolidin-5-yl} methyl) ethanethioamide, (S) -N - ((3- (5- (4-pyridyl) pyrid-2-yl) -2-hydroxy-5-oxazolidinyl) methyl) acetamide hydrochloride and the like aminoglycosides (kanamycin, tobramycin, netilmicin and the like similar), aminocyclitols, amphenicol, ansamycin, carbafenem, cefamycin, rifampicin, monobactam, oxacefem, streptogramines (such as quinupristine, dalphopristine and the like), cycloserines, mupirocin, urea hydroxamates, such as folate, and the like folimetopri antibiotic-type antitumor agents (such as aclarubicin, actinomycin D, actinoplanon, an aerosilisin derivative, Nippon Soda anisomycin, anthracycline, azinomycin-A, buzucaberin, bleomycin sulfate, bryostatin-1, calichemicin, chromoximycin, d inomycin, daunorubicin, dithrizarubicin B, doxorubicin, doxorubicin-fibrinogen, elsamycin-A, epirubicin, erbstatin, esorubicin, esperamycin-A1b, fostriecin, glidocactin, gregatin gimdinamidin gincinimidin-grimcinamidin-amyridin g-aminaricin-amidin-g-maricin-amyridin-g-aminaricin-g-maricin-amyridin-g-aminaricin m , mitoxanthorone, mutamycin, mycophenolate mofetil, neoenactin, oxalysine, oxaunomycin, peplomycin, pilatine, pyrarucin, porotramycin, pyrindamycin A, rapamycin, rhizoxin, rhodorubicin, sibanomycin, sireficin, A, sarangimycin, A, sarangimycin, A, sarangimycin, A, sarangimycin, entetsin, trazin, trikrozarin A, zorubicin, systemic antibacterials (such as 2,4-diaminopyrimidine), nitrofuransulfony, Marbofloxacin, and the like, and combinations thereof, but is not limited thereto.

Preferred antibacterial agents are cephalosporins, including ceftiofur hydrochloride, ceftiofur in the form of a free acid, for example crystalline ceftiofur in the form of a free acid, ceftiofur sodium, other salts of ceftiofur, cefalexin, cefradine, cefchin, cefacetril, cefalon, cefcefrefcefcefcefcefimer cefsetfime cefem-heptahydrate, cephalosporin di- or trihydrate, cefadroxyl monohydrate, cefazolin sodium monohydrate, cefiximin, ceftaxime, ceftisoxime, ceftriaxone, o-formylcefamandol, sol derivatives of 3-acetoxymethyl-7- (iminocetamido) -cephalosporanic acid, monohydrate 7- (D-alpha-amino-alpha- (para-hydroxyphenyl) acetamino) -3-methyl-3-cephem-1-carboxylic acid, hydrochloric acid salt of syn -7 - ((2-amino-1-thiazolyl) (methoxyimino) acetyl) amino) -3-methyl-3-cephem-4-carboxylic acid, acid and cefem addition salts, (pivaloyloxy) methyl-7-beta- ( 2- (2-amino-4-thiazolyl) acetamido) -3 - (((1- (2- (dimethylamino) ethyl) -1H-tetraazol-5-yl) thio) methyl) -3-cefem-4-carboxylate , cephalexin, cephalexin monohydrate, 7- (D-2-naphthiglycylamino) -3-methyl-3-cefem-4-carbonic acid tetrahydrate lots and the like, but not limited to them. The most preferred cephalosporins for use in the present invention are ceftiofur and pharmaceutically acceptable salts thereof. Ceftiofur in the free acid form, especially in crystalline form, and ceftiofur hydrochloride are particularly preferred.

When the antibacterial substance is ceftiofur or its other salt form, the preferred concentration range in the composition of the invention is from about 1 to about 1000 mg / ml, more preferably from about 5 to about 750 mg / ml, and even more preferably from about 10 to about 100 mg / ml. For antibacterial substances other than ceftifur, suitable concentration ranges that are equivalent in antibacterial effect can be determined by one skilled in the art based on published data.

In another embodiment, the second agent is an antitumor agent. Suitable antitumor agents include anastrozole, calcium carbonate, capecitabine, carboplatin, cisplatin, docetaxel, eflornithine, etoposide, exemestane, fluoxymestrin, gemcitabine, goserelin, irinotecan, ketoconazole, letrozolene, meloceloin leloverolin, levolefin lelevozolenolezolenolezolenolezolenelovenolenelozenolino leverolin selenomethionine), sulindaxulfone, tamoxifen, thiotepa, topotecan, toremifene, vinbastine, vincristine, vinorelbine and the like, and combinations thereof, but are not limited to.

In another embodiment, the second agent is an anesthetic agent. Anesthetic agents include ambucaine, amolanone, amylocaine, benoxinate, benzocaine, betoxicaine, biphenamine, bupivacaine, butacaine, butambenum, butambenpicrate, butanilcaine, butetamine, butoxicaine, cercaine, dopamine, chloroprocaine, cocainetimenokinokinokin dokinokinokinokin dokinokinokinokin dokinokin , diclonin, ekgonidin, ekgonin, ethyl chloride, ethidocaine, β-eukain, fomocaine, hexylcaine, hydroprocaine, hydroxyprocaine, hydroxytetracaine, isobucaine, isobutyl para-aminobenzoate, ketocaine, leucinocaine, levoxadrol, lidocaine, lidocaine, lidocaine cain, meprilkain, metabutoksikain, metabutetamin, mirtekain, oktakain, ortokain, oxethazaine, oksiprokain, paretoksikain, fenakain, phenol, piperokain, piridokain, polidocanol, pramoxine, prilocaine, procaine, primakain, proparacaine, propipokain, propoksikain, psevdokokain, pirrokain, replivikan, ropivacaine, salicylic alcohol, tetracaine, tolcaine, trimecaine, xylocaine and the like, and combinations thereof, but are not limited to.

Preferred anesthetic agents include lidocaine, bupivacaine, prilocaine, ropivacaine and their tautomers, stereoisomers, enantiomers, salts, hydrates, prodrugs and combinations.

In another embodiment, the second agent is a sodium channel blocker. Sodium channel blockers useful for the invention include blockers that supplement the effect of the anti-inflammatory agent with any mechanism, including, but not limited to, reducing pain, reducing edema, and the like.

Sodium channel blockers useful according to the invention can be selected from the following non-limiting list: subtype NaV1.8 (PN3) of sodium channel blockers, subtype NaV1.3 (Type III) of sodium channel blockers, carboxamides, phenamates, oxycams, propanamides, pyrazinoylguanidine semicarbazones, semicarbazides etc.

Alternatively, sodium channel blockers suitable for use according to the invention can be selected from the following non-limiting list: amiloride, 4-amino-2- (4-methylpiperazin-1-yl) -5- (2,3,5-trichlorophenyl) pyrimidine, amitriptyline, angidrotetrodotoksin, aprindine, azure A, benzamil, benzothiazole, benzoksazinat, carvedilol deoksitetrodotoksin, disopyramide, encainide, etoksitetrodotoksin, euprotsin, fenalkomin, fluarizin, gabapentin, isoflurane, lifarizin, lorkainid, 1-methanesulfonyl-3- (4-phenoxy) phenyl-1H-pyrazole, methoxyflurane xylocaine, methoxytetrode otixin, methyl chloride, 2-methyl-1- [3- (4-phenoxyphenyl) -1H-pyrazole] propanone, mexiletine, N-acenaphth-5-yl-N′-4-methoxynaphthyl-guanidine, napaine, N- (2 -chloro-6-methylphenyl) -N-4-pyridinyl-urea, N- [3- (2,6-dimethyl-1-piperidinyl)] - α-phenylbenzeneacetamide, N-methylstrychnine, 1- [3- [4- (4-nitrophenoxy) phenyl] -1H-pyrazole] ethanone, okskabazepin, oksesazein, oksiburokain, oksitazain, pancuronium, fenamil, fenilbenzotiazol, phenytoin, pregabalin, procainamide, propafenone, propanokaina ralitolin, riluzole, saxitoxin, tekakain, tetrodiaminotoksin, tetrodonovaya acid, tetrodotoxin, topira at, 5- (2,3,5-trichlorophenyl) -2,4-diamino-pyrimidine, 6- (2,3,5-trichlorophenyl) -1,2,4-triazin-5-ylamine, verapamil, zolamine, zonisamide and the like, and combinations thereof.

Amphipathic oils applicable to the present invention include all amphipathic oils that are water dispersible and insoluble in ethanol.

Preferably, such amphipathic oils are polyglycolized glycerides obtained by alcoholysis of natural triglycerides with polyethylene glycols, and examples include the following oils from Gattefossé or substantially equivalent oils from another manufacturer: Labrafil ™ M-1944CS, Labrafil ™ M-1966CS, Labrafil ™ M-1969CS , Labrafil ™ M-1980CS, Labrafil ™ M-2125CS, Labrafil ™ WL-2609BS, Labrafil ™ ISO and combinations thereof, but are not limited to.

Even more preferred amphipathic oils are polyglycolized glycerides, prepared as described above, containing either oleic or linoleic acid as the main fatty acid component, and examples include the following oils from Gattefossé or substantially equivalent oils from another manufacturer: Labrafil ™ M-1944CS, Labrafil ™ M-1966CS, Labrafil ™ M-1969CS, Labrafil ™ M-1980CS, Labrafil ™ M-2125CS, Labrafil ™ WL-2609BS, and combinations thereof, but are not limited to.

Even more preferred amphipathic oils are polyglycolized glycerides, prepared as described above, containing oleic acid as the main fatty acid component, and examples include the following oils from Gattefossé or substantially equivalent oils from another manufacturer: Labrafil ™ M-1944CS, Labrafil ™ M-1966CS , Labrafil ™ M-1980CS, and combinations thereof, but are not limited to.

The most preferred amphipathic oil is pegicol-5-oleate, for example Labrafil ™ M-1944CS from Gattefossé Corporation.

A preferred concentration range of the amphipathic oil in the composition of the invention is from about 0.01% to about 99% w / v, more preferably from about 1% to about 80% w / v. and even more preferably from about 3% to about 25 wt.% / vol.

Microcrystalline wax is as defined, for example, in the Handbook of Pharmaceutical Excipients, 3rd ed. or in National Formulary, 19rd ed. (NF 19), and can be purchased from many manufacturers, including Witco Corporation.

A preferred range for the concentration of microcrystalline wax in the composition of the invention is from about 0.001% to about 50 wt.% / Vol., More preferably from about 0.1% to about 40 wt.% / Vol. and even more preferably from about 1% to about 15 wt.% / vol.

The pharmaceutically acceptable non-aqueous vehicles of the invention may be fully saturated or partially or completely unsaturated. Examples of non-aqueous vehicles include, but are not limited to, vegetable oils, mineral oils, synthetic oils, and combinations thereof. Examples of fully saturated non-aqueous vehicles include medium to long chain fatty acid esters (such as, but not limited to, fatty acid triglycerides with chain lengths of from about ₆ to about ₂₄ ). Mixtures of fatty acids are isolated from natural oils (e.g., coconut oil, palm kernel oil, babassu oil and the like) and refined. In some embodiments, medium chain triglycerides (from about ₈ to about ₁₂ ) are useful. An exemplary saturated non-aqueous vehicle comprises capric acid (from about 20% to about 45%) and caprylic acid (from about 45% to about 80%). Other fully saturated non-aqueous vehicles include saturated coconut oil (which usually includes a mixture of lauric, myristic, palmitic, capric and caproic acids), including those sold under the trademark Miglyol ™ from Huls and bearing the trade names 810, 812, 829 and 840) but are not limited to them. NeoBee ™ products sold by Drew Chemicals are also mentioned. Isopropyl myristate is another example of a non-aqueous carrier useful in the compositions of the invention. Examples of synthetic oils include triglycerides and propylene glycol diesters of saturated or unsaturated fatty acids having from 6 to 24 carbon atoms, such as, for example, hexanoic acid, octanoic (caprylic), nonanoic (pelargonic), decanoic (capric), undecanoic, lauric, , tetradecanoic (myristic), pentadecanoic, hexadecanoic (palmitic), heptadecanoic, octadecanoic (stearic), nonadecanoic, heptadecanoic, eicosanoic, geneicosanoic, docosanoic and lignoceric acid and the like e. Examples of unsaturated carboxylic acids include oleic, linoleic and linolenic acids and the like. Obviously, the non-aqueous carrier may contain mono-, di- and triglyceryl fatty acid esters or mixed glycerides and / or propylene glycol diesters, where at least one glycerol molecule is esterified with fatty acids of varying lengths of carbon atoms. A non-limiting example of “non-oil” useful as a carrier in the compositions of the invention is polyethylene glycol.

Preferred non-aqueous vehicles are vegetable oils such as cottonseed oil, corn oil, sesame oil, soybean oil, olive oil, fractionated coconut oil, peanut oil, sunflower oil, safflower oil, almond oil, avocado oil, palm oil, palm kernel oil, Babassu oil, beech nut oil, linseed oil, rapeseed oil and the like. The most preferred non-aqueous carrier is cottonseed oil. As an example, cottonseed oil can be purchased as a 70% unsaturated fatty acid preparation from Sigma Chemical Co.

A preferred concentration range of the non-aqueous carrier in the composition of the invention is from about 0.5% to about 99% w / v, more preferably from about 10% to about 95% w / v, and even more preferably from about 40% up to about 90 wt.% / vol.

The composition of the invention may optionally further comprise any conventional pharmaceutical excipient that does not undesirably react with the main ingredients of the composition. Such excipients include antioxidants, preservatives, suspending agents, stabilizers, solubilizing agents, wetting agents, lubricating agents, emulsifiers, salts affecting the osmotic pressure, coloring agents, alcohols, isotonic agents, buffering agents, permeability agents, anti-irritants, and combinations thereof, but not limited to them.

The composition of the invention can be administered to treat mastitis by introducing a catheter nozzle of a mastitis syringe into the external opening of the nipple channel of the udder of the animal producing milk, and infusing the composition into the udder.

The composition of the invention can be administered to treat or prevent an ear disorder by administering an ear syringe, an ear drop dispenser, or other suitable device for delivering into the ear into the external auditory canal of the subject's ear and infusing the composition into the ear.

It is understood that preferred amounts of compositions for administration in a particular case will vary depending on the particular composition used, the method of use, the particular site and organism being treated, and other factors. The dosage for this purpose can be determined using traditional considerations, for example, by routinely comparing the differential activities of the test compositions and a known agent, for example, using a suitable traditional pharmaceutical protocol.

Although the present invention is directed mainly to the local delivery of the anti-inflammatory agent to the site of inflammation in the organ into which it is administered, it is contemplated that the compositions of the invention are also useful for systemic delivery of the anti-inflammatory agent to an animal producing milk by intramammary infusion. For example, it is often more effective and convenient to administer a therapeutic agent to an animal producing a milk, such as a cow, by intramammary infusion, compared to other routes, such as oral or parenteral. Thus, in the treatment of inflammatory conditions in any place other than the udder, including, for example, arthritic conditions, the composition, as described herein, can be administered by intramammary infusion.

An illustrative suspension composition according to the invention, containing an anti-inflammatory agent, for example a selective COX-2 inhibitor deracoxib, has the following composition:

COX-2 selective inhibitor 1-350 mg / ml Labrafil ™ M-1944CS 1-75% microcrystalline wax 0.1-25% cottonseed oil how much is required up to 100%

EXAMPLES

The following examples illustrate aspects of the present invention, but should not be construed as limitations.

Example 1

A suspension for administration by intramammary infusion is prepared having the following composition:

parecoxib free acid 100 mg / ml Labrafil ™ M-1944CS 50 mg / ml microcrystalline wax NF (National Pharmacopoeia) 70 mg / ml cottonseed oil NF how much is required

Microcrystalline wax and approximately 27% of the total amount of cottonseed oil are heated to 85-98 ° C with stirring in a reactor. The remainder of the cottonseed oil is heated to 85-98 ° C with stirring in a production vessel. After the microcrystalline wax has completely melted, the microcrystalline wax / cottonseed oil mixture in the reactor is transferred to a production vessel containing cottonseed oil and mixed thoroughly. The resulting mixture was cooled to 38-45 ° C and Labrafil ™ M-1944CS was added to the production vessel with stirring to form a filler. Then parecoxib is added to the excipient and the resulting composition is mixed to form a homogeneous suspension. The suspension is filtered and 12 ml mastitis syringes made of high density polyethylene are filled with it. The packaged product is finally sterilized with gamma radiation at a dose of 25-40 kGy.

The above suspension is administered by intramammary infusion into each infected lobe of the udder of a lactating cow at a dose of 1200 mg parecoxib / lobe / day. The suspension is effective in the treatment of mastitis in lactating cows.

A suspension for administration by intramammary infusion is prepared having the following composition:

deracoxib 170 mg / ml Labrafil ™ M-1966CS 100 mg / ml microcrystalline wax NF 50 mg / ml cottonseed oil NF how much is required

Microcrystalline wax and corn oil are heated to 85-98 ° C with stirring in a production vessel. After the microcrystalline wax has completely melted, the mixture is cooled to 30-45 ° C and added to the Labrafil ™ M-1966CS production vessel with stirring to form a filler. Deracoxib is added to the excipient and mixed to form a homogeneous suspension. The suspension is filtered and 12 ml mastitis syringes made of high density polyethylene are filled with it. The packaged product is finally sterilized with gamma radiation at a dose of 25-40 kGy.

The above suspension is administered in all four lobes of a dry cow at a dose of 3400 mg of deracoxib / lobe by intramammary infusion. The suspension is effective in the treatment of mastitis of dry cows.

Example 3

A suspension for administration by ear infusion is prepared having the following composition:

rofecoxib 25 mg / ml Labrafil ™ M-1980CS 500 mg / ml microcrystalline wax NF 0.10 mg / ml propyl gallate 1.0 mg / ml mineral oil how much is required

Microcrystalline wax and approximately 27% of the total amount of mineral oil are heated to 85-98 ° C with stirring in a reactor. The remainder of the mineral oil is heated to 85-98 ° C with stirring in a production vessel. After the microcrystalline wax has completely melted, the microcrystalline wax / mineral oil mixture in the reactor is transferred to a production vessel containing mineral oil and mixed thoroughly. The resulting mixture was cooled to 38-45 ° C and Labrafil ™ M-1980CS was added to the manufacturing vessel with stirring. Propyl gallate is added to the production vessel with stirring to form a filler. Rofecoxib is added to the resulting excipient and mixed to form a homogeneous suspension. The suspension is filtered through a sieve and filled with 20 ml polypropylene containers.

The above suspension is administered at a dose of 2.5 mg of rofecoxib / kg body weight by infusion into the ear of a dog. The suspension is effective in treating otitis externa in dogs.

Example 4

A suspension for administration by intramammary infusion is prepared having the following composition:

deracoxib 300 mg / ml Labrafil ™ M-1944CS 50 mg / ml microcrystalline wax NF 70 mg / ml cottonseed oil NF how much is required

Microcrystalline wax and approximately 27% of the total amount of cottonseed oil are heated to 85-98 ° C with stirring in a reactor. The remainder of the cottonseed oil is heated to 85-98 ° C with stirring in a production vessel. After the microcrystalline wax has completely melted, the microcrystalline wax / cottonseed oil mixture in the reactor is transferred to a production vessel containing cottonseed oil and mixed thoroughly. The resulting mixture was cooled to 38-45 ° C and Labrafil ™ M-1944CS was added to the production vessel with stirring to form a filler. Deracoxib is added to the resulting suspension and mixed to form a homogeneous suspension. The suspension is filtered through a sieve and filled with 12 ml mastitis syringes from high density polyethylene. The packaged product is finally sterilized with gamma radiation at a dose of 25-40 kGy.

The above suspension is administered in all four lobes of a dead cow at a dose of 12000 mg of deracoxib / quarter by intramammary infusion. The suspension is effective in the treatment of mastitis of dry cows.

Example 5

A suspension for administration by intramammary infusion is prepared having the following composition:

valdecoxib 1.5 mg / ml Labrafil ™ WL-2609BS 75 mg / ml microcrystalline wax NF 100 mg / ml Miglyol ™ 812 how much is required

Microcrystalline wax and approximately 30% of the total amount of Miglyol ™ 812 are heated to 85-98 ° C with stirring in a reactor. The remainder of Miglyol ™ 812 is heated to 85-98 ° C with stirring in a production vessel. After the microcrystalline wax has completely melted, the microcrystalline wax / Miglyol ™ 812 mixture in the reactor is transferred to a manufacturing vessel containing Miglyol ™ 812 and mixed thoroughly. The resulting mixture was cooled to 38-45 ° C and Labrafil ™ WL-2609BS was added to the production vessel with stirring to form a filler. Valdecoxib is added to the excipient and mixed to form a homogeneous suspension. The suspension is filtered through a sieve and filled with 12 ml mastitis syringes from high density polyethylene. The packaged product is finally sterilized with gamma radiation at a dose of 25-40 kGy.

The above suspension is administered in all four lobes of a dead cow at a dose of 30 mg valdecoxib / lobe by intramammary infusion. The suspension is effective in the treatment of mastitis of dry cows.

Example 6

A suspension for administration by ear infusion is prepared having the following composition:

ceftiofur hydrochloride (micronized) 100 mg / ml deracoxib 100 mg / ml Labrafil ™ M-1944CS 700 mg / ml microcrystalline wax NF 0.05 mg / ml mineral oil how much is required

Microcrystalline wax and approximately 27% of the total amount of mineral oil are heated to 85-98 ° C with stirring in a reactor. The remainder of the mineral oil is heated to 85-98 ° C with stirring in a production vessel. After the microcrystalline wax has completely melted, the microcrystalline wax / mineral oil mixture in the reactor is transferred to a production vessel containing mineral oil and mixed thoroughly. The resulting mixture was cooled to 38-45 ° C and Labrafil ™ M-1944CS was added to the production vessel with stirring to form a filler. Ceftiofur hydrochloride and deracoxib are added to the resulting filler and mixed to form a homogeneous suspension. The suspension is filtered through a sieve and filled with 50 ml polypropylene containers.

The above suspension is administered at a dose of 4 mg ceftiofur hydrochloride / kg body weight and 4 mg deracoxib / kg body weight by infusion into the ear of the subject. The suspension is effective in the treatment and / or prevention of otitis media.

Example 7

A suspension for administration by ear infusion is prepared having the following composition:

ceftiofur hydrochloride (micronized) 100 mg / ml parecoxib free acid 100 mg / ml Labrafil ™ M-1944CS 700 mg / ml microcrystalline wax NF 0.1 mg / ml cottonseed oil how much is required

Microcrystalline wax and cottonseed oil are heated to 85-98 ° C with stirring in a production vessel. After the microcrystalline wax has completely melted, the mixture is cooled to 38-45 ° C and Labrafil ™ M-1944CS is added to the production vessel with stirring to form a filler. Ceftiofur hydrochloride and parecoxib are added to the resulting filler and mixed to form a homogeneous suspension. The suspension is filtered through a sieve and filled with 60 ml polypropylene containers.

The above suspension is administered at a dose of 4 mg ceftiofur hydrochloride / kg body weight and 4 mg parecoxib / kg body weight by infusion into the ear of the subject. Combination therapy is effective in the treatment and / or prevention of otitis externa.

Example 8

A suspension for administration by ear infusion is prepared having the following composition:

lidocaine 100 mg / ml parecoxib free acid 100 mg / ml Labrafil ™ M-1944CS 700 mg / ml microcrystalline wax NF 0.1 mg / ml cottonseed oil how much is required

Microcrystalline wax and cottonseed oil are heated to 85-98 ° C with stirring in a production vessel. After the microcrystalline wax has completely melted, the mixture is cooled to 38-45 ° C and Labrafil ™ M-1944CS is added to the production vessel with stirring to form a filler. Lidocaine and parecoxib are added to the resulting excipient and mixed to form a homogeneous suspension. The suspension is filtered through a sieve and filled with 60 ml polypropylene containers.

The above suspension is administered at a dose of 4 mg lidocaine / kg body weight and 4 mg parecoxib / kg body weight by infusion into the ear of the subject. Combination therapy is effective in the treatment and / or prevention of otitis externa.

Example 9

A cephalosporin ceftiofur suspension was prepared containing 12.5 mg / ml ceftiofur hydrochloride in a thickened filler comprising 20 mg / ml glyceryl monostearate in peanut butter. Despite clinical efficacy, the activity of this composition, when packaged in plastic syringes, fell below 90% of the original after storage for less than 18 months at room temperature. It was found that the oxidative degradation of ceftiofur hydrochloride is the main cause of this decline in activity. For an intramammary suspension, a shelf life at room temperature is desirable at which at least 90% of the initial activity is retained for a minimum of 24 months.

A number of compositions were prepared and packaged in oxygen-permeable syringes in the form of a suspension of ceftiofur hydrochloride in a number of thickened fillers. Ceftiofur hydrochloride preparations with a concentration of 12.5 mg / ml were made. The basis of all fillers was cottonseed oil with the following additional components:

1) 50 mg / ml microcrystalline wax.

2) 70 mg / ml microcrystalline wax + 1.0 mg / ml propyl gallate.

3) 100 mg / ml microcrystalline wax + 50 mg / ml Labrafil ™ M-1944CS.

4) 40 mg / ml Gelucire ™ 62/05 + 10 mg / ml Gelucire ™ 33/01.

5) 70 mg / ml Lexemul ™ AR.

6) 2.5 mg / ml Coagulan ™ GP-1.

7) 10 mg / ml microcrystalline wax + 5 mg / ml Hydrofol Glycerides ™ T 57L.

8) 30 mg / ml Drewpol ™ 10-10-S.

9) 15 mg / ml beeswax mixture.

10) 60 mg / ml Drewpol ™ 10-10-S.

11) 10 mg / ml mixture based on beeswax + 50 mg / ml Labrafil ™ M-1944CS.

12) 100 mg / ml microcrystalline wax + 1.0 mg / ml propyl gallate.

13) 70 mg / ml microcrystalline wax + 100 mg / ml Labrafil ™ M-1944CS.

14) 70 mg / ml microcrystalline wax + 100 mg / ml Labrafil ™ M-1944CS + 0.2 mg / ml bottled hydroxytoluene.

15) 70 mg / ml microcrystalline wax + 50 mg / ml Labrafil ™ M-1944CS + 1.0 mg / ml propyl gallate.

16) 70 mg / ml microcrystalline wax + 50 mg / ml Labrafil ™ M-1944CS + 0.2 mg / ml bottled hydroxytoluene.

17) 50 mg / ml microcrystalline wax + 1.0 mg / ml propyl gallate.

18) 100 mg / ml microcrystalline wax + 100 mg / ml Labrafil ™ M-1944CS + 1.0 mg / ml propyl gallate.

19) 100 mg / ml microcrystalline wax + 100 mg / ml Labrafil ™ M-1944CS + 0.2 mg / ml bottled hydroxytoluene.

20) 100 mg / ml microcrystalline wax + 50 mg / ml Labrafil ™ M-1944CS + 1.0 mg / ml propyl gallate.

21) 100 mg / ml microcrystalline wax + 50 mg / ml Labrafil ™ M-1944CS + 0.2 mg / ml bottled hydroxytoluene.

22) 50 mg / ml microcrystalline wax + 100 mg / ml Labrafil ™ M-1944CS + 0.2 mg / ml bottled hydroxytoluene.

Labrafil ™ M-1944CS is an amphipathic oil that is water dispersible and substantially insoluble in ethanol at 20 ° C. Gelucire ™ 62/05 and Gelucire ™ 33/01 are essentially inert excipients derived from natural hydrogenated fats and food grade oils. Lexemul ™ AR is an acid-resistant cationic, self-emulsifying glyceryl monostearate. A “beeswax-based mixture” refers to a mixture containing clarified beeswax, carnauba wax and candelilla wax. Coagulan ™ GP-1 is N-acylglutamic acid diamide, an amino acid gelling agent for oil. Drewpol ™ is a modified glyceride.

It was found that after storage for 24 months at room temperature in oxygen-permeable polyethylene syringes, only those ceftiofur hydrochloride compositions containing both Labrafil ™ M-1944CS and microcrystalline wax provided preparations that retained at least 90% of the original activity. The established shelf life at room temperature for ceftiofur hydrochloride preparations containing both Labrafil ™ M-1944CS and microcrystalline wax in cottonseed oil was 2.4–3.7 times higher than the established shelf life at room temperature for comparison preparations, which did not contain Labrafil ™ M-1944CS. In addition, although a ceftiofur hydrochloride composition containing Labrafil ™ M-1944CS and a beeswax-based mixture in cottonseed oil stored at room temperature had an activity of less than 90% after storage for 24 months in oxygen-permeable plastic syringes at room temperature, the hydrochloride preparation a ceftiofur of comparable viscosity containing Labrafil ™ M-1944CS and microcrystalline wax in cottonseed oil, after 24 months of storage under the same conditions, showed an activity of more than 90% of the original.

Compositions containing ceftiofur hydrochloride were prepared and interfacial voltage was determined.

Composition 1

A suspension was prepared having the following composition:

ceftiofur hydrochloride (micronized) 12.5 mg / ml Labrafil ™ M-1944CS 50 mg / ml microcrystalline wax NF 70 mg / ml cottonseed oil NF how much is required

Microcrystalline wax and cottonseed oil (approximately 27% of the total) with heating were heated to 85-98 ° C in a reactor. The remainder of the cottonseed oil with stirring was heated to 85-98 ° C in a production tank. After the microcrystalline wax had completely melted, the mixture of microcrystalline wax and cottonseed oil was transferred from the reactor to a cottonseed production vessel and mixed thoroughly. In order to form a filler, the resulting mixture was cooled to 38-45 ° C and Labrafil ™ M-1944CS was added to the production vessel with stirring. Then, ceftiofur hydrochloride was added to this filler, and the resulting composition was mixed to form a uniform suspension. The suspension was filtered and 12 ml mastitis syringes made of high density polyethylene were filled with it. The packaged product was finally sterilized by gamma radiation at a dose of 25-40 kGy.

The interfacial tension of the aforementioned suspension was determined using the method of droplet volume with deionized water at 39 ° C, by comparison with the interfacial tension of a control suspension prepared using 70 mg / ml microcrystalline wax in cottonseed oil, but without Labrafil ™ M-1944CS.

The interfacial tension of the suspension containing both Labrafil ™ M-1944CS and microcrystalline wax in cottonseed oil was 6.5 dyne / cm (6.5 × 10 ^-3 N / m), which is approximately 3.4 times less than interfacial tension control suspension (22.5 dyne / cm (22,5 × 10 ^-3 N / m)).

Composition 2

A suspension was prepared having the following composition:

ceftiofur hydrochloride (micronized) 12.5 mg / ml Labrafil ™ M-1944CS 50 mg / ml microcrystalline wax NF 100 mg / ml cottonseed oil NF how much is required

Microcrystalline wax and cottonseed oil were heated to 85-98 ° C with stirring in a production vessel. After the microcrystalline wax had completely melted, the mixture was cooled to 38-45 ° C and Labrafil ™ M-1944CS was added to the production vessel with stirring to form a filler. Ceftiofur hydrochloride was added to the resulting filler and mixed to form a uniform suspension. The suspension was filtered and 12 ml mastitis syringes made of high density polyethylene were filled with it. The packaged product was finally sterilized by gamma radiation at a dose of 25-40 kGy.

The interfacial tension of the aforementioned suspension was determined using the method of droplet volume with deionized water at 39 ° C, by comparison with the interfacial tension of a control suspension prepared with 100 mg / ml microcrystalline wax in cottonseed oil, but without Labrafil ™ M-1944CS.

The interfacial tension of the suspension containing both Labrafil ™ M-1944CS and microcrystalline wax in cottonseed oil was 7.1 dyne / cm (7.1 × 10 ^-3 N / m), which is about 4.0 times less than interfacial tension of the control suspension (28.1 dyne / cm (28.1 × 10 ^-3 N / m)).

Composition 3

A suspension was prepared having the following composition:

ceftiofur hydrochloride (micronized) 12.5 mg / ml Labrafil ™ M-1944CS 200 mg / ml microcrystalline wax NF 100 mg / ml cottonseed oil NF how much is required

Microcrystalline wax and cottonseed oil were heated to 85-98 ° C with stirring in a production vessel. After the microcrystalline wax was completely cooled to 38-45 ° C and Labrafil ™ M-1944CS was added to the production vessel with stirring to form a filler. Ceftiofur hydrochloride was then added to the obtained filler and mixed to form a uniform suspension. The suspension was filtered and 12 ml mastitis syringes made of high density polyethylene were filled with it. The packaged product was sterilized by gamma radiation at a dose of 25-40 kGy.

The interfacial tension of the above suspension was determined using the method of droplet volume with deionized water at 39 ° C, by comparison with the interfacial tension of a control suspension prepared from 100 mg / ml microcrystalline wax in cottonseed oil, but without Labrafil ™ M-1944CS.

The interfacial tension of a suspension containing both Labrafil ™ M-1944CS and microcrystalline wax in cottonseed oil was less than 1 dyne / cm (less than 1 × 10 ^-3 N / m), which is approximately more than 28 times less than the interfacial tension control suspension (28.1 dyne / cm (28.1 × 10 ^-3 N / m)).

After the invention has been described in detail and by reference to its preferred embodiments, it is obvious that modifications and changes are possible without departing from the scope of the attached claims.

Claims (65)

1. A method of treating and / or preventing an inflammatory condition in an organ containing a liquid and having a natural outer opening, comprising administering a pharmaceutical composition containing an anti-inflammatory agent into this organ through an external opening, wherein said composition further comprises an excipient that contains (a) amphipathic an oil that is water-dispersible and insoluble in ethanol, (b) microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier, and when combined administration of a second agent with the indicated anti-inflammatory agent, selected from the group consisting of antibacterial agents, analgesics, antipyretic drugs, anesthetics, sodium channel blockers, antitumor agents and decongestants, where this second agent is administered by a route other than the route of administration of the anti-inflammatory agent. 2. The method according to claim 1, where the body containing the liquid is an udder of an animal producing milk, and where the composition is administered by intramammary infusion. 3. The method according to claim 2, where the inflammatory condition is associated with mastitis. 4. The method according to claim 1, where the body containing the liquid is an ear of the subject, and where the composition is administered by infusion into the ear. 5. The method according to claim 4, where the inflammatory condition is associated with an ear disorder or is a complication of an ear disorder, where the ear disorder is selected from the group consisting of otitis externa, otitis media, otorrhea, acute mastoiditis, infections associated with ear surgery, otosclerosis, otalgia, ear pain, ear inflammation, ear bleeding, Lermoyet's syndrome, Meunier's disease, vestibular neuronitis, benign paroxysmal positional dizziness, herpes zoster herpes, Ram syndrome Hunt, viral neuronitis, ganglionitis, herpes of the crankshaft, labyrinthitis, including purulent labyrinthitis and viral endolymphatic labyrinthitis, perilymph fistula, presbycusis, drug-induced ototoxicity, acoustic neurinoma, myocardial leukaryngitis, myocardial ulcer disease, myocardial ulcer, myocardiomyelitis, myocarditis basal cell carcinoma, other ear cancers, ear precancerous conditions, nonchromaffin paragangliomas, hemodectomas, jugular glomus tumors, glomus timp tumors anicum, perichondritis, auricular eczematoid dermatitis, malignant external otitis media, subperichondrial hematoma, cerumine, sulfur plugs, cysts of the sebaceous gland, osteomas, keloids, ear noise, dizziness, tympanic membrane infection, tympanitis, ear boils, petrozuric neurosurgery, conduit abscess, thrombosis of the lateral sinus, subdural empyema, otitis hydrocephalus, Dandy syndrome, bullous myringitis, diffuse external otitis media, foreign bodies, obstructive keratosis (keratosis obturans), about omikoza, trauma, acute barootita, acute obstruction of the Eustachian tube, postsurgical otalgia. 6. The method according to claim 4, where the inflammatory condition is associated with an ear disorder selected from the group consisting of otitis externa, otitis media, otorrhea, and infections having an inflammatory component that are associated with ear surgery. 7. The method according to claim 1, where the specified second agent is introduced into the composition in which the specified filler contains (a) amphipathic oil, which is dispersible in water and insoluble in ethanol, (b) microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier . 8. The method according to claim 1, where the specified second agent contains an antibacterial agent. 9. The method of claim 8, where the antibacterial agent is selected from the group consisting of natural and synthetic antibiotics of the penicillin group, cephalosporins, macrolides, linkosamides, pleuromutilins, polypeptides, polymyxins, sulfonamides, chloramphenicol, thiamphenicol, florfenicol, antibiotics tetra fluoroquinolones, tiamulin, ciprofloxacin, colistin, dodeclocycline, mafenide, metacyclin, norfloxacin, ofloxacin, pyrimethamine, silver sulfadiazine, sulfacetamide, sulfisoxazole, tobramycin, van mulin, oxazolidinones, glycopeptides, aminoglycosides and aminocyclitols, amphenicol, ansamycin, carbaphenem, cefamycin, vancomycin, monobactam, oxacefem, systemic antibacterial agents, antitumor agents, antibiotic type, nitrofuransulfo isomers, marbofen sulfonomers and marbofen sulfonomers, marbofen sulfonomers and marbofen isomers, marbofen sulfonomers and marbofen isomers, marbofen isomers, marbofen isomers, and 10. The method of claim 8, where the antibacterial agent contains oxazolidinone. 11. The method according to claim 10, where oxazolidinone is selected from the group consisting of eperezolid, linezolid, N ((5S) -3- (3-fluoro-4- (4- (2-fluoroethyl) -3-hydroxy-1- piperazinyl) phenyl-2-hydroxy-5-oxazolidinyl) methyl) acetamide, (S) -N - ((3- (5- (3-pyridyl) thiophen-2-yl) -2-hydroxy-5-oxazolidinyl) methyl ) acetamide, 2,2-difluoro-N - ({(5S) -3- [3-fluoro-4- (4-glycololoylpiperazin-1-yl) phenyl] -2-oxo-1,3-oxazolidin-5- yl} methyl) ethanethiamide and (S) -N - ((3- (5- (4-pyridyl) pyrid-2-yl) -2-hydroxy-5-oxazolidinyl) methyl) acetamide hydrochloride. 12. The method of claim 8, where the antibacterial agent contains cephalosporin. 13. The method of claim 12, wherein the cephalosporin is selected from the group consisting of ceftiofur, cephalexin, cephradine, tsefhinoma, tsefatsetrila, Cephalon, cefuroxime, tsefazidima, cefoperazone, sodium tsefemetkarboksilata, cephem, cefadroxil, cefazolin sodium, tsefiksimina, tseftaksima, tseftizoksima, ceftriaxone, ortho-formylcefamandole, salts of derivatives of 3-acetoxymethyl-7- (iminocetamido) -cephalosporanic acid, 7- (D-α-amino-α- (para-hydroxyphenyl) acetamino) -3-methyl-3-cefem-1- carboxylic acid, hydrochloric acid salt of syn-7 - ((2-amino-1-thiazolyl) (methoxyimino) acetyl) amines o) -3-methyl-3-cefem-4-carboxylic acid, cefemic acid, (pivaloyloxy) methyl-7-beta- (2- (2-amino-4-thiazolyl) acetamido) -3 - (((1- (2- (dimethylamino) ethyl) -1H-tetraazol-5-yl) thio) methyl) -3-cefem-4-carboxylate, cephalexin, 7- (D-2-naphthiglycylamino) -3-methyl-3-cefem- 4-carboxylic acids and their tautomers, stereoisomers, enantiomers, salts, hydrates and prodrugs. 14. The method of claim 13, wherein the cephalosporin is ceftiofur or a pharmaceutically acceptable salt or form thereof. 15. A method of treating and / or preventing an inflammatory condition in an organ containing a liquid and having a natural outer opening, comprising administering a pharmaceutical composition containing an anti-inflammatory agent into this organ through an external opening, wherein said composition further comprises an excipient that contains (a) amphipathic an oil that is water-dispersible and insoluble in ethanol, (b) microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier; and said composition further comprises a second agent selected from the group consisting of analgesics, antipyretic drugs, anesthetics, sodium channel blockers, antitumor agents, and decongestants. 16. The method according to claim 4 or 15, where the inflammatory condition is associated with neoplasia, and the second agent contains an antitumor agent. 17. The method according to claim 1 or 15, where the anti-inflammatory agent is selected from the group consisting of aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid, S-adenosylmethionine, alklofenac, alklomethazone, alklomethazone, alklomethasone, alklomethanone, alklomethanone, alclomethazone, alklomethanone, alclomethazone, alcometone, alfloestazone, alklomethazone, alclomethanone, alflethazone, alclomethazone, alflethazone, alclomethanone, alflethazone, alklomethazone, alflethazone, alflethazone, alklomethanone, alklomethanone, alklomethanone, alklomethanone, alflethazone, alklomethanone, alflethazone, alklomethanone, alklomethanone, , alaminoprofen, aloxiprine, alfaprodin, bis (acetylsalicylate) aluminum, amcinonide, amfenac, aminochlortenoxazine, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylone, aminopyrin, amixetrin, ammonium salicylate, xicam, amtolmethine of guacyl, anileridine, antipyrine, anthraphenin, apazone, beclomethasone, bendazac, benorilate, benoxaprofen, benzpiperilone, benzidamine, benzylmorphine, bermoprofen, betamethasone, betamethasone-17-paramethylbenamerate, bimethylacetamide, bimetrate, 5-bromosalicylic acid, bromosaligenin, bucetin, buccloic acid, bucolum, budesonide, bufexamak, bozdizona, buprenorphine, butacetin, butibufen, butorphanol, carbifen, carprofen, karsalam, chlorobutanol, chlorpredoxenoxone, x zina, choline salicylate, cinchophene, cinmethacin, ciramadol, clidanac, clobetasol, clocortolone, clomethacin, clonitazene, clonixin, clopirac, cloprednol, clove, cortisone, cortazazone dezonezamethasone dezone, defrotasone diazestaside, defrotasone azide, deprotamethasone dezonazide -21-isonicotinate, dexoxadrol, dextromoramide, dextropropoxyphene, deoxycorticosterone, desocin, diampromide, diclofenac, diphenamisole, diphenpyramide, diflorazone, diflucortolone, diflunisal, difluprednat, gidroksialyuminiya acetylsalicylate, dimenoxadol, dimefeptanola, dimetiltiambutena, dioksafetila butyrate, dipipanone, diprotsetila, dipyrone, ditazola, droksikama, emorfazone, enfenamovoy acid enoksolona, epirizole, eptazotsina, etersalata, ethenzamide, etogeptazina, etoksazena, etilmetiltiambutena, ethylmorphine, etodolac, etofenamate, etonitazena , eugenol, felbinac, fenbufen, phenclose acid, fendosal, phenoprofen, fentiazac, fepradinol, feprazone, flactafenin, fluazacort, flucloronide, flufenamic acid, flumetazone , Flunisolide, flunixin, flunoksaprofena, fluocinolone acetonide, fluocinonide, fluocinolone acetonide, fluokortinbutila, fluocortolone, fluorezona, fluorometholone, fluperolona, flupirtine, Fluprednidene, fluprednisolone, fluprokvazona, flurandrenolide, flurbiprofen, fluticasone, formocortal, fosfozala, gentisic acid glafenina, glyukametatsina, glycol salicylate, guaiazulene, halcinonide, halobetasol, halomethasone, haloprednone, hydrocortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone succinate, hydrocortiso for hemisuccinate, hydrocortisone-21-lysinate, hydrocortisone cypionate, hydroxypetidine, ibupenac, ibuprofen, ibuproxam, imidazolsalicylate, indomethacin, indoprofen, isofesolac, isoflupredone, isoflupredone acetate, isofetone isonetonefenetone isonetonefenetone isonetonefenetone isonefenone -lactofenetide, lefetamine, lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate, mazipredone, meclofenamic acid, medrisone, mefenamic acid, meloxicam, meperidine, meprednisone, meptazinol, mezalamine, metazocine, methadone, metotrimeprazine, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone suleptanate, methiazinic acid, metofolin, methopone, mofebutazone, mofezalofacetone, mofetalazone nalabacone nalabazone nalabolazone nalabacone nalazone nalabacone nefopam, nifenazone, niflumic acid, nimesulide, 5′-nitro-2′-propoxyacetanilide, norpipanone, olsalazine, oxacetrol, oxamethacin, oxaprozin, oxycodone, oxymorphone, oxyphenbutazone, p ramethasone, paraniline, parsalmide, pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenylacetylsalicylate, phenylbutazipinoprofenoperipinoperipene piperiphenophenone pyroperiphenone pyroperiphenone pyroperiphenone pyrene pyroperiphenone piperofenone , predicarbate, prednisolone, prednisone, prednisone, prednilidene, proglumetacin, proheptazine, promedol, propacetamol, properidine, propiram, propoxyphene, propiphenazone, proquazone, p rotizinic acid, proxazole, ramifenazone, remifentanil, rimazolium methyl sulfate, salacetamide, salicinum, ortho-acetic acid, salicylic acid, salicylsulfuric acid, salsalate, salverin, simetride, sufalisufenulfan sufalisenofisulfin sufasulfin sufalisenofisulfin sufasulfin tenadapa, tenoxicam, terofenamate, tetrandrin, thiazolinobutazone, thiaprofenic acid, thiaramide, tilidine, tinoridine, thixocortol, tolfenamic acid, tolmetin, tramadol, triamcinolone, tria tsinolona acetonide, Tropézina, viminola, ksenbutsina, ksimoprofena, zaltoprofen and zomepirac. 18. The method according to claim 1 or 15, where the anti-inflammatory agent is a steroid. 19. The method according to claim 1 or 15, where the anti-inflammatory agent is a non-steroidal anti-inflammatory drug. 20. The method according to claim 1 or 15, where the anti-inflammatory agent is a selective inhibitor of COX-2 (cyclooxygenase-2). 21. The method according to claim 20, where the selective COX-2 inhibitor is

compound of the formula where R ₅ represents a methyl or amino group, R ⁶ represents hydrogen, or a C _1-4 alkyl or alkoxy group, X ′ represents N or CR ⁷ , where R ⁷ represents hydrogen or halogen, and Y and Z independently represent atoms carbon or nitrogen, which define adjacent atoms of the five-six membered ring, which is optionally substituted at one or more positions by oxo, halo, methyl or halogenomethyl groups. 22. The method according to claim 20, where the selective COX-2 inhibitor is selected from the group consisting of deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, lumiracoxib, 2- (3,5-difluorophenyl) -3- [4- ( methylsulfonyl) phenyl] -2-cyclopenten-1-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] piperidin-4-carboxylate, 4- [5- (phenyl) -3 - (tr ifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, their salts and prodrugs. 23. The method of claim 22, wherein the COX-2 selective inhibitor is deracoxib. 24. The method of claim 22, wherein the COX-2 selective inhibitor is parecoxib or a salt thereof. 25. The method according to item 22, where the selective COX-2 inhibitor is celecoxib. 26. The method according to item 22, where the selective COX-2 inhibitor is valdecoxib. 27. A pharmaceutical composition containing an excipient that contains (a) an amphipathic oil that is water dispersible and insoluble in ethanol, (b) microcrystalline wax and (c) a pharmaceutically acceptable non-aqueous carrier, wherein the excipient contains a stably dispersed anti-inflammatory agent therein in an amount effective against inflammation and additionally contains a second agent selected from the group consisting of analgesics, antipyretic drugs, anesthetics, sodium channel blockers fishing agents, antitumor agents and decongestants. 28. The composition according to clause 27, where the anti-inflammatory agent is selected from the group consisting of aceclofenac, acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid, S-adenosylmethionine, alklofenac, alklomerofenone, alclomethrofenophenone, , aloxiprine, alpha-prodin, bis (acetylsalicylate) aluminum, amcinonide, amfenac, aminochlorotenoxazine, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylone, aminopyrine, amixetrin, ammonium salicylate, ampiro xicam, amtolmethine of guacyl, anileridine, antipyrine, anthraphenin, apazone, beclomethasone, bendazac, benorilate, benoxaprofen, benzpiperilone, benzidamine, benzylmorphine, bermoprofen, betamethasone, betamethasone-17-paramethylbenamerate, bimethylacetamide, bimetrate, 5-bromosalicylic acid, bromosaligenin, bucetin, buccloic acid, buccolum, budesonide, bufexamak, bozdizona, buprenorphine, butacetin, butibufen, butorphanol, carbifen, carprofen, karsalam, chlorobutanol, chlorpredennisone, x azine, choline salicylate, cinchophene, cinmethacin, ciramadol, clidanac, clobetasol, clocortolone, clomethacin, clonitazene, clonixin, clopirac, cloprednol, clove, cortisone, cortazazone defonetamethasone dezonazole, defrotasimetasone dezonazide, deprotamethasone dezonazide -21-isonicotinate, dexoxadrol, dextromoramide, dextropropoxyphene, deoxycorticosterone, deocin, diampromide, diclofenac, diphenamisole, diphenpyramide, diflorazone, diflucortolone, diflunisal, difluprednat, igidroksialyuminiya acetylsalicylate, dimenoxadol, dimefeptanola, dimetiltiambutena, dioksafetila butyrate, dipipanone, diprotsetila, dipyrone, ditazola, droksikama, emorfazone, enfenamovoy acid enoksolona, epirizole, eptazotsina, etersalata, ethenzamide, etogeptazina, etoksazena, etilmetiltiambutena, ethylmorphine, etodolac, etofenamate, etonitazena , eugenol, felbinac, fenbufen, phenclose acid, fendosal, phenoprofen, fentiazac, fepradinol, feprazone, flactafenin, fluazacort, flucloronide, flufenamic acid, flumetazo a, flunisolide, flunixin, flunoksaprofena, fluocinolone acetonide, fluocinonide, fluocinolone acetonide, fluokortinbutila, fluocortolone, fluorezona, fluorometholone, fluperolona, flupirtine, Fluprednidene, fluprednisolone, fluprokvazona, flurandrenolide, flurbiprofen, fluticasone, formocortal, fosfozala, gentisic acid glafenina, glyukametatsina , glycol salicylate, guaiazulene, halcinonide, halobetazole, halomethasone, haloprednone, hydrocortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone succinate, hydrocortis it is hemisuccinate, hydrocortisone-21-lysinate, hydrocortisone cypionate, hydroxypetidine, ibupenac, ibuprofen, ibuproxam, imidazolsalicylate, indomethacin, indoprofen, isofesolac, isoflupredone, isoflupredone acetate, isofenoxone isofenone isofenone isonefenone -lactophenetide, lefetamine, lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate, mazipredone, meclofenamic acid, medrisone, mefenamic acid, meloxicam, meperidine, meprednisone, meptazinol , mesalamine, metazocine, methadone, metotrimeprazine, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone suleptanate, methiazinic acid, metofolin, methopone, mofefalinazone, nalofone salin, mofetone salone , nefopam, nifenazone, niflumic acid, nimesulide, 5′-nitro-2′-propoxyacetanilide, norpipanone, olsalazine, oxacetrol, oxamethacin, oxaprozin, oxycodone, oxymorphone, oxyfenbutazone, aramethazene, paraniline, parsalmide, pentazocine, perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenylacetylsalicylate, phenylbutazinoferiphenopheniphenophenediphenophenidefenipyrindiphenophenide pyroperiphenophenide pyroperiphenophenediphenophenediphenophenide pyroperiphenediphenophenide pyroperiphenophenediphenophenediphenone , predicarbate, prednisolone, prednisone, prednisone, prednilidene, proglumetacin, proheptazine, promedol, propacetamol, properidine, propiram, propoxyphene, propiphenazone, proquazone, protizinic acid, proxazole, ramifenazone, remifentanil, rimazolium methyl sulfate, salacetamide, salicin, orthoacetic acid, salicylic acid, salicylsulfuric acid, salsalate, salverin, simetridisulfin sufasulfin sufasulfin sufasulfin sufasinasefin tenadap, tenoxicam, terofenamate, tetrandrin, thiazolinobutazone, thiaprofenic acid, thiaramide, tilidine, tinoridna, thixocortol, tolfenamic acid, tolmetin, tramadol, triamcinolone, three mtsinolona acetonide, Tropézina, viminola, ksenbutsina, ksimoprofena, zaltoprofen and zomepirac. 29. The composition according to item 27, where the anti-inflammatory agent is a steroid. 30. The composition according to item 27, where the anti-inflammatory agent is a non-steroidal anti-inflammatory drug. 31. The composition according to item 27, where the anti-inflammatory agent is a selective inhibitor of COX-2. 32. The composition according to p, where the selective COX-2 inhibitor is a compound of the formula

where R ₅ represents a methyl or amino group, R ⁶ represents hydrogen, or a C _1-4 alkyl or alkoxy group, X ′ represents N or CR ⁷ , where R ⁷ represents hydrogen or halogen, and Y and Z independently represent atoms carbon or nitrogen, which define adjacent atoms of the five-six membered ring, which is optionally substituted at one or more positions by oxo, halo, methyl or halogenomethyl groups. 33. The composition of claim 31, wherein the COX-2 selective inhibitor is selected from the group consisting of deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, lumiracoxib, 2- (3,5-difluorophenyl) -3- [4- ( methylsulfonyl) phenyl] -2-cyclopenten-1-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] piperidin-4-carboxylate, 4- [5- (phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, their salts and prodrugs. 34. The composition of claim 31, wherein the COX-2 selective inhibitor is deracoxib. 35. The composition according to p, where the selective COX-2 inhibitor is parecoxib or its salt. 36. The composition of claim 31, wherein the COX-2 selective inhibitor is celecoxib. 37. The composition of claim 31, wherein the COX-2 selective inhibitor is valdecoxib. 38. The composition according to p, where the specified selective inhibitor of COX-2 is present in a concentration of from about 0.01 to about 1000 mg / ml 39. The composition according to p, where the specified selective inhibitor of COX-2 is present in a concentration of from about 0.1 to about 750 mg / ml 40. The composition according to p, where the specified selective inhibitor of COX-2 is present in a concentration of from about 5 to 250 mg / ml 41. The composition according to any one of paragraphs.27-40, where the amphipathic oil is a polyglycolized glyceride obtained by the alcoholysis reaction of natural triglycerides with polyethylene glycols. 42. The composition according to paragraph 41, where the polyglycosylated glyceride contains as the main fatty acid component oleic acid or linoleic acid. 43. The composition according to paragraph 41, where the polyglycolized glyceride contains oleic acid as the main fatty acid component. 44. The composition according to paragraph 41, where the polyglycolized glyceride is a pegicol-5-oleate. 45. The composition according to item 27, where the amphipathic oil is from about 1 to about 80% wt./about. composition. 46. The composition according to item 27, where the amphipathic oil is from about 3 to about 25% wt./about. composition. 47. The composition according to item 27, where the amphipathic oil is from about 0.01 to about 99% wt./about. composition. 48. The composition according to item 27, where the microcrystalline wax is from about 0.001 to about 50% wt./about. composition. 49. The composition according to item 27, where the microcrystalline wax is from about 0.1 to about 40% wt./about. composition. 50. The composition according to item 27, where the microcrystalline wax is from about 1 to about 15% wt./about. composition. 51. The composition according to any one of paragraphs.27-40, wherein the non-aqueous carrier is selected from the group consisting of vegetable oils, mineral oils, medium to long chain fatty acids and their alkyl esters, propylene glycol diesters and chain fatty acids from medium to long mono-, di- and triglyceryl esters of fatty acids and polyethylene glycols. 52. The composition of claim 51, wherein the non-aqueous carrier is a vegetable oil. 53. The composition of claim 51, wherein the vegetable oil is selected from the group consisting of cottonseed oil, corn oil, sesame oil, soybean oil, olive oil, fractionated coconut oil, peanut oil, sunflower oil, safflower oil, almond oil, avocado oil , palm oil, palm kernel oil, babassu oil, beech nut oil, flaxseed oil and rapeseed oil. 54. The composition of claim 53, wherein the vegetable oil is cottonseed oil. 55. The composition according to item 27, where the non-aqueous carrier is from about 0.5 to about 99% wt./about. composition. 56. The composition according to item 27, where the non-aqueous carrier is from about 10 to about 95% wt./about. composition. 57. The composition according to item 27, where the non-aqueous carrier is from about 40 to about 90% wt./about. composition. 58. The composition according to item 27, which further comprises at least one excipient selected from the group consisting of antioxidants, preservatives, stabilizers, moisturizing agents, suspending agents, lubricating agents, solubilizing agents, emulsifiers, salts that affect the osmotic pressure, coloring agents, alcohols, permeability agents, anti-irritants, isotonic agents and buffering agents. 59. The composition according to item 27, where the specified second agent contains an anesthetic. 60. The composition according to item 27, where the specified second agent contains a sodium channel blocker. 61. The composition according to item 27, where the specified second agent contains an anesthetic in therapeutically effective amounts. 62. The composition of claim 61, wherein the polyglycolized glyceride is pegicol-5-oleate, the non-aqueous carrier is cottonseed oil, the anti-inflammatory agent is selected from the group consisting of deracoxib, parecoxib, celecoxib, valdecoxib, rofecoxib, etoricoxib, lumi 2 (3,5-difluorophenyl) -3- [4- (methylsulfonyl) phenyl] -2-cyclopenten-1-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- (trifluorome il) -1H-pyrazol-1-yl] benzenesulfonamide, tert-butyl-1-benzyl-4 - [(4-oxopiperidin-1-yl) sulfonyl] piperidin-4-carboxylate, 4- [5- (phenyl) - 3- (trifluoromethyl) -1H-pyrazol-1-yl] benzenesulfonamide, their salts and prodrugs, and the second agent is lidocaine. 63. A dosage form comprising a container or delivery device having an oxygen-permeable wall, and the composition contained therein according to item 27. 64. The dosage form of claim 63, wherein said wall is made of an oxygen-permeable material containing polyethylene. 65. The dosage form of claim 63, wherein the composition exhibits long-term chemical and / or physical stability.