Novel use of glucocorticoids for the treatment of epithelial microbial infections of fluid-containing organs with natural external openings in mammals

Abstract

To provide methods for the treatment of epithelial microbial infections in fluid-containing organ having a natural exterior orifice in mammals.SOLUTION: The present invention provides a medicine for use in the treatment and / or prevention of an epithelial microbial infection of the ear in a nonhuman mammal through the inhibition of microbial overgrowth or multiplication of pathogenic bacteria, yeasts and / or fungi, the medicine comprising hydrocortisone, hydrocortisone monoester, hydrocortisone diester or salts thereof. The epithelial microbial infection is external otitis. The medicine does not contain any of an antibiotic agent, an antifungal agent, an antiviral agent or an antimicrobial agent in an effective amount for the treatment of external otitis.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a non-invasive method that does not require antibiotics for treating epithelial microbial infections in mammals.

[0002] More specifically, the present invention relates to glucocorticoids for treating epithelial microbial infections of fluid-containing organs having natural outer openings in mammals. This new therapeutic use is of particular interest in the treatment of epithelial microbial infections of the ear (such as otitis externa), breast (such as mastitis), and uterus (such as endometritis).

Background Art

[0003] Each year, a large number of animals and humans suffer from otitis externa, that is, a painful inflammation of the ear accompanied by a microbial infection of the affected tissue. Animals with pendulous ears, such as many dog breeds, are particularly susceptible. Their covered external ear canals provide an environment prone to inflammation and support the local proliferation of growing microorganisms. Various bacteria, viruses, fungi, and mites can cause otitis externa.

[0004] Most ear disorders are the result of a painful inflammatory response to ear infections, allergic reactions, or trauma. These ear disorders often result from inflammation, which favors bacteria and allows them to overgrow. The disordered local microbiota is the result of an inaccurate inflammation / anti-inflammation balance. Ear infections can be associated with bacterial, fungal, or viral infections, and accurate determination of the etiology is often not practical because isolation and culture of the organisms are difficult.

[0005] In animals (in contrast to humans), otitis externa is initially localized. Subsequently, due to the inflammation, damage to the eardrum reaches the middle ear (tympanic cavity). Since the eardrum can heal, both otitis can progress separately. Otitis externa (outer ear infection), otitis media (middle ear infection), and otorrhea (otitis media with exudation due to eardrum rupture) are included in the most common ear disorders.

[0006] Otitis externa affecting the ear canal part of the outer ear is a common otological problem that mainly occurs in hot and humid weather. In the initial stage, the symptoms include itching and pain in the ear canal, as well as tenderness when pressing around the external auditory canal, pulling the earlobe, or moving the jaw. In some cases, suppuration may occur in the ear canal, and there is a risk of hearing loss. More than 90% of otitis externa cases are caused by inflammation associated with bacterial and fungal infections.

[0007] Otitis externa is usually treated by the topical application of a combination of therapeutic agents showing antimicrobial activity and / or antifungal activity, and anti-inflammatory effects. Topically effective broad-spectrum antibiotic ear suspensions containing antibacterial agents, such as neomycin sulfate, colistin sulfate, polymyxin B or combinations thereof (all with broad-spectrum effects), are used to destroy pathogenic bacteria. Topically acting antifungal agents, such as nystatin and clotrimazole, are used to eliminate underlying fungal diseases. In addition, the antiviral agent acyclovir may also be used in the treatment of viral otitis externa including herpes zoster. Anti-inflammatory agents, such as hydrocortisone, hydrocortisone acetate and dexamethasone sodium phosphate, which are often included in the topically acting suspensions shown above, are used to control the inflammatory process of otitis externa. In most cases, antimicrobial agents and anti-inflammatory agents are used in combination for the treatment of the inducing causative disorders, such as microbial infections, and the inflammatory process itself. These are also, in most cases, administered to the affected ear in the form of drops for topical administration as suspensions to improve and provide more uniform and sustainable delivery to the ear canal.

[0008] An example of a commercially available product used for the treatment of otitis externa in dogs is Surolan (trademark), which combines miconazole (an antifungal agent), prednisolone (an anti-inflammatory agent) and polymyxin B (an antibiotic).

[0009] Another commonly seen epithelial microbial infection is mastitis, especially mastitis in livestock such as dairy cows and goats that are raised for milk production. Mastitis is a disease caused by infection of the mammary glands of animals with staphylococci (e.g., Staphylococcus aureus), streptococci, Escherichia coli, or other pathogenic bacteria that cause inflammation, or a disease associated with such bacteria. Mastitis is a very damaging disease to the dairy industry due to its high incidence, as well as the resulting decrease in milk production, decrease in milk quality, and increase in culling (removal) of animals from the dairy herd. For this reason, mastitis is a very serious disease in livestock, and a commonly used known therapy is administration by directly injecting an antimicrobial drug into the mammary glands of livestock suffering from mastitis. Most cases of mastitis are cured or alleviated by such injections for the treatment of mastitis. However, due to the decreasing sensitivity of mastitis-causing bacteria to existing antimicrobial drugs for the treatment of mastitis, there is currently an increasing number of cases of mastitis for which the therapeutic effect of known drugs cannot be obtained. However, due to the decreasing sensitivity of mastitis-causing bacteria to existing antimicrobial drugs for the treatment of mastitis, there is currently an increasing number of cases of mastitis for which the therapeutic effect of known drugs cannot be obtained.

[0010] Another organ with an external opening in livestock such as cows, which is generally affected by epithelial microbial infections, is the uterus. Myometritis and endometritis are common uterine infections, usually caused by an inaccurate inflammatory balance after parturition that generates microorganisms and results in many cases of myometritis. The use of corticosteroids has been ineffective so far.

[0011] Antimicrobial resistance is a global burden, and inappropriate or excessive use of antimicrobial agents is a major contributing factor. In this regard, the WHO has issued several recommendations and is promoting the development of new non-antibiotic antimicrobial agents.

[0012] In this regard, the inventors have surprisingly found that glucocorticoids, particularly hydrocortisone aceponate, which are well-known for their anti-inflammatory activity, can treat epithelial microbial infections in fluid-containing organs with natural outer openings, including but not limited to otitis externa of the ear, mastitis of the breast, and endometritis of the uterus, which are accompanied by the colonization of pathogenic microorganisms in the inflammatory state. This surprising effect was observed even without administering any antimicrobial agent. Administration of hydrocortisone aceponate (HCA) further results in the recovery of the normal epithelial microbiota. This observation is even more surprising because corticosteroids are known to induce immunosuppressive effects.

[0013] The use of anti-inflammatory agents for the treatment of inflammatory disorders of fluid-containing organs with outer openings is disclosed. Patent Document 1 describes such use of anti-inflammatory agents (particularly selective COX-2 inhibitors) in specific formulations based on amphiphilic oils and microcrystalline waxes for the treatment of inflammatory disorders of the ear and breast. However, the use of anti-inflammatory agents, particularly glucocorticoid agents, for the treatment of microbial infections themselves has not been disclosed heretofore.

[0014] As discussed above herein, inflammation of fluid-containing organs with natural outer openings may be associated with the emergence of microorganisms that result in an abnormal and unbalanced microbiota.

[0015] Without being bound by theory, it is possible that the inflammation itself may actually cause the emergence of abnormal microorganisms. Inflammation of the epithelium promotes the emergence of bacteria, and both inflammation and infection are maintained by a vicious cycle. Recently, inflammatory disorders and epithelial microbial infections such as otitis have been treated with general treatments that act on both inflammation and infection. Such treatments require a combination of antibiotics and / or antifungal agents and anti-inflammatory agents. This enables the treatment of infections within the deadline before frequent recurrences.

[0016] Nevertheless, the inventors have demonstrated that the use of glucocorticoids such as hydrocortisone aceponate (HCA) for the treatment of inflammation occurring in epithelial microbial infections of fluid-containing organs having natural outer openings results in the treatment of the infection itself.

[0017] Thus, glucocorticoids, particularly HCA, exhibit the advantage of enabling the treatment of both inflammation and infection without affecting the natural microbiota of the fluid-containing organ, in contrast to the use of antibiotics and / or antifungal agents that affect not only the microorganisms involved in the infection but also the natural microflora. The unexpected effect of glucocorticoids on the treatment of infection advantageously reduces or avoids the use of other antimicrobial agents for the treatment of the infection. The natural balance is corrected by glucocorticoids such as HCA, i.e., the microbiome is stabilized again without the need to kill the pathogen, enabling a more normal natural microbiome after treatment.

[0018] The inventors have also developed new formulations that are particularly suitable for the improved and efficient delivery of glucocorticoids to fluid-containing organs having natural outer openings. These preferred formulations according to the invention provide a uniform local coating that spreads over the area to be treated and thus exhibit the advantage of improved epithelial adhesion, which gives a broader ability of the anti-inflammatory agent to treat the infection locally.

Prior Art Documents

Patent Documents

[0019]

Patent Document 1

Summary of the Invention

[0020] For this reason, the present invention relates to at least one glucocorticoid used for the treatment and / or prevention of epithelial microbial infections of fluid-containing organs having natural outer openings in mammals, preferably non-human mammals.

[0021] Terms such as "treat", "treating", "treatment", and "control", when used in this specification, refer to any act that benefits a subject suffering from a pathological condition or disease, including alleviation or suppression of at least one symptom, delay in the progression of the disease, prevention or delay in the onset of the disease, etc. Treatment of an epithelial microbial infection includes alleviation of the clinical symptoms of the epithelial microbial infection and / or inhibition of the microbial overgrowth / proliferation of pathogenic bacteria, yeasts, and / or fungi.

[0022] In the context of the present invention, the area for treatment purposes is a fluid-containing organ having an outer opening. Such organs include organs having natural outer openings such as the ear, breast, vagina, uterus, mouth, nostrils, etc.

[0023] The fluid-containing organ having a natural outer opening according to the present invention includes the ear of an animal. For example, in a cat or a dog, the natural outer opening of the ear is the opening of the external auditory canal.

[0024] The fluid-containing organ according to the present invention also includes the mammary gland, for example, the breast of a lactating animal such as a cow, a goat, or a sheep. A "lactating animal" can be a female of any mammalian species, but animals such as cows, goats, or sheep that are bred for the purpose of obtaining milk are preferred, and such animals are included regardless of whether they lactate during an inflammatory and / or infectious pathological condition or during treatment. The natural outer opening of the mammary gland is the opening of the lactiferous duct.

[0025] The fluid-containing organ further includes the vagina or uterus of an animal. The natural outer opening of the uterus is the vagina. The natural outer opening of the vagina is the vulva.

[0026] Other examples of fluid-containing organs having natural outer openings include the digestive tract and the respiratory tract.

[0027] Other protected skin or outer mucosal regions of the animal's body, such as folds of the animal's skin, genital areas, axillae, or underlegs, and interdigital areas, can also be treated in the context of the present invention.

[0028] The epithelial microbial infections according to the present invention include inflammatory disorders associated with infections of the skin, epithelium or outer mucosa of fluid-containing organs including natural outer openings by pathogenic microorganisms including bacteria, yeasts and / or fungi. The terms "infection" or "infected" can be defined herein by an (abnormal) overgrowth / proliferation of pathogenic bacteria, yeasts and / or fungi.

[0029] Preferably, the present invention includes glucocorticoids used for the treatment and / or prevention of epithelial microbial infections of fluid-containing organs having natural outer openings selected from the group consisting of ears, mammary glands and uterus in mammals.

[0030] Preferably, the present invention includes glucocorticoids used for the treatment and / or prevention of epithelial microbial infections of fluid-containing organs having natural outer openings by topical application or topical administration of glucocorticoids to the epithelial region of the fluid-containing organs having natural outer openings.

[0031] According to a preferred embodiment, the present invention relates to hydrocortisone or a salt thereof, preferably hydrocortisone aceponate, used for the treatment and / or prevention of epithelial microbial infections of the ear in non-human mammals. In that case, the hydrocortisone or a salt thereof, preferably hydrocortisone aceponate, is preferably used by topical administration to the epithelial region of the ear.

[0032] Preferably, the present invention includes use for the treatment of a subject suffering from otitis externa infections including erythematous and ceruminous (erythroceruminous ) otitis externa.

[0033] In a particular embodiment, the otitis externa infection is non-suppurative otitis and / or is not accompanied by abnormalities of the eardrum such as a ruptured eardrum.

[0034] Preferably, the ear epithelial microbial infection treated according to the present invention can be caused by bacteria, fungi and / or yeast. According to a preferred embodiment, the ear epithelial microbial infection to be treated is caused by bacteria such as Gram-positive bacteria, for example Staphylococcus aureus and Streptococcus spp., and Gram-negative bacteria such as Escherichia coli. According to another embodiment, the ear epithelial microbial infection to be treated is caused by fungi and / or yeast, for example Trichophyton spp., Microsporum spp., Malassezia spp., preferably Malassezia pachydermatis, Candida spp., particularly Malassezia spp., preferably Malassezia pachydermatis.

[0035] In the most preferred embodiment, the ear epithelial microbial infection treated according to the present invention can be caused by Gram-positive bacteria, for example Staphylococcus aureus and Streptococcus spp., and Gram-negative bacteria such as Escherichia coli, fungi and / or yeast, for example Malassezia pachydermatis, Candida spp.

[0036] The use according to the present invention also enables the treatment of mastitis in livestock (mammals).

[0037] In a preferred embodiment, the use according to the present invention also enables the treatment of mild mastitis in livestock (mammals).

[0038] In a preferred embodiment, the breast epithelial microbial infection treated according to the present invention includes, but is not limited to, Staphylococcus spp. (Staphylococcus aureus, Staphylococcus chromogenes, Staphylococcus epidermidis, Staphylococcus hyicus, Staphylococcus simulans, etc.), Escherichia coli, Klebsiella spp., Trueperella pyogenes, Streptococcus spp. (Streptococcus agalactiae, Streptococcus... chromogenes, Staphylococcus epidermidis, Staphylococcus hyicus, Staphylococcus simulans, etc.), Escherichia coli, Klebsiella spp., Trueperella pyogenes, Streptococcus spp. (Streptococcus agalactiae, Streptococcus... S. uberis, S. parauberis, S. salivarius, S. sanguinis, S. dysgalactiae, etc.), Corynebacterium spp. (C. bovis, etc.), Enterococcus spp. (E. faecium, E. faecalis, E. saccharolyticus, etc. ), Pseudomonas spp., Mycoplasma spp. (M. bovis, M. alkalescens, M. bovigenitalium, M. bovirhinis, M. californicum, M. canadense, etc.), Prototheca spp., Candida spp. (C. kefyr, C anida humicola, C. rugosa, C. inconspicua, C. krusei, C. lu sitaniae, etc.), Rhodotorula, Trichosporon, Saccharomyces genus, Pichia genus, Cryptococcus genus, Aspergillus genus, Penicillium genus, Epicoccum genus, Forma genus and Alternaria genus, and can be caused by bacteria selected from the group consisting of.

[0039] In the most preferred embodiment, the epithelial microbial infection of the breast treated according to the present invention can be caused by Streptococcus spp., Staphylococcus aureus, Escherichia coli, Klebsiella spp., Corynebacterium spp., particularly C. bovis, Mycoplasma spp. and / or Pseudomonas spp.

[0040] In another embodiment, the use according to the invention also enables the treatment of metritis and / or endometritis in livestock (mammals).

[0041] In a preferred embodiment, the epithelial microbial infections of the uterus treated according to the invention are caused by bacteria selected from the group consisting of, but not limited to, Escherichia coli, Trueperella (Arcanobacterium) pyogenes, Gram-negative anaerobic bacteria such as Prevotella melaninogenica and Fusobacterium necrophorum.

[0042] In another embodiment, the glucocorticoid is used for the prevention of epithelial microbial infections of fluid-containing organs having a natural outer opening in mammals. The term "prevention" as used according to the invention includes the prevention of recurrence or reduction of the risk of recurrence of epithelial microbial infections of fluid-containing organs having a natural outer opening. The prevention of epithelial microbial infections includes the prevention of recurrence of clinical symptoms of epithelial microbial infections or reduction of the risk of recurrence, and / or inhibition of microbial overgrowth / proliferation of pathogenic bacteria, yeasts and / or fungi.

[0043] More specifically, the present invention is useful for the prevention of otitis externa such as otitis media including erythematous and ceruminous conditions, mastitis, endometritis and / or metritis.

[0044] The subject according to the invention is preferably a mammal, more preferably a non-human mammal, such as domesticated farm animals (such as cows, horses, pigs) or pets (such as dogs, cats).

[0045] When the present invention is for the treatment of infectious otitis externa, the non-human mammal is preferably a companion animal including but not limited to dogs or cats.

[0046] Dogs that are frequently subjects of otitis externa include, but are not limited to, dogs with pendulous ears that cover the external ear canal (e.g., cocker spaniels, dachshunds, etc.), dogs with a lot of hair in the ear canal (e.g., poodles, bichons, etc.), dogs with a narrow ear canal (e.g., shar-peis, French bulldogs, etc.), and dogs that secrete excessive earwax (e.g., Belgian shepherds, German shepherds, etc.).

[0047] In a specific embodiment where the glucocorticoid according to the present invention is used for the prevention of otitis externa in dogs, the glucocorticoid is preferably HCA, and it is preferred that the above dogs are not atopic dogs. The above dogs are preferably cocker spaniels.

[0048] When the present invention is for the treatment of mastitis (mastitis), the mammal is preferably a non-human lactating mammal. Examples of non-human lactating mammals include ruminants, especially not only bovines such as cows and buffalos, but also goats, sheep and camels. Preferably, the non-human lactating mammal is a bovine, and even more preferably, the animal is a cow or a buffalo.

[0049] When the present invention is for the treatment of uterine infection and / or vaginal infection (myometritis, endometritis), the mammal is preferably a mammal having a uterus. Examples of such mammals include humans, ruminants (e.g., not only bovines including cows and buffalos, but also goats, sheep and camels) and female pigs, but are not limited thereto. Preferably, the above mammal is a non-human mammal, and even more preferably, the animal is a bovine including cows and buffalos.

[0050] In another embodiment, the subject according to the present invention is a mammal having an epithelial microbial infection caused by one or more pathogenic microorganisms that are resistant to conventional treatments such as antibiotics.

[0051] Glucocorticoids (also called steroids, corticosteroids or cortisone analogs) are compounds commonly used for topical application (nose, skin, eyes, etc.). The glucocorticoids can be mono-esters or di-esters. The glucocorticoids of the present invention are preferably di-esters.

[0052] The glucocorticoids according to the present invention are alclometasone dipropionate, alclometasone propionate, amcinonide, beclomethasone dipropionate, betamethasone acetate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone benzoate, betamethasone valerate, budesonide, clobetasol propionate, clobetasol butyrate, clocortolone pivalate, desonide, dexamethasone acetate, dexamethasone nicotinate, dexamethasone propionate, dexamethasone valerate, dexamethasone sodium phosphate, desoxymethasone, diflorasone diacetate, diflucortolone valerate, halobetasol propionate, flumethasone pivalate, fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halcinonide, halobethasone propionate, halometasone, hydrocortisone, for example benzodrocortisone (hydrocortisone 17-benzoate), hydrocortamate (hydrocortisone 21-(diethylamino)acetate), hydrocortisone aceponate (hydrocortisone 21-acetate 17α-propionate), hydrocortisone acetate, hydrocortisone Vendazac, hydrocortisone buteprate (hydrocortisone 17α-butyrate 21-propionate), hydrocortisone butyrate (hydrocortisone 17α-butyrate), hydrocortisone 21-butyrate, hydrocortisone cypionate (hydrocortisone cyclopentanepropionate), hydrocortisone hydrogen succinate, hydrocortisone phosphate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone succinate (hydrocortisone hemisuccinate), hydrocortisone tebutate, hydrocortisone valerate, hydrocortisone xanthate and hydrocortisone probutate, methylpredniso It can be selected from the group including methylprednisolone acetate, methylprednisolone sodium succinate, methylprednisolone aceponate, mometasone furoate, prednisolone sodium phosphate, prednisolone acetate, prednisolone valerate, prednicarbate, prednisone, triamcinolone acetate, triamcinolone diacetate, triamcinolone acetonide.

[0053] Preferably, the glucocorticoid is hydrocortisone or a salt thereof, and more preferably, the glucocorticoid is a hydrocortisone diester.

[0054] Even more preferably, the glucocorticoid according to the present invention is hydrocortisone aceponate.

[0055] When used for the treatment and / or prevention of epithelial microbial infections of fluid-containing organs with natural external openings in mammals, at least one glucocorticoid is preferably formulated in a pharmaceutical composition containing a pharmaceutically acceptable liquid and / or solid carrier(s).

[0056] According to a specific embodiment, at least one glucocorticoid is the only active substance in the pharmaceutical composition. That is, the above pharmaceutical composition does not contain any other active substances selected from antibacterial agents, antifungal agents or antiviral agents.

[0057] Therefore, the present invention relates to a pharmaceutical composition comprising hydrocortisone or a salt thereof, preferably hydrocortisone aceponate, and a pharmaceutically acceptable carrier, for the treatment and / or prevention of ear epithelial microbial infections in non-human mammals, and does not contain any antibacterial agents, antifungal agents and / or antiviral agents. The above composition is preferably administered by topical application to the ear epithelial region.

[0058] According to the present invention, the active substance is a pharmaceutical or veterinary compound exhibiting a therapeutic effect, and such a compound is also referred to as a pharmaceutical active ingredient (API).

[0059] According to another specific embodiment, the above pharmaceutical composition contains at least one further active ingredient in addition to the above at least one glucocorticoid and the above pharmaceutically acceptable liquid or solid carrier(s). In this case, the pharmaceutical composition contains one or more active substances together with one or more pharmaceutically acceptable carriers for delivery to a subject, including various diluents or additives known to those skilled in the art.

[0060] In a specific embodiment, the above at least one further active ingredient is a non-antibiotic antimicrobial agent.

[0061] Particularly in animals, otitis externa is often associated with the invasion of parasites, most commonly ear mites, i.e., the invasion of Otodectes cynotis (ear mites). For ear mites Local treatment has often been carried out by relatively long-term topical insecticidal therapy, for example using a pyrethrin-containing composition. However, recently, Shorter-term therapies have been achieved by administering mectin compounds and macrolide compounds, such as avermectins (ivermectin and selamectin, etc.) and milbemycins, otically, by injection or transdermally. If clinically necessary, such anti-parasiticidal compounds can be co-administered as an adjunct within or separately from the composition of the present invention. Further, if clinically necessary, antiviral compounds such as acyclovir can be administered in place of or as an adjunct to the antibiotic compound.

[0062] Advantageously, in the pharmaceutical composition according to the present invention, which comprises a glucocorticoid and a further active ingredient as disclosed above herein, the amount of the further active ingredient can be reduced due to the mechanism of action of the glucocorticoid itself. According to the demonstration of the present inventors, glucocorticoids can treat infections alone, and thus, when used in combination with typical active ingredients used for the treatment of epithelial microbial infections of fluid-containing organs having a natural outer opening, an improvement in the treatment of infections can be obtained. Thereby, the amount of the other active ingredient can be reduced.

[0063] At least one glucocorticoid can also be administered together with membrane-reconstituting proteins such as glycoaminoglycan, ceramide, chitosan, etc.

[0064] Another aspect of the present invention is a composition comprising an active ingredient and a pharmaceutically acceptable carrier for the treatment of epithelial microbial infections of fluid-containing organs having a natural outer opening in a mammal, wherein the active ingredient is a glucocorticoid, preferably hydrocortisone or a salt thereof, and even more preferably hydrocortisone aceponate.

[0065] Another aspect of the present invention is a pharmaceutical composition comprising a glucocorticoid, preferably hydrocortisone or a salt thereof, more preferably hydrocortisone aceponate, and a pharmaceutically acceptable carrier, for the treatment and / or prevention of epithelial microbial infections of fluid-containing organs having a natural outer opening in a mammal, preferably a non-human mammal, preferably the ear.

[0066] A particularly preferred pharmaceutically acceptable carrier is methyl ether propylene glycol.

[0067] The composition to be administered may additionally contain additives, adjuvants, thickeners, and other substances that enable more effective administration. Examples include oils, emollients, or other substances that enhance the effectiveness and comfort of ear drops, nasal sprays, and inhalation compositions. This may also include substances that improve the odor or taste.

[0068] Preferred compositions and formulations according to the present invention cover the organ having a natural outer opening to be treated locally.

[0069] Preferred additives exhibit bactericidal activity and include alcohols (such as alcohol benzoate, benzyl alcohol, ethanol, etc.), solvents (such as propylene glycol, glycerin), surfactants, emollients (such as macrogol cetostearyl ether, diisopropyl adipate, etc.), dispersants (such as nikkol so-15 VL sorbitan sesquioleate, etc.), flavoring agents (such as vanilla), chelating agents (such as disodium EDTA salt), oils (such as olive oil (containing oleic acid, linolenic acid, and linoleic acid), coconut oil, caprylic / capric triglyceride, caprylic / capric coconut alkyl (Coco-Caprylate / Caprate)), extracts (essential oils or non-essential oils) (such as turmeric oil, melaleuca oil, calendula, Oregon grape, thyme, garlic, sage, lemon Oils such as glass, Japanese cypress, peppermint, catnip, tea tree, valerian, rosemary, citrus fruits, eucalyptus, and silver fir), additives (such as nitric oxide, Sodium benzoate, silicon dioxide, titanium dioxide, tannic acid, curcumin (turmeric)), polygonal, thymol, nisin, polyhexanide, chlorobutanol, hydrogen peroxide, benzethonium chloride, silver (such as silver nitrate, silver chloride or colloidal silver), silver salts, iodine or iodine derivatives (such as povidone (PVP) iodine), bactericides (such as chlorhexidine, chloramine T, potassium permanganate), preservatives (such as bronopol, E-280 (propionic acid), E281 (sodium propionate), E282 (calcium propionate), E36 (formic acid), phenoxyethanol, thimerosal, potassium sorbate, polylysine, citric acid, a mixture of citric acid (25%) and sorbic acid (16.7%), sodium thiosulfate, sodium thiosulfate pentahydrate), sweeteners (such as honey) can be selected from the group consisting of, but not limited to these.

[0070] In a preferred embodiment, the additive having bactericidal activity is selected from the group consisting of caprylic / capric acid coconut alkyl, diisopropyl adipate, coconut oil, nisin, PVP iodine, alcohol benzoate, caprylic / capric acid triglyceride, glycerin, olive oil (including oleic acid, linolenic acid and linoleic acid), polylysine, honey, propylene glycol, macrogol cetostearyl ether, nikkol so-15 VL sorbitan sesquioleate, and silicon dioxide.

[0071] In a more preferred embodiment, the additive having bactericidal activity is PVP iodine, caprylic / capric acid coconut alkyl, diisopropyl adipate, coconut oil and nisin.

[0072] A particularly preferred pharmaceutically acceptable carrier is methyl ether propylene glycol.

[0073] Other examples of formulations for topical application of glucocorticoids such as HCA, which are particularly suitable for administration to the ear, include Suspensions of lipid-based particles having a solid matrix, preferably solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), comprising at least one lipid and preferably at least one emulsifier. Since the lipid particles are solid at room temperature, they can comprise a single solid lipid or a mixture of lipids which may partly contain at least one solid lipid.

[0074] Suitable solid lipids are, for example, Hydrocarbons such as solid paraffin, Fatty acids such as myristic acid, palmitic acid, stearic acid, Monoglycerides such as glyceryl monostearate, glyceryl hydroxystearate, glyceryl behenate, Diglycerides such as glyceryl palmitostearate, Triglycerides such as glyceryl tristearate, glyceryl trimyristate, hydrogenated castor oil, hydrogenated coconut oil, Waxes such as beeswax, carnauba wax, cetyl palmitate.

[0075] A preferred solid lipid is glyceryl palmitostearate.

[0076] Suitable non-solid lipids are, for example, Hydrocarbons such as liquid paraffin, squalene (unsaturated hydrocarbon), Vegetable oils such as soybean oil, castor oil, Fatty acid esters such as isopropyl myristate, Medium-chain triglycerides such as caprylic-capric triglyceride, Fatty acids such as oleic acid, linoleic acid, Propylene glycol fatty acid esters such as propylene glycol dicaprylocaprate, Vitamin E.

[0077] The melting point range of the solid lipid is preferably 30°C to 100°C, more preferably 40°C to 90°C. When used in combination with a non-solid lipid, the solid lipid may have a melting point lower than or higher than the range of 30°C to 100°C.

[0078] Generally, at least one surfactant is required to form a suspension of lipid-based particles having a solid matrix and to assist in the dispersion process of the melted lipid(s) into the heated aqueous phase necessary to stabilize the lipid particle dispersion after cooling.

[0079] Many types of lipophilic or hydrophilic surfactants as follows can be used for the preparation and stabilization of lipid particle suspensions: Nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters, sorbitan esters, macrogol 15 hydroxystearate, glyceryl monostearate, polyoxyethylene castor oil derivatives, polyoxyl glycerides, glyceryl stearate and PEG-75 stearate, cetyl alcohol and ceteth-20 and steareth-20, Anionic surfactants such as sodium dodecyl sulfate, sodium deoxycholate, sodium glycocholate, sodium oleate, Cationic surfactants such as benzalkonium chloride, cetrimide, stearylamine, Amphoteric surfactants such as egg lecithin, soy lecithin, phosphatidylcholine, egg phospholipid, soy phospholipid, phosphatidylethanolamine, Block copolymers such as poloxamer.

[0080] Combinations of surfactants can be used, and the selection of the surfactant(s) is determined by the lipid(s) used.

[0081] Preferably, a nonionic surfactant is used, and more preferably, the surfactant is selected from the group of polyoxyethylene sorbitan fatty acid esters. A preferred surfactant is polysorbate 80.

[0082] Thickeners, skin softeners, co-surfactants, buffers, pH adjusters, salts, antioxidants and other additives such as preservatives can be used for the stability of the composition, more effective administration and the comfort of the composition.

[0083] Suspensions of lipid-based particles with a solid matrix can be prepared according to various standard methods. A preferred method is sonication following high-shear homogenization. The lipid phase, which may contain at least a surfactant (s), is melted. The glucocorticoid is preferably dissolved or dispersed in the melted lipid. An aqueous phase at the same temperature as the melted lipid phase, which may contain at least a surfactant (s), is added to the lipid phase. Nevertheless, the API may be present in the aqueous phase. The mixture is then passed through a high-shear mixer to produce a coarse emulsion, followed by sonication. The selection of process parameters is determined by the equipment and the composition.

[0084] An in-situ gelling system that is liquid or viscous at room temperature and gels at body temperature, comprising at least one polymer exhibiting thermoreversible gelling properties such as poloxamer.

[0085] A preferred polymer exhibiting thermoreversible gelling properties is poloxamer 407.

[0086] Thickeners, solvents, skin softeners, co-surfactants, buffers, pH adjusters, salts, antioxidants and other additives such as preservatives can be used for the stability of the composition, more effective administration and the comfort of the composition.

[0087] The in-situ gelling system suspension can be prepared according to various methods. It is preferred to dissolve or disperse all components except the poloxamer (s) in water. The poloxamer (s) is then dissolved in a pre-cooled aqueous mixture at approximately 5 °C. The active ingredient can be added to the aqueous phase containing the polymer such as poloxamer (s) at 5 °C, either alone or in combination with other additives (s).

[0088] In-situ phospholipid gelation system: The above system is fluid and gels upon contact with water. This is particularly suitable for administration to the ear after cleaning the ear before the treatment is carried out. The above gelation system enables better retention of the product locally. Such a system may contain at least one phospholipid such as phosphatidylcholine derivatives.

[0089] A preferred jellifying agent is Phospholipon 90G.

[0090] Other additives such as thickeners, solvents, emollients, co-surfactants, buffers, pH adjusters, salts, antioxidants and preservatives can be used for the stability of the composition, more effective administration and the comfort of the composition.

[0091] Examples of preferred solvents include isopropyl myristate and ethanol.

[0092] A jellified formulation that exhibits improved viscosity and thus enables improved retention of the product in the ear. Such a formulation may contain a thickener. Examples of thickeners include povidone K 90, glycerol, PEG400, carbomer (Acrypol (trademark) 971) / acrylic polymer, hypromellose (hydroxypropylmethylcellulose 2910 60HD6), hydroxypropylmethylcellulose and other common thickeners (gums, poloxamers). Preferred thickeners are povidone K90 and glycerol.

[0093] Other additives such as solvents, emollients, co-surfactants, buffers, pH adjusters, salts, antioxidants and preservatives can be used for the stability of the composition, more effective administration and the comfort of the composition.

[0094] A micellar solution containing at least one dispersed surfactant. At least one non-solid lipid can be added.

[0095] Suitable surfactants are preferably hydrophilic, exhibit a high hydrophilic-lipophilic balance value, are water-soluble, and act as solubilizers for lipophilic substances by maintaining the lipophilic substances in a micellar solution. More preferably, the surfactant is a nonionic surfactant such as polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, macrogol 15 hydroxystearate, polyoxylglyceride, and poloxamer.

[0096] A preferred surfactant is polysorbate 80.

[0097] Other additives such as thickeners, solvents, skin softeners, co-surfactants, buffers, pH adjusters, salts, antioxidants, and preservatives can be used for the stability of the composition, more effective administration, and the comfort of the composition.

[0098] The micellar solution is prepared by adding a surfactant at a concentration sufficient to form a micellar solution to a liquid medium. The concentration of the surfactant(s) is mostly above the critical micelle concentration so as to form micelles. Then, the lipophilic substance(s) is added and solubilized in the micellar solution under gentle stirring.

[0099] A cyclodextrin inclusion complex containing at least one cyclodextrin that acts as a solubilizer for lipophilic substances by encapsulating and maintaining the lipophilic substances in the hydrophobic internal cavity of the solubilizing cyclodextrin molecules.

[0100] Other additives such as thickeners, solvents, skin softeners, co-surfactants, buffers, pH adjusters, salts, antioxidants, and preservatives can be used for the stability of the composition, more effective administration, and the comfort of the composition.

[0101] A preferred cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0102] An aqueous cyclodextrin inclusion complex is prepared by adding cyclodextrin(s) to an aqueous medium. Subsequently, a lipophilic substance(s) is added and solubilized in the cyclodextrin(s) molecule under gentle stirring.

[0103] Other additives such as thickeners, solvents, skin softeners, co-surfactants, buffers, pH adjusters, salts, antioxidants, and preservatives can be used for the stability of the composition, more effective administration, and the comfort of the composition.

[0104] Oil-in-water or water-in-oil emulsion: An emulsion containing at least one lipid, at least one emulsifier, and at least water.

[0105] Suitable lipids are, for example, Hydrocarbons such as solid paraffin, liquid paraffin, squalene (unsaturated hydrocarbon), Fatty acids such as myristic acid, palmitic acid, stearic acid, Monoglycerides such as glyceryl monostearate, glyceryl hydroxystearate, glyceryl behenate, Diglycerides such as glyceryl palmitostearate, Triglycerides such as glyceryl tristearate, glyceryl trimyristate, hydrogenated castor oil, hydrogenated coconut oil, soybean oil, castor oil, caprylic-capric triglyceride, Waxes such as beeswax, carnauba wax, cetyl palmitate, Fatty acid esters such as isopropyl myristate, Fatty acids such as oleic acid, linoleic acid, Propylene glycol fatty acid esters such as propylene glycol dicaprylocaprate, Vitamin E.

[0106] Generally, at least one surfactant is required to assist the dispersion process and stabilize the emulsion. Combinations of surfactants can be used.

[0107] Many types of lipophilic or hydrophilic surfactants as follows can be used: Polyoxyethylene sorbitan fatty acid esters, sorbitan esters, macrogol 15 hydroxystearate, glyceryl monostearate, polyoxyethylene castor oil derivatives, polyoxylglycerides, glyceryl stearate, and PEG-7 stearate Nonionic surfactants such as 5, cetyl alcohol, ceteth-20, and steareth-20 Anionic surfactants such as sodium dodecyl sulfate, sodium deoxycholate, sodium glycolate, and sodium oleate Cationic surfactants such as benzalkonium chloride, cetrimide, and stearylamine Amphoteric surfactants such as egg lecithin, soy lecithin, phosphatidylcholine, egg phospholipid, soy phospholipid, and phosphatidylethanolamine Block copolymers such as poloxamer

[0108] It is preferable to use nonionic surfactants.

[0109] Other additives such as thickeners, emollients, co-surfactants, buffers, pH adjusters, salts, antioxidants, and preservatives can be used for the stability of the composition, more effective administration, and the comfort of the composition.

[0110] A formulation particularly suitable for the treatment of mastitis in non-human animals, also called an intramammary infusion, usually consists of a vehicle or carrier combined with an active ingredient. The intramammary formulation can be in the form of a liquid product such as a solution, A suspension, paste, gel, or cream formulation, a semi-solid or thixotropic product.

[0111] In a preferred embodiment, the composition according to the invention comprises at least one glucocorticoid as described above solubilized in a pharmaceutically acceptable carrier. In another preferred embodiment, the glucocorticoid according to the invention is in particulate form in the intramammary formulation.

[0112] The intramammary composition of the present invention may further comprise any suitable pharmaceutically acceptable components known in the pharmaceutical field, selected from the group consisting of oils, medium-chain triglycerides, waxes (such as microcrystalline wax), fatty acids, fatty acid derivatives, viscosity modifiers or thickeners (stearates, silicon dioxide, cellulose); pigments, opacifiers, dispersants; emulsifiers; stabilizers; surfactants, wetting agents; antioxidants; antibacterial agents, antifungal agents, preservatives, emollients, polymers, any compound conferring functional properties (flavors, dyes, perfumes, etc.), water, and combinations thereof. The oil used is selected from plant origin (such as natural vegetable oils) or mineral origin (such as paraffin, white petrolatum, yellow petrolatum, etc.). Fatty acid derivatives are organic or inorganic compounds such as aluminum stearate, magnesium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil, etc. Mineral particles such as silica, clay, calcium carbonate, etc. (not only these) are the final additives that can be used as thickeners. The formulation may also contain non-toxic heavy metals.

[0113] The intramammary implant containing a glucocorticoid according to the present invention in the form of particles that can be encapsulated in a pharmaceutically acceptable carrier is aimed at protection by long-term effects and ensures the desired treatment time and efficacy.

[0114] The composition according to the present invention can be administered by various routes of administration, including but not limited to topical administration or oral administration, especially when the target is the digestive tract and intestinal epithelium.

[0115] The composition according to the present invention is preferably administered by topical application or topical administration to the epithelial region of a fluid-containing organ having a natural outer opening. In particular, the above composition is topically applied or topically administered to a fluid-containing organ having a natural outer opening, i.e., into its lumen, i.e., through the opening of the fluid-containing organ, and to the epithelial region of the fluid-containing organ suffering from a microbial disorder.

[0116] Preferably, the present invention relates to the epithelium of a fluid-containing organ having a natural outer opening, in particular to a fluid-containing organ having a natural outer opening, i.e., into its lumen, i.e., the fluid-containing organ also provides a method for locally treating epithelial microbial infections by local administration of glucocorticoids to the epithelial region of the fluid-containing organ having a microbial disorder through the opening of the fluid-containing organ and suffering from microbial disorders.

[0117] "Local administration" means applying at least one glucocorticoid used according to the present invention to an epithelial region suffering from (treatment) or having suffered from (prevention of recurrence) a microbial disorder.

[0118] In certain embodiments, at least one glucocorticoid used according to the present invention, preferably hydrocortisone or a salt thereof, more preferably hydrocortisone aceponate, is applied to the outer ear canal, i.e., the outer ear side of the tympanic membrane (eardrum). Local administration to the ear canal is achieved, for example, by introducing the composition of the present invention into the ear canal by any medically acceptable means, for example, inserting a needleless syringe, dropper or cotton swab into the ear canal and applying the carrier composition to the membrane. The administration is repeated as necessary to achieve a therapeutically effective dose level of a given glucocorticoid compound.

[0119] When the method of the present invention involves injection or infusion of at least one glucocorticoid into the breast via the lactiferous ducts or into the uterus via the vagina, effective treatment of mastitis and myometritis / endometritis can be achieved, respectively. "Intramammary infusion" is the act of flowing a liquid composition into the breast (teat cistern and / or gland cistern) via the lactiferous ducts, regardless of the time scale involved. "Intrauterine (Uterus) infusion" is the act of flowing a liquid composition into the uterus via the vagina, regardless of the time scale involved. In this context, "infusion" and "injection" are substantially synonymous.

[0120] In certain embodiments, at least one glucocorticoid can be administered for the treatment of mastitis by inserting the cannula nozzle of a syringe into the outer opening of the nipple duct of the mammary gland of a lactating animal and injecting at least one glucocorticoid into the mammary gland.

[0121] In certain embodiments, at least one glucocorticoid can be administered for the treatment of myometritis and / or endometritis by inserting the cannula nozzle of a syringe into the vagina of a mammal having a uterus and injecting at least one glucocorticoid into the vagina and / or uterus of the animal.

[0122] For the treatment and prevention of epithelial microbial infections of fluid-containing organs having natural outer openings encompassed by the present invention, a glucocorticoid is administered in an amount of 0.01 mg to 150 mg per administration. Accordingly, the pharmaceutical composition of the present invention comprises a glucocorticoid in a content selected such that a single dose of the pharmaceutical composition contains the required amount of glucocorticoid.

[0123] Such glucocorticoids can be administered once or twice a day for 1 to 20 days. Depending on the severity of the infection, the glucocorticoid can be administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days (i.e., up to 20 days).

[0124] In certain cases of the treatment of otitis externa, the amount of glucocorticoid applied, preferably hydrocortisone or a salt thereof, more preferably hydrocortisone aceponate, is preferably included in the range of 0.01 mg to 10 mg. Such glucocorticoids can be administered once or twice a day for 2 to 20 days. Depending on the severity of the infection, the glucocorticoid can be administered for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days and can be administered.

[0125] In the treatment of otitis externa, the amount of glucocorticoid administered, preferably hydrocortisone or a salt thereof, more preferably hydrocortisone aceponate, is preferably included in the range of 0.05 mg to 5 mg, more preferably 0.1 mg to 1.2 mg. Even more preferably, the amount of glucocorticoid is included in the range of 0.1 mg to 0.5 mg. In the most preferred embodiment, the above amount is included in the range of 0.25 mg to 0.3 mg.

[0126] For example, 0.5 ml of the pharmaceutical composition according to the present invention is used, and the content of glucocorticoid in the pharmaceutical composition is 0.584 mg / ml.

[0127] In another preferred embodiment, the above glucocorticoid used for the treatment of otitis externa, preferably hydrocortisone or a salt thereof, more preferably hydrocortisone aceponate, is applied into the ear once or twice a day for 1 to 14 days, preferably 7 to 14 days. In the most preferred embodiment, the above glucocorticoid used for the treatment of otitis externa is administered once a day for 7 to 14 days.

[0128] According to a preferred embodiment related to the treatment of otitis externa, the amount of glucocorticoid administered, preferably hydrocortisone or a salt thereof, more preferably hydrocortisone aceponate, is included in the range of 0.1 mg to 0.5 mg and is administered once a day for 7 to 14 days, preferably 7 days.

[0129] According to a more preferred embodiment related to the treatment of otitis externa, the above pharmaceutical composition contains HCA. The animal is preferably a dog. The above dog is preferably not an atopic dog. The above dog is preferably a cocker spaniel.

[0130] According to another embodiment, the treatment can be carried out continuously. The term "continuously" or "continuous treatment" corresponds to the administration of glucocorticoid over a first treatment period, followed by a second period with the treatment discontinued, and then followed by an additional treatment period. The continuous treatment can be repeated as necessary.

[0131] According to another embodiment related to the prevention of otitis externa, the amount of glucocorticoid administered, preferably hydrocortisone or a salt thereof, more preferably hydrocortisone aceponate, is included in the range of 0.01 mg to 10 mg and is administered into the ear at least once a week for 10 to 20 weeks.

[0132] For the prevention of otitis externa, the amount of glucocorticoid administered, preferably hydrocortisone or a salt thereof, more preferably hydrocortisone aceponate, is preferably included in the range of 0.05 mg to 5 mg, more preferably 0.1 mg to 1.2 mg. Even more preferably, the amount of glucocorticoid is included in the range of 0.1 mg to 0.5 mg. In the most preferred embodiment, the above amount is 0.25 mg to 0.3 mg.

[0133] The above glucocorticoid is preferably HCA. The animal is preferably a dog. The above dog is preferably not an atopic dog. The above dog is preferably a Cocker Spaniel.

[0134] In another preferred embodiment, the pharmaceutical composition containing glucocorticoid, preferably hydrocortisone or a salt thereof, more preferably hydrocortisone aceponate, used for the prevention of otitis externa is applied into the ear at least once a week, preferably twice a week, for 10 to 20 weeks, preferably 12 to 18 weeks, more preferably 16 weeks. The composition is Preferably administered continuously for 2 days a week.

[0135] According to a preferred embodiment related to the treatment of otitis externa, the amount of glucocorticoid administered, preferably hydrocortisone or a salt thereof, more preferably hydrocortisone aceponate, is included in the range of 0.1 mg to 0.5 mg and is administered into the ear twice a week for 16 weeks.

[0136] Preferably, the glucocorticoid is HCA. Preferably, the animal is a dog. Preferably, the dog is not an atopic dog. Preferably, the dog is a Cocker Spaniel.

[0137] In a specific case of the treatment of mastitis, the amount of glucocorticoid applied to the breast through the lactiferous duct is preferably included in the range of 1 mg to 50 mg. Such glucocorticoid can be administered at least once a day for 1 day to 10 days. Depending on the importance of the infection, the glucocorticoid can be administered for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days or 10 days.

[0138] Preferably, the amount of glucocorticoid administered is included in the range of 10 mg to 40 mg, more preferably 15 mg to 25 mg. The most preferred embodiment is a dosage of 20 mg of glucocorticoid.

[0139] For example, a 10 ml pharmaceutical composition containing the glucocorticoid according to the present invention is administered to the breast through the lactiferous duct, and the concentration of the glucocorticoid in the pharmaceutical composition is preferably included in the range of 0.05% to 1% (w / w), preferably 0.2%.

[0140] The pharmaceutical composition for the treatment of mastitis containing the glucocorticoid according to the present invention is preferably administered to the breast through the lactiferous duct once or twice a day, preferably twice a day, for 1 day to 10 days, preferably 1 day to 5 days, more preferably 1 day to at most 2 days.

[0141] In the most preferred embodiment, the glucocorticoid according to the present invention is administered to the mammary gland through the papillary duct twice a day for up to two days in a glucocorticoid amount of 10 mg to 40 mg.

[0142] In a preferred embodiment, each nipple of the mammary gland of a mammal is treated with the pharmaceutical composition according to the present invention. The glucocorticoid is preferably HCA. The animal is preferably a cow.

[0143] According to another embodiment related to the prevention of mastitis, the amount of glucocorticoid administered is included in the range of 0.01 mg to 50 mg, preferably 10 mg to 40 mg, even more preferably 15 mg to 25 mg, and is administered to the mammary gland through the papillary duct at least once a week. The glucocorticoid is preferably HCA. The animal is preferably a cow.

[0144] In a specific case of the treatment of myometritis / endometritis, the amount of glucocorticoid applied to the uterus is preferably included in the range of 1 mg to 150 mg, preferably 10 mg to 120 mg, even more preferably 30 mg to 120 mg.

[0145] According to an embodiment related to the treatment of myometritis / endometritis, the glucocorticoid can be administered once or several times. In a preferred embodiment, the glucocorticoid is administered once. The glucocorticoid is preferably HCA.

[0146] According to another embodiment related to the prevention of myometritis / endometritis, the amount of glucocorticoid is included in the range of 1 mg to 150 mg, preferably 10 mg to 120 mg, even more preferably 30 mg to 120 mg, and is administered to the uterus once or several times.

[0147] The present invention further provides a method for preventing or treating epithelial microbial infections of a fluid-containing organ having a natural outer opening, preferably the ear, which comprises topically administering to the epithelium suffering from said microbial infection at least one glucocorticoid, preferably hydrocortisone or a salt thereof, even more preferably hydrocortisone aceponate.

[0148] Another aspect of the present invention is a) a pharmaceutical composition according to the present invention, b) instructions for use of the product, c) any administration device, and a kit comprising the same.

[0149] The pharmaceutical composition in the kit according to the present invention may be provided within a ready-to-use administration device or separately from the administration device.

[0150] Examples of administration devices include, but are not limited to, pump sprays, syringes, and tubes.

[0151] An administration device particularly suitable for the treatment and / or prevention of otitis externa is a pump having a cannula.

[0152] An administration device particularly suitable for the treatment and / or prevention of mastitis, myometritis and / or endometritis is a syringe.

Mode for Carrying Out the Invention

Examples

[0153] Example 1 - Evaluation of the Efficacy of a Hydrocortisone Aceponate (HCA) Formulation (Cortavance™) for the Treatment of Otitis Externa in Dogs Objective: Erythematous ceruminous otitis is mainly caused by inflammation, and microbial growth is only a secondary symptom of this disease. The effectiveness of topical corticotherapy with hydrocortisone aceponate (HCA) as a single therapy has been previously evaluated for the prevention of recurrence of allergic otitis, but there are no convincing data in veterinary medicine regarding its use for the treatment of acute flare of otitis externa. The main objective of this study was to evaluate whether the use of HCA alone in the ear canal could be effective in the treatment of otitis externa in dogs. The Cortavance (trademark) product consists of 0.0584% hydrocortisone aceponate in propylene glycol methyl ether (QSP

[0154] 100%). Materials and Methods: Dogs with clinical signs (OTIS3 score ≥ 4) and cytological signs (score > 1) of acute onset of otitis externa (erythematous ceruminous, non-parasitic) were included in this double-blind randomized controlled multi-site clinical field trial. The dogs were assigned to two groups and treated once daily with 0.5 mL of HCA (Cortavance (trademark) group) for 7 days or 14 days if symptoms persisted, or twice daily with 0.5 mL of the veterinary medicinal product Surolan (trademark) containing a combination of an antifungal agent, an anti-inflammatory agent and an antibiotic agent (miconazole, prednisolone and polymyxin B) (Surolan (trademark) group). At D7, D14 and D28, the clinical OTIS3 score (according to Nuttal and Bensignor, Vet dermatol, 2014), the cytological score (according to Budach and Mueller, Vet Derm, 2012) and pruritus (according to Rybnicek and a

[0155] l, Vet Derm, 2008) were compared to the baseline. Treatment was considered successful if remission occurred at D7 or D14 and no recurrence was seen at D28. If remission occurred at D7 or D14 and no recurrence was seen at D28, the treatment was considered successful.

[0156] Results: Fifty-three dogs with unilateral or bilateral otitis externa were enrolled in this clinical field trial, but four dogs were excluded from the analysis due to protocol non-compliance (dogs that attended follow-up visits only once or only the first two times). The analysis was performed on 49 dogs (73 ears), and 23 dogs (34 ears) and 26 dogs (39 ears) were assigned to the Cortavance™ group and the Surolan™ group, respectively.

[0157] At baseline, for each of body weight (21.42 kg ± 13.61 vs 19.05 kg ± 16.11, Wilcoxon test p = 0.37), unilateral or bilateral otitis (52.2% vs 50.0% unilateral or 47.8% vs 50.0% bilateral, chi-square test p = 0.88), clinical score OTIS3 (6.2 ± 0.9 vs 6.0 ± 1.4, Wilcoxon test p = 0.35), total cytological score (4.0 ± 1.6 vs 4.5 ± 1.7, Wilcoxon test p = 0.24), type of otitis (bacteria: 5.9% vs 5.1%, bacteria and Malassezia: 61.8% vs 74.4%, Malassezia: 32.3% vs 20.5%, Fisher's exact test p = 0.47), and pruritus score (5.9 ± 1.8 vs 5.7 ± 2.2, Student's test p = 0.72), the homogeneity of the Cortavance™ group vs the Surolan™ group was considered. The dogs were significantly younger in the Cortavance™ group than in the Surolan™ group (4.24 years ± 3.26 vs 6.16 years ± 3.30, Wilcoxon test p = 0.02).

[0158] In D7, clinical signs, cytological signs, and pruritus signs improved with both treatments, and the success rate was not significantly higher with Cortavance (trademark) than with Surolan (trademark) (50.0% vs. 30.8%, chi-square test p = 0.09). The decrease in the total cytological score was similar between groups (61.5% ± 23.4 vs. 61.7% ± 22.7, Wilcoxon test p = 0.89), and the decrease in the clinical score (62.7% ± 22.6 vs. 46.3% ± 20.8, Student's test p = 0.002) and the decrease in pruritus (70.0% ± 17.5 vs. 57.1% ± 25.3, Student's test p = 0.047) were significantly higher with Cortavance (trademark) than with Surolan (trademark), respectively.

[0159] In D14, the success rate was similar (74.1% vs. 73.5%, chi-square test p = 0.96), and the decrease in the clinical score (82.3% ± 15.4 vs. 77.6% ± 18.5, Wilcoxon test p = 0.27), the decrease in the total cytological score (82.2% ± 26.7 vs. 76.2% ± 28.3, Wilcoxon test p = 0.31), and the decrease in pruritus (88.9% ± 9.8 vs. 80.5% ± 19.2, Wilcoxon test p = 0.15) were not significantly higher with Cortavance (trademark) than with Surolan (trademark), respectively.

[0160] In D28, the recurrence-free rate was not significantly lower (83.3% vs. 95.2%, Fisher's exact probability test p = 0.35), and the decrease in the clinical score (80.2% ± 24.3 vs. 71.1% ± 22.7, Wilcoxon test p = 0.07), the decrease in the cytological score (84.1% ± 19.7 vs. 73.5% ± 26.1, Wilcoxon test p = 0.09), and the decrease in pruritus (86.1% ± 20.0 vs. 76.3% ± 21.4, Wilcoxon test p = 0.08) were not significantly higher with Cortavance (trademark) than with Surolan (trademark), respectively.

[0161] Complementary analyses were performed by individually examining the cytological scores for bacteria, Malassezia, and neutrophils. The bacterial scores compared to baseline were 58.7% ± 35.1 vs. 49.7% ± 34.5 at D7 (Wilcoxon test p = 0.45), 84.4% ± 30.1 vs. 6 9.9% ± 39.2 (Wilcoxon test p = 0.22), and 80.3% ± 22.8 vs. 70.8% ± 34.4 (Wilcoxon test p = 0.44) for Cortavance™ vs. Surolan™, respectively. The Malassezia scores compared to baseline were 58.6% ± 31.9 vs. 63.1% ± 26.8 at D7 (Wilcoxon test p = 0.64), 79.2% ± 31.4 vs. 77.8% ± 41.3 (Wilcoxon test p = 0.87), and 84.1% ± 23.6 vs. 72.8% ± 37.5 (Wilcoxon test p = 0.28) for Cortavance™ vs. Surolan™, respectively. Note that during the course of the study, only the Malassezia score of one ear increased, and that ear was in the Surolan™ group. The neutrophil scores compared to baseline were 75.0% ± 46.3 vs. 58.3% ± 46.9 at D7 (Wilcoxon test p = 0.41), 100% ± 0.0 vs. 81.8% ± 40.5 (Wilcoxon test p = 0.28), and 100% vs. 100% at D28 for Cortavance™ vs. Surolan™, respectively.

[0162] The overall success rate was not significantly higher for Cortavance™ compared to Surolan™ (60.6% vs. 57.1%, chi-square test p = 0.77). Furthermore, statistical analysis further emphasized a better manifestation of the action of Cortavance™ from D7, with both the itching score and the clinical score being significantly lower compared to Surolan™.

[0163] No adverse events were recorded during the trial.

[0164] Conclusion: This clinical field study emphasizes that HCA is as effective as the reference treatment containing at least an anti-inflammatory agent, an antibiotic, and an antifungal agent in the treatment of canine erythematous otitis externa, and controls the growth of bacteria and fungi.

[0165] Example 2 - Evaluation of the Efficacy of Hydrocortisone Aceponate (HCA) Formulations for the Intramammary Treatment of Mastitis in Lactating and Non-Pregnant Cows The objective of this multi-site clinical field study was to evaluate the efficacy and safety of HCA at a dose of 20 mg in a 10 ml petrolatum oil-based formulation for the intramammary treatment of mild clinical mastitis in lactating cows every 12 ± 2 hours (h hours) (minimum 1 and maximum 4 treatments). Specifically, to assess the efficacy (clinical cure rate) of HCA alone in the treatment of mammary inflammation (mild clinical mastitis) under field conditions, as well as the safety and the risk of exacerbation or recurrence during and after treatment with HCA alone.

[0166] Animals (50 lactating and non-pregnant cows presenting clinical signs of mastitis) were treated intramammarily using a single syringe (10 mL) containing 20 mg of HCA at each time point of a minimum of 1 and a maximum of 4 treatments at intervals of 12 ± 2 hours (each morning or evening milking time). Depending on the results of the clinical examination and clinical status classification, animals were either clinically cured, classified as unsuccessful, or treated until a maximum of 4 treatments were reached.

[0167] Before the treatment trial, milk samples from each animal were collected and tested for the bacteriology of standard pathogenic bacteria. Of the 50 animals, 34 produced milk containing pathogenic bacteria, and no pathogenic bacteria were detected in the milk of the remaining 16 animals, but the possibility that these 16 animals were infected with pathogenic bacteria not tested could not be excluded.

[0168] Results: No adverse effects of the treatment were observed, and tolerance was good.

[0169] Sixteen animals out of 50 were cured after three or four administrations of HCA (32%). Among these animals, 7 out of 34 animals that were bacteriologically positive at D0 (assessed in milk samples collected for bacteriology before treatment initiation) were cured (20.6%), and 9 out of 16 animals that were bacteriologically negative at D0 were cured (56.3%). Of the 16 animals that were bacteriologically negative at D0, 9 animals were cured (56.3%).

[0170] Conclusion: This clinical field study emphasizes that HCA can be used as a primary treatment to treat infectious mastitis, thereby restricting the use of antibiotics and the emergence of antimicrobial resistance as much as possible.

[0171] Example 3 - Solid lipid nanoparticle formulation

[0172] [Table 1]

[0173] Example 4 - In situ gelling system

[0174] [Table 2]

[0175] Example 5 - Micellar solution

[0176] [Table 3]

[0177] Example 6 - Cyclodextrin inclusion complex formulation

[0178] [Table 4]

[0179] Example 7 - Emulsion

[0180] [Table 5]

[0181]

Table 6

[0182]

Table 7

[0183] Example 8: Intramammary formulation

[0184]

Table 8

[0185]

Table 9

[0186] Example 9: Intramammary formulation with antibiotics

[0187]

Table 10

[0188] Example 10: In situ gelling phospholipid system for ear administration

[0189]

Table 11

[0190] Example 11: Gelling formulation for ear administration

[0191]

Table 12

[0192] The above-mentioned formulation resulted in a 7-fold improvement in viscosity compared to Cortavance™.

[0193]

Table 13

[0194] The above-mentioned formulation resulted in a 12-fold improvement in viscosity compared to the Cortavance™ formulation.

[0195] Such a formulation with increased viscosity can extend the residence time of the product in the ear and thus extend the duration of the product's activity. This shows the advantage of being able to reduce the number of administrations.

[0196] The above System 1 and System 2 were tested for in vivo tolerance in dogs. When the formulation was administered once a day into the ears of dogs at a dose of 1 ml for 3 consecutive days, the tolerance was good.

Claims

1. A pharmaceutical composition comprising hydrocortisone, a hydrocortisone monoester, a hydrocortisone diester, or a salt thereof, for use in the treatment and / or prevention of epithelial microbial infection of the mammary gland in non-human mammals by inhibiting the overgrowth or proliferation of pathogenic bacteria, yeasts, and / or fungi, wherein the epithelial microbial infection is mastitis, and the pharmaceutical composition does not contain any antibacterial agent, antifungal agent, antiviral agent, or antimicrobial agent in an effective therapeutic amount for mastitis.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is for topical application or administration.

3. The pharmaceutical composition according to claim 1 or 2, wherein the epithelial microbial infection of the mammary gland is caused by bacteria, fungi, and / or yeasts.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the epithelial microbial infection of the mammary gland is caused by bacteria.

5. The pharmaceutical composition according to claim 4, wherein the bacteria are selected from the group consisting of Gram-positive bacteria and Gram-negative bacteria.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the epithelial microbial infection of the mammary gland is caused by fungi and / or yeasts.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the non-human mammal is a lactating mammal.

8. The amount of hydrocortisone, a hydrocortisone monoester, a hydrocortisone diester, or a salt thereof applied to the mammary gland for the treatment of mastitis is included in the range of 1 mg to 50 mg and is administered at least once a day for 1 to 10 days. The pharmaceutical composition according to any one of claims 1 to 7.

9. The amount of hydrocortisone, a hydrocortisone monoester, a hydrocortisone diester, or a salt thereof applied to the mammary gland for the prevention of mastitis is included in the range of 0.01 mg to 50 mg and is administered at least once a week. The pharmaceutical composition according to any one of claims 1 to 7.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the hydrocortisone monoester or hydrocortisone diester is hydrocortisone aceponate.

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