Compositions containing antibiotic and corticosteroid

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: pharmaceutical composition for treating an infection containing mometasone furoate or a solvate thereof, Orbifloxacin, a fatty acid containing 3 to 18 carbon atoms and having a melting point of no more than about 60°; a method of treating an infection in an animal involving administration thereof, using the above composition for preparing a drug for treating the infection in the animal and a therapeutic kit for treating the infection comprising the above composition. The storage stability of the declared composition at room temperature is shown. The examples of the stable formulations of suspensions, e.g. for treating eye infection are provided.

EFFECT: preparing the pharmaceutical composition for treating the infection.

14 cl, 11 tbl, 3 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to compositions comprising an antibiotic (usually hinolan or naphthyridine), corticosteroid and an organic acid (usually fatty acid). In addition, the present invention relates to methods of treatment that employ these compositions, the use of these compositions for the manufacture of medicines, and therapeutic kits comprising these compositions.

BACKGROUND of the INVENTION

In published patent application U.S. No. 2006-0122159 discusses pharmaceutical compositions suitable for the treatment of infections in animals, particularly ear infections. These compositions typically include a corticosteroid, an antibiotic, and triazole. Among these compounds include, for example, a suspension containing mometasone furoate monohydrate, orbifloxacin and Posaconazole. A particular composition, are given as illustrations in published patent application U.S. No. 2006-0122159 shown in table 1.

Table 1
The composition of example 1 was published patent application
U.S. No. 2006-0122159
Ingredientmg/g
Fine orbifloxacin 10,0
Fine mometasone furoate monohydrate1,0
Fine Posaconazole1,0
Mineral oil USP (40 CST)685,0
Base ointment - plasticized hydrocarbon gel (Plastibase® 50W containing 5% polyethylene and 95% mineral oil)a quantity sufficient to bring the total weight up to 1 g

The inventors have observed an increase in the content of the at least one product destruction mometasone over time, if the above composition was stored at room temperature. In addition, the authors found that the presence orbifloxacin accelerates the formation of this product destruction. Typically, the formation of the product of destruction can be reduced to a minimum in the case of storage of the composition at low temperatures (for example, 5°C). However, there is a need for compositions that can remain stable at higher temperatures (e.g. at room temperature). Such a composition proposed in the present invention.

The INVENTION

Briefly, the present invention mainly relates to compositions (e.g. the measures the suspensions), which include corticosteroid and an antibiotic. These compositions are generally stable at room or higher temperature (for example, at 50°C) for an extended period of time (e.g., 5 months). The advantages of such stable compositions typically include, for example, elimination of expenses and labor costs associated with cooling, eliminating the risk of loss of product due to the failure of refrigeration equipment, as well as the absence of the dangers of decomposed product to the patient after negligent storage without refrigeration.

Thus, the present invention relates especially to pharmaceutical compositions. This composition comprises a corticosteroid, an antibiotic and an organic acid. Among the organic acids are mainly composed of fatty acids, which, in turn, include from about 3 to about 18 carbon atoms and have a melting temperature not exceeding about 60°C. In some embodiments, the implementation of a number of antibiotics are quinolones (in particular, fluoroquinolone, salt fluoroquinolone, MES fluoroquinolone or its salts). In other embodiments, implementation of the antibiotics include naphthyridine (in particular, fornutrition, salt fornutrition, MES of fornutrition or its salt).

Also the present invention relates, among other things, sposobu treating infection in an animal by injecting the animal described above composition.

In addition, the present invention relates especially to the use of the above composition to obtain drugs for the treatment of infection in the animal.

In addition, the present invention relates, among other things, to therapeutic kit. This set includes the above-described composition and the additional component. This additional component can be, for example, a diagnostic tool, the cleaning solution auditory pathways, a device for cleaning auditory pathways, instructions for introducing the composition to the animal or device for introducing the composition to the animal.

Other advantages of the invention of the authors of this application will be clear to the expert in the art after reading the present description.

A DETAILED description of the PREFERRED OPTIONS

For carrying out the INVENTION

The present detailed description of preferred embodiments of the invention is intended for reference only experts in the field of technology with the invention of applicants, with its main ideas and practical application, so that the experts in this field could adapt and apply the invention in its numerous forms, so that these forms could be the best way to meet the requirements of a particular application. This is detailed description and specific examples, although demonstrate preferred embodiments of the present invention, are intended for illustrative purposes only. Therefore, the present invention is not limited to the preferred variant implementation disclosed herein, and may be subjected to various modifications.

I. Composition

The pharmaceutical composition of the present invention, generally includes a corticosteroid, an antibiotic and an organic acid. First of all, you must realize that this list of ingredients is not exhaustive. Therefore, the composition of the present invention may (and usually will) contain additional ingredients. These additional ingredients may include, for example, one or more additional corticosteroids, antibiotics and/or organic acids. In addition, as will be discussed in more detail hereinafter, these additional ingredients may include one or more other active ingredients. And, as will be discussed below, these additional ingredients can (and usually will) include one or more fillers.

The compositions of the present invention mainly can take various forms, in particular non-solid form. For example, these compositions can take the form of suspen the AI, solution, emulsion, ointment, etc. In some embodiments, the implementation of the composition according to the present invention takes the form of a suspension.

A. Corticosteroid

Corticosteroids usually are natural and synthetic analogues of the hormones secreted by the system hypothalamus - anterior pituitary - adrenal cortex (also known as the pituitary gland). It is well known that corticosteroids (particularly corticosteroids are powerful anti-inflammatory agents. In addition, they typically demonstrate antipruritic and vasoconstrictor action. Various corticosteroids are used, for example, topically for the treatment of dermatosis sensitive to their effects, such as psoriasis and atopic dermatitis.

Examples of corticosteroids include compounds shown in table 2 (as well as salts of these compounds and the solvate of the compounds and their salts).

Table 2
Examples of corticosteroids
CorticosteroidThe published examples of trade names of products containing the corticosteroidStructure
beclomethasone dipropionateBeclovent®
QVAR®
Vanceril
betamethasone dipropionateDiprosone
Diprolene®
betamethasone valerateCelestone®M
Bentovate®

budesonideEntocort®EC
Rhinocort Aqua®
ciclesonideAlvesco®
Omnaris®
deflazacortCalcort
dexamethasoneAzium®
Dexacort
Decadron®

fluoqinolona acetonideDerma-Smoothe/FS
Retisert®
fluticasone propionate Flixotide
Flovent®
Flixonase
fluticasone furoateVeramyst®
loteprednol etabonateAlrex®
Lotemax®

methylprednisoloneMedrol®
prednisolonePrelon®
Meti-Derm
prednisoneDeltasone
Orasone®
Meticorten
rofleponide
triamcinolone acetonideNasacort®
Tricortone

In some embodiments, the implementation of the corticosteroid in the composition of the present invention to include ticosteroid, selected from the group consisting of compounds of table 2, their salts and solvate compounds and their salts.

In other embodiments, the implementation of corticosteroid includes mometazon, salt mometasone or MES mometasone or salt mometasone. Mometazon is a synthetic glucocorticosteroid and has the following structure:

In other embodiments, implementation of a number of corticosteroids include ester mometasone, salt of ester mometasone or MES of ester mometasone or salt of ester mometasone.

In some such embodiments ester mometasone comprises mometasone furoate. Mometasone furoate has the following structure:

Chemical name of this compound: of 9.21-dichloro-11(beta),17-dihydroxy-16(alpha)-methylpregna-1,4-diene-3,20-dione 17-(2-furoate). Mometasone furoate is, for example, the active component of cream, lotion and ointment Elocon®and it can be purchased from Schering-Plough Corporation (Kenilworth, NJ).

Corticosteroids may exist in different enantiomeric forms. In addition, they can exist in different crystalline forms. For example, as described above, can be used MES mometasone furoate. In some embodiments, the implementation of the MES includes, for example, the Hydra is so The hydrate may represent, for example, a monohydrate.

In some embodiments, the implementation of corticosteroid includes mometasone, mometasone furoate or MES mometasone or mometasone furoate (for example, a monohydrate of mometasone furoate).

Typically, the total amount of corticosteroid in the composition of the present invention sufficient to corticosteroid was therapeutically effective in the dosage, which enter the composition. In some embodiments, the overall concentration of the corticosteroid (e.g., mometasone, mometasone furoate and/or MES mometasone or mometasone furoate) in the composition is at least about 0.01 percent by weight). In some such embodiments, for example, the total concentration is from about 0.01 to about 1% (by weight).

B. Antibiotic

In some embodiments, implementation of the present invention in a number of antibiotics are quinolones. As a rule, quinolones include a fluoroquinolone, salt fluoroquinolone or MES fluoroquinolone or its salts. Fluoroquinolone antibiotics include, for example, 6-ftorhinolon-4(1H)-ones salt 6-ftorhinolon-4(1H)-ones and a solvate of 6-ftorhinolon-4(1H)-ones and their salts. Examples of 6-ftorhinolon-4(1H)-ones include the compounds shown in table 3.

Table 3
Examples of 6-ftorhinolon-4(1H)-ones
6-ftorhinolon-4(1H)-heThe published examples of trade names of products containing this 6-ftorhinolon-4(1H)-heStructure
amifloxacin
balofloxacin
ciprofloxacinCipro®, Ciprobay, and Ciproxin

clinafloxacin
danofloxacinAdvocin and Advocid
difloxacinDicural®and Vetequinon
enrofloxacinBaytril®
Megalone

flumequinFlubactin
garenoxacin
GatifloxacinTequin®and Zymar®
grepafloxacinRaxar
ibafloxacin
levofloxacinLevaquin®, Gatigol, Tavanic, Lebact, Levox and Cravit

lomefloxacinMaxaquin®
marbofloxacinMarbocyl®and Zenequin
moxifloxacinAvelox®and Vigamox®
nadifloxacinAcuatin, Nadoxia and Nadixa
norfloxacinNoroxin®, Lexinor, Quinabic and Janacin
ofloxacinFloxin®, Oxaldin and Tarivid

orbifloxacinOrbax®and Victas
pazufloxacin
pefloxacin
pradofloxacin
prulifloxacin

rufloxacinUroflox
sarafloxacinFloxasol, Saraflox, Sarafin
sitafloxacin
sparfloxacinZagam
temafloxacinOmniflox

Other examples of 6-ftorhinolon-4(1H)-ones include the compounds shown in table 4.

Table 4
Additional examples of 6-ftorhinolon-4(1H)-ones

See Chu et al., “Minireview: Structure-Activity Relationships of the Fluoroquinolones”, Antimicrobial Agents and Chemotherapy, 33(2), pp.131-135 (Feb.1989).

In some embodiments, implementation, antibiotics include the Academy of Sciences of abiotic, selected from the group consisting of 6-ftorhinolon-4(1H)-ones are shown in table 3, these salts 6-ftorhinolon-4(1H)-ones, as well as the solvate of these 6-ftorhinolon-4(1H)-ones and their salts.

In some embodiments, the implementation of the antibiotics include an antibiotic selected from the group consisting of amifloxacin, balofloxacin, ciprofloxacin, clinafloxacin, fleroxacin, garenoxacin, Gatifloxacin, grepafloxacin, lomefloxacin, moxifloxacin, norfloxacin, pefloksatsina, pradofloxacin, sitafloxacin, sparfloxacin and temafloxacin; salts of these 6-ftorhinolon-4(1H)-ones; and the solvate of these 6-ftorhinolon-4(1H)-ones and their salts.

In some embodiments, the implementation of the antibiotics include an antibiotic selected from the group consisting of danofloxacin, difloxacin, enrofloxacin and sarafloxacin; salts of these 6-ftorhinolon-4(1H)-ones; and the solvate of these 6-ftorhinolon-4(1H)-ones and their salts.

In some embodiments, the implementation of the antibiotics include an antibiotic selected from the group consisting of 6-ftorhinolon-4(1H)-ones are shown in table 4, these salts 6-ftorhinolon-4(1H)-ones, as well as the solvate of these 6-ftorhinolon-4(1H)-ones and their salts.

In some embodiments, the implementation of the antibiotics include orbifloxacin, salt orbifloxacin or MES orbifloxacin or salt orbifloxacin. Orbifloxacin presented yet a known effective antibacterial agent with broad-spectrum, safe and effective for the treatment of various diseases, in particular dogs and cats.

In some embodiments, the implementation of the antibiotics include 6-ftorhinolon-4(1H)-he, which contains three cycles, condensed with each other. In some of these embodiments, for example, in the number of antibiotic is antibiotic selected from the group consisting of flumequine, ibafloxacin, levofloxacin, nadifloxacin, ofloxacin, pazufloxacin, prulifloxacin and rufloxacin; salts of these 6-ftorhinolon-4(1H)-ones; and the solvate of these 6-ftorhinolon-4(1H)-ones and their salts. In other embodiments, implementation of the antibiotic includes marbofloxacin, salt marbofloxacin or MES of marbofloxacin or salt of marbofloxacin.

In other embodiments, implementation of a number of antibiotics are naphthyridinone. As a rule, naphthyridinone include fornutrition, salt fornutrition or solvate fornutrition or their salts. Formattazione antibiotics include, for example, 6-fluoro-1,8-naphthiridine-4(1H)-ones, salts of 6-fluoro-1,8-naphthiridine-4(1H)-ones and a solvate of 6-fluoro-1,8-naphthiridine-4(1H) - ones and their salts. Examples of 6-fluoro-1,8-naphthiridine-4(1H)-ones include the compounds shown in table 5.

Table 5
Examples of 6-fluoro-1,8-naphthiridine-4(1H)-ones
6-fluoro-1,8-naphthiridine-4(1H)-heThe published examples of trade names of products containing this 6-fluoro-1,8-naphthiridine-4(1H)-heStructure
enoxacinPenetrex and Enroxil
gemifloxacinFactive
tosufloxacin
trovafloxacinTrovan

In some embodiments, the implementation in the number of antibiotic is antibiotic selected from the group consisting of 6-fluoro-1,8-naphthiridine-4(1H)-ones are shown in table 5, these salts 6-fluoro-1,8-naphthiridine-4(1H)-ones and the solvate of these 6-fluoro-1,8-naphthiridine-4(1H)-ones and their salts.

In some embodiments, the implementation in the number of antibiotic is antibiotic selected from the group consisting of enoxacin, gemifloxacin, tosufloxacin and trovafloxacin; salts of these 6-fluoro-1,8-naphthiridine-4(1H)-ones; and the solvate of these 6-fluoro-1,8-naphthiridine-4(1H)-ones and their salts.

the other examples of 6-fluoro-1,8-naphthiridine-4(1H)-ones include:

See Chu et al., Antimicrobial Agents and Chemotherapy, on page 132. In some embodiments, the implementation of the antibiotic includes this compound, its salt or MES of this compound or its salts.

Typically, the concentration of antibiotic in the composition of the present invention sufficient to ensure that the antibiotic was therapeutically effective in the dosage, which enter the composition. In some embodiments, the implementation of the concentration of the antibiotic in the composition (i.e. the total concentration of all antibiotics in the composition is at least about 0.01 percent by weight). In some embodiments, the implementation of this concentration is from about 0.01 to about 30% (by weight), from about 0.1 to about 10% by weight or from about 0.5 to about 5% (by weight).

C. an Organic acid

Organic acids generally include fatty acids. These fatty acids preferably contain at least about 3 carbon atoms. In some embodiments, the implementation of the fatty acid includes, for example, from about 3 to about 18 carbon atoms. In other embodiments, implementation of the fatty acid contains from about 4 to about 18 carbon atoms. In another group of embodiments, this fatty acid contains from about 7 to about 18 carbon atoms.

The fatty acid can is to be natural fatty acid or synthetic acid. In addition, it may be saturated or unsaturated. In some embodiments, the implementation of the fatty acid includes an unbranched aliphatic chain which contains at least about 4 carbon atoms and is saturated or unsaturated. Preferably, this fatty acid has a melting point of more than about 60°C.

This fatty acid is preferably dissolves or mixes with the carrier present in the composition at the temperature at which the composition is applied. In addition, the fatty acid preferably dissolves or mixes with the carrier present in the composition at the temperature at which the storage of the composition. For example, in some embodiments, the implementation in which the composition is a suspension comprising a carrier on the basis of mineral oil, fatty acid able to be mixed with mineral oil at room temperature (i.e. from about 20 to about 25°C). In such scenarios, the implementation of the fatty acid is also preferably able to be mixed with mineral oil at lower or higher temperatures at which the composition can be applied or stored.

In some embodiments, the implementation of a number of fatty acids include propionic acid (which contains 3 carbon atoms). In others the other variants of implementation among the fatty acids include myristic acid (which contains 14 carbon atoms). In other embodiments, implementation of a number of fatty acids include lauric acid (which contains 12 carbon atoms). In another group of embodiments in the number of fatty acids include oleic acid (which contains 18 carbon atoms). It should be understood that the composition of the present invention may include more than one fatty acid. For example, in some embodiments, the implementation of the composition includes as oleic, and lauric acid.

Typically, the concentration of fatty acid in the composition is sufficient to effectively reduce (and preferably a partial or complete suppression of the education breakdown product of at least one corticosteroid (e.g., mometasone or mometasone furoate) for at least 1 month, at least 2 months, at least 5 months when stored in plastic bottles made of high density polyethylene (“HDPE”), c caps, made of low density polyethylene (“LDPE”) at a temperature of not less than 15°C, not less than 20°C, not less than 25°C not less than 40°C or over 50°C. In some embodiments, the implementation of the concentration of fatty acid is at least about 0.01 percent by weight). In some such embodiments, for example, the concentration is from about 0.01 to about 5.0 percent (by weight). In other embodiments, implementation of oncentrate is from about 0.1 to about 2.0 percent (by weight). In some embodiments, the implementation of the composition according to the present invention includes oleic acid, and the concentration of oleic acid in the composition is from about 0.1 to about 2.0 percent (by weight). In other embodiments, the implementation of the composition comprises lauric acid, and the concentration of lauric acid is from about 0.1 to about 1.0% (by weight).

D. Additional ingredients included in the composition

As noted above, the composition according to the present invention can (and usually will) contain other ingredients. These ingredients may constitute, for example, one or more other active ingredients and/or one or more fillers.

i. Other active ingredients

It is assumed that the composition of the present invention can include a number of other active ingredients, in addition to corticosteroid and antibiotic. Any of these active ingredients preferably are appropriate for those situations in which use of the composition according to the present invention, and do not have a significant negative impact on the activity of corticosteroids and antibiotics.

In some embodiments, the implementation of the composition according to the present invention includes a fungicide. Some of these options Khujand who exercise in the number of antifungal agents include, for example, imidazoles, salts of imidazoles or solvate of imidazoles or their salts. The imidazoles include, for example, compounds shown in table 6.

Table 6
Examples of antifungal imidazoles
The imidazoleThe published examples of trade names of products containing the imidazoleStructure
clotrimazoleCanesten®, MyCelex®, Lotrimin®, Lotrimin AF®, Agisten, Clotrimaderm and Clotrimazole-Teva
econazoleSpectazole®

isoconazoleTravogen
ketoconazoleNizoral®
miconazoleMonistat®
neticonazole Atolant
oxiconazoleOxistat®

sertaconazoleErtaczo®
sulkonazolExelderm®
tioconazoleVagistat®

In some embodiments, the implementation of antifungal agents include antifungal agent selected from the group consisting of imidazoles, are shown in table 6, these salts of imidazoles and the solvate of these imidazoles and their salts.

In other embodiments, implementation of a number of antifungal agents include triazoles, salts of triazoles or solvate triazoles or their salts. Triazoles include, for example, compounds shown in table 7.

Table 7
Examples of antifungal triazoles
TriazoleExamples op slikovnih trade names of products, contains the triazoleStructure
fluconazoleDiflucan®and
Trican
ItraconazoleSporanox®
PosaconazoleNoxafil®
saperconazole

terconazoleTerazol®
voriconazoleVfend®

In some embodiments, the implementation of antifungal agents include antifungal agents selected from the group consisting of triazoles, shown in table 7, the salts of these triazoles and the solvate of these triazoles and their salts.

In some embodiments, the implementation of a number of antifungal agents include Posaconazole, salt patacones the La or MES of Posaconazole or its salts. In some such embodiments antibiotics include, for example, Posaconazole. It is known that Posaconazole has antifungal activity against wide range of fungi, including Aspergillis, Candida, Cryptoccoccus, Fusarium and other opportunistic fungi. Discussion related to Posaconazole can be found, for example, in U.S. patents 5661151; 5834472 and 5846971.

In some embodiments, the implementation of a number of antifungal agents include nystatin, salt nystatin or MES nystatin or salt of nystatin. Nystatin has the following structure:

Typically, the concentration of the antifungal agent in the composition is sufficient to this fungicide was therapeutically effective in the dosage, which introduces the song. If the track has more than one antifungal agents, the total concentration of all antifungal agents is sufficient for the combination of antifungal agents was therapeutically effective in the dosage, which enter the composition. In some embodiments, the implementation of the concentration of the antifungal agent in the composition (i.e. the total concentration of all antifungal agents in the composition is at least about 0.01 percent by weight). In some vari is ntah the implementation of the concentration is, for example, from approximately 0.01 to approximately 1.0% (by weight).

In some embodiments, the implementation of the composition according to the present invention includes one or more antibiotics (in addition to the quinolone or naphthyridinone antibiotic (antibiotics)). These antibiotics may include, for example, the following antibiotics (as well as their salts, solvate and solvate their salts).

A. Chloramphenicol, thiamphenicol and fluorinated analogs of chloramphenicol and thiamphenicol (for example, florfenicol or D-(threo)-1-n-phenyl methylsulphonyl-2-deflorated-3-fluoro-1-propanol).

B. Tetracyclines, such as chlortetracycline and oxytetracycline.

C. Amoxicillin, ampicillin, ampicillin trihydrate, ampicillin sodium, apalcillin, aspoxicillin, azlotillin, bacampicillin, carbenicillin, carbenicillin sodium, carfecillin, carindacillin, ciclacillin, cloxacillin sodium, cloxacillin the benzathine, dicloxacillin, dicloxacillin sodium, Flucloxacillin, hetacillin, inanition, mecillinam, metampicillin, methicillin, mezlocillin, nafcillin, nafcillin sodium, oxacillin, Penicillium acid, penicillin G, penicillin G benzathine, penicillin G potassium, penicillin G sodium, penicillin V, phenethicillin, phenethicillin potassium, piperacillin, piperacillin sodium, pivampicillin, sulbenicillin, sultamicillin, talampicillin the tikarcillin, cefaclor, cephalo-Smoking, cephalo-Smoking monohydrate, cefamandole, cefamandole lithium, cefamandole nonfat, cefamandole sodium, Cefazolin, cefotetan, Cefazolin, Cefazolin sodium, aplidin, cefdinir, cefepime, cefetamet, cefixime, celepram, cefmenoxime, cefmetazole sodium, cefodizime, cefonicid, cefoperazone, cefoperazone sodium, ceforanide, cefoselis, Cefotaxime, Cefotaxime sodium, cefotiam, cefozopran, cefpimizole, cefpimizole sodium, cefpiramide, cefpirome, cefpodoxime, cefprozil, rethinam, cefroxadine, cefsulodin, cefsulodin sodium hydrate, ceftazidime, ceftazidime pentahydrate, ceftezole, ceftibuten, septilin, ceftizoxime, Ceftriaxone disodium salt of Ceftriaxone, Ceftriaxone sodium, cefuroxime, carusona, cefacetrile, cephalexin, tsefaloridin, cephalosporin C, cephalothin, cephalothin sodium, cephapirin, cephapirin sodium, cefradine, loracarbef, cefbuperazone, cefoxitin, cefoxitin sodium, cefminox, cefmetazole, cefotetan, by themselves or in combination with inhibitors of β-lactamase, for example, clavulanic acid, potassium clavulanate, sulbactam japaneselanguage acid, 6-brompheniramine acid, olivanova acid and tazobactam.

D. Macrolide antibiotics, such as azithromycin, brefeldin, clarithromycin, erythromycin, erythromycin estolate, erythromycin ethylsuccinate, erythromycin stearate, josemi is in, kitasamycin, tulathromycin and tilmicosin.

In some embodiments, the implementation of the composition according to the present invention includes one or more anti-inflammatory ingredients, in addition to corticosteroid(s). These anti-inflammatory ingredients may include, for example, one or more non-steroidal anti-inflammatory drugs (“NSAIDs”). NSAIDs include, for example, salicylates, arylalkenes acid, 2-arylpropionic acid (or progeny"), N-irelandlavalife acid, derivatives of pyrazolidine, oxicam, COX-2 inhibitors, sulfonanilide and licofelone. In some embodiments, the implementation of NSAIDs include aspirin, ibuprofen, or naproxen. Anti-inflammatory ingredients can include, for example, antihistamines. In a number of antihistamines include, for example, agonists of receptor H1, agonists of receptor H2, agonists of receptor H3, agonists of receptor H4the stabilizers of mastocytes and vitamin C.

ii. Fillers

Suitable fillers compositions of the present invention include, for example, liquid carriers, means for improving the viscosity, surface-active substances (surfactants), preservatives, stabilizers, resins, fillers, binders, lubricants, tools to improve slip, dezintegriruetsja tools, sorest oriali, as well as dyes or pigments, pharmaceutical grade.

In some embodiments, the implementation of the compositions of the present invention are in the form of suspensions. These compositions typically include a liquid base (or carrier), such as water, hydrocarbons, animal fats, vegetable oils, mineral oil or synthetic oil. Also, the number of speakers can be included physiological saline solution or glycols (e.g. ethylene glycol, propylene glycol or polypropylenglycol). In some embodiments, the implementation of the carrier liquid comprises mineral oil.

Compositions of the present invention, typically include one or more means for increasing the viscosity (or "thickeners"). Concentration means for increasing the viscosity of the composition is usually not less than about 0.1% (by weight). For example, in some embodiments, the implementation of this concentration is from about 0.1 to about 15% (by weight). In some such embodiments, the concentration is, for example, from approximately 0.1 to approximately 5%. In other embodiments, the implementation of this concentration is from about 2 to about 10% by weight or from about 4 to about 8% (by weight). In some embodiments, the implementation of a means for increasing the viscosity comprises polyethylene. Polyethylene is made the focus of an inert hydrocarbon with high molecular weight and high melting point. It can be used as a thickener to increase the viscosity, for example mineral oil base. In some embodiments, the implementation of the polyethylene is introduced into the composition in the form of Plastibase®50W (available from Bristol-Myers Squibb). Plastibase®50W contains 5% polyethylene 95% mineral oil. In addition (or alternatively)may be used and other means proposed to increase viscosity. In some embodiments, the implement including means for increasing the viscosity include, for example, methylcellulose, carboxymethylcellulose sodium, hydroxypropyl-methylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, gum Arabic, guar gum, xanthan gum or tragakant. In other embodiments, the implementation of a means for increasing the viscosity includes methylcellulose, carbomer, xanthan gum, guar gum, povidone, sodium carboxymethylcellulose or magnesium silicate of aluminum. In other embodiments, the implementation of means to improve the viscosity includes carboxyvinyl polymers; carrageenan; hydroxyethyl cellulose; laponite; and water-soluble salts and ethers of cellulose, for example, sodium carboxymethylcellulose and sodium carboxymethyl hydroxyethyl cellulose. In another group of embodiments, the means for improving the viscosity may present the identification of a natural gum, such as gum karaya, xanthan gum, gum Arabic or gum tragakant. In another group of embodiments the means for increasing the viscosity include colloidal magnesium silicate aluminum or finely ground silica, which can be used as an integral part of the thickening agent to further improve the texture. In other embodiments, the implementation of tools to improve the viscosity include homopolymers of acrylic acid, cross stitched alkilany ether of pentaerythritol or alkilany ether of sucrose, or carbomer. Carbomer available from B.F. Goodrich, as series products Carbopol®. In some embodiments, the implementation of the carbomer is a Carbopol®934, 940, 941, 956, or their mixture. Copolymers lactide and glycolide monomers can be used for delivery of active substances, in particular, if the copolymer has a molecular weight of from about 1000 to about 120000 (Brednikova molecular weight). These polymers are described in U.S. patents 5198220; 5242910 and 4443430.

Suitable surfactants include, for example, esters of polyoxyethylenesorbitan and fatty acids; monoalkyl ethers of polyoxyethylene; complex monetary sucrose; simple and complex esters of lanolin; salts of alkyl sulphates; and sodium, potassium and ammonium salts of fatty acids.

Suitable conse the guys include for example, phenol; alkalemia esters by parahydroxybenzoic acid (for example, methyl p-hydroxybenzoate (or "methylparaben") and propyl p-hydroxybenzoate (or "propylparaben")); sorbic acid; o-phenylphenol benzoic acid and its salts; chlorobutanol; benzyl alcohol; thimerosal; the acetate and nitrate of finalstate; nitromersol; benzalkonium chloride; and cetylpyridinium chloride. Particularly suitable preservative is sorbic acid. If the composition of the present invention includes a preservative, the concentration of preservative in the composition typically does not exceed about 5% (by weight). In some embodiments, the implementation of the concentration of the preservative is, for example, from about 0.01 to about 5% (by weight).

Suitable stabilizers include, for example, hepatoblastoma agents, such as edetate sodium. In addition, suitable stabilizers include, for example, antioxidants, such as butylamine hydroxyanisol and monothioglycerol sodium.

Suitable binders include, for example, gelatin, gum Arabic and carboxymethylcellulose.

Suitable lubricants include, for example, magnesium stearate, stearic acid and talc.

Suitable dezintegriruetsja tools include, for example, corn starch and alginic acid.

In the composition according to the present izaberete the Oia if desired, you can add other inert ingredients. It is assumed that these ingredients can include, for example, lactose, mannitol, sorbitol, calcium carbonate, sodium carbonate, tizamidine calcium phosphate, disubstituted calcium phosphate, sodium phosphate, kaolin, compressible sugar, starch, calcium sulfate, dextro or microcrystalline cellulose, colloidal silicon dioxide, starch, starch glycolate, sodium, crosspovidone, crosscarmellose sodium, microcrystalline cellulose, tragakant, hydroxypropylcellulose, Pregelatinised starch, povidone, ethylcellulose, hydroxypropylcellulose, hypromellose and methylcellulose.

E. Salt

As noted above, many compounds present in the compositions of the present invention, may include in its composition in the form of salts. For example, the form of salts can have many of the above antibiotics, corticosteroids and antifungal agents. Salt can have an advantage due to one or more of its physical properties, such as pharmaceutical stability at different values of temperature and humidity; crystalline properties; and/or a desirable solubility in water, oil or other solvent. Salts of acids and bases, and most often can be obtained, for example, mixing the connection, respectively, with an acid or a base and applying a variety of techniques known is in the technique. As a rule, if the connection of the present invention is introduced in vivo (i.e. animals) to achieve a therapeutic result, all salts in the composition are preferably pharmaceutically acceptable.

Acid additive salts, as a rule, can be obtained by the interaction of the compounds in free base form with an approximately stoichiometric amount of an inorganic or organic acid. Examples of common inorganic acids suitable for receiving pharmaceutically acceptable salts include hydrochloric, Hydrobromic, yodiewonderdog, nitric, carbonic, sulfuric and phosphoric acid. Examples of common organic acids suitable for receiving pharmaceutically acceptable salts, mainly includes, for example, aliphatic, cycloaliphatic, aromatic, analiticheskie, heterocyclic, carboxylic and organic sulfonic acids. Specific examples of suitable common organic acids include cholic, sorbic, lauric, acetic, triperoxonane, formic, propionic, succinic, glycolic, gluconic, digluconate, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, Pirovano, aspartic, glutamic acid, arylcarbamoyl sour is you (for example, benzoic acid), Anthranilic acid, methanesulfonate, stearic, salicylic, p-hydroxybenzoic, phenylacetic, almond, ambalavao (pambou), alkylsulfonyl (for example, econsultancy), arylsulfonyl (for example, benzosulfimide), Pantothenic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexanesulfonyl, β-hydroxybutiric, galactarate, galacturonic, adipic, alginic, oil, camphor, camphorsulfonate, cyclopentanepropionate, dodecylthio, glucoheptonate, glycerophosphate, heptane, hexane, nicotine, 2-naphthalenesulfonate, oxalic, palmitic, pectin, 3-phenylpropionate, picric, Pavlinov, ticinobuy, toluensulfonate and undecanoyl acid.

Basically additive salts, as a rule, can be obtained by the interaction of the compounds in the form of the free acid with an approximately stoichiometric amount of an inorganic or organic base. Examples of primary additive salts may include, for example, metal salts and salts of organic bases. Metal salts include, for example, salts of alkali metals (group Ia), salts of alkaline earth metals (group IIa) and other physiologically acceptable metal salts. Such salts can be obtained from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. For example, a connection in the form with the rim of the acid can be mixed with sodium hydroxide to obtain such basic additive salt. Salts of organic bases can be obtained from amines, such as trimethylamine, diethylamine, N,N'-dibenziletilendiaminom, chloroprocaine, ethanolamine, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine. Basic nitrogen-containing groups can be quaternity such reagents as C1-C6alkylhalogenide (for example, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), diallylsulfide (e.g., dimethyl, diethyl, dibutil and diamyl sulfates, halides with long chains (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), arylalkylamine (for example, benzyl and phenethyl bromides), and other compounds.

II. Obtaining compositions of the present invention

The compositions of the present invention often can be obtained, for example, using techniques well known in the art. As a rule, any carrier (s)that you want to use in the song (or part of such holder (s)), add in the vessel for mixing, then add the remaining excipients, active substances and fatty acid. As a rule, the order of adding the components in the vessel is not critical.

III. Methods of treatment using the compositions of the present invention

The compositions of the present invention in annonomous be used for treatment of infections in animals. It is envisaged that the composition may be used to treat a variety of animals, particularly mammals. These mammals include, for example, of people. Other mammals include, for example, farm animals and livestock (such as pigs, cows, sheep, goats etc), laboratory mammals (e.g. mice, rats, gerbils etc), domestic mammals (e.g. dogs, cats, horses etc), as well as wild mammals and inhabitants of zoos (Buffalo, deer etc). In some embodiments, the implementation of the compositions of the present invention is applicable for the treatment of canids (e.g., dogs). In other embodiments, implementation of the composition is applicable for the treatment of feline (e.g., domestic cats). It is envisaged that the compositions are suitable for the treatment of animals that are not mammals, for example, birds (e.g., turkeys, chickens etc) and fish (e.g. salmon, trout, ornamental carp and so on).

Compositions of the present invention, generally administered in a dosage that provides a therapeutically effective amount of the composition (and in particular, active ingredients) in the site of infection. For anti-inflammatory drugs (eg, corticosteroids such as mometasone furoate monohydrate) "therapeutically effective amount" is the Wallpaper so much, which is enough for relief, suppression or elimination of the target inflammation or symptoms of pruritus or vasoconstrictor action in the target tissue. For anti-infective means (e.g., antibiotic or antifungal agents) "therapeutically effective amount"represents a number, which is enough for relief, suppression or destruction of the target pathogenic infection. In some embodiments, the implementation introduce a sufficient amount of the composition to achieve a concentration of the antibiotic, which is equivalent to at least level MIC90(minimum inhibitory concentration, i.e. the concentration that inhibits growth in 90% of the target pathogen) of the antibiotic to the target pathogen. If the composition of the present invention includes a number of active ingredients, providing a combined impact on the desired target tissue or pathogen, the amount of each ingredient, which is "therapeutically effective amount" represents a number, which when combined with other active ingredients, causes the desired effect on the target tissue or pathogen.

It is envisaged that the composition of the present invention can be entered rectally, vaginally, by inhalation (e.g., the form of aerosol), transdermal, for example by using a transdermal patch, or parenteral (for example, using subcutaneous injections, intravenous injections, intramuscular injections, and so on). It is also envisaged that the compositions can be administered orally. For example, the composition can be added to food intended animal recipient, either directly or as part of a pre-prepared mixture; or in separate dosage forms.

In some embodiments, the implementation of the composition of the present invention is used to treat ear infections. In some such embodiments ear infection has dogs. In other embodiments, the implementation of an ear infection has a cat. In the case of the use for the treatment of ear infections, the composition of the present invention, generally injected into the affected ear (ears) of the animal. Although preferably the introduction of a single daily dose, provided that the composition may be introduced in the form of multiple doses during the day. In many cases, for the treatment of infection a single dose, especially if the composition includes, for example, mometasone furoate monohydrate, orbifloxacin and Posaconazole. However, in other situations it may be desirable (or necessary) to enter the second dose, for example, 48 hours after the first dose for the full islice the Oia animal (or guarantee, the cure is complete). In other cases, the composition can be administered daily for up to 7 days (or more).

Determining the proper dosage, usually within the competence of the specialist in this field. The exact dosage will depend on various factors. These factors may include, for example, the type (e.g., species or breed), age, size, sex, diet, activity and status of the intended recipient; pharmacological considerations such as the activity, efficacy, pharmacokinetic and Toxicological profile of a particular input of the composition; and whether the input composition is part of a combination therapy in conjunction with one or more active ingredients. For example, in some embodiments, the implementation, where the composition of the present invention is used to treat ear infections in dogs, the dosage is from about 1 to about 10 drops. In other variants of implementation, in which the composition of the present invention is used to treat ear infections in dogs, the dosage is from about 25 to about 500 mg. In some of these embodiments, the dosage is, for example, from about 25 to about 250 mg.

IV. Therapeutic kits

The present invention is also directed to kits that are coming up is, for example, for use in implementing the above described methods of treatment. Typically, such a kit will comprise a therapeutically effective amount of a composition of the present invention, as well as the additional component (s). This additional component (s) can represent, for example, one or more items from the following list: a diagnostic tool, instructions introduction the composition or device for the introduction of the composition (for example, a syringe or soft bottle). In some embodiments, the implement for the treatment of ear diseases, the kit may include a composition of the present invention, in combination, for example, with a device for cleaning the ears and/or solution for cleaning the ears. Examples of suitable devices for ear cleaning include cleaning pieces of matter (for example, dry cloth or pads soaked in alcohol or cleaning ears with enhanced efficiency (for example, the system Auriflush®sold by Schering-Plough Corp.). Examples of suitable solvents include ear cleaning solution Virbac Animal Health's Cerulytic®Solution (containing propylene glycol dicaprylate/dicaprate, benzyl alcohol, flavor and butylsilane hydroxytoluene), the solution Pfizeer Inc.,s Oti-Clens®Solution (including derivatives of propylene glycol and malic acid, benzoic acid, Salic the gross acid), the solution Vet Solutions Ear Cleaning Solution (containing propylene glycol, aloe Vera gel, SD (special treatment) alcohol 40-2, lactic acid, glycerin, dioctyl sodium sulfosuccinate, salicylic acid, flavor, benzoic acid and benzyl alcohol) and a solution of IVX Animal Health's OtiRinse®Solution (including dictinary sulfosuccinate, salicylic acid, lactic acid, benzoic acid, and aloe Vera).

EXAMPLES

The following examples are merely illustrative and are in no way limit the rest of the contents of this application.

Example 1. Stabilization of the suspension with the use of oleic acid or lauric acid

The purpose of this experiment was to demonstrate the fact that oleic or lauric acid may reduce the formation of at least one product of the destruction of mometasone suspension, including mometasone furoate monohydrate in combination with orbifloxacin. In this experiment, the suspension had the composition shown in table 8:

Table 8
Suspension, comprising a derivative of mometasone and
ftorhinolonovy antibiotic
ComponentConcentration (mg/g)
Fine orbifloxacin 10,0
Fine mometasone furoate monohydrate1,0
Fine Posaconazole1,0
Mineral oil685,0
Base ointment - plasticized hydrocarbon gel (Plastibase® 50W)a quantity sufficient to bring the total weight up to 1 year (after adding the appropriate quantity of oleic or lauric acid)

This suspension was divided into several samples of smaller mass. Each sample was mixed with oleic acid to achieve a certain concentration of oleic acid (equal 0,1%, 0,2%, 0,5%, 1,0% or 2.0%), with lauric acid to achieve a certain concentration of lauric acid with 0.1%, 0.2%and 0.5% or 1.0%) or not mixed with oleic or lauric acids (in the sample). Samples were Packed in 7.5 g of HDPE bottles with lids from LDPE and placed in storage to study the stability in the vertical position. To avoid any contamination from the label, none of the packages was not a commercial label. Each bottle has been stored at one of the following combinations of environmental conditions: (a) temperature of 40°C and relative in agnosti 75% or (b) 50°C under natural moisture.

The specimens were examined using HPLC at the beginning of the experiment and then at intervals of 1 month, 2 months and 5 months, to determine the concentration of decomposition products of mometasone. Observed concentrations of decomposition products mometasone shown in table 9.

Table 9
The observed concentration decay product mometasone over time under different conditions and different concentrations of oleic acid and lauric acid
It is time to relax. acidElapsed time (in months) and conditions
ex.112255
40°C
75% Rel. owner.
50°C
natures. wet.
40°C
75% Rel. owner.
50°C
natures. wet.
40°C
75% Rel. owner.
50°C
natures. wet.
control (none)ND0,35% 0,26%0,46%0,30%0,60%0,25%
0,1%
olein.
the
NDNDNDNDNDNDND
0,2%
olein.
the
NDNDNDNDNDNDND
0,5%
olein.
the
NDNDNDNDNDNDND

1,0%
olein.
the
NDNDNDNDNDNDND
2,0%
olein.
the
NDND NDNDNDNDND
0,1%
the Laurin.
the
NDNDNDNDNDNDND
0,2%
the Laurin.
the
NDNDNDNDNDNDND
0,5%
the Laurin.
the
NDNDNDNDNDNDND
1,0%
the Laurin.
the
NDNDNDNDNDNDND

In table 9 the abbreviation "ND" means "not detected". As you can see from the above data, the presence of both acids at all investigated concentrations inhibited the contraction in the Finance decay product mometasone for 5 months at 40°C and a relative humidity of 75%, and at 50°C and natural relative humidity. The proposal also did not observe any changes in the physical properties of the samples and did not detect any new degradation products by adding oleic or lauric acid.

Example 2. Illustrative ear composition containing oleic acid

The following table 10 shows the composition of the present invention, including oleic acid.

Table 10
Illustrative ear, comprising oleic acid
ComponentConcentration (mg/g)
Fine orbifloxacin10,0
Fine mometasone furoate monohydrate1,0
Fine Posaconazole1,0
Mineral oil685,0
Oleic acid20
Base ointment - plasticized hydrocarbon gel (Plastibase® 50W)a quantity sufficient to bring the total weight up to 1 g

Example 3. Illustrative ear composition containing oleic acid

The following table 11 shows the composition of the present invention, including lauric acid.

Table 11
Illustrative ear, comprising lauric acid
ComponentConcentration (mg/g)
Fine orbifloxacin10,0
Fine mometasone furoate monohydrate1,0
Fine Posaconazole1,0
Mineral oil685,0
Lauric acid20
Base ointment - plasticized hydrocarbon gel (Plastibase® 50W)a quantity sufficient to bring the total weight up to 1 g

The words "include," "includes" and "including" should be understood in the including, but not exclusive sense. It is assumed that the interpretation of these words is the same as the interpretation given in the patent law of the military States.

The term "pharmaceutically acceptable" is used as an adjective to denote that it defines a noun suitable for use in a pharmaceutical product. When this term is applied, for example, to describe salt or filler, he characterizes this salt filler or the like compatible with other ingredients of the composition and are not detrimental to the intended animal to the recipient in such a way that a negative action (action) exceeded beneficial effects (actions) of the said salt or filler.

All references cited in this patent application included in the application with references.

The above detailed description of preferred embodiments is intended only to explore other specialists in this field with the present invention, its main ideas, and its practical application, so that other experts in this field could adapt and apply the invention in its numerous forms, so it was best suited to the requirements of the application. Therefore, the present invention is not limited to the above implementation options and can be modified in various ways.

1. Pharmaceutical composition for treatment of infections where the specified composition includes: mometasone furoate or MES, orbifloxacin, fatty acid containing from about 3 to about 18 carbon atoms and having a melting temperature not exceeding about 60°C.

2. The composition according to claim 1, where the composition has the form of a suspension.

3. The composition according to claim 1, comprising monohydrate mometasone furoate.

4. The composition according to claim 1, where the composition additionally contains an antifungal agent.

5. The composition according to claim 4, where the antifungal agent include triazole, salt of a triazole or MES triazole or its salts.

6. The composition according to claim 5, where the triazole include triazole selected from the group consisting of fluconazole, Itraconazole, saperconazole, terconazole and voriconazole.

7. The composition according to claim 5, where the triazole include Posaconazole.

8. The composition according to claim 1 where the fatty acid include lauric acid.

9. The composition according to claim 1 where the fatty acid comprises oleic acid.

10. The composition according to claim 1, where the composition additionally contains mineral oil.

11. A method of treating infection in an animal, where the method includes the introduction of the animal the composition defined in claim 1.

12. The method according to claim 11, where the infection include ear infection in dogs.

13. The use of a composition according to claim 1 for obtaining a medicinal product for the treatment of infection in the animal.

14. therapeutic kit for the treatment of infections, where the set includes:
the composition p is any of claims 1 to 10, and
an additional component selected from the group consisting of:
diagnostic tools,
solution for cleaning ears,
device for cleaning the ears,
instructions for introducing the composition to the animal, and
device for introducing the composition to the animal.



 

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1 ex

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1 ex

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27 cl, 1 dwg, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to otolaryngology, and may be used for treating tinnitus in a person in need thereof. That is ensured by introducing a therapeutically effective dose of a 1-aminoalkylcyclohexane derivative specified in neramexane or its pharmaceutically acceptable salt. The therapeutically effective dose of neramexane is introduced daily for a first period making at least three months and followed by a second period making at least one month. The second period involves introducing neramexane in a dose making 0-75% of the therapeutically effective dose provided when neramexane is not introduced during the second period, the treatment of the first period is repeated after the second period.

EFFECT: group of inventions provides clinical effectiveness in treating and preventing tinnitus, as well as a need of maintenance therapy.

24 cl, 1 dwg, 8 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: nutrient composition contains the nonpathogenic bacterial strain Lactococcus rhamnosus ATCC 53103 or Lactococcus rhamnosus CGMCC 1.3724 able to stimulate a systemic immune response, and the nonpathogenic bacterial strain Micrococcus varians MCV8 or Streptococcus salivarius DSM 13 084 able to have bacteriostatic and bactericidal effect on pathogens related to the onset of otitis, such as Streptococcus pneumoniae, non-typed Haemophilus influenzae and Moraxella catarrhalis The composition contains 104 to 1012 CFU/g of fresh weight of the composition of each strain. The composition additionally contains Streptococcus thermophilus and additionally contains at least one prebiotic in the amount of 0.3 to 6% of composition weight. The composition represents a baby formula or a food additive.

EFFECT: invention provides an effective protection against nasopharyngeal mucosa colonisation with pathogenic bacteria related with the onset of otitis.

7 cl, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is offered is application of 1-aminoalkylcyclohexane neramexane derivative or its salts for treating or preventing tinnitus, where treatment takes place within three to twelve months since presentation of tinnitus (subacute tinnitus) (versions), a related method of treating, and a pharmaceutical composition of the same purpose containing neramexane or its salts in a combination with an auxiliary pharmaceutical agent selected from antidepressants or anxiolytics, dopamine antagonists, alpha2delta-ligands and NK1 antagonists.

EFFECT: clinical effectiveness and safety before the stage of centralisation of the diseases, the patients appeared to show a good response on neramexane therapy.

21 cl, 1 dwg, 9 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and pharmaceutical industry and concerns a solution of a high-efficacy pharmaceutical substance and excipients allowing to form a fine particle aerosol to penetrate into the bronchi and pulmonary alveoli. As an active ingredient, the solution for producing the preparation for inhalation contains ipratropium bromide monohydrate; and as excipients - sodium benzoate, edible organic acid, purified water in the following proportions provided pH is 3.2-3.5.

EFFECT: solution has high respirabile fractions.

5 cl, 4 ex

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