MXPA01003293A - Antibiotic compositions for treatment of the eye, ear and nose - Google Patents

Abstract

Ophthalmic, otic and nasal compositionscontaining a new class of antibiotics (e.g., moxifloxacin) are disclosed. The compositions preferably also contain one or more anti-inflammatory agents. The compositions may be utilized to treat ophthalmic, otic and nasal conditions by topically applying the compositions to the affected tissues.

Description

ANTIBIOTIC COMPOSITIONS FOR THE TREATMENT OF EYES, PIDOS AND NOSE BACKGROUND OF THE INVENTION The present is directed to the provision of topical antibiotic pharmaceutical compositions for the treatment of ophthalmic, otic and nasal infections, particularly bacterial infections, and to methods of treating ophthalmic, otic and nasal infections by application of these compositions to the affected tissues. The compositions and methods of the invention are based on the use of a new class of antibiotics. The compositions of the present invention may also contain one or more anti-inflammatory agents. The use of quinolone antibiotics to treat infections represents the state of the art in the field of ophthalmic pharmaceutical compositions and methods of treatment. For example, a topical ophthalmic composition containing the quinolone ciprofloxacin is sold by Alcon Laboratories, Inc. under the name of CILOXAN ™ (0.3% Ciprofloxacin), ophthalmic solution. The following quinolones have also been used in ophthalmic antibiotic compositions.

Quinolone Product Manufacturer Ofloxacin OCUFLOX ™ Allergan Norfloxacin CHIBROXIN ™ Merck Lomefloxacin LOMEFLOX ™ Senju The above quinolone antibiotic compositions are generally effective for treating ophthalmic infections, and have different advantages over prior ophthalmic antibiotic compositions, particularly those having relatively limited spectra of antimicrobial activity, such as: neomycin, polymyxin B, gentamicin and tobramycin, which are primarily useful against gram negative pathogens; and bacitracin, gramicidin, and erythromycin, which are mainly active against gram-positive pathogens. However, despite the overall efficacy of currently available quinolone ophthalmic therapies, there is a need for improved compositions and methods for treatment that rely on the use of antibiotics that are more effective than existing antibiotics against key ophthalmic pathogens. , and that are less likely to develop resistance for these pathogens. There is still a greater need for effective topical compositions and methods for treating otic and nasal infections, particularly bacterial infections. The use of oral antibiotics to treat otic infections in children has limited efficacy, and creates a serious risk of resistance in children. pathogens to orally administered antibiotics. Ophthalmic, otic and nasal infections are often accompanied by inflammation of infected ophthalmic, otic and nasal tissues and even by surrounding tissues. Similarly, ophthalmic, otic and nasal surgical procedures that create a risk of microbial infections also frequently cause inflammation of the affected tissues. Thus, there is also a need for ophthalmic, otic and nasal pharmaceutical compositions that combine the anti-infective activity of one or more antibiotics with the anti-inflammatory activity of one or more steroidal or non-steroidal agents in a single composition.

BRIEF DESCRIPTION OF THE INVENTION The invention is based on the use of a new potent class of antibiotics to treat ophthalmic, otic and nasal infections, as well as the prophylactic use of these antibiotics after surgery or other trauma to ophthalmic, otic or nasal tissues. The compositions of the present invention can also be administered to the affected tissues during ophthalmic, otic or nasal surgical procedures to prevent or alleviate post-surgical infections. Preferably the compositions also contain one or more anti-inflammatory agents to treat inflammation related to infections of the ophthalmic, otic or nasal tissues. The anti-inflammatory component of the compositions is also useful for treating inflammation related to physical trauma in ophthalmic tissues, otic or nasal, including inflammation that results from surgical procedures. The compositions of the present invention are therefore particularly useful for treating inflammation related to trauma to ophthalmic, otic or nasal tissues where there is an infection or risk of an infection resulting from trauma. Examples of ophthalmic conditions that should be treated with the compositions of the present invention include conjunctivitis, keratitis, blepharitis, dacryocystitis, hordeolus and corneal ulcers. The compositions of the invention can also be used prophylactically together with various ophthalmic surgical procedures that create a risk of infection. Examples of ear conditions to be treated with the compositions of the present invention include otitis externa and otitis media. With regard to the treatment of otitis media, the compositions of the present invention are mainly useful in cases where the tympanic membrane has ruptured or tympanotomy tubes have been implanted. The compositions can also be used to treat infections related to otic surgical procedures, such as tympanotomy, or to prevent such infections. The compositions of the present invention are formulated especially for topical application to ophthalmic, otic and nasal tissues. The compositions are preferably sterile and have physical properties (e.g., osmolality and pH) that are especially suitable for application to ophthalmic, otic and nasal tissues, including tissues that have been affected as a result of disease, trauma, surgery or other pre-existing physical conditions. .

DETAILED DESCRIPTION OF THE INVENTION The antibiotics used in the compositions and methods of the present invention have the following formula: (O wherein: A is CH, CF, CCI, C-OCH3, or N; X1 is H, halogen, NH2 or CH3; R 1 is C 1 to C 3 alkyl, FCH 2 CH 2, cyclopropyl or phenyl, optionally mono-, di- or tri-substituted by halogen, or A and R 1 can together form a bridge of the formula C-O-CH 2 -CH (CH 3); R2 is H, C1 to C3 alkyl (optionally substituted by OH, halogen or NH2) or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl; and B is selected from the group consisting of: where: And it is O or CH2; R3 is C2-C5 alkoxy, CH2CO-C6H5, CH2CH2CO2R, R'O2C-CH = C-CO2R, > CH = CH-CO2R 'or CH2CH2-CN, where: R 'is H or Ci to C3 alkyl; R4 is H, C1 to C3 alkyl, C2-C5 alkoxy) CH2-CO-C6H5, CH2CH2CO2R ', RO2C-CH = C-C02R, > CH = CH-C02R ', CH2CH2-CN or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, wherein: R 'is H or Ci to C3 alkyl; Y its hydrates and pharmaceutically useful salts.

The compound Moxifloxacin is the most preferred. Moxifloxacin has the following structure: Further details in relation to the structure, preparation, and physical properties of Moxifloxacin and other compounds of formula (I) are provided in the U.S. patent. No. 5,607,942. The concentrations of the antibiotics of the formula (I) in the compositions of the present invention will vary depending on the intended use of the compositions (e.g., treatment of existing infections or prevention of post-surgical infections), and the relative antimicrobial activity of the specific antibiotics selected. The antimicrobial activity of antibiotics is usually expressed as the minimum concentration that is required to inhibit the growth of a specific pathogen. This concentration is also referred to as "the minimum inhibition concentration" or "MIC". The term "MIC90" refers to the minimum concentration of antibiotic that is required to inhibit the growth of ninety percent (90%) of the strains of a species. The concentration of an antibiotic required to completely kill a specific bacterium is referred to as the "minimum bactericidal concentration" or "MBC". The minimum concentration of Moxifloxacin inhibition for many bacteria commonly associated with ophthalmic, otic and nasal infections is provided in the following table: Microorganism MICgo S.at / oseus / methicillin-sensitive 0.13 S.ai / rews / methicillin-resistant 4.0 S.aureivs / quinolone-resistant 4.0 S.epidermis / methicillin-sensitive 0.25 S.ep / derm / s / methicillin-resistant 4.0 S.pneymon / ae / sensitive to penicillin 0.25 S.pnei / mon / 'ae / penicillin-resistant 0.25 P.aeruginosa 8.0 / - ./nffuepzae / β-lactamase positive 0.06 H. / ivenzae / ß-lactamase negative 0.06 All the above concentrations are expressed as micrograms per milliliter ("mcg / ml"). The concentration of antibiotic suitable for ophthalmic compositions will generally be an amount of one or more antibiotics of formula (I) sufficient to provide a concentration in the aqueous humor and lacrimal fluid of the eye equal to or greater than the MIC90 level for the antibiotic (s) selected, in relation to gram-negative and gram-positive organisms commonly associated with ophthalmic infections. The appropriate concentration for otic and nasal compositions will generally be an amount of one or more antibiotics of formula (I) sufficient to provide a concentration in the infected tissues equal to or greater than the MIC90 level for the selected antibiotic (s), in connection with Gram-negative and gram-positive organisms commonly associated with otic or nasal infections. Said amounts are referred to herein as "an antimicrobial effective amount". The compositions of the present invention will typically have one or more compounds of formula (I) in a concentration of from about 0.1 to about 1.0 weight percent ("% by weight") of the compositions. The compositions of the present invention may also have one or more anti-inflammatory agents. The anti-inflammatory agents used in the present invention are broadly classified as steroidal or non-steroidal. The preferred steroidal antiinflammatory agents are glucocorticoids. Preferred glucocorticoids for ophthalmic and otic use include dexamethasone, loteprednol, rimexolone, prednisolone, fluorometholone, and hydrocortisone. Preferred glucocorticoids for nasal use include mometasone, fluticasone, beclomethasone, flunisolide, triamcinolone and budesonide. The dexamethasone derivatives described in the patent of E.U.A. No. 5,223,493 (Boltralik) are also preferred steroidal antiinflammatory agents, particularly in relation to compositions for treating ophthalmic inflammation. The following compounds are especially preferred: These compounds are referred to herein as "derivatives of dexamethasone-21-ether". The 21-benzyl ether derivative (ie, compound AL-2512) is particularly preferred. Preferred non-steroidal antiinflammatory agents are: prostaglandin H synthetase inhibitors (Cox I or Cox II), are also mentioned as cyclooxygenase inhibitors type I and type II, such as diclofenac flurbiprofen, ketorolac, suprofen, nepafenac, amfenac, indomethacin, naproxen , ibuprofen, bromfenac, ketoprofen, meclofenamate, piroxicam, sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin, fenoprofen, benoxaprofen, nabumetoma, etodolac, phenylbutazone, aspirin, oxyphenbutazone, NCX-4016, HCT-1026, NCX-284, NCX- 456, tenoxicam and carprofen; selective inhibitors of cyclooxygenase type II, such as NS-398, vioxx, celecoxib, P54, etodolac, L-804600 and S-33516; PAF antagonists, such as SR-27417, A-137491, ABT-299, apafant, bepafant, minopafant, E-6123, BN-50727, nupafant and modipafanat; PDE IV inhibitors, such as ariflo, torbafilina, rolipram, filaminast, piclamilast, cipamfilin CG-1088, V-11294A, CT-2820, PD-168787, CP-293121, DWP-205297, CP-220629, SH-636, BAY-19-8004, and roflumilast; inhibitors of cytokine production, such as inhibitors of the transcription factor of NFkB; or other anti-inflammatory agents known to those skilled in the art. The concentrations of the anti-inflammatory agents contained in the compositions of the present invention will vary based on the agent or agents selected in the type of inflammation to be treated. The concentrations will be sufficient to reduce inflammation in the objective ophthalmic, otic or nasal tissues following the topical application of the compositions to said tissues. Said amount is referred to herein as "an effective anti-inflammatory amount". The compositions of the present invention will typically have one or more anti-inflammatory agents in an amount of from about 0.01 to about 1.0% by weight.

The compositions are typically administered to affected ophthalmic, otic or nasal tissues by topically applying one to four drops of a sterile solution or suspension, or a comparable amount of an ointment, gel or other solid or semi-solid composition, one to four times a day. . However, the compositions can also be formulated as irrigation solutions that are applied to affected ophthalmic, otic or nasal tissues during surgical procedures. The ophthalmic, ear and nasal compositions of the present invention will have one or more compounds of the formula (I) and preferably one or more anti-inflammatory agents, in pharmaceutically acceptable vehicles. The compositions will typically have a pH in the range of 4.5 to 8.0. Ophthalmic compositions should also be formulated to have osmotic values that are compatible with the aqueous humor of the eye and the ophthalmic tissues. Said osmotic values will generally be in the range of about 200 to about 400 milliosmoles per kilogram of water ("mOsm / kg"), but will preferably be about 300 mOsm / kg. The ophthalmic, otic and nasal products are typically packaged in multiple dose form. The preservatives are required in this way to avoid microbial contamination during use. Suitable preservatives include: polyquatemium-1, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, or other agents known to those skilled in the art. The use of polyquaternium-1 as an antimicrobial preservative is preferred. Typically said preservatives are employed at a level of about 0.001% to 1.0% by weight. The solubility of the components of the compositions herein, it can be improved by means of a surfactant or other suitable co-solvent in the composition. Such co-solvents include polysorbate 20, 60, and 80, polyoxyethylene / polyoxypropylene surfactants (eg, Pluronic F-68, F-84 and P-103), cyclodextrin, or other agents known to those skilled in the art. Typically said co-solvents are employed at a level of from about 0.01% to about 2% by weight. The use of viscosity improving agents may be desired to provide the compositions of the invention with viscosities greater than the viscosity of simple aqueous solutions to increase ocular absorption of the active compounds by target tissues or to increase the retention time in the eye. , ear or nose. Such viscosity-forming agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose or other agents known to those skilled in the art. Such agents are typically employed at a level of from about 0.01% to about 2% by weight. The following examples are provided to further illustrate the ophthalmic, ear, and nasal compositions of the present invention.

EXAMPLE 1 Ophthalmic / nasal / nasal solution Ingredient Quantity (% by weight) Moxifloxacin 0.35 Sodium acetate 0.03 Acetic acid 0.04 Mannitol 4.60 EDTA 0.05 Benzalkonium chloride 0.006 Water c.b. 100 EXAMPLE 2 Ophthalmic / nasal / nasal suspension Ingredient Quantity (% by weight) Moxifloxacin 0.3 Dexamethasone, micronized, USP 0.10 Benzalkonium chloride 0.01 Disodium edetate, USP 0.01 Sodium chloride, USP 0.3 Sodium sulfate, USP 1.2 Tyloxapol, USP 0.05 Hydroxyethylcellulose 0.25 Sulfuric acid and / or Sodium hydroxide, NF c.b.p. for pH adjustment to 5.5 Purified water, USP c.b.p. to 100 EXAMPLE 3 Ophthalmic ointment Ingredient Quantity (% by weight) Moxifloxacin 0.35 Mineral oil, USP 2.0 Petrolatum white, USP c.b. 100 EXAMPLE 4 Ophthalmic ointment Ingredient Quantity (% by weight) Moxifloxacin 0.3 Fluorometholone acetate, USP 0.1 Chlorobutanol, anhydrous, NF 0.5 Mineral oil, USP 5 White petrolatum, USP c.b.o. 100 The invention has been described herein by reference to certain preferred embodiments. However, since obvious variations in the same will be apparent to those skilled in the art, the invention should not be considered as limiting.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A topical ophthalmic, otic or nasal pharmaceutical composition comprising an effective antimicrobial amount of one or more compounds of the formula: (1) wherein: A is CH, CF, CCI, C-OCH3, or N; X1 is H, halogen, NH2 or CH3; R1 is Ci to C3 alkyl, FCH2CH2, cyclopropyl or phenyl, optionally mono-, di- or tri-substituted by halogen, or A and Ri can form a bridge of the formula C-O-CH2-CH (CH3); R2 is H, Ci to C3 alkyl (optionally substituted by OH, halogen or NH2) or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl; and B is selected from the group consisting of: where: Y is O or CH2; R3 is C2-C5 alkoxy, CH2-CO-C6H5, CH2CH2CO2R ', RO2C-CH = C-C02R', CH = CH-C02R 'or CH2CH2-CN, where: R' is H or Ci to C3 alkyl; R4 is H, Ci to C3 alkyl, C2-C5 alkoxy, CH2-CO-C6H5, CH2CH2CO2R ', R, O2C-CH = C-CO2R,) CH = CH-CO2R', CH2CH2-CN or 5-methyl -2-oxo-1,3-dioxol-4-yl-methyl, wherein: R 'is H or Ci to C3 alkyl; and their pharmaceutically useful hydrates and salts; and a pharmaceutically acceptable vehicle thereof.

2. The topical composition according to claim 1, further characterized in that the composition further comprises an anti-inflammatory effective amount of a steroidal or nonsteroidal anti-inflammatory agent.

3. The topical composition according to claim 2, further characterized in that the anti-inflammatory agent comprises a glucocorticoid.

4. The topical composition according to claim 3, further characterized in that the glucocorticoid is selected from the group consisting of dexamethasone, rimexolone, prednisolone, fluorometholone, hydrocortisone, mometasone, fluticasone, beclomethasone, flunisolide, triamcinolone and budesonide.

5. The topical composition according to claim 2, further characterized in that the anti-inflammatory agent comprises a non-steroidal agent selected from the group consisting of prostaglandin H synthetase inhibitors, PAF antagonists, and PDE IV inhibitors.

6. The topical composition according to claim 2, further characterized in that the compound of formula (I) comprises moxifloxacin.

7. The topical composition according to claim 6, further characterized in that the anti-inflammatory agent comprises dexamethasone.

8. The use of a composition as claimed in claim 1, for the manufacture of a topical medicament for treating or preventing ophthalmic, otic or nasal infections.

9. The use of a composition as claimed in claim 2, for the manufacture of a topical medicament for treating or preventing ophthalmic, otic or nasal infections and concomitant inflammation.

10. The use of a composition as claimed in claim 6, for the manufacture of a topical medicament for treating or preventing ophthalmic, otic or nasal infections and concomitant inflammation.