MXPA01003300A - Antibiotic compositions for treatment of the eye, ear and nose - Google Patents

Abstract

Ophthalmic, otic and nasal pharmaceutical compositions containing one or more oxazolidinone antimicrobial agents are disclosed. The compositions preferably also contain one or more anti-inflammatory agents. The compositions may be utilized to treat ophthalmic, otic or nasal conditions by applying those compositions to the affected tissues.

Description

ANTIBIOTIC COMPOSITIONS FOR THE TREATMENT OF EYES AND NOSE BACKGROUND OF THE INVENTION The present invention is directed to the provision of topical antimicrobial 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 said compositions to the affected tissues. The compositions and methods of the invention are based on the use of a new class of antimicrobial agents known as oxazolidinones. The compositions of the present invention may also contain one or more anti-inflammatory agents. The use of oxazolidinones as experimental agents for the treatment of infections is described in the following publications: European patent No. 127902, published European application No. 693491, published European application No. 127902, PCT publication No. 9525106 and PCT publication No. 9730995 Linezolid is an oxazolidinone that is developed by Pharmacia Upjohn as an antimicrobial agent that inhibits the translation of mRNA. Esperezolide (qv) is a similar compound that has also been developed by Pharmacia Upjohn.

The present invention is directed to the use of oxazolidinones to treat ophthalmic, otic and nasal infections. This use of oxazolidinones is not described in the aforementioned publications. There is a great need for improved compositions and treatment methods that are based on the use of antibacterials that are more effective than existing agents against key ophthalmic pathogens, and less prone to develop resistance. for those pathogens. There is still a greater need for topical compositions and effective methods for treating otic and nasal infections, particularly bacterial infections. The use of oral antibacterials to treat otic infections in children has limited efficacy, and creates a serious risk of pathogen resistance to orally administered antibacterials. 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 oxazolidinone antimicrobial agents to treat ophthalmic, otic and nasal infections, as well as the prophylactic use of these antibacterial agents after surgery or other injury in the ophthalmic, otic or nasal tissues. The compositions of the present invention should 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, otic or nasal tissues, including inflammation resulting 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 can 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 in connection 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 pharmaceutical 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 (eg, 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 antimicrobial agents mentioned herein as "oxazolidinones" include compounds of the following structural formula: (i) wherein: R2 is aryl, heteroaryl or R3 is aryl, heteroaryl, C (= O) R, heterocycle or S (= O) nR5 where n = 1 or 2 and R5 is alkyl or N; and R1 is alkyl, optionally substituted with N or O, N, or a phenyl group fused to the ring. The following oxazolidicins are preferred in the compositions and methods of the present invention: wherein: R1 represents azido; hydroxy; or a group of the formula -OR2, -O-SO2 -R3 or NR4R5, wherein R2 denotes a straight or branched chain acyl having up to 8 carbon atoms or a hydroxyl-protecting group, R3 indicates a straight chain alkyl or branched having up to 4 carbon atoms or being optionally substituted wherein the substituent is a straight or branched chain alkyl having up to 4 carbon atoms, R4 and R5 are identical or different and indicate hydrogen, or an amino group protector, or R4 and R5 indicate a group of the formula -CO-Rβ, wherein R6 denotes cycloalkyl having from 3 to 6 carbon atoms, straight or branched chain alkyl having up to 8 carbon atoms, phenyl or hydrogen; and A represents a 5-membered aromatic heterocyclic radical, having up to 3 heteroatoms selected from the group consisting of S, N, or O, directly linked through a carbon atom and may additionally have a ring fused to naphthyl or benzene , wherein the cyclic heterocyclic radicals are in each case replaced up to 3 times in an identical or different form by means of a carboxyl; halogen; cyano; mercapto; formyl; trifluoromethyl; nitro; C 1 -C 6 straight or branched chain alkoxy, straight chain C 1 -C 1 alkoxycarbonyl; C 1 -C 6 alkylthio chain or branched chain; straight or branched chain C? -C6 acyl; or optionally substituted straight or branched chain alkyl having up to 6 carbon atoms, wherein the substituents are hydroxyl, straight or branched chain C5 alkyl alkoxy, C1-C5 acyl or a group of the formula -NR7R8, wherein R7 and R8 are identical or different and indicate hydrogen, straight or branched chain alkyl having up to 4 carbon atoms or phenyl, or R7 and R8 together with the nitrogen atom form a saturated heterocyclic radical with optionally substituted 5 to 6 members which optionally has an additional heteroatom selected from the group consisting of N, S or O wherein the substituents are straight or branched chain C 1 -C 2 alkyl or straight or branched chain C 1 -C 3 acyl, and / or the heterocyclic radicals as defined in A are replaced by a group of the formula -NR7'R8 ', wherein R7' and R8 'are identical or different and have the aforementioned meaning of R7 and R8 and are identical or different from these, and / or the cyclic heterocyclic radicals as defined in A are substituted by optionally mono- or disubstituted (Ci-Cβ) alkenylphenyl, optionally mono- or disubstituted phenyl or by a saturated or unsaturated mono- or disubstituted heterocyclic radical of 5 or 6 members having up to 3 heteroatoms selected from the group consisting of S, N, or O, wherein the optional substituents are carboxyl; halogen; cyano; mercapto; formyl; trifluoromethyl; nitro; phenyl; C-i-Cß alkoxy straight or branched chain; straight or branched chain C6 alkoxycarbonyl; straight or branched chain CrC 6 alkylthio; straight chain C? -C6 acyl; straight or branched chain C-C alquilo alkyl wherein said alkyl is optionally substituted by hydroxyl, straight or branched chain C 1 -C 5 alkoxy, straight chain or branched chain acyl or a group of the formula -NR 18 R 19, wherein R 18 and R19 have the aforementioned meaning of R7 and R8 and are identical to or different from these, or are substituted once by a group of the formula -CO-NR9R10, -NR11 R12, -NR13 -S (O) 2 -R14, R15R16N-SO2- or R17-S (O) a- wherein A denotes 0, 1 or 2, R9, R10, R13, R15 and R16 are identical or different and indicate hydrogen, straight or branched chain alkyl having up to 6 carbon atoms or phenyl, R11 and R12 are identical or different and have the aforementioned meaning of R7 and R8 and are identical or different from these, R14 and R17 they are identical or different and have the aforementioned meaning of R3 and are identical or different from it, and / or the cyclic heterocyclic radicals are substituted by means of a radical of the formula wherein n indicates 0, 1 or 2; or a salt or S-oxide thereof. The oxazolidinones of the formula (I) and formula (II) above are known compounds. Additional details are provided regarding the structure, preparation and physical properties of the oxazolidinones of the formula (II) in the patent of E.U.A. No. 5,698,574. The concentrations of the oxazolidinones 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 oxazolidinone. The activity of antimicrobials is generally expressed as the minimum concentration of a compound 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 an antimicrobial compound that is required to inhibit the growth of ninety percent (90%) of the strains of a species. The concentration of a compound required to completely annihilate a specific bacterium is referred to as the "minimum bactericidal concentration" or "MBC". The appropriate concentration for ophthalmic compositions will generally be an amount of oxazolidinone 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 selected oxazolidinone, relative to the gram-negative and gram-negative organisms. positives commonly associated with ophthalmic infections. Appropriate concentrations 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 amount is referred to herein as "an antimicrobial effective amount". The compositions of the present invention will typically have one or more oxazolidinones 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 U.S.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, torbafilin, 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 and the type of inflammation to be treated. The concentrations will be sufficient to reduce inflammation in the objective ophthalmic, otic or nasal tissues after 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 of the present invention are typically administered to the 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, a 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, otic and nasal compositions of the present invention will have one or more oxazolidinones in pharmaceutically acceptable carriers. 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: polyquaternium-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 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 the simple aqueous solutions to increase the 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 Inqredient Amount (% by weight) Oxazolidinone 0.35 Sodium acetate 0.03 Acetic acid 0.04 Mannitol 4.60 EDTA 0.05 Benzalkonium chloride 0.006 Water c.b.o. 100 EXAMPLE 2 Ophthalmic / nasal / nasal suspension Ingredient Amount (% by weight) Oxazolidinone 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 Hydroxide sodium, NF c .bp for pH adjustment to 5.5 Purified water, USP c.b.p. a 100 EXAMPLE 3 Ophthalmic ointment Ingredient Amount (% by weight) Oxazolidinone 0.35 Mineral oil, USP 2.0 White petrolatum, USP c.b. 100 EXAMPLE 4 Ophthalmic ointment Ingredient Amount (% by weight) Oxazolidinone 0.3 Fluorometholone acetate, USP 0.1 Chlorobutanol, anhydrous, NF 0.5 Mineral oil, USP 5 White petrolatum, USP c.b.D. 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 (6)

NOVELTY OF THE INVENTION CLAIMS

1. - A topical ophthalmic, otic or nasal pharmaceutical composition comprising an antimicrobial effective amount of an oxazolidinone and a pharmaceutically acceptable carrier 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 a 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 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. 7- 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.