Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-22
2002-05-28
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S174000, C514S179000, C514S180000, C514S181000, C514S413000, C514S619000
Reexamination Certificate
active
06395746
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention 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 applying those 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 current 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 marketed by Alcon Laboratories, Inc. under the name CILOXAN™ (Ciprofloxacin 0.3%) Ophthalmic Solution. The following quinolones have also been utilized in ophthalmic antibiotic compositions:
Quinolone
Product
Manufacturer
Ofloxacin
OCUFLOX ™
Allergan
Norfloxacin
CHIBROXIN ™
Merck
Lomefloxacin
LOMEFLOX ™
Senju
The foregoing quinolone antibiotic compositions are generally effective in treating ophthalmic infections, and have distinct advantages over prior ophthalmic antibiotic compositions, particularly those having relatively limited spectrums 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 primarily active against gram positive pathogens. However, despite the general efficacy of the ophthalmic quinolone therapies currently available, there is a need for improved compositions and methods of treatment based on the use of antibiotics that are more effective than existing antibiotics against key ophthalmic pathogens, and less prone to the development of resistance by those pathogens.
There is an even 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 pathogen resistance to the orally administered antibiotics.
Ophthalmic, otic and nasal infections are frequently accompanied by inflammation of the infected ophthalmic, otic and nasal tissues and perhaps even surrounding tissues. Similarly, ophthalmic, otic and nasal surgical procedures that create a risk of microbial infections frequently also 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 steroid or non-steroid agents in a single composition.
SUMMARY OF THE INVENTION
The invention is based on the use of a potent new class of antibiotics to treat ophthalmic, otic and nasal infections, as well as the prophylactic use of these antibiotics following surgery or other trauma to ophthalmic, otic or nasal tissues. The compositions of the present invention may also be administered to the affected tissues during ophthalmic, otic or nasal surgical procedures to prevent or alleviate post-surgical infections.
The compositions preferably also contain one or more anti-inflammatory agents to treat inflammation associated with infections of ophthalmic, otic or nasal tissues. The anti-inflammatory component of the compositions is also useful in treating inflammation associated with physical trauma to ophthalmic, otic or nasal tissues, including inflammation resulting from surgical procedures. The compositions of the present invention are therefore particularly useful in treating inflammation associated with trauma to ophthalmic, otic or nasal tissues wherein there is either an infection or a risk of an infection resulting from the trauma.
Examples of ophthalmic conditions that may be treated with the compositions of the present invention include conjunctivitis, keratitis, blepharitis, dacyrocystitis, hordeolum and corneal ulcers. The compositions of the invention may also be used prophylactically in connection with various ophthalmic surgical procedures that create a risk of infection.
Examples of otic conditions that may be treated with the compositions of the present invention include otitis externa and otitis media. With respect to the treatment of otitis media, the compositions of the present invention are primarily useful in cases where the tympanic membrane has ruptured or tympanostomy tubes have been implanted. The compositions may also be used to treat infections associated with otic surgical procedures, such as tympanostomy, or to prevent such infections.
The compositions of the present invention are specially formulated 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 specially suited for application to ophthalmic, otic and nasal tissues, including tissues that have been compromised as the result of preexisting disease, trauma, surgery or other physical conditions.
DETAILED DESCRIPTION OF THE INVENTION
The antibiotics used in the compositions and methods of the present invention have the following formula:
wherein
R1 is hydrogen, a pharmaceutically acceptable cation, or (C1-C6) alkyl;
Y, when taken independently, is ethyl, t-butyl, vinyl, cyclopropyl, 2-fluoroethyl, p-fluorophenyl, or o,p-difluorophenyl;
W is hydrogen, F, C1, Br, C1-C4 alkyl, C1-C4 alkoxy, NH2 or NHCH3;
A is CH, CF, CC1, COCH3, C—CH3, C—CN or N; or
A is carbon and is taken together with Y and the carbon and nitrogen to which A and Y are attached to form a five or six membered ring which may contain oxygen or a double bond, and which may have attached thereto R8 which is methyl or methylene; and
R2 is
wherein:
R3, R4, R5, R6, R7, R9, R10 and R25 are each independently H, CH3, CH2NH2, CH2NHCH3 or CH2NHC2H5, and R5, R6, R7 and R9 may also independently be NH2, NHCH3 or NHC2H5, provided that not more than three of R3, R4, R5, R6, R7, R9, R10 and R25 are other than hydrogen, and if three of these substituents are not hydrogen, at least one of them is methyl.
The antibiotics utilized in the present invention also include prodrugs of the compounds of formula (I) having a free amino group, as well as pharmaceutically useful hydrates and salts of the compounds of formula (I).
The compound Trovafloxacin is most preferred. Trovafloxacin has the following structure:
Further details regarding the structure, preparation, and physical properties of Trovafloxacin and other compounds of formula (I) are provided in U.S. Pat. No. 5,164,402.
The concentrations of the antibiotics of 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 antibiotic selected. The antimicrobial activity of antibiotics is generally expressed as the minimum concentration required to inhibit the growth of a specified pathogen. This concentration is also referred to as the “minimum inhibitory concentration” or “MIC”. The term “MIC90” refers to the minimum concentration of antibiotic required to inhibit the growth of ninety percent (90%) of the strains of a species. The concentration of an antibiotic required to totally kill a specified bacteria is referred to as the “minimum bactericidal concentration” or “MBC”. The minimum inhibitory concentration of Trovafloxacin for several bacteria commonly associated with ophthalmic, otic and nasal infections are provided in the following table:
Microorganism
MIC
90
S. aureus
/methicillin sensitive
0.03
S. aureus
/methicillin resistant
2.0
S. aureus
/quinolone resistant
4.0
S. epidermidis
/methicillin sensitive
0.06
S. epidermidis
/methicillin resistant
4.0
S. pneumoniae
/penicillin sensiti
Abshire Robert L.
Cagle Gerald
Stroman David W.
Yanni John M.
Alcon Manufacturing Ltd.
Brown Gregg C.
Jarvis William R. A.
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