Topical antibiotic composition for treatment of eye infection

Details Topical antibiotic composition for treatment of eye infection Topical antibiotic composition for treatment of eye infection

2001-10-10

2003-04-22

Azpuru, Carlos (Department: 1615)

Drug, bio-affecting and body treating compositions

Topical body preparation containing solid synthetic organic...

Ophthalmic preparation

Reexamination Certificate

active

06551584

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition useful for topical application to an eye for treatment or prevention of infective disease of the eye. In particular, the present invention relates to an ophthalmic formulation of an oxazolidinone antibiotic that can be applied to the eye for treatment or prevention of ophthalmic infection by a gram-positive bacterial agent. The field of the present invention also includes therapeutic or prophylactic use of such a formulation, and use of such a formulation in preparation of a medicament.
BACKGROUND OF THE INVENTION
Numerous oxazolidinone compounds have been reported having therapeutically and/or prophylactically useful antibiotic, in particular antibacterial, effect. Among such compounds are those illustratively disclosed in the following patents, each of which is individually incorporated herein by reference.
U.S. Pat. No. 5,164,510 to Brickner.
U.S. Pat. No. 5,231,188 to Brickner.
U.S. Pat. No. 5,565,571 to Barbachyn & Brickner.
U.S. Pat. No. 5,627,181 to Riedl et al.
U.S. Pat. No. 5,652,238 to Barbachyn et al.
U.S. Pat. No. 5,688,792 to Barbachyn et al.
U.S. Pat. No. 5,698,574 to Riedl et al.
U.S. Pat. No. 6,069,145 to Betts.
Compounds disclosed in above-cited U.S. Pat. No. 5,688,792 include for example the compound (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, also referred to herein as linezolid. Linezolid has the structure shown in formula (I):
and is in commercial use as a medicament under the trademark Zyvox® of Pharmacia Corporation. Linezolid exhibits strong antibacterial activity against gram-positive organisms including those of the following genera: Staphylococcus (e.g.,
Staphylococcus aureus, Staphylococcus epidermidis
), Streptococcus (e.g.,
Streptococcus viridans, Streptococcus pneumoniae
), Enterococcus, Bacillus, Corynebacterium, Chlamydia and Neisseria. Many such gram-positive organisms have developed significant levels of resistance to other antibiotics. About 65% of all cases of bacterial keratitis and about 85% of all cases of bacterial conjunctivitis are attributable to infection by gram-positive organisms such as those listed above.
Above-cited U.S. Pat. No. 5,688,792 discloses that the subject antibiotic oxazolidinone compounds, including linezolid, can be formulated as a gel or cream for topical application to skin.
International Patent Publication No. WO 00/03710, incorporated herein by reference, discloses a method of treating bacterial keratitis or bacterial conjunctivitis in an eye, comprising topical administration of an oxazolidinone antibiotic to the infected eye. Preferred oxazolidinone compounds for use according to the method of WO 00/03710 include (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (linezolid) and (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]lphenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (eperezolid). The oxazolidinone compound is said to be administered in a formulation such as a solution, cream, ointment, emulsion, suspension or slow release formulation, a solution being preferred. Formulations exemplified include 10% and 12% weight/volume solutions of linezolid. It is suggested that the formulation be administered 2-4 times daily for 7-10 days or until the infection is gone, and that preferably about 1 drop to about 5 drops of the formulation are administered each time. It is further disclosed in WO 00/03710 that the oxazolidinone compound can be used individually, in combination with another oxazolidinone compound, in combination with other antibacterial agents, or in combination with non-antibacterial agents.
International Patent Publication No. WO 00/18387, incorporated herein by reference, discloses ophthalmic compositions comprising an oxazolidinone antimicrobial agent. Preferred oxazolidinone compounds according to WO 00/18387 are those of above-cited U.S. Pat. No. 5,627,181. Optionally the compositions can further comprise an anti-inflammatory agent. Typically 1-4 drops of a solution or suspension, or a comparable amount of an ointment, gel or other solid or semisolid composition, are said to be applied 1-4 times a day.
A challenge for topical administration of drugs to the eye is a high rate of drug loss from the exterior of the eye. Only a small volume of fluid can be accommodated in the exterior of the eye, including the conjunctival sac, and under normal conditions lacrimal fluid fills most of the available volume. The additional volume of fluid in the form of a drug formulation that can be accepted by a human eye without washout varies from about 3 &mgr;l to about 25 &mgr;l, but is normally about 10 &mgr;l. Furthermore, turnover rate of lacrimal fluid is high, typically about 16% per minute, and this can lead to rapid loss of an instilled drug by normal lacrimal drainage. Thus under normal conditions, only about 10% to about 20% of a drug dose is retained in the exterior of the eye 5 minutes after placement therein of 1-2 drops of a solution or suspension composition of the drug, and the composition is almost completely eliminated within 15 minutes. See for example Sorensen & Jensen (1979),
Acta Ophthalmol
. (Copenhagen) 57, 564-581. Reflex blinking and lacrimation caused by irritation from the topical administration can result in even faster drug loss.
Increasing viscosity of the instilled formulation and hence of the lacrimal fluid can reduce the rate of lacrimal drainage and thereby increase residence time of the drug in the exterior of the eye. Ointments are often used for this reason; however, ointments often cause discomfort by interfering with vision and free movement of the eyelids. Clear aqueous solutions and suspensions are therefore usually a preferred choice, especially for daytime administration.
U.S. Pat. No. 3,867,519 to Michaels, incorporated herein by reference, discloses a device for delivering a drug at a controlled rate to an eye, the device comprising an inner reservoir of the drug confined in a biodegradable matrix and an outer bioerodible membrane through which the drug passes into the eye.
U.S. Pat. No. 3,914,402 to Shell, incorporated herein by reference, discloses an ophthalmic dosage form comprising solid particles of a drug enclosed within a bioerodible polymer such as a polyester, cross-linked gelatin or a polycarboxylic acid. The polymer is said to gradually erode in the eye, releasing the drug at a controlled rate.
U.S. Pat. No. 3,960,150 to Hussain et al., incorporated herein by reference, discloses a bioerodible ocular insert containing a drug. Through erosion of the ocular insert in the eye, the drug is said to be released at a controlled rate.
U.S. Pat. No. 3,963,025 to Whitaker & Gad, incorporated herein by reference, discloses a bioerodible ocular drug delivery device said to have improved retention in an eye.
U.S. Pat. No. 4,014,335 to Arnold, incorporated herein by reference, discloses an ocular drug delivery device comprising a shaped body having a drug reservoir enclosed by walls, one of which is formed of a material that is permeable to the drug and controls the release rate of the drug.
U.S. Pat. No. 4,057,619 to Higuchi & Hussain, incorporated herein by reference, discloses an ocular drug delivery system comprising an ethylene-vinyl ester copolymer through which a drug can diffuse.
U.S. Pat. No. 4,186,184 to Zaffaroni, incorporated herein by reference, discloses an ocular drug delivery system that can be inserted in an eye and that has a drug-releasing portal which can be oriented towards a preselected tissue of the eye for controlled release of the drug thereto.
U.S. Pat. No. 4,474,751 to Haslam et al., incorporated herein by reference, discloses liquid aqueous ophthalmic compositions comprising a drug, preferably a water-soluble drug, together with 10% to 50% by weight of a thermosetting polymer that forms a gel at a human body temperature. Upon placement of such a liquid composition in an eye, a gel

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