WO2002100309A1 - Quinolone carboxylic acid compositions and related methods of treatment - Google Patents

Abstract

The present invention relates to the use of quinolone carboxylic acid formulations in the treatment of ocular and periocular infections. The present invention also relates to sustained release compositions comprising specific quinolone carboxylic acid compounds. The invention also relates to quinolone carboxylic acid compositions and methods of preparing the same.

Description

QUINOLONE CARBOXYLIC ACID COMPOSITIONS AND RELATED METHODS OF TREATMENT

FIELD OF THE INVENTION

This application is a continuation-in-part of U.S. Patent Application 09/840,871, filed

April 25, 2001.

The present invention relates to the use of quinolone carboxylic acid formulations in the

treatment of ocular and periocular infections. The present invention also relates to sustained

release compositions comprising specific quinolone carboxylic acid compounds in a vehicle that

permits administration in drop form. The invention also relates to quinolone carboxylic acid

compositions and methods of preparing the same.

BACKGROUND OF THE INVENTION Treatment of ocular and periocular infections can be effected by the application of

ointments or the instillation of topical antibiotic suspensions to the eye. Such compositions can

employ, for example, one or more of the following antibiotic agents: neomycin, polymixin B,

bacitracin, trimethoprim, tobramycin, terramycin, sulfacetamide (e.g., CORTICOSPORTN™,

Monarch Pharmaceuticals, Bristol, Tennessee; NEODECADRON™, Merck & Co., West Point,

Pennsylvania; POLYSPORTN™, Glaxo Wellcome Inc., Research Triangle Park, North Carolina;

POLYTRTM™ AND BLEPHAMTDE™, Allergan Inc., Irvine, California; TOBRADEX™,

Alcon Laboratories, Fortworth, Texas; TERA-COTRIL™, Pfizer Inc., New York, New York

etc.). Compositions such as: CHIBOXD ™ (Merck and Co., West Point, Pennsylvania),

CLLOXAN™ (Alcon Laboratories, Fortworth, Texas) and OCUFLOX™ (Allergan Inc., Irvine,

California) employ quinolone antimicrobials in aqueous solution or aqueous suspension. As in the topical administration of other medicaments to the eye, the delivery of

antimicrobial agents is influenced by a variety of factors, among them comfort, consistency and

accuracy of dosage, type and time of any vision interference, ease of administration, and timing

of delivery. These factors have been discussed, for example, in Davis et al., US Pat. No.

5,192,536.

While the art has produced a variety of compositions for the treatment of ocular and

periocular infections, there is still a need for broad-spectrum antimicrobial compositions with the

characteristics of high bioavailabity and adsorption. Such compositions would be even more

desirable provided they comprise a vehicle that readily permits accurate administration of

dosages in a convenient form such as drops. It is also desirable that the composition be non- irritating and soothing to already irritated ocular and periocular tissues. The aforementioned

compositions are even more desirable when they also provide sustained release of the

antimicrobial compositions and are not subject to rapid dilution or rapid removal of the

antibiotics by lacrimation. There is a need in the art for topically applied anti-microbial agents and compositions

useful in their administration.

SUMMARY OF THE INVENTION

The present invention includes and provides a topical ophthalmic composition

comprising a quinolone carboxylic acid derivative of formula (I),

wherein R¹ is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which

can be hydrolyzed in vivo, R is a hydrogen atom or an amino group which may be substituted by

one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH₂, O, S, SO, SO₂,

or N-R , wherein R is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two

hydrogen atoms.

The present invention includes and provides a method of treating or preventing an infection in the ocular or periocular region comprising: delivering to the ocular or periocular

region a composition comprising a quinolone carboxylic acid derivative of formula (I),

wherein R¹ is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which

can be hydrolyzed in vivo, R is a hydrogen atom or an amino group which may be substituted by

one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH₂, O, S, SO, SO₂, or N-R³, wherein R is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two

hydrogen atoms. The present invention includes and provides a method of preparing a sustained release

topical ophthalmic delivery system, comprising: preparing an composition comprising a

quinolone carboxylic acid derivative of formula (I),

wherein R¹ is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which

can be hydrolyzed in vivo, R is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH , O, S, SO, SO ,

or N-R , wherein R is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two

hydrogen atoms; and, packaging said composition for administration to the eye.

BRIEF DESCRIPTION OF THE FIGURES

Figure la shows the structure of quinolone antimicrobials 8-chloro-l-cyclopropyl-6-

fluoro-7-(2, 3, 4, 5, 6, 7-hexahydro-5-oxo-lH-l,4-diazepin-l-yl)-l,4-dihydro-4-oxoquinoline-3-

carboxylic acid, which is referred to herein as SS732.

Figure lb shows the structure of (R )-(+) -7-(3-amino-2, 3, 4, 5, 6, 7-hexahydro-lH-

azepin- 1 -yl)-8-chloro- 1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-4-oxoquinoline-3-carboxylic acid,

which is referred to herein as SS734.

Figure 2 is a line graph showing tear fluid concentration of (R )-(+) -7-(3-amino-2, 3, 4,

5, 6, 7-hexahydro-lH-azepin-l-yl)-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline- 3-carboxylic acid over time following the instillation of three different topical eyedrop

formulations containing the compound.

Figure 3 is a line graph showing conjunctival concentration of (R )-(+) -7-(3-amino-2, 3,

4, 5, 6, 7-hexahydro-lH- azepin- l-yl)-8-chloro- l-cyclopropyl-6-fluoro-l,4-dihydro-4- oxoquinoline-3 -carboxylic acid following the instillation of three different eyedrop formulations

containing the compound.

Figure 4 is a line graph showing tear fluid concentration of (R )-(+) -7-(3-amino-2, 3, 4,

5 , 6, 7-hexahydro- IH- azepin- 1 -yl)-8-chloro- 1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-4-oxoquinoline-

3 -carboxylic acid over time compared to the tear fluid concentration of the quinolone antibiotics CILOXAN™, OCUFLOX™ and CΗB3OXIN™ as published in the International ournal of

Therapeutics, 35(5) 1997, pages 214-217.

Figure 5 is a line graph showing conjuntival concentration of (R )-(+) -7-(3-amino-2, 3,

A, 5, 6, 7-hexahydro- lH-azepin-1 -yl)-8-chloro-l -cyclopropyl-6-fluoro-l,4-dihydro-4- oxoquinoline-3-carboxylic acid over time compared to the conjuntival concentration of the

quinolone antibiotic in OCUFLOX™ after a single dose administration of each composition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes and provides compositions for the treatment of ocular

infections comprising broad-spectrum quinolone antimicrobials in the form of ointments or

instillants, such as solutions and suspensions, as are known in the art, for application to the

ocular and periocular region. Other embodiments of the present invention include compositions

for ocular and periocular administration comprising a vehicle that permits administration at a suitable initial viscosity, which then substantially increases upon contact with tissues or fluids

because the tissues or fluids raise the pH of the administered composition.

In some embodiments of this invention, suspensions of quinolone carboxylic acids of formula (I) are formed by micronization of the desired quinolone carboxylic acid. Micronization

has the advantage of increasing the bioavailibility of poorly soluble drugs. Chaumeil J.C.,

Methods Find. Exp. Clin. Pharmacology, 20(3) 211 (1998). Micronization can be accomplished

by a variety of methods known in the art such as milling or grinding the materials alone or in

suspension in a non-solvent, reviewed by Setnikar in Boll. Chim. Farm. 116(7): 393-410. _Other

methods of micronization including micronization in supercritical carbon dioxide may also be

employed. Kerc, et. al, Int. J. Pharm. 182(1): 33 (1999). Micronized suspensions of quinolone

carboxylic acids can be employed in the presence or absence of polymeric suspending agents to

prepare ophthalmic formulations. Moreover, micronized preparations of quinolone carboxylic

acids of formula (I) can advantageously be employed with polymeric vehicles which substantially increases in viscosity upon contact with tissues or fluids.

In a preferred embodiment, the quinolone carboxylic acid antimicrobial agent is a

compound having formula (I),

wherein R¹ is a hydrogen atom, an alkyl group, an aralkyl group, or an ester residual group which

can be hydrolyzed in vivo, R² is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH₂, O, S, SO, SO₂, or N-R.³, wherein R³ is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two

hydrogen atoms.

Specific examples of groups represented by R¹ in formula (I) include, without limitation: linear or branched alkyl groups having 1-12 carbon atoms; aralkyl groups (e.g., benzyl, phenyl

ethyl, methyl benzyl, naphtyl methyl, etc.) and ester residual groups which can be hydrolyzed in

vivo, or upon exposure to the tissues or fluids of a living body, including the tissues and tear fluid

of the ocular and periocular region (e.g., a alkanoyloxyalkyl, alkoxycarbonyloxyalkyl,

carbamoylalkyl, alkoxyalkyl, and the like; specifically, acetoxymethyl, 1-acetoxyethyl,

ethoxycarbonyloxymethyl, carbamoylmethyl, carbamoylethyl, methoxymethyl, methoxyethyl

etc.).

Specific examples of amino groups that may be substituted by one or two lower alkyl

groups, represented by R² , include, without limitation: amino, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, and diisopropylamino. When R in formula (I) is

not hydrogen, the carbon atom to which R² is bonded is asymmetrical, which gives rise to optical

isomers, R and S, for compounds of formula (I). The sustained release formulations of the

present invention include formulations employing either optical isomer separately or in

combination, including the racemate.

Specific examples of halogen atoms represented by X include, without limitation:

chlorine, fluorine, bromine, iodine, and the like.

Lower alkyl groups may be linear or branched alkyl groups having 1-5 carbon atoms,

(e.g., methyl, ethyl, i-propyl, sec-butyl, t-butyl, amyl, etc.). The preparation and use of quinolone carboxylic acids of formula (I) as antimicrobial

agents are disclosed by Konno et al. in U.S. Patent No. 5,385,900 and U. S. Patent No.

5,447,926.

Formulation of the instant invention may also advantageously employ salts of compounds

of formula (I). As examples of useful salts of compounds of formula (I), salts of alkali metal,

inorganic acid, organic acid, and the like are given. More specific examples include: lithium

salts, sodium salts, potassium salts, and the like, as salts of alkali metal; hydrochloride, sulfate,

nitrate, hydrobromide, phosphate, and the like, as salts of inorganic acids; and acetate, fumarate, maleate, lactate, citrate, tartarate, malate, oxalate, methanesulfonate, benzenesulfonate, p-

toluenesulfonate, and the like, as salts of organic acid.

The preparation of quinolone carboxylic acids of formula (I) agents are described by

Konno et al. in U.S. Patent No. 5,385,900 and U. S. Patent No. 5,447,926.

In a preferred embodiment, the quinolone carboxylic acid is (R )-(+) -7-(3-amino-2, 3, 4,

5, 6, 7-hexahydro- 1 H- azepin- 1 -yl)-8-chloro- 1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-4-oxoquinoline-

3-carboxylic acid, as shown in Figure lb.

In another preferred embodiment, the quinolone carboxylic acid is 8-chloro-l-

cyclopropyl-6-fluoro-7-(2, 3, 4, 5, 6, 7-hexahydro-5-oxo-lH-l,4-diazepin-l-yl)-l,4-dihydro-4- oxoquinoline-3-carboxylic acid, as shown in Figure 1 a.

The quinolone carboxylic acid antimicrobials of the present invention can be incorporated

in any of the formulations of this invention, including solutions and suspensions, in

therapeutically active amounts, comparable to amounts administered in other dosage forms.

These amounts range from about 0.005% to about 10% by weight, and preferably from about 0.007% to about 5%, and even more preferably from 0.02% to 2.5% by weight, based on the total weight of the formulation. In other embodiments the quinolone carboxylic acid antimicrobials

can be present from about 0.1% to about 0.5% by weight, from about 0.5% to about 1.0% by weight, from about 2.0% to about 3.0% by weight, or from about 3.0 to about 5.0% by weight, based upon the total weight of the composition. In one embodiment, from about 0.01% to about

1 % by weight of quinolone antibiotics of formula (I) can be administered in this manner.

Any composition suitable capable of delivering the quinolone antibiotics of the present

invention to the eye can be employed, including solutions and suspensions, which are generally

well known in the art. In one embodiment of the present invention, the quinolone carboxylic

acid antimicrobial agents described herein are in solution in a composition. In another

embodiment, the quinolone carboxylic acid antimicrobial agents of the present invention are in

solution and suspension in a composition. In another embodiment, the quinolone carboxylic

acids are in suspension, wherein the particles of the desired quinolone carboxylic acid are prepared by micronization to yield a population of particles having an average diameter of about

30 microns or less, or more preferably about 20 microns or less, or more preferably about 15

microns or less, or more preferably about 10 microns or less, or more preferably about 5 microns

or less. Particles of micronized quinolone carboxylic acids having a diameter about 4 microns or

less, or about 2 microns or less, or about 1 micron or less may also be employed. Alternatively,

the quinoline carboxylic acids may be micronized to prepare a population of particles having an

average diameter from about 30 microns to about 1 micron, or about 20 microns to about 5

microns, or about 15 microns to about 5 microns, or about 10 to about 5 microns. By controlling

the size of quinolone carboxylic acid particles present, it is possible to affect the stability of the formulation and the bioavailibility of the quinolone carboxylic acid antimicrobials. Preparations of micronized quinolone carboxylic acids of formula (I) may prepared in

vehicles containing one or more suspending or viscosity modifying agents conventionally known

in the art including hydrophilic polymers. Examples of suspending or viscosity modifying agents

that may be employed include: polyvinyl pyrrolidone, polyvinyl alcohols, polyethylene glycols,

polysaccharides, dextrans and cellulosic polmyers such as hydroxypropylcellulose,

hydroxyethylcellulose, hydroxypropyl-methylcellulose. In other embodiments micronized

preparations of quinolone carboxylic acids may also be advantageously used in combination with polymeric vehicles to prepare compositions, which can be administered at a suitable initial

viscosity and which then substantially increases in viscosity upon contact with tear fluid.

Preparations of micronized quinolone carboxylic acids offer a variety of advantages. As

opposed to quinolone carboxylic acid compositions prepared by precipitating soluble drug by adjusting the pH upward to reduce solubility, compositions containing micronized preparations

of quinolone carboxylic acids resist the formation of crystals that can render the composition

unsuitable for ophthalmic use. Furthermore, the use of micronized quinolone carboxylic acids in

combination with the polymer containing vehicles of this invention, particularly those which

under go an increase in visosity upon contact with tear fluid, offer additional advantages. The

small particles of micronized materials are readily suspended in the polymer containing vehicles.

The micronized materials maintain a saturated or nearly saturated solution more readily, which in

combination with the polymeric vehicles that keep the composition in contact with the eye, lead

to increased bioavailability. Moreover, the polymeric suspending agents prevent the

agglomeration of drug particles that, like crystal growth, can make the composition unsuitable for ophthalmic administration. In still yet another embodiment of the present invention, a solubilizer is included in a

composition to increase the amount of quinolone carboxylic acid antimicrobial agent in solution. Any suitable solubilizer for ophthalmic compositions can be used, including, but not limited to,

cyclodextrans. In a preferred embodiment, a composition of the present invention comprises

hydroxypropyl-β-cyclodextran. In a preferred embodiment of the present invention,

hydroxypropyl-β-cyclodextran is about 1.0% to about 30.0%, and more preferably from about

5.0% to about 20.0% by weight of said composition, based on the total weight of said

composition.

In one embodiment, the vehicles useful for ocular and periocular administration of

quinolone antimicrobials of formula (I), at a suitable initial viscosity which then substantially

increases in viscosity upon contact with tear fluid, are described in Davis et al. U.S. Patent No. 5,192,535. Ocular administration vehicles, such as those set forth in Davis et al, comprise

lightly crosslinked polymers of acrylic acid or the like which are, in general, well known in the

art. In a preferred embodiment, such polymers are prepared from at least about 50%, more

preferably at least about 60%, more preferably at least about 70%, more preferably at least about

80%, more preferably least about 90%, and even more preferably from about 95% to about

99.9% by weight, based on the total weight of monomers present, of one or more carboxyl-

containing monoethylenically unsaturated monomer. In a preferred embodiment, acrylic acid is

used as a carboxyl-containing monoethylenically unsaturated monomer. In a further

embodiment, unsaturated, polymerizable carboxyl-containing monomers, such as methacrylic acid, ethacrylic acid, β-methylacrylic acid (crotonic acid), cis-α-methylcrotonic acid (angelic

acid), trans-α-methylcrotonic acid (tiglic acid), α-butylcrotonic acid, α-phenylacrylic acid, α-

benzylacrylic acid, α-cyclohexylacrylic acid, β-phenylacrylic acid (cinnamic acid), coumaric acid (o-hydroxycinnamic acid), umbellic acid (p-hydroxycoumaric acid), and the like can be used in addition to, or instead of acrylic acid.

Preferred vehicles that employ lightly crosslinked polymers can be crosslinked by using a

small percentage, i.e., less than about 5%, such as from about 0.5% or from about 0.1% to about

5%, and preferably from about 0.2% to about 1%, based on the total weight of monomers

present, of a polyfunctional crosslinking agent. In another embodiment, the instant invention

also contemplates the use of lightly crosslinked polymers crosslinked with from about 0.01% to

about 0.05%, from about 0.06% to about 0.1%, from about 0.11% to about 0.5%, from about

0.55% to about 1.0%, from about 1.5% to about 2.5%, from about 2.6% to about 3.5%, or from

about 3.6% to about 4.5%, of crosslinking agent in by weight, based on the total weight of the monomers present. Included among such crosslinking agents are non-polyalkenyl polyether

difunctional crosslinking monomers such as: divinyl glycol; 2,3-dihydroxyhexa-l,5-diene; 2,5-

dimethyl-l,5-hexadiene; divinylbenzene; N,N-diallylacrylamide; N,N-diallylmethacrylamide and

the like. A preferred crosslinking agent is divinyl glycol. Also included are polyalkenyl

polyether crosslinking agents containing two or more alkenyl ether groupings per molecule,

preferably alkenyl ether groupings containing terminal H₂C=C< groups, prepared by etherifying a

polyhydric alcohol containing at least four carbon atoms and at least three hydroxyl groups with

an alkenyl halide such as allyl bromide or the like, e.g., polyallyl sucrose, polyallyl

pentaerythritol, or the like; see, e.g., Brown U.S. Pat. No. 2,798,053. Diolefinic non-hydrophilic macromeric crosslinking agents having molecular weights of from about 400 to about 8,000,

such as insoluble di- and polyacrylates and methacrylates of diols and polyols, diisocyanate-

hydroxyalxyl acrylate or methacrylate reaction products, and reaction products of isocyanate

terminated prepolymers derived from polyester diols, polyether diols or polysiloxane diols with hydroxyalkylmethacrylates, and the like, can also be used as the crosslinking agents; see, e.g.,

Mueller et al. U.S. Pat. Nos. 4,192,827 and 4,136,250.

It is possible to prepare lightly crosslinked polymers employing one or more carboxyl-

containing monomers as the only monomers present, together with a crosslinking agent or agents.

In one embodiment, lightly crosslinked polymers can be polymers in which up to about 1%, 2%,

5%, 10%, 15%, 20%, 30% or 40% by weight, of the carboxyl-containing monoethylenically

unsaturated monomer or monomers have been replaced by one or more non-carboxyl-containing

monoethylenically unsaturated monomers containing only physiologically and

ophthalmologically innocuous substituents. Non-carboxyl-containing monoethylenically

unsaturated monomers may be present in any range from 0% to about 40% by weight of the monomers present, and are preferably present from about 0% to about 20% by weight. Non-

carboxyl-containing monoethylenically unsaturated monomers useful in preparing the polymers

include: acrylic and methacrylic acid esters such as methyl methacrylate, ethyl acrylate, butyl

acrylate, 2-ethylhexylacrylate, octyl methacrylate, 2-hydroxyethyl-methacrylate, 3-

hydroxypropylacrylate, and the like; vinyl acetate, N-vinylpyrrolidone, and the like; see Mueller

et al. U.S. Pat. No. 4,548,990, for a listing of additional monoethylenically unsaturated

monomers that can be used in compositions of the present invention. Particularly preferred

polymers are lightly crosslinked acrylic acid polymers wherein the crosslinking monomer is 2,3-

dihydroxyhexa-l,5-diene or 2,3-dimethylhexa-l,5-diene.

It is preferable to prepare lightly crosslinked polymers that can be used in conjunction with the vehicles of this invention by suspension or emulsion polymerizing the monomers, using

conventional free radical polymerization catalysts, to a dry particle size of not more than about

30 μm in equivalent spherical diameter. In a preferred embodiment the dry particle size ranges from about 1 to about 30 μm, and preferably from about 3 to about 20 μm, in equivalent

spherical diameter. In one embodiment, such polymers are estimated to range in molecular

weight (in daltons) from 1 to 10 billion and preferably about 2-5 billion.

The relationship between the degree of crosslinking and particle size is significant for the

lightly crosslinked polymers of the vehicles that increase in viscosity upon administration. As

the particles are present in a suspension, the degree of crosslinking is necessarily at a level such

as to avoid substantial dissolution of the polymer. As the polymers undergo rapid gelation in

response to the pH change resulting from contact with tear fluid, the degree of crosslinking is

necessarily not so great that gelation is precluded. The increased gelation occurs with a change in the pH of the formulation upon contact with tear fluid. As will be appreciated by those in the

art, the formulations of the invention, which are designed to increase in viscosity subsequent to

administration, can be delivered at a pH of from about 3 to about 6.5 and an osmotic pressure of

from about 10 to about 400 mOsM. As will be appreciated, tear fluid is at a higher pH of about

7.2 to about 7.4. With the pH increase, carboxylic acid (COOH) undergoes a sodium

replacement (to COONa), and the sodium form disassociates, causing the polymer to expand. If

the polymer particle size is too large, induced swelling can tend to take up voids in the volume

between large particles that are in contact with one another, rather than cause gelation.

If the polymer employed in vehicles designed to undergo increases in viscosity

subsequent to administration were in a dissolved state, as it would be if there were insufficient crosslinking because of a too low of a ratio of crosslinker to monomer, particle size would be less

relevant. In a suspension, however, particle size can be relevant to comfort. In a preferred

system of the present invention, the small particle size and light crosslinking synergistically yield

rapid gelation of the administered composition upon exposure to tear fluid, which increases the pH of the composition. In various embodiments the present invention includes and provides for

the use of particles less than about 30 μm, less than about 20 μm, less than about 10 μm, or less

than about 6 μm. Particle size below 30 μm is preferred in obtaining the increased viscosity.

Moreover, at the 30 μm size and below, eye comfort is improved.

Aqueous suspensions containing polymer particles prepared by suspension or emulsion

polymerization whose average dry particle size is appreciably larger than about 30 μm in

equivalent spherical diameter are less comfortable when administered to the eye than suspensions

otherwise identical in composition containing polymer particles whose equivalent spherical

diameters are, on the average, below about 30 μm. It has also been discovered that lightly

crosslinked polymers of acrylic acid or the like prepared to a dry particle size appreciably larger

than about 30 μm in equivalent spherical diameter and then reduced in size, e.g., by mechanically

milling or grinding, to a dry particle size of not more than about 30 μm in equivalent spherical

diameter do not work as well as polymers made from aqueous suspensions.

Without wishing to be bound by any theory or mechanism advanced to explain the

functioning of this invention, one possible explanation for the difference of such mechanically

milled or ground polymer particles as the sole particulate polymer present is that grinding

disrupts the spatial geometry or configuration of the larger than 30 μm lightly cross-linked

polymer particles, perhaps by removing uncrosslinked branches from polymer chains, by

producing particles having sharp edges or protrusions, or by producing ordinarily too broad a

range of particle sizes to afford satisfactory delivery system performance. A broad distribution of

particle sizes can impair the viscosity-gelation relationship of the more preferred embodiments.

In any event, such mechanically reduced particles are less easily hydratable in aqueous suspension than particles prepared to the appropriate size by suspension or emulsion polymerization, and also are less able to gel in the eye under the influence of tear fluid to a

sufficient extent, and are less comfortable once gelled than gels produced in the eye using the

aqueous suspensions of this invention. However, up to about 5%, more preferably 10%, 15%,

20%, 30%, or more preferably 40%, by weight, based on the total weight of lightly crosslinked particles present, of such milled or ground polymer particles can be admixed with solution or

emulsion polymerized polymer particles having dry particle diameters of not more than about 30

μm when practicing this invention. Such mixtures will also provide satisfactory viscosity levels

in the ophthalmic medicament delivery systems and in the in situ gels formed in the eye coupled with ease and comfort of administration and satisfactory sustained release of the medicament to

the eye, particularly when such milled or ground polymer particles, in dry foπn, average from

about 0.01 to about 30 μm, preferably from about 0.05 to about 15 μm, more preferably from

about 0.25 to about 7.5 μm, and most preferably from about 1 to about 5 μm, in equivalent

spherical diameter. In other embodiments, milled or ground polymer particles, in dry form,

averaging from about 5.0 to about 10 μm, or milled or ground particles averaging from about 10

to about 20 μm, or milled or ground particles averaging from about 20 to about 30 μm, can be

admixed with solution or emulsion polymerized polymer particles having dry particle diameters

of not more than about 30 μm.

In the most preferred embodiments of the invention, the vehicles employed in the

formulations comprise particles having a narrow particle size distribution within a 10 μm band of

major particle size distribution which contains at least 80%, more preferably at least 90%, and

most preferably at least 95% of the particles. Also, there is no more than 20%, preferably no

more than 10%, and most preferably no more than 5% particles of fines (i.e., particles having a

particle size below 1 μm). The presence of large amounts of such fines has been found to inhibit the desired gelation upon eye contact. In addition, the use of a monodispersion of particles will

give maximum viscosity and an increased eye residence time of the ophthalmic medicament

delivery systems for a given particle size. Monodispersed particles having a particle size of 30

μm and below are most preferred. It is also preferred that as the average particle size is lowered

from 30 μm to lower sizes such as 6 μm, that the band of major particle size distribution be also

narrowed (for example to 5 μm). Preferred sizes for particles within the band of major particle

distribution are less than about 30 μm, more preferably less than about 20 μm and most

preferably from about 1 μm to about 5 μm. Good particle packing is aided by a narrow particle

size distribution.

Preferred formulations of this invention will contain amounts of lightly crosslinked

polymer particles ranging from about 0.1% to about 6.5% by weight, more preferably from about

0.5% to about 4.5% and even more preferably from about 1.0% to about 3.0% by weight, based on the total weight of the suspension. In other embodiments the formulations of this invention may contain amounts of lightly crosslinked polymer particles ranging from about 0.1% to about

6.5% by weight, or 0.25% to about 4.0% by weight, or preferably about 0.5% to about 1% by

weight, based on the total weight of the suspension. The formulations can preferably be prepared

using pure, sterile water, preferably deionized or distilled, having no physiologically or

ophthalmologically harmful constituents, and can be adjusted to any desirable pH, and preferably

below about 6.5 with ophthalmologically acceptable pH adjusting acids, bases or buffers, e.g.,

acids such as acetic, boric, citric, lactic, phosphoric, hydrochloric, or the like, bases such as

sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, THAM (trishydroxymethylaminomethane), or the like and salts and buffers such as citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases. In a preferred embodiment, the polymer is a carboxy containing polymer. In a

another preferred embodiment, the polymer is a cross-linked carboxy containing polymer.

When formulating the aqueous suspensions of this invention, their osmotic pressure (π)

will be adjusted to from about 10 milliosmolar (mOsM) to about 400 mOsM, and preferably

from about 100 to about 250 mOsM, using appropriate amounts of physiologically and

ophthalmologically acceptable salts. Sodium chloride is preferred to approximate physiologic

fluid, and amounts of sodium chloride ranging from about 0.01% to about 1% by weight, and preferably from about 0.05% to about 0.45% by weight, based on the total weight of the aqueous

suspension, will give osmolalities within the above-stated ranges. Equivalent amounts of one or

more salts made up of cations such as potassium, ammonium and the like and anions such as

chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfite and the

like, e.g., potassium chloride, sodium thiosulfate, sodium bisulfite, ammonium sulfate and the like can also be used in addition to or instead of sodium chloride to achieve osmolalities within

the above-stated ranges.

When preparing compositions comprising the lightly crosslinked polymer particles, the

amounts of lightly crosslinked polymer particles, the pH, and the osmotic pressure chosen from

within the above-stated ranges can be correlated with each other and with the degree of

crosslinking to give aqueous suspensions with desired visocities, preferably having viscosities

ranging from about 500 to about 10,000, more preferably from 1,000 to about 5,000, 1500 to

3500, and even more preferably from 2000 to 3000 centipoise, as measured at a shear rate of 2.25

sec^"1 using a Brookfield Digital LV-CP viscometer equipped with a CP-40 spindle at 25°C. (Brookfield Engineering Laboratories Inc.; Middleboro, Massachusetts). At viscosities greater than 5000 cps, the handling and administration of the composition via an eye dropper can become unnecessarily cumbersome and error prone. At viscosities less than 1000 cps, the

composition may be too easily washed from the eye by tearing and the like and may not have enough residence time in the eye. Also, because the viscosity is predominantly a function of the

kind and amount of crosslinked carboxy-containing polymer (as a function of pH), the amount of

crosslinked carboxy-containing polymer present at such a low viscosity is generally too low to

provide the desired release profile of medicament.

The viscous gels that result from fluid eyedrop formulations delivered by means of the

aqueous suspensions of the more preferred embodiments of this invention have residence times

in the eye ranging from about 2 to about 12 hours, e.g., from about 3 to about 6 hours. The

quinolone carboxylic acids contained in these formulations will be released from the gels at rates

that depend on such factors as the drug itself and its physical form, the extent of drug loading and the pH of the system, as well as on any drug delivery adjuvants, such as ion exchange resins

compatible with the ocular surface, which may also be present. For the fluoroquinolone

antimicrobial SS734, which is shown in Figure lb, for example, release in the rabbit eye is in

excess of four hours, as measured by the conjunctival and tear fluid concentrations of SS734 (see

figures 3 and 4, for example).

Pro-drug containing counterparts of the inventive formulations are also within the scope

of the present invention. One may for example employ pro-drug formulations of quinolone

antimicrobials of formula (I), wherein Rl is an ester residual group that can be hydrolyzed in

vivo. Hydrolysis of pro-drugs in vivo is specifically intended to include the hydrolysis of pro-

drugs of the quinolone antimicrobials of formula (I) in the ocular and periocular regions. The Rl group of such pro-drug containing formulations could be selected from alkanoyloxyalkyl,

alkoxycarbonyloxyalkyl, carbamoylalkyl, alkoxyalkyl, and the like; more specifically, acetoxym ethyl, 1 -acetoxyethyl, ethoxycarbonyloxymethyl, carbamoylmethyl, carbamoylethyl, methoxymethyl and methoxyethyl.

Formulations of this invention may also contain excipients, such as ophthalmologically

acceptable pH adjusting acids, bases, or buffers. Additional excipients may include, for example

without limitation, chelating agents (e.g., ETDA etc), surfactants and additional polymeric agents

(e.g., block copolymer of ethylene oxide and propylene oxide, such as Poloxamer™ polymers)

and preservatives. Those skilled in the art will be able to readily appreciate that diverse

excipients, such as those set forth in "Remington's Pharmaceutical Sciences," Mack Publishing

Co., Easton, Pennsylvania, can be incorporated into the compositions of this invention.

The aqueous topical ophthalmic medicament delivery compositions of this invention can be prepared in any of several ways. For example a convenient method involves adding the drug and other formulation components to about 95 percent of the final water volume and stirring for a

sufficient time to dissolve the components or saturate the solution. Solution saturation can be

determined in a known manner, e.g., using a spectrophotometer. The pH and concentration of

the composition are then adjusted to their final values.

The preparation of compositions containing lightly crosslinked polymers can be achieved

in a variety of ways, for example, the lightly crosslinked polymer particles, and the osmolality-

adjusting salt can be preblended in dry form, added to all or part of the water, and stirred

vigorously until apparent polymer dispersion is complete, as evidenced by the absence of visible

polymer aggregates. The antibiotics of the invention can be introduced by addition in dry form to the preblended dry materials, prior to their addition to water. Alternatively, the quinolone

antibiotics can be added to the aqueous dispersion in dry form, as a suspension or predissolved

(in solution) as the dispersion is stirred. Sufficient pH adjusting agent is subsequently added incrementally to reach the desired pH, and more water to reach 100 percent formula weight can

be added at this time, if necessary.

In an alternative method of preparing formulations of the invention bearing lightly

crosslinked polymeric particles, the lightly crosslinked polymer particles and the osmolality-

adjusting salt are first blended in dry form and then added to an antibiotic saturated suspension and stirred until apparent polymer hydration is complete. Following the incremental addition of

sufficient pH adjusting agent to reach the desired pH, the remainder of the water is added, with

stirring, to bring the suspension to 100 percent formula weight. Yet another method by which to

prepare the formulation is to separately prepare a solution comprising the desired quinolone antimicrobial and a suspension comprising the carboxyl-containing particles. The quinolone

antimicrobial solution can be prepared in about one third portion of the vehicle solvent (typically

water) at a pH at which it is fully soluble and the suspension comprising the carboxyl-containing

particles can be prepared in about one third portion of vehicle solvent. After the carboxyl- containing particles have fully hydrated, the solution of quinolone antimicrobial and the

suspension of particles are mixed together with stirring and the addition of sufficient base or acid

as required to maintain the pH in the desired range. After mixing is complete water is added to

100 percent formula.

Preparations containing micronized quinolone carboxylic acids can be prepared by a

variety of means. In one preferred method for the preparation of compositions in which the suspended quinolone carboxylic acid is micronized the pH - solubility profile of the desired

quinolone carboxylic acid is first measured to determine a pH at which the compound has a low

solubility. The desired quinolone carboxylic acid is then micronized to a desired average particle size. In some embodiments the average diameter of the particles will be about 30 microns, in other embodiments it will be about 15 microns, in other embodiments it will be about 10 microns

and in still other embodiments it will be about 8 microns and in yet other embodiments it will be

about 5 microns. The vehicle, including any polymeric agents, is then prepared and adjusted to a

pH where the solubility of the desired quinolone carboxylic acid is low, and the micronized drug is added. The pH of the formulation is then adjusted as necessary to a pH range suitable for

ophthalmic administration while retaining the low solubility of the quinolone carboxylic acid.

Formulations of the invention can be packaged in preservative-free, single-dose non-

reclosable containers. In a preferred method, the formulations are prepared and packaged at a

desired viscosity, from about 1 ,000 to about 30,000 centipoise, for administration to the eye in drop form. This permits a single dose of the medicament to be delivered to the eye one drop at a

time, with the container discarded after use. Such containers eliminate the potential for

preservative-related irritation and sensitization of the comeal epithelium, as has been observed to

occur particularly from ophthalmic medicaments containing mercurial preservatives. Multiple- dose containers can also be used, if desired, particularly since the relatively low viscosities of the

aqueous suspensions of this invention permit constant, accurate dosages to be administered

dropwise to the eye as many times each day as necessary. In those suspensions where

preservatives are to be included, suitable preservatives are chlorobutanol, Polyquat,

benzalkonium chloride, cetyl bromide, sodium perborate, chlorhexadine, and the like.

As formulations of the invention comprise quinolone antimicrobials active against a

broad variety of microorganisms, they are useful in the treatment of infections and associated

conditions affecting the ocular and periocular regions associated with the spectrum of

microorganisms susceptible to the action of the quinolone antimicrobials. Formulations of the invention are useful in the treating infections of Gram negative and Gram positive bacteria and also in the treatment of mixed infections of Gram negative and Gram positive bacteria including

infections of the following Gram negative organisms: Escherichia coli, Salmonella typhi,

Shigella βexneri, Klebsiellia pneumonia, Proteus vulgaris, Proteus rettgeri, Haemophilus

inβuenzae, Pseudomonas aeruginosia, Serratia marcescens, Moraxella morganii, Moraxella lacunata and Moraxella catarrhalis; and infections of the following Gram positive

microorganisms: Bacillus subtilis, Staphylococcus aureus (including methicillin resistant and

susceptible strains), Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus

hominis, Staphylococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis and Micrococcus lysodeikticus. Formulations of the invention are particularly useful in the treatment

of ocular and periocular infections of Streptococcus pneumoniae, Staphylococcus aureus

(including methicillin resistant and susceptible strains), Haemophilus inβuenzae, Pseudomonas

aeruginosia, Moraxella morganii, Moraxella lacunata Moraxella catarrhalis, or mixed

infections thereof. In a preferred embodiment, formulations of the invention are useful for treatment of an infection of a bacteria selected from the group consisting of Escherichia coli,

Salmonella typhi, Shigella βexneri, Klebsiellia pneumonia, Proteus vulgaris, Proteus rettgeri,

Haemophilus inβuenzae, Pseudomonas aeruginosia, Serratia marcescens, Moraxella morganii,

Moraxella lacunata, Moraxella catarrhalis, Bacillus subtilis, Staphylococcus aureus,

Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis,

Staphylococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis, Micrococcus

lysodeikticus and combinations thereof.

For the purpose of this invention, ocular and periocular regions are defined as the eye and

tissues immediately adjacent to the eye, particularly those regions which are exposed to the fluid secretions of the lachrymal apparatus. These include the eyelid, cornea, sclera, conjuntiva, lachrymal apparatus and lachrymal ducts. As will be obvious to those skilled in the art, injury

and infection may expose or involve surrounding or underlying tissues in the ocular and

periocular region tissues, such as the conjunctival tissues, that may also be advantageously treated using the formulations of the invention.

Treatment of ocular or periocular microbial infections and conditions associated with

microbial infections comprises instillation of a sufficient amount of the antibiotic formulation

(i.e., a sufficient volume of the formulation to deliver sufficient antibiotic to achieve an

antimicrobial effect). In a more preferred embodiment the method of treatment utilizes a relatively low viscosity form of the formulation (i.e., one of suitable viscosity to be readily

delivered in drop form which undergoes an increase in viscosity upon contact with the tear fluid

and tissues of the ocular or periocular region) to deliver a therapeutically effective dose (a dose

sufficient to effect an antimicrobial effect in a subject) of the quinolone antimicrobial agent.

Upon contact with the tissues or fluids of the ocular and periocular region, the formulation undergoes an increase in viscosity to a highly viscous form capable of sustained delivery of the

quinolone antimicrobials useful in the treatment of ocular infections. Examples of specific

conditions that may be treated with the formulation of the invention include: conjunctivitis

associated with Haemophilus inβuenzae, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Moraxella morganii, Moraxella lacunata, and Moraxella catarrhalis

infections, corneal ulcers associated with Pseudomonas aeruginosia, Serratia marcescens,

Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Moraxella

morganii, Moraxella lacunata, and Moraxella catarrhalis infections and keratitis associated with

corneal infections associated with organisms sensitive to the quinolone antibiotics of formula (I). Treatments employing the formulations of this invention are additionally intended to include

prophylactic use of the formulations.

In one embodiment of the present invention, the compositions are sustained release formulations for ocular and periocular administration comprising a quinolone in a vehicle that

permits administration at a suitable initial viscosity, which increases to a viscosity greater than

that of the form administered upon contact with tear fluid or tissues of the ocular and periocular

region. Among the advantages of such formulations are the ability to provide for a sustained

release of the quinolone antimicrobial agents and the ability to deliver higher levels of quinolone

antimicrobials to the ocular and periocular regions as compared to the short duration release and

levels of quinolone antimicrobials that can be achieved with simple aqueous solutions or

suspensions of quinolone antimicrobials. Other advantages of the instant invention include the

ability to effectively treat a broad spectrum of Gram negative, Gram positive or mixed infections of Gram negative and Gram positive bacterial infections using fewer administrations of the

antimicrobial agent. This has advantages to both physicians and patients as it increases the

ability of the physician to prescribe an effective treatment at the earliest time a patient is seen,

rather than waiting until sensitivity in culture is determined. In addition, as sustained release formulations of the invention require fewer administrations the level of patient compliance is

more likely to be high, thereby resulting in more positive outcomes from treatment.

Compositions of this invention are advantageous in their presentation of quinolone

carboxylic acids to the tissues of the ocular and periocular regions for numerous reasons. First the formulations of this invention permit the presentation of unexpectedly high levels of quinolone antibiotics to the ocular and periocular region. In one embodiment, when employing

sustained release compositions and compositions that increase in viscosity upon application to the tissues of the ocular and periocular regions, the levels of quinolone antimicrobials obtained

are superior to those that can be achieved with other conventional eyedrops that do not increase in viscosity upon administration and contact with lachrymal secretions, the eye, or the tissues

surrounding the eye. Second, the formulations of this invention permit the release of quinolone

antibiotic compounds over an unexpectedly prolonged time period, thereby reducing requirement

for frequent repeated dosing. Third, as the quinolone antibiotics of formula I have increased

absorption they display an increased bioavailiblity in the tissues of the eye and around the eye.

Fourth, the quinolone antibiotics of formula I display an increased potency against gram positive

organisms (e.g., S. aureus) while retaining a high level of efficacy against gram negative

organisms. This results in the ability to employ the formulation of this invention in the treatment of a broad spectrum of infections and in mixed gram positive and gram negative infections. Because the quinolone antibiotic formulations of the present invention comprise broad spectrum

antibiotics, they permit physicians dealing with ocular and periocular infections to prescribe an

effective treatment at the earliest time a patient is seen, rather than waiting until sensitivity in

culture is determined. In addition, as the formulations of the invention provide sustained release

of the quinolone antimicrobials, they require fewer administrations. Hence, the level of patient

compliance is more likely to be high, resulting in more positive outcomes from treatment. For at

least the forgoing reasons, the formulations and methods of treatment of the instant invention

represent a significant advance in the treatment of ocular and periocular infections.

In order that those skilled in the art can more fully appreciate aspects of this invention, the following examples are set forth. These examples are given solely for purposes of

illustration, and should not be considered limiting. Example I An exemplary formulation of the quinolone antimicrobial SS734 is shown in this

example. Table I summarizes an exemplary formulation comprising the quinolone antimicrobial

SS734 according to the invention, and two comparison formulations containing SS734. All

components are given as their weight percent of a 100 ml solution (i.e., grams/100 ml), except

for NaOH and water. NaOH is added to yield a final pH of about 5.5 to about 5.8 and water is added to yield a final volume of 100 ml. Noveon AA-1™ is the trade name of polymers of

acrylic acid crosslinked with divinyl glycol and is a product of B. F. Goodrich; Cleveland, OH.

Poloxamer™ 407 is a block copolymer of ethylene oxide and propylene oxide manufactured by

the BASF Company; Ludwigshafen, Germany. Hydroxypropyl-β-cyclodextrin has been

abbreviated as HBPC. Table I.

Formulation LD A B C

Noveon AA-1 0.8 Not Added 0.8

Hydroxypropyl- Not 1.0 Not Added methylcellulose Added

HPBC 5.0 Not Added Not Added

SS734 0.3 0.3 0.3

EDTA 0.1 0.1 0.1

NaCl 0.4 0.4 0.4

Mannitol 1.0 1.0 1.0

Benzalkonium chloride 0.01 0.01 0.01

Poloxamer 407 0.1 0.1 0.1

NaOH to a final pH of: 5.5-5.8 5.5-5.8 5.5-5.8

Water to a final volume 100 ml 100 ml 100 ml of:

The formulations are prepared by addition of a separately prepared drug solubilizer solution/suspension to a mixture containing hydrated Noveon, when present, and the remaining

excipients with continuous stirring. The resulting composite mixtures are titrated to a final pH of

5.5-5.8, and the final formulation weight of SS734 is adjusted by addition of water to each formulation. Formulations are filled in glass vials, capped, and crimped. Formulation A is

translucent, with the quinolone antimicrobial completely dissolved. Formulations B and C are

suspensions. The solubility fraction of the drug in these suspensions is about 0.3%.

Example II

In this example, ocular administration studies with SS734 are performed. For tear fluid

concentration studies formulations A, B and C are prepared according to Example I. Following

an initial measurement, 25 μl aliquots of the respective formulations are instilled into the eyes of

New Zealand white rabbits. The concentration of compound SS734 in tear fluid is measured at

the desired subsequent time points. Quantitation of SS734 concentration in tear fluid is

conducted employing LCMS for the analysis. Results are shown in figure 2.

For conjunctival concentration studies, formulations A, B, and C are prepared according

to Example I, except that each sample contains 0.192 % citric acid, which is used to dissolve the

SS734 in acidic conditions. Following an initial measurement, 25 μl aliquots of the respective

formulations are instilled into the eyes of New Zealand white rabbits. The concentration of

compound SS734 available to conjunctival tissue is measured at the desired subsequent time

points. Quantitation of SS734 concentration in samples is conducted employing the HPLC

system described in Example II. Results are shown in figure 3.

The results demonstrate that the inventive formulations according to one of the preferred

embodiments of the invention, formulation C, provide extended release of compound SS734

based upon both conjunctival and tear fluid measurements. Example LU

In this example, formulation SS734 of the present invention is compared to the published

results of several known compounds. Results are shown in Figures 4 and 5.

The above discussion of this invention is directed primarily to certain embodiments of the invention. It will be apparent to those of skill in the art that further changes and modifications

can be made in the actual implementation of the concepts described herein without departing

from the spirit of the invention as defined in the following claims.

Example TV

Exemplary formulations of micronized quinolone antimicrobial SS734 are set forth in this example. All components are given as their weight percent of a 100 ml solution (i.e., grams/100

ml), except for NaOH and water. NaOH is added to yield a final pH of about 5.5 to about 5.8

and water is added to yield a final volume of 100 ml. To prepare the compositions the pH —

solubility profile of the drug was first measured and the drug was found to have low solubility at pH 6.5.

Formulation ID A B

Noveon AA-1 Not Added 0.8

Hydroxypropyl- 1.0 Not Added methylcellulose

Micronize SS734 0.3 0.3

EDTA 0.1 0.1

NaCl 0.4 0.4

Mannitol 1.0 1.0

Benzalkonium chloride 0.01 0.01

Poloxamer 407 0.1 0.1

NaOH to a final pH of: 6.5 6.5

Water to a final volume 100 ml 100 ml of: The formulations are prepared by separately subjecting antimicrobial SS734 to

micronization to yield particles in the range of 10 microns average diameter. The vehicle

components of the formulation, including the hydrated Noveon when present, and the remaining

excipients are separately prepared in sufficient water, and the pH adjusted to 6.5 by addition of

NaOH as required. With continuous stirring the micronized SS734 is added to the vehicle

components. The final formulations are adjusted to pH 6.5 as required, and the composition is

adjusted to a final volume and SS734 concentration by addition of water to each formulation.

The formulations are subjected to heat sterilization at 123° C for 30 minutes with all components

present, and presterilized individual vials are aseptically fill with individual doses. No significant alteration in particle size distribution following heat sterilization.

Each patent, journal article, or other reference herein cited is herein incorporated by

reference in its entirety.

Claims

What is claimed is:

1. A topical ophthalmic composition comprising:

a quinolone carboxylic acid derivative of formula (I),

wherein R¹ is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which

can be hydrolyzed in vivo, R is a hydrogen atom or an amino group which may be substituted by

one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH₂, O, S, SO, SO₂,

or N-R³, wherein R³ is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms.

2. The composition of claim 1, wherein said composition provides sustained release of said

quinolone carboxylic acid derivative.

3. The composition of claim 1, further comprising a carboxy containing polymer.

4. The composition of claim 3, wherein said carboxy containing polymer comprises from about

0.1% to about 6.5% by weight of said composition, based on the total weight of said

composition.

5. The composition of claim 4, wherein said polymer contains up to about 40% by weight of

non-carboxyl containing monoethylenically unsaturated monomers.

6. The composition of claim 5, wherein said quinolone carboxylic acid derivative of formula (I) comprises particles prepared by micronization.

7. The composition of claim 6, wherein said particles have an average diameter less than about

10 microns.

8. The composition as in claim 1 , wherein said quinolone carboxylic acid derivative of formula (I) is present from about 0.005% to about 10% by weight based upon the total weight of the

composition.

9. The composition of claim 8, wherein said quinolone carboxylic acid derivative of formula (I)

is present from about 0.02%-2.5% by weight based upon the total weight of the composition.

10. The composition as in claim 1, further comprising one or more excipients.

11. The composition as in claim 1, in which said quinolone carboxylic acid derivative of formula

(I) is a pro-drug form of said quinolone carboxylic acid derivative.

12. The composition as in claim 1, wherein said quinolone carboxylic acid derivative of formula

(I) is the free acid (R )-(+) -7-(3-amino-2, 3, 4, 5, 6, 7-hexahydro- lH-azepin-1 -yl)-8-chloro-l -

cyclopropyl-6-fluoro-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt thereof, or

hydrochloride thereof.

13. The composition as in claim 1 , wherein said quinolone carboxylic acid derivative of formula

(I) is the free acid 8-chloro-l-cyclopropyl-6-fluoro-7-(2, 3, 4, 5, 6, 7-hexahydro-5-oxo-lH-l,4-

diazepin-l-yl)-l ,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt thereof, or hydrochloride

thereof.

14. The composition of claim 1, wherein said quinolone carboxylic acid derivative of formula (I)

comprises particles prepared by micronization.

15. The composition of claim 14, wherein said particles have an average diameter less than about 10 microns.

16. The composition of claim 1, further comprising a solubilizer.

17. The composition of claim 16, wherein said solubilizer is hydroxypropyl-β-cyclodextrin.

18. The composition of claim 17, wherein said hydroxypropyl-β-cyclodextrin is about 5.0% to

about 20.0% by weight of said composition, based on the total weight of said composition.

19. The composition of claim 1, further comprising a cross-linked carboxy containing polymer.

20. The composition of claim 19, wherein said cross-linked carboxy containing polymer

comprises from about 0.1% to about 6.5% by weight of said composition, based on the total weight of said composition.

21. The composition of claim 20, wherein said cross-linked carboxy containing polymer

comprises from about 0.5% to about 1.0% by weight of said composition, based on the total

weight of said composition.

22. A method of treating or preventing an infection in the ocular or periocular region

comprising:

delivering to the ocular or periocular region a composition comprising a quinolone carboxylic

acid derivative of formula (I),

wherein R¹ is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which

can be hydrolyzed in vivo, R is a hydrogen atom or an amino group which may be substituted by

one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH₂, O, S, SO, SO₂,

or N-R , wherein R is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms.

23. The method of claim 22, wherein said composition provides sustained release of said

quinolone carboxylic acid derivative.

24. The method of claim 22, wherein said composition further comprises a carboxy containing polymer.

25. The method of claim 24, wherein said carboxy containing polymer comprises from about

0.1 % to about 6.5% by weight of said composition, based on the total weight of said

composition.

26. The method of claim 25, wherein said polymer contains up to about 40% by weight of non- carboxyl containing monoethylenically unsaturated monomers.

27. The method of claim 26, wherein said quinolone carboxylic acid derivative of formula (I)

comprises particles prepared by micronization.

28. The method of claim 27, wherein said particles have an average diameter less than about 10

microns.

29. The method as in claim 22, wherein said quinolone carboxylic acid derivative of formula (I)

is present from about 0.005% to about 10% by weight based upon the total weight of the

composition.

30. The method of claim 29, wherein said quinolone carboxylic acid derivative of formula (I) is present from about 0.02%-2.5% by weight based upon the total weight of the composition.

31. The method of claim 22, wherein said quinolone carboxylic acid derivative of formula (I)

comprises particles prepared by micronization.

32. The method of claim 31, wherein said particles have an average diameter less than about 10

microns.

33. The method of claim 22, wherein said composition further comprises one or more

excipients.

34. The method as in claim 22, in which said quinolone carboxylic acid derivative of formula (I)

is a pro-drug form of said quinolone carboxylic acid derivative.

35. The method as in claim 22, wherein said quinolone carboxylic acid derivative of formula (I) is the free acid (R )-(+) -7-(3-amino-2, 3, 4, 5, 6, 7-hexahydro-lH-azepin-l-yl)-8-chloro-l-

cyclopropyl-6-fluoro-l ,4-dihydro-4-oxoquinoline-3 -carboxylic acid, a salt thereof, or

hydrochloride thereof.

36. The method as in claim 22, wherein said quinolone carboxylic acid derivative of formula (I) is the free acid 8-chloro-l-cyclopropyl-6-fluoro-7-(2, 3, 4, 5, 6, 7-hexahydro-5-oxo-lH-l,4-

diazepin-l-yl)-l,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt thereof, or hydrochloride

thereof.

37. The method of claim 22, wherein said composition further comprises a solubilizer.

38. The method of claim 37, wherein said solubilizer is hydroxypropyl-β-cyclodextrin.

39. The method of claim 38, wherein said hydroxypropyl-β-cyclodextrin is about 5.0% to about

20.0% by weight of said composition, based on the total weight of said composition.

40. The method of claim 22, wherein said composition further comprises a cross-linked carboxy

containing polymer.

41. The method of claim 40, wherein said cross-linked carboxy containing polymer comprises from about 0.1% to about 6.5% by weight of said composition, based on the total weight of said

composition.

42. The method of claim 40, wherein said cross-linked carboxy containing polymer comprises

from about 0.5% to about 1.0% by weight of said composition, based on the total weight of said

composition.

43. The method as in claim 22, wherein said composition is a solution, composition, ointment,

or instillant.

44. The method as in claim 22, wherein said infection is an infection of Gram positive bacteria,

Gram negative bacteria, or a mixed infection of Gram positive and Gram negative bacteria.

45. The method as in claim 44, wherein said infection is an infection of a bacteria selected from

the group consisting of Escherichia coli, Salmonella typhi, Shigella βexneri, Klebsiellia

pneumonia, Proteus vulgaris, Proteus rettgeri, Haemophilus inβuenzae, Pseudomonas

aeruginosia, Serratia marcescens, Moraxella morganii, Moraxella lacunata, Moraxella

catarrhalis, Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis,

Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus pyogenes, Streptococcus

pneumoniae, Enterococcus faecalis , Micrococcus lysodeikticus, and combinations thereof.

46. The method of claim 42, wherein the infection is a mixed infection of Gram negative

bacteria and Gram positive bacteria.

47. A method of preparing a sustained release topical ophthalmic delivery system, comprising:

preparing an composition comprising a quinolone carboxylic acid derivative of formula

(I),

wherein R is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which

can be hydrolyzed in vivo, R is a hydrogen atom or an amino group which may be substituted by

one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH₂, O, S, SO, SO₂, or N-R³, wherein R³ is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two

hydrogen atoms; and,

packaging said composition for administration to the eye.

48. The method of claim 47, wherein said composition further comprises a carboxy containing

polymer present from about 0.1% to about 6.5% by weight of said composition, based on the

total weight of said composition.

49. The method of claim 48, wherein said quinolone carboxylic acid derivative of formula (I) is

present as particles having an average diameter less than about 10 microns, and wherein said

particles are prepared by micronization of said quinolone carboxylic acid.