ZA200201957B - Topical treatment for prevention of ocular infections. - Google Patents

Description

'& ‘ . Co A

TOPICAL TREATMENT FOR PREVENTION OF OCULAR INFECTIONS

BACKGROUND OF THE INVENTION

1. Cross-reference to Related Application

This application is a continuation-in-part of Application Serial No. 09/394,617, which was filed September 13, 1999. 2. Field of the Invention

The present invention relates to a method for treating or preventing infections in the eye and to compositions useful therein. ; 3. Description of the Related Arts

The eye is susceptible to bacterial and parasitic infections arising from both traumatic and non-traumatic related events. Infections are a concern after ocular surgery and precautions are correspondingly taken to prevent the onset of infection. However, even without the invasive trauma of a surgical procedure, infections in the eye lids, conjunctiva, cornea, and other ocular tissues can arise.

Treating infections in ocular tissues can be challenging and/or problematic because of the difficulty in delivering an antibiotic to the affected tissue. In general, ocular ) infections are treated by local injection, systemic administration, or topical application of an antibiotic. The route of administration depends on the antibiotic selected, the location ) of the infection and the type of infection.

The simple and direct approach of topically applying the antibiotic to the exterior of the eye has several benefits, including the avoidance of side effects and the reduced chance of developing resistant strains of bacteria as compared to systemic administration.

However, for a variety of reasons, many antibiotics are not amenable or suitable for topical application to the eye.

For example, in order for a topical application to be effective, the antibiotic must be able to penetrate the desired tissue. This may include penetrating the conjunctiva and the cornea. Also, the penetration rate must be sufficient to impart an effective dose. Many drugs do not possess a requisite penetration ability with regard to the tissues of the eye. It should be noted that the external layers of the eye are quite different from the tissues encountered in the stomach and intestinal tract. Thus, while a certain drug may be readily absorbed in the intestines and introduced into the blood supply for systemic 1

SUBSTITUTE SHEET (RULE 26)

administration, the same drug may be incapable of being absorbed by, or of passing through, the substantially avascular outer layers of the conjunctiva or cornea at a minimally acceptable therapeutic concentration. The mechanism of transport or uptake of the drug is entirely different for topical administration than for oral administration.

Another concern is that the antibiotic will be toxic to the eye. A toxic response includes redness, swelling and/or discharge. Toxicity is especially problematic for topical administration because it is a concentration dependent phenomenon. The concentration ratio between tear fluid and ocular tissue in topical administration is generally in the range of about 1:500 to 1:1000, due to the penetration gradient. Thus, while a drug may be non- toxic at the minimum effective concentration, the S00% to 1000% increase in concentration associated with topical administration may well induce a toxic response.

Again, the fact that oral or systemic administration shows the drug to be compatible with ocular tissue does not predict or address the toxicity issue associated with topical administration.

A further potential unsuitability of an antibiotic is the practicality of topical administration by the patient. Assuming that sufficiently high concentrations of the antibiotic can be used to achieve an effective dose within the target tissue without a toxic : response, the application may nonetheless be irritating. An irritation response includes temporary burning, stinging and/or watering of the eye. Beyond whether the increased - watering of the eyes washes away so much of the antibiotic composition that an effective dose is prevented, the patient may simply be resistant to complying with the dosage regimen because of the irritation. By failing to comply with the dosing regimen, the treatment efficacy is reduced or eliminated.

Some antibiotics have been found to sufficiently meet the above requirements so as to be applicable to topical administration. Examples of antibiotics that are reported to be useful in ocular topical administration include tobramycin, gentamycin, fluoroquinolone derivatives including norfloxacin, ofloxacin, and ciprofloxacin, naphthyridine, tetracyclines, and erythromycin. However, in view of the rise in resistant strains of bacteria, it would be desirable to find additional antibiotics that can be topically applied to the eye. It would be further desirable to provide an ophthalmic topical formulation that is effective against gram-positive aerobic bacteria as well as anaerobic organisms. 2

SUBSTITUTE SHEET (RULE 26)

SUMMARY OF THE INVENTION

The present invention relates to a process for treating an eye that comprises topically applying an oxazolidinone antibiotic to an eye in an amount effective to treat or prevent infection in a tissue of the eye. Applicant has discovered that oxazolidinone antibiotics, which are class of known oral antibiotics, are suitable for topical administration to the eye. Preferably the oxazolidinone antibiotic is a phenyloxazolidinone, more preferably an oxazinc or thiazine phenyloxazolidinone.

The invention also relates to a topical ophthalmic composition containing an oxazolidinone antibiotic. In one embodiment, the ophthalmic composition is a sustained release composition comprised of an aqueous suspension of the oxazolidinone antibiotic and a polymer suspending agent.

The present invention includes and provides an aqueous polymeric suspension comprising water, 0.05% to 5.0% of an oxazolidinone antibiotic, and 0.1 to 10% of a polymeric suspending agent, wherein said polymeric suspending agent comprises a water- swellable water-insoluble crosslinked carboxy-vinyl polymer.

The present invention includes and provides a composition comprising water, a polymeric suspending agent, and a compound of formula I'V.

The present invention includes and provides a composition comprising water, an oxizolidinone, a polymeric suspending agent, and a solubility enhancer.

DETAILED DESCRIPTION OF THE INVENTION

“Oxazolidinone antibiotic” as used herein means a compound having an oxazolidinone nucleus that exhibits antimicrobial activity. Typically the compound nucleus is substituted as shown in the following structure fragment: 0 0-0 — "

NH

The phenyl ring can be substituted by a variety of groups as is well known in the oxazolidinone antibiotic art and can form a fused ring with the substituents and/or the oxazolidinone ring itself. The carbonyl moiety is bonded to one of a number of well 3

SUBSTITUTE SHEET (RULE 26)

EEE known terminal groups. An “phenyloxazolidinone” means a oxazolidinone ring with a phenyl group bonded to the ring nitrogen as shown in the above fragment, with or without the amidemethylene substituent.

More specifically, the oxazolidinone antibiotics used in the present invention can generally be represented by the following formulas I and II and the pharmaceutically acceptable salts thereof: " lo}

Re A

N 0} I

J

R* Yom NH-C—R!

YT 1 . (a x II y' N [o] i

NH-C—R wherein:

R'is selected from the group consisting of (1) -H, (2) NHj, (3) C;-Cs alkylamine, (4) C;-

Cs dialkylamine, (5) C;-Cs alkoxy, (6) C:-C;, alkyl optionally substituted with 1-3 CJ, (7) C5-Cy; cycloalkyl, (8) Cs-C;; alkenyl containing one double bond, (9) C;-Cs acyloxy, (10) O-CH’-phenyl, (11) phenyl optionally substituted with 1-3 -OH, -OCHj, -

OC,Hs, -NO,, -F, -Cl, -Br, -COOH and SO;H, -NR! HR"); where R'! and R'? are the same or different and are —-H, C;-Cs alkyl, (12) furanyl, (13) tetrahydrofuranyl, (14) 2-thiophene, (15) pyrrolidinyl, (16) pyridinyl, (17) -OR"?, where R'? is C;-C4 alkyl, (18) -NH,, (19) -NHR™, 4

SUBSTITUTE SHEET (RULE 26)

where R'™ is C,-Cs alkyl or phenyl, (20) -NR'“R'?, where R'? is C;-C3 alkyl and R'* is as defined above, and where R'* and R"™ can be taken together with the attached nitrogen atom to form a saturated mono-nitrogen

Cs-Cs heterocyclic ring including O, (21) CH,-OH, and (22) CH,-OR"®, where R'® is C,-Cy alkyl, or CO-R'” is C,-C; alkyl or -phenyl;

R? and R* are the same or different and are selected from the group consisting of (1) H, (2) -OH, (3) halogen, (4) CF;, (5) OCH; provided that only one of R? or R*is —H, and (6) 0-CO-R™, where R*! is C,-C; alkyl or —phenyl;

R? is selected from the group consisting of (1) H, (2) halogen, (3) -O-CHj, (4) -O-C;Hs, (5) piperdine, (6) 4-hydroxypyridine, (7) piperazine, unsubstituted or substituted with

Q where Q is a 5, 6-, 7- or 8-membered heterocyclic ring of the general formula -

C*H=CH-CH=Z-Y*=W* where the atoms or symbols representing an atom marked with an asterisk (*) are bonded to each other resulting in the formation of a ring where one of Z, Y? and W is -N= and the others are C=, unsubstituted or : substituted with substituents selected from the group consisting of H, -C,-C4 alkyl, -NO,, -NH,, -NH-CO-[C,-C; alkyl], -CN, -COOH, -O-[C,-C4 alkyl], halogen and N-oxides thereof; or Q is C;-C,4 alkyl unsubstituted or substituted with substituents selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, benzyl, phenyl, pyridyl, acetyl, difluoroacetyl, hydroxyacetyl, benzoyl, methoxy carbonyl, ethoxy carbonyl, 2-chloroethoxy carbonyl, 2-hydroxyethoxy carbonyl, 2-benzyloxyethyoxy carbonyl, 2- methoxyethoxy carbonyl, 2,2,2-trifluroethoxy carbonyl, cyanomethyl, 2- cyanoethyl, carbomethoxymethyl, 2-carbomethoxyethyl, 2-fluoroethoxy carbonyl, benzyloxy carbonyl, tertiary-butoxy carbonyl, methyl sulfonyl, phenyl sulfonyl, or paratoluenesulfonyl, (8) phenyl, (9) pyridyl, (10) pyrazidyl, (11) pyridazinyl, (12) pyrimidinyl, (13) 1,2,3- triazinyl, (14) 1,2,4-triazinyl, (15) 1,2,5-triazinyl, (16) quinolinyl, (17) isoquinoliny],

SUBSTITUTE SHEET (RULE 26)

(18) quinoxalinyl, (19) quinazolinyl, (20) phthalazinyl, (21) cinnolinyl, (22) naphthylpyridinyl, (23) indolyl having nitrogen optionally substituted with R*!", (24) pyrrolopyridinyl having the saturated nitrogen substituted with R*"", (25) furanopyridinyl, (26) thienopyridinyl, (27) benzothiazolyl, (28) benzoxazolyl, (29) imidazolyl having the saturated nitrogen substituted with R*'”, (30) pyrazolyl having the saturated nitrogen substituted with R*""!, (31) thiazolyl, (32) isothiazolyl, (33) oxazolyl, (34) isoxazolyl, (35) pyrrolyl having nitrogen substituted with R*'", (36) furanyl, (37) thiophenyl wherein substituents 1-37 are optionally substituted with U and

V, (38) 1,2,3-triazolyl, (39) 1,2,4-triazolyl having the saturated nitrogen substituted with R!! where R*! is H, C,-C, alkyl unsubstituted or substituted with one or more halogens,

C;3-Cs cycloalkyl, or C(O)R*'?, where R*' is -H, C;-C, alkyl unsubstituted or substituted with one or more halogens, or phenyl unsubstituted or substituted with one or more halogens; wherein 1,2,3-triazolyl and 1,2,4-triazolyl are unsubstituted or substituted with U; each occurrence of V is independently selected from substituents selected from the group consisting of H, halogen, R*", OR*’; - where R*! is -H or C,-C, alkyl or NO; each occurrence of U is independently selected from the group consisting of (1) H, . (2) C,-Cg alkyl unsubstituted or substituted with one or more substituents selected -- from the group consisting of halogens, -OH, =O other than at alpha position,

S(O)R*?, where R*? is C,-C, alkyl or C3-Cs cycloalkyl and NR**R3#, where R*? and R** are the same or different and are selected from the group consisting of H, C,-Cy alkyl, C;-C; cycloalkyl, -(CH,),CHOR*?, and (CH,).NR**R*7, or where R*? and R** taken together are selected from the group consisting of (CH;)O(CH;), (CH,)CH(CO)R*8, and (CH,)N(R* (CHa), where R*? is H, or C;-C, alkyl, or R*® and R*” are the same or different : and are H, or C;-C, alkyl or taken together are (CH,);; (3) C-Cs alkenyl, (4) C3-C;z cycloalkyl, (5) OR>3 where R* is as defined above, (6) -CN, (7) S-(O)n-R** 6

SUBSTITUTE SHEET (RULE 26)

where R** is C,-C,4 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, OH, CN, NR* ’R** where R*? and R** are as defined above, and CO,R*? where R*? is as defined above, C,-C; alkenyl, NR¥@R™, where R*? is H, C,-C, alkyl, or C3-Cg cycloalkyl and R*"? is ~H, C,-Cs4 alkyl, C;-C, alkenyl, C3-C,4 cycloalkyl, -OR*?, or NR**R*7, where R* 3 R*% and R*7 are as defined above; Nj, NHC(O)R*!!: where R*!! is C;-C, alkyl optionally substituted with one or more halogens, (8) -S(0),N=S(O)R*™R*"’, where R*™* and R*' are the same or different and are C,-C; alkyl or taken together are (CHy)q-, (9)-S-C(O)-R**! where R*!! is as defined above; (10) tetrazoyl, (11) NR>*R** where R*? and R>* are as defined above, (12) N(R**)COR>!! where R*? and R* '! are as defined above; (13) -N(R**)-S-(0),R*"! where R** and R*!! are as defined above, (14) -CONR*3R**# where R*>> and R** are as defined above, (15) -C(O)R™"® where R* is —H, C,-C; alkyl optionally substituted with -OR*?, -OC(O)R*?,

NR**R™, $(0),R*"", C3-Cg cycloalkyl, or C,-Cs alkenyl optionally : substituted with CHO or ~CO,R**, where R*3, R** and R*? are as defined above and where R*" is C;-C, alkyl or C3-Cs cycloalkyl, (16) -C(=NR*'*)R*"'® where R*'® is as defined above and where R>% js -NR**R>**, -OR*? or NHC(O)R>*® where R*® and R** are as defined above, (17) CR*(OR*'?)OR >? where R*"'% is as defined above and R>'® and R**° are the same or different and are C;-C, alkyl or taken together are -(CHy);-, (18) -CNR*R*?) (ROR), (19) -COR*)R*)R*), (20) -C(O-C(OR™

RMR), (21) -COR™)(CH)-NRZPR™)(R™)), (22) -CNR*R™)H(R” 16) R39), 4

SUBSTITUTE SHEET (RULE 26)

where R*?, R**, R*®, and R*' are as defined above and where R*?! is R** or ~NR**R*® where R** and R** are as defined above; with the proviso that at least one of the R%, R* and R* is H,

X' is selected from the group consisting of NR'*, CR'*R", S, SO, SO, or O;

RY is selected from the group consisting of (1) -H, (2) C3-Cs alkyl, (3) -(CH;),-Aryl, (4) (CHa)y-C(=0)-R™", (5)-C(=0)-R"*" (6) -C(=0)-(CHa)-C(=O)R*", (7) SO»-

R'*?, (8) (C=0)-Het, (9) 2-pyridyl, (10) 2-pyrimidinyl, (11) 3-pyridazinyl or (12) 2- quinolyl; where R"*! is selected from the group consisting of -H, C;-Cg alkyl, Aryl, (CHy),-

Aryl, or ~(CH,),-OR"*?%; where R12 is selected from the group consisting of -H, C,-Cs alkyl, Aryl, (CHa)p-Aryl, or ~C(=0)-C;-Cs alkyl; where R'*? is C;-Cg alkyl, or Aryl;

Aryl is phenyl, unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, C;-Cg alkyl, C,-C,4 alkoxy, C;-C4 : alkylthio, -OH, -NH,, SH, -NO, or —-0-C(=0)-OCHj;

Het is a 5-, 6-, 8-, 9-, or 10-membered heteroaromatic moiety having one or more . atoms selected from the group consisting of N, O, and S;

R'® and R'7 are each and independently selected from the group consisting of (1) =H, (2) C1-Cs alkyl, (3) C,-C; alkoxy, (4) C;-Cg alkylthio, (5) -(CH;),-OR'5",(6) NR'® ’R"72, (7) -N=CH-NR'*R"3, (8) -C(=0)-NR'*?’R'"2, (9) (CH,)s-C(=0)-R"**, and (10) (CHz)-Q', -(CH)u-W'; where R'®" is —H, C;-Cs alkyl, -(CHz),-OR'®?, -(CH,),-C(=0)-R'**, -C(=0)- (CH2),-OR'®3, or tosyl; where R'*? and R'"? are each and independently selected from the group consisting of —H, C;-Cs alkyl, -(CH,),-OR!®3, -C(=0)-R'¢*, -C(=0)-NR'*R'™ 3, -(CHa)-Ary), and Het; where R$? and R?* are each and independently selected from the group consisting of -H, C;-C¢ alkyl or methoxymethyl; where R'®? and R'"? are each and independently selected from the group consisting of =H, C;-Cs alkyl, -C(=0)-R'**, and (CH,),-Aryl; 8

SUBSTITUTE SHEET (RULE 26)

where R'®* is selected from the group consisting of —H, -OH, C;-Cs alkyl, C,-Cs alkoxy, -O-CH,-O-C(=0)-R'®* and -(CH,),-C(=0)-OR'¢>;

Q' is a saturated 5-membered heterocyclic moiety having 1-2 atoms selected from the group consisting of N, O, and S;

W' is a saturated 6-membered heterocyclic moiety having 1-2 atoms selected from the group consisting of N, O, and S; or where R'® and R" taken together are =O, =NR'"*, =S, =CR!**R"?3 or Qh where R'"* is selected from the group consisting of ~OR'®", C,-Cs alkyl, C;-Cs alkoxy, and —(CH,),-Aryl;

Y'isHor halogen;

Ym: Yis CR" and misO, 1, or 2, when m is 0, the Y moiety is not present, and therefore there is no central ring in formula I (i.e., the dotted line in formula I represents no bond); when mis 1, Y forms a tricyclic-fused S-membered ring with carbon 3 of the oxazolidinone ring, and R’ is either one or two moieties, when R’ is two moieties comprising R’" and R’*, each is bound to the same : carbon in the tricyclic-fused 5-membered ring, which in turn is bound to carbon 3 of the oxazolidinone ring (i.e., the dotted line in formula lis a - single bond), andR’™! and R"~? are each independently H, C;-C; alkyl, CI,

Br, OH, or I; when R’ is one moiety, either: there is a double bond between the carbon atom to which R is attached and carbon 3 of the oxazolidinone ring (i.e., the dotted line in formula I is a double bond), or there is a single bond between the carbon atom to which R’ is attached and carbon 3 of the oxazolidinone ring (i.e., the dotted line in formula I is a single bond), and R” is —-C(=0)H; and when mis 2, Y,, is CR'CR®, which forms a tricyclic-fused 6-membered ring with carbon 3 of the oxazolidinone ring, and R’ and R® are each either one or two moieties, 9

SUBSTITUTE SHEET (RULE 26)

v “wo 01/19366 PCT/US00/24914 when R7 and R? are both one moiety, a double bond is formed between the carbon atoms that comprise Y to which they are attached, and R’ and R® are both H, when R” and R?® are both two moieties, R’ comprisesR’" and R72, where one of R” and R’? is H and the other is H, OH, or OC(=O)R’~, where R”” is

C,-C; alkyl or phenyl, optionally substituted with 1 or 2 F, Cl, OH, or

OCH3, and R® comprises R*! and R®*?, where one of R®' and R®”? is H and the other 1s H, OH, or OC(=0)R%?, where R®3 is C,-C; alkyl or phenyl, optionally substituted with 1 or 2 F, Cl, OH, or OCH;.

Z'is-0, -N, -S, -80,, SO, NR'®, -SNR*", or S(O)NR*”, where R'® is selected from the group consisting of —H, C,-C alkyl, -C(=0)-R'*", -

C(=0)-OR'*! and C(=0)-(CH;),-C(=O)R'*", where R'*" is H, C,-Cs alkyl, -(CHz)p-Aryl, or {CHy),-OR'*%; where RZ is _H, C,-Cs alkyl, or (CH,),-Aryl; where R* is independently —H, C,-C; alkyl (optionally substituted with —Cl, -F, -OH,

C;-C4 alkoxy, NH;, C;-Cg alkylamine or C,-Cg dialklylamine), —p-toluenesulfonyl,

CR’R') where R’ and R" are each and independently -H, -C,-Cg alkyl, -C;-C alkoxy, -C;-Cs alkylthio, -(CHz)n-OR’*', -O-(CH2)m-OR’', NR*¥R*, -N=CH-NR*R*, -C(=0)- . NR¥R%, -C(=0)-NR*’R% or -(CHz)n-C(=A")-R*!, or they may combine together to form =O, =NR*, =S, CR*R*, or an optionally substituted, unsaturated or saturated 5- or 6-membered hetero ring having 1-3 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom;

R* is -H, -(CH?)»-OH, C,-Cs alkyl, C,-Cj alkoxy, -O-CH,-0-C(=0)-R"!, or — (CH) C(=0)-OR; where R'' is =H, -H, C;-Cs alkyl, methoxymethyl,

R* and R™ are each and independently —H, -(CHp)o-OR"., C;-C; alkyl, -C(=0)-

RY, C(=0)-NR"'R", -(CH;),-phenyl, thiazol-2-yl, or they may combine together to form a pyrrolidino group, a piperidino group, a piperazino group, a morpholino group, or a thiomorphinolino group, each of may be substituted by

C,-C4 alkyl or (CH;),,-OH; where R'' and R'? are each independently —H, C;-C; alkyl, methoxymethyl,

SUBSTITUTE SHEET (RULE 26)

R43 is -H, -OR’!, C,-C; alkyl, C,-Cs alkoxy, -(CH,),-phenyl, -NR*R*?, -NH-

C(=NH)-NH,, [1,2,4]triazol-4-yl, or cyano;

R* and R™ are each and independently -H, C;-Cs-alkyl, -C(=0)-R*', or ~(CH,),- phenyl;

R'is -H, C;-Csg alkyl, C;-Cg alkyl substituted by one or more hydroxy, C,-Cq alkenyl, C;-Cg halogenoalkyl, -(CHy)m-OR"!, «(CH;)m-C(=0)-Ry;, -C(=0)- (CH,)m-OR™ or tosyl;

R® optionally is COOR’? where R®*? is ~C(0)-R’?, -PO; or -P(O)(OH),; where R*? is

C1-Cs alkyl, -N(R’*),, C,-Cs alkyl-N(R®*),, -phenyl-N(R**),, -phenyl-

NHC(O)CH;NH,, -C,Hy4-, morpholinyl, pyridinyl, C,-C¢ alkyl-OH, C,-Cg alkyl-

OCHj;, C;-Ce alkyl-C(O)CHs;, -O-C,-Cg alkyl-OCHj3;, C,-C5 alkyl-piperazinyl (optionally substituted with C;-C3 alkyl), imidazolyl, C;-Cs alkyl-COOH, -

C(CH,OH),CHj, where R** is —H or C;-Cg alkyl; -(CH,),-R®® where R* is —H, -

CH;, CH,CH,;, isopropyl, tert-butyl, phenyl, pyridyl, acetyl, difluoroacetyl, hydroxyacetyl, benzoyl, methoxy carbonyl, ethoxy carbonyl, 2,2,2-trifluoroethoxy carbonyl, cyanomethyl, 2-cyanoethyl, carbomethoxymethyl, 2- carbomethoxyethyl, 2-fluoroethoxy carbonyl, benzyloxy carbonyl, tertary-butoxy carbonyl, methyl sulfonyl, phenyl sulfonyl, or paratoluenesulfonyl;

R’ optionally is a five membered heterocyclic ring (azoyl) of the general form

C*H=N-D-B-A*- where the atoms or symbols representing an atom marked with ' an asterisk (*) are bonded to each other resulting in the formation of a ring, wherein A, B, and D are independently oxygen, nitrogen, sulfur or carbon, in all cases the piperazine nitrogen is attached to the carbon atom of the carbon-nitrogen double bond;

A' is oxygen atom or ethyleneketal; 1’s are each and independently 0 or 1; j’s are each and independently 2 or 3; k’s are each and independently 1 or 2; m’s are each and independently 0, 1,or 2; n’s are each and independently 0, 1, or 2; p’s are each and independently 1, 2, 3 or 4; q’s are each and independently 3, 4, or 5; 11

SUBSTITUTE SHEET (RULE 26)

t’s are each and independently 1, 2, or 3.

In one aspect of the present invention, the oxazolidinone antibiotic is a compound of the formula III:

R* RY > I ” OS Im a — 0

RE R* NH?

X is O, S, SO, SO,SNR¥ or S(O)NR*

Ris hydrogen, C;-Cs alkyl unsubstituted or substituted with one or more of the following: F, Cl, hydroxy, C,-Cs alkoxy, C,-Cg acyloxy or —O-CH,-phenyl; C,-Cs cycloalkyl, amino, C,-Cjs alkyamino, C,-Cg dialkylamino or C;-C; alkoxy;

R* is H; CH;, CN, CO;H, CO,R, or (CH;)=R* except when X is not O then R* is H;

R?? and R? are each and independently H, F, or Cl;

R¥isH except when X is O and R* is CH; then R® can be H or CH?

R* is independently H, C;-C, alkyl (unsubstituted or substituted with chloro, fluoro, hydroxy, C,-C;z alkoxy, amino, C,-Cs alkylamino, or C,-C; dialkyamino) or p- toluenesulfonyl;

R*! is hydrogen, OH, OR?', OCOR”, NH;, NHCOR?' or N(R**); and m is 0, 1 or 2.

The compounds of formula III are described in U.S Patents 5,688,792 and 5,880,118. These compounds are preferred, in part, because of their efficacy against multiply-resistant staphylococci and their low minimum inhibitory concentration values.

Oxazolidinone antibiotics and their synthesis are well known in the art. Examples of oxazolidinone antibiotics and specific synthesis schemes can be found in the following

U.S. Patents: 5,929,248, 5,922,707, 5,880,118, 5,837,870, 5,801,246, 5,756,732, 5,736,545, 5,700,799, 5,652,238, 5,688,792, 5,668,286, 5,654,435, 5,654,428, 5,565,571, 5,547,950, 5,247,090, 5,231,188, 4,977,173, 4,948,801, 4,461,773, and 4,340,606, the entire contents of each patent being incorporated herein by reference. A particularly preferred oxazolidinone is a compound of formula IV: 12

SUBSTITUTE SHEET (RULE 26)

0) /\ A o) \__/ .C.

F Iv

It has now been discovered that oxazolidinone antibiotics in general and the compounds of formulas III and IV in particular are amenable to topical administration on the eye. The oxazolidinone antibiotic can be supplied to the eye surface in a variety of ways, including as an aqueous ophthalmic solution or suspension, as an ophthalmic ointment, and as an ocular insert, but application is not limited thereto. Any technique and ocular dosage form that supplies an oxazolidinone antibiotic to the external eye surface is included within the notion of “topically applying.” Although the external surface of the eye is typically the outer layer of the conjunctiva, it is possible that the sclera, cornea or other ocular tissue could be exposed such as by rotation of the eye or by surgical procedure and thus be an external surface.

The amount of oxazolidinone antibiotic topically supplied is effective to treat or prevent infection in a tissue of the eye. This means that the conditions of application result in a retarding or suppression of the infection. Typically at least about MICs for the targeted bacteria or parasite is delivered to the ocular tissue by the topical application of an effective amount. More concretely, the concentration within the ocular tissue is desired to be at least about 0.25 ug/g, preferably at least 1 ug/g, and more preferably about 10-50 ug/g. Generally, tissue concentrations that exceed about 50 pg/g, especially greater than 100 ng/g, are nearing or within a toxic response range. The amount of oxazolidinone antibiotic actually supplied to the external eye surface will almost always be much higher than the tissue concentration. This reflects the penetration hold up of the oxazolidinone antibiotic by the outer tissue layers of the eye, the loss of antibiotic due to natural clearing processes and that penetration is to some extent concentration driven. Thus, supplying greater amounts to the exterior will drive more antibiotic into the tissues.

The topical application of an oxazolidinone antibiotic can be used to treat or prevent a variety of conditions associated with ocular infection. For example, conditions of the lids including blepharitis, blepharconjunctivitis, meibomianitis, acute or chronic hordeolum, chalazion, dacryocystitis, dacryoadenities, and acne rosacea; conditions of the 13

SUBSTITUTE SHEET (RULE 26)

conjunctiva including conjunctivitis, ophthalmia neonatorum, and trachoma; conditions of the cornea including comeal ulcers, superficial and interstitial keratitis, keratoconjunctivitis, foreign bodies, and post operative infections; and conditions of the anterior chamber and uvea including endophthalmitis, infectious uveitis, and post operative infections, are a few of the tissues and conditions that can be treated by topical application of an oxazolidinone antibiotic. The prevention of infection includes pre- operative treatment prior to surgery as well as other suspected infectious conditions or contact. Examples of prophylaxis situations include treatment prior to surgical procedures such as blepharoplasty, removal of chalazia, tarsorrhapy, procedures for the canualiculi and lacrimal drainage system and other operative procedures involving the lids and lacrimal apparatus; conjunctival surgery including removal of ptyregia, pingueculae and tumors, conjunctival transplantation, traumatic lesions such as cuts, burns and abrasions, and conjunctival flaps; comeal surgery including removal of foreign bodies, keratotomy, and corneal transplants; refractive surgery including photorefractive procedures; glaucoma surgery including filtering blebs; paracentesis of the anterior chamber; iridectomy; cataract surgery; retinal surgery; and procedures involving the extra-ocular muscles. The prevention of ophthalmia neonatorum is also included. : More generally, the oxazolidinone antibiotics can be used to treat or prevent ocular infections caused by a variety of bacteria or parasites, including but not limited to one or . more of the following organisms: Staphylococcus including Staphylococcus aureus and

Staphylococcus epidermidis; Streptococcus including Streptococcus pneumoniae and

Streptococcus pyogenes as well as Streptococci of Groups C, F, and G and Viridans group of Streptococci; Haemophilus influenza including biotype III (H. Aegyptius); Haemophilus ducreyi; Moraxella catarrhalis; Neisseria including Neisseria gonorrhoeae and Neisseria meningitidis, Chlamydia including Chlamydia trachomatis, Chlamydia psittaci, and

Chlamydia pneumoniae; Mycobacterium including Mycobacterium tuberculosis and

Mycobacterium avium-intracellular complex as well as atypical mycobacterium including

M. marinum, M. fortuitm, and M. chelonae; Bordetella pertussis; Campylobacter jejuni;

Legionella pneumophila; Bacteroides bivius; Clostridium perfringens; Peptostreptococcus species; Borrelia burgdorferi; Mycoplasma pneumoniae; Treponema pallidum;

Ureaplasma urealyticum; toxoplasma; malaria; and nosema.

The oxazolidinone antibiotic is applied to the exterior surface of the eye, usually in an ophthalmically acceptable composition which comprises an ophthalmically acceptable 14

SUBSTITUTE SHEET (RULE 26)

carrier and the oxazolidinone antibiotic. The “ophthalmically acceptable carrier” is used in a broad sense and includes any material or composition that can contain and release the oxazolidinone antibiotic and that is compatible with the eye. Typically the ophthalmically acceptable carrier 1s walter or an aqueous solution or suspension, but also includes oils such as those used to make ointments and polymer matrices such as used in ocular inserts.

Generally, oxazolidinone antibiotics are soluble in water. Accordingly, an aqueous solution of an oxazolidinone antibiotic can be formed and used for topical application. A polymeric suspending agent may also be used to provide sustained release of the antibiotic. The polymeric suspending agent may be insoluble, thereby forming a polymeric suspension, or soluble, in which case no polymeric suspension is formed.

Oxazolidinone can be present in suspension or solution, or both. One embodiment of the present invention is an aqueous composition comprising a soluble polymeric suspending agent in solution, with oxazolidinone in solution or suspension, or both. Ointments and solid dosage forms can also be used as delivery compositions as are well known in the art.

The concentration of oxazolidinone antibiotic present in the ophthalmic composition depends upon the dosage form, the release rate, the dosing regimen, and the location and type of infection. Generally speaking, the concentration is from about 0.01 to 5%, more typically 0.1 to 2%, for fluid compositions and 0.5 to 50% for solid dosage forms, however, the compositions are not limited thereto.

The fluid ophthalmic compositions of the present invention, including aqueous . solutions, ointments and suspensions, have a viscosity that is suited for the selected route of administration. A viscosity in the range of from about 1,000 to 30,000 centipoise is useful for a drop. About 30,000 to about 100,000 centipoise is an advantageous viscosity range for ophthalmic administration in ribbon form. The viscosity can be controlled in many ways known to the worker skilled in the art.

The ophthalmic compositions may contain one or more of the following: surfactants, adjuvants including additional medicaments, buffers, antioxidants, tonicity adjusters, preservatives, thickeners or viscosity modifiers, and the like. Additives in the formulations may desirably include sodium chloride, EDTA (disodium edetate), and/or

BAK (benzalkonium chloride), sorbic acid, methyl paraben, propyl paraben, chlorhexidine, glycerin, and sodium perborate. In a preferred embodiment, solutions can clude sodium chloride, EDTA (disodium edetate), and/or BAK (benzalkonium chloride),

SUBSTITUTE SHEET (RULE 26)

sorbic acid, chlorhexidine, glycerin, and sodium perborate. In another preferred embodiment, ointments can include methyl paraben, propyl paraben, and chlorbutanol.

A further aspect of the present invention involves the above-mentioned use of additional medicaments in combination with the oxazolidinone antibiotic. A composition comprising an oxazolidinone antibiotic, an additional medicament, and an ophthalmically acceptable carrier can advantageously simplify administration and allow for treating or preventing multiple conditions or symptoms simultaneously. The “additional medicaments,” which can be present in any of the ophthalmic compositional forms described herein including fluid and solid forms, are pharmaceutically active compounds having efficacy in ocular application and which are compatible with an oxazolidinone antibiotic and with the eye. Typically, the additional medicaments include other antibiotics, antivirals, antifungals, anesthetics, anti-inflammatory agents including steroidal and non-steroidal anti-inflammatories, and anti-allergic agents. Examples of suitable medicaments include aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin; macrolides like azithromycin and erythromycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; sulfonamides; polymyxin; chloramphenicol; ‘ neomycin; paramomomycin; colistimethate; bacitracin; vancomycin; tetracyclines; rifampin and its derivatives (“rifampins™); cycloserine; beta-lactams; cephalosporins; . amphotericins; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac; suprofen; comolyn; lodoxamide; : levocabastin; naphazoline; antazoline; and pheniramimane. These other medicaments are generally present in a pharmaceutically effective amount as is understood by workers of ordinary skill in the art. These amounts are generally within the range of from about 0.01 to 5%, more typically 0.1 to 2%, for fluid compositions and from 0.5 to 50% for solid dosage forms.

The aqueous ophthalmic compositions (solutions or suspensions) for use in the present invention use water which has no physiologically or ophthalmically harmful constituents. Typically purified or deionized water is used. The pH is adjusted by adding any physiologically and ophthalmically acceptable pH adjusting acids, bases or buffers to within the range of about 5.0to 8.5. Examples of acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like, and examples of bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, 16

SUBSTITUTE SHEET (RULE 26)

tromethamine, THAM (trishydroxymethylamino-methane), and the like. Salts and buffers include citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases.

The osmotic pressure (x) of the aqueous ophthalmic composition is generally from about 10 milliosmolar (mOsM) to about 400 mOsM, more preferably from 260 to 340 mOsM. If necessary, the osmotic pressure can be adjusted by using appropriate amounts of physiologically and ophthalmically acceptable salts or excipients. 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 composition, are typically used. 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, bisulfate, sodium bisulfate, ammonium sulfate, and the like can also be used in addition to or instead of sodium chloride to achieve osmolalities within the above-stated range. Similarly, a sugar such as mannitol, dextrose, sorbitol, glucose and the like can also be used to adjust osmolality.

A preferred form of the present invention provides achieving a sufficiently high tissue concentration with a minimum of doses so that a simple dosing regimen can be used : to treat or prevent bacterial or parasitic infections. To this end, a preferred technique involves forming or supplying a depot of oxazolidinone antibiotic in contact with the . external surface of the eye. A depot refers to a source of oxazolidinone antibiotic that is not rapidly removed by tears or other eye clearance mechanisms. This allows for continued, sustained high concentrations of oxazolidinone antibiotic to be present in the fluid on the external surface of the eye by a single application. In general, it is believed that absorption and penetration are dependent on both the dissolved drug concentration and the contact duration of the external tissue with the drug-containing fluid. As the drug is removed by clearance of the ocular fluid and/or absorption into the eye tissue, more drug is provided, e.g. dissolved, into the replenished ocular fluid from the depot.

A depot can take a variety of forms so long as the oxazolidinone antibiotic can be provided in sufficient concentration levels therein and is releasable therefrom and that the depot is not readily removed from the eye. A depot generally remains for at least about 30 minutes after administration, preferably at least 2 hours and more preferably at least 4 hours. The term “remains” means that neither the depot composition nor the 17

SUBSTITUTE SHEET (RULE 26)

, “ oxazolidinone antibiotic is exhausted or cleared from the surface of the eye prior to the indicated time. In some embodiments, the depot can remain for up to eight hours or more.

Typical ophthalmic depot forms include aqueous polymeric suspensions, ointments, and solid inserts.

Ointments are well known ophthalmic compositions and are essentially an oil- based delivery vehicle. Typical ointments use a petroleum and/or lanolin base to which is added the active ingredient, usually as 0.1 to 2%, and excipients. Common bases include mineral oil, petrolatum and combinations thereof, but oil bases are not limited thereto. An ointment is usually applied as a ribbon onto the lower eye lid. The disadvantage of ointments is that they are difficult to administer, are messy, and uncomfortable/inconvenient to the patient; i.e. temporarily blurred vision is common.

Inserts are another well known ophthalmic dosage form and are comprised of a matrix containing the active ingredient. The matrix is typically a polymer and the active ingredient is generally dispersed therein or bonded to the polymer matrix. The active ingredient is slowly released from the matrix through dissolution or hydrolysis of the covalent bond, etc. In some embodiments, the polymer is bioerodible (soluble) and the dissolution rate thereof can control the release rate of the active ingredient dispersed ’ therein. In another form, the polymer matrix is a biodegradable polymer that breaks down such as by hydrolysis to thereby release the active ingredient bonded thereto or dispersed : therein. The matrix and active ingredient can be surrounded with a polymeric coating such as in the sandwich structure of matrix/matrix+active/matrix, to further control release as is well known in the art. The kinds of polymers suitable for use as a matrix are well known in the art. The oxazolidinone antibiotic can be dispersed into the matrix material or dispersed amongst the monomer composition used to make the matrix material prior to polymerization. The amount of oxazolidinone antibiotic is generally from about 0.1 to 50%, more typically about 2 to 20%. The insert can be placed, depending on the location and the mechanism used to hold the insert in position, by either the patient or the doctor and is generally located under the upper eye lid. A variety of shapes and anchoring configurations, if any, are well known in the art. Preferably a biodegradable or bioerodible polymer matrix is used so that the spent insert does not have to be removed.

As the biodegradable or bioerodible polymer is degraded, dissolved, or eroded, the trapped oxazolidinone antibiotic is released. Although inserts can provide long term release and 18

SUBSTITUTE SHEET (RULE 26)

hence only a single application of the insert may be necessary, they are generally difficult to insert and are uncomfortable to the patient.

The preferred form is an aqueous polymeric suspension. Here, at least one of the oxazolidinone antibiotic or the polymeric suspending agent is suspended in an aqueous medium having the properties as described above. Typically the oxazolidinone antibiotic is in solution, although it is possible for the oxazolidinone antibiotic to be in suspension or both in solution and in suspension in significant amounts generally no less than 5% in either phase (weak to moderate water solubility and relatively high total concentrations).

The polymeric suspending agent is preferably a suspension (i.e. water insoluble and/or water swellable), although water soluble suspending agents are also suitable for use with a suspension of the oxazolidinone antibiotic. The suspending agent serves to provide stability to the composition and to increase the residence time of the dosage form on the eye. It can also enhance the sustained release of the drug in terms of both longer release times and a more uniform release curve.

Examples of polymeric suspending agents include dextrans, polyethylene glycols, polyvinylpyrrolidone, polysaccharide gels, Gelrite®, cellulosic polymers like hydroxypropyl methylcellulose, and carboxy-containing polymers such as polymers or copolymers of acrylic acid, as well as other polymeric demulcents. A preferred polymeric ’ suspending agent is a water swellable, water insoluble polymer, especially a crosslinked carboxy-containing polymer. :

Crosslinked carboxy-containing polymers used in practicing this invention are, in general, well known in the art. In a preferred embodiment such polymers may be prepared from at least about 90% and preferably from about 95% to about 99.9% by weight, based on the total weight of monomers present, of one or more carboxy-containing monoethylenically unsaturated monomers (also occasionally referred to herein as carboxy- vinyl polymers). Acrylic acid is the preferred carboxy-containing monoethylenically unsaturated monomer, but other unsaturated, polymerizable carboxy-containing monomers, such as methacrylic acid, ethacrylic acid, B-methylacrylic acid (crotonic acid), cis-a-methylcrotonic acid (angelic acid), trans-a-methylcrotonic acid (tiglic acid), a- butylcrotonic acid, a-phenylacrylic acid, a-benzylacrylic acid, a-cyclohexylacrylic acid,

B-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. 19

SUBSTITUTE SHEET (RULE 26)

Such polymers may be crosslinked by a polyfunctional crosslinking agent, preferably a difunctional crosslinking agent. The amount of crosslinking should be sufficient to form insoluble polymer particles, but not so great as to unduly interfere with sustained release of the oxazolidinone antibiotic. Typically the polymers are only lightly crosslinked. Preferably the crosslinking agent is contained in an amount of from about 0.01% to about 5%, preferably from about 0.1% to about 5.0%, and more preferably from about 0.2% to about 1%, based on the total weight of monomers present. Included among such crosslinking agents are non-polyalkenyl polyether difunctional crosslinking monomers such as divinyl glycol; 2,3-dihydroxyhexa-1,5-diene; 2,5-dimethyl-1,5- hexadiene; divinylbenzene; N,N-diallylacrylamide; N,N-diallymethacrylamide and the like. Also included are polyalkenyl polyether crosslinking agents containing two or more alkenyl ether groupings per molecule, preferably alkenyl ether groupings containing terminal H;C=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, the entire contents of which are incorporated herein by reference. 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-hydroxyalkyl acrylate or methacrylate 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, the entire contents of each Patent being incorporated herein by reference.

The crosslinked carboxy-vinyl polymers may be made from a carboxy-vinyl monomer or monomers as the sole monoethylenically unsaturated monomer present, together with a crosslinking agent or agents. Preferably the polymers are ones in which up to about 40%, and preferably from about 0% to about 20% by weight, of the carboxy- containing monoethylenically unsaturated monomer or monomers has been replaced by one or more non-carboxyl-containing monoethylenically unsaturated monomer or monomers containing only physiologically and ophthalmically innocuous substituents, including 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

SUBSTITUTE SHEET (RULE 26)

Claims (54)

4 ~ - CLAIMS

1. An aqueous polymeric suspension comprising water, 0.05% to 5.0% of an oxazolidinone antibiotic, and 0.1 to 10% of a polymeric suspending agent, wherein said polymeric suspending agent comprises a water-swellable water-insoluble crosslinked carboxy-vinyl polymer.

2. The suspension of claim 1, wherein said suspension comprises 0.1% to

2.0% of said oxazolidinone antibiotic and 0.5% to 6.5% of said polymeric suspending agent.

3. The suspension of claim 1, wherein said polymeric suspending agent further comprises at least 90% acrylic acid monomers and 0.1% to 5% crosslinking agent.

4. The suspension of claim 3, wherein said crosslinking agent comprises a difunctional crosslinking agent.

5. The suspension of claim 4, wherein said crosslinking agent is selected from . the group consisting of divinyl glycol, 2,3-dihydroxyhexa-1,5-diene, 2,5-dimethyl-1,5- hexadiene, divinylbenzene, N,N-diallylacrylamide, N,N-diallylmethacrylamide, and mixtures thereof.

© 6. The suspension of claim 4, wherein said crosslinking agent is selected from the group consisting of 2,3-dihydroxyhexa-1,5-diene and 2,3-dimethylhexa-1,5-diene.

7. The suspension of claim 1, wherein said polymeric suspending agent further comprises a polycarbophil.

8. The suspension of claim 7, wherein said suspension comprises 0.5% to

1.0% of said polycarbophil.

9. The suspension of claim 1, further comprising an additional medicament.

10. The suspension of claim 9, wherein said additional medicament is selected from the group consisting of antibiotics, antivirals, antifungals, anesthetics, anti- inflammatory agents, and anti-allergic agents. 28 SUBSTITUTE SHEET (RULE 26) }

11. The suspension of claim 10, wherein said additional medicament is about

0.01% to about 5.0% of said suspension.

12. The suspension of claim 1, wherein said polymeric suspending agent has a monodisperse particle size distribution.

13. An aqueous polymeric suspension comprising water, 0.05% to 5.0% of an oxazolidinone antibiotic, and 0.1 to 10% of a polymeric suspending agent, wherein said polymeric suspending agent comprises a polycarbophil.

14. The suspension of claim 13, wherein said suspension comprises 0.1% to

2.0% of said oxazolidinone antibiotic and 0.5% to 6.5% of said polycarbophil.

15. The suspension of claim 14, wherein said suspension comprises 0.6% to

0.8% of said polycarbophil.

16. The suspension of claim 13, wherein said polymeric suspending agent has a monodisperse particle size distribution.

17. The suspension of claim 13, further comprising an additional medicament.

18. The suspension of claim 17, wherein said additional medicament is selected from the group consisting of antibiotics, antivirals, antifungals, anesthetics, anti- inflammatory agents, and anti-allergic agents.

19. The suspension of claim 18, wherein said additional medicament is about

0.01% to about 5.0% of said suspension.

20. The suspension of claim 13, further comprising 0.1% to 5% difunctional crosslinking agent.

21. The suspension of claim 20, wherein said crosslinking agent is selected from the group consisting of divinyl glycol, 2,3-dihydroxyhexa-1,5-diene, 2,5-dimethyl- 1,5-hexadiene, divinylbenzene, N,N-diallylacrylamide, N,N-diallylmethacrylamide, and mixtures thereof. 29 SUBSTITUTE SHEET (RULE 26)

LIER

22. The suspension of claim 20, wherein said crosslinking agent is selected from the group consisting of 2,3-dihydroxyhexa-1,5-diene and 2,3-dimethylhexa-1,5- diene.

23. A composition comprising water, a polymeric suspending agent, and a compound of formula IV: 0 7 A Q Q N N O C \/ {neg F H

Iv.

24. The composition of claim 23, wherein said composition comprises 0.1 to

5.0% of said compound of formula IV.

25. The composition of claim 23, wherein said composition comprises 0.2 to

4.0% of said compound of formula IV.

26. The composition of claim 23, further comprising a difunctional crosslinking agent.

27. The composition of claim 26, wherein said crosslinking agent is selected from the group consisting of divinyl glycol, 2,3-dihydroxyhexa-1,5-diene, 2,5-dimethyl- 1,5-hexadiene, divinylbenzene, N,N-diallylacrylamide, N,N-diallylmethacrylamide, and mixtures thereof.

28. The composition of claim 27, wherein said crosslinking agent is selected from the group consisting of 2,3-dihydroxyhexa-1,5-diene and 2,3-dimethylhexa-1,5- diene.

29. The composition of claim 23, further comprising an additional medicament.

30. The composition of claim 29, wherein said additional medicament is selected from the group consisting of antibiotics, antivirals, antifungals, anesthetics, anti- inflammatory agents, and anti-allergic agents. SUBSTITUTE SHEET (RULE 26)

31. The composition of claim 30, wherein said additional medicament comprises about 0.01% to about 5.0% of said composition.

32. The composition of claim 23, wherein said polymeric suspending agent has a monodisperse particle size distribution.

33. The composition of claim 23, wherein said polymeric suspending agent comprises a polycarbophil.

34. The composition of claim 33, wherein said composition comprises 0.5% to

6.5% of said polycarbophil.

35. The composition of claim 34, wherein said composition comprises 0.6% to

0.8% of said polycarbophil.

36. The composition of claim 23, wherein said polymeric suspending agent comprises a water-swellable, water-insoluble crosslinked carboxy-vinyl polymer.

37. The composition of claim 23, wherein said polymeric suspending agent comprises a cellulosic polymer.

38. The composition of claim 23, wherein said polymeric suspending agent comprises at least 90% acrylic acid monomers.

39. A composition comprising water, an oxazolidinone, a polymeric suspending agent, and a solubility enhancer.

40. The composition of claim 39, wherein said suspension comprises 0.1 to

5.0% of a compound of formula IV and wherein said solubility enhancer is a cyclodextrin: 0 /\ A Q 0) N N © C —/ (NCH; F H

Iv. 31 SUBSTITUTE SHEET (RULE 26)

41. The composition of claim 40, wherein said composition comprises 0.2 to

4.0% of said compound of formula IV and 0.1% to 20% of said cyclodextrin, wherein said cyclodextrin is hydroxypropyl-B-cyclodextrin.

42. The composition of claim 40, further comprising a difunctional crosslinking agent.

43. The composition of claim 42, wherein said crosslinking agent is selected from the group consisting of divinyl glycol, 2,3-dihydroxyhexa-1,5-diene, 2,5-dimethyl- 1,5-hexadiene, divinylbenzene, N,N-diallylacrylamide, N,N-diallylmethacrylamide, and mixtures thereof.

44. The composition of claim 43, wherein said crosslinking agent is selected from the group consisting of 2,3-dihydroxyhexa-1,5-diene and 2,3-dimethylhexa-1,5- diene.

45. The composition of claim 40, further comprising an additional medicament.

46. The composition of claim 45, wherein said additional medicament is ‘ selected from the group consisting of antibiotics, antivirals, antifungals, anesthetics, anti- inflammatory agents, and anti-allergic agents.

47. The composition of claim 46, wherein said additional medicament is about

0.01% to about 5.0% of said composition.

48. The composition of claim 40, wherein said polymeric suspending agent has a monodisperse particle size distribution.

49. The composition of claim 40, wherein said polymeric suspending agent comprises a cellulosic polymer.

50. The composition of claim 40, wherein said polymeric suspending agent comprises at least 90% acrylic acid monomers.

51. The composition of claim 39, wherein said solubility enhancer is ethoxylated castor oil. 32 SUBSTITUTE SHEET (RULE 26)

52. The composition of claim 40, wherein said cyclodextrin is an a- cyclodextrin.

53. The composition of claim 40. wherein said cyclodextrin is a 3-cyclodextrin.

54. The composition of claim 40, wherein said cyclodextrin is a y-cyclodextrin. 33 SUBSTITUTE SHEET (RULE 26)