WO2006059221A2

WO2006059221A2 - Topical hydro-alcoholic formulations of oxazolidinone antibacterial agents

Info

Publication number: WO2006059221A2
Application number: PCT/IB2005/003639
Authority: WO
Inventors: Lorraine E. Pena; Pamela J. Secreast
Original assignee: Pharmacia & Upjohn Company Llc
Priority date: 2004-12-03
Filing date: 2005-11-23
Publication date: 2006-06-08
Also published as: WO2006059221A3

Abstract

The present invention is directed to a hydro-alcoholic formulation suitable for topical administration comprising an oxazolidinone antibacterial agent, such as linezolid, dissolved in a solution comprising water and a monohydric non-aromatic alcohol of one to seven carbon atoms, such as ethanol or isopropanol, wherein the oxazolidinone antibacterial agent is present at a concentration at least 1.5 times the equilibrium solubility of the oxazolidinone antibacterial agent in water. Formulations of the present invention enable one to topically administer a high concentration of an oxazolidinone antibacterial agent to a subject, in solubilized form.

Description

TOPICAL HYDRO-ALCOHOLIC FORMULATIONS OF OXAZOLIDINONE

ANTIBACTERIAL AGENTS

FIELD OF THE INVENTION

[0001] The present invention relates to hydro-alcoholic formulations of oxazolidinone antibacterial agents suitable for topical administration, wherein the oxazolidinone antibacterial agents are solubilized in the formulations. The invention, more specifically, relates to liquid formulations of oxazolidinone compounds in a mixture of water and a low molecular weight monohydric non-aromatic alcohol, and to compositions and methods of using the same for treatment and prevention of bacterial infection.

BACKGROUND

[0002] Numerous oxazolidinone compounds have been reported as being useful antibacterial agents. U.S. Patent No. 5,688,792 (Barbachyn et al.) discloses one set of such oxazolidinone antibacterial agents, including (S)-N-[[3-[3-fluoro-4-(4- morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, referred to herein as

«

"linezolid." Treatment of infections by administration to the skin of a mammal of a pharmaceutical formulation of an oxazolidinone antibacterial agent in the form of a solution, suspension, or emulsion is disclosed in WO 03/030906 (PHARMACIA & UPJOHN COMPANY). Treatment of eye infections with an oxazolidinone antibacterial agent is disclosed in WO 00/03710 (PHARMACIA & UPJOHN COMPANY). [0003] High concentration, low volume solutions of antibacterial agents are needed to ensure the efficacy of topical formulations. However, oxazolidinone antibacterial agents tend to be only sparingly soluble in common solvents used in topical formulations, such as water or alcohol. Cyclodextrins have been used as solubility enhancers to produce high concentration aqueous formulations of oxazolidinone antibacterial agents. See, for example, US Pat No 6,551,584 (Bandyopadhyay et al); and WO 02/15940, WO 03/07275, and WO 02/15940 (all PHARMACIA & UPJOHN COMPANY). However, cyclodextrins are costly at the concentrations required to ensure topical delivery of an effective amount of an oxazolidinone, such as linezolid.

[0004] What is needed is a liquid formulation suitable for topical delivery of a biologically effective amount of an oxazolidinone antibacterial agent in a low volume, a formulation which need not include a solubility enhancer, such as a cyclodextrin. BRIEF SUMMARY OF THE INVENTION

[0005] The present invention relates to a hydro-alcoholic formulation of an oxazolidinone, and to a method of treatment of a bacterial infection by topical application of the formulation to a subject.

[0006] The hydro-alcoholic formulation of the present invention comprises an oxazolidinone antibacterial agent dissolved in a solution, comprising water and a monohydric non-aromatic alcohol of one to seven carbon atoms, wherein the oxazolidinone antibacterial agent is present at a concentration at least 1.5 times the equilibrium solubility of the oxazolidinone antibacterial agent in water. In one embodiment, the hydro-alcoholic formulation further comprises a cosmetic oil. [0007] The term "cosmetic," as used herein refers to materials, such as oils, which are noncomedogenic, sebum dissolving, and either evaporate or readily rub into the skin upon application such that a greasy residue does not remain.

[0008] The term "hydro-alcoholic," as used herein, refers to a composition containing a monohydric non-aromatic alcohol and water.

[0009] The term "aromatic alcohol" refers to a hydroxy-containing unsaturated cyclic hydrocarbon containing one or more rings. Examples of aromatic alcohols include phenol and benzyl alcohol.

[0010] The term "monohydric non-aromatic alcohol" refers to a hydroxy-containing organic compound with only one hydroxy group, wherein the organic compound does not include an unsaturated cyclic hydrocarbon. Examples of monohydric non-aromatic alcohols include ethanol, isopropanol, butanol, isoamyl alcohol, and n-propanol. [0011] The term "multihydric alcohol" refers to a hydroxy-containing organic compound with two or more hydroxy groups. Examples of multihydric alcohols include diols, such as glycols; triols, such as glycerol and derivatives; and polyols. [0012] The term "noncomedogenic" refers to materials which do not tend to produce comedones (i.e. blackheads) or aggravate acne, when applied to the skin of a mammal. Comedogenicity can be determined by the standard rabbit ear model described by A.M. Kligman and A.G. Katz, Arch. Der. 98, 53 (1968).

[0013] The term "sebum," as used herein, refers to the semifluid secretion of the sebaceous glands, consisting primarily of fat and cellular debris. [0014] The term "sebum-targeted," as used herein, refers to material which has the capacity to wick into the hair follicle and sebaceous glands of the skin of a mammal when topically applied thereto.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention, in one aspect, is a hydro-alcoholic formulation of an oxazolidinone antibacterial agent. The oxazolidinone antibacterial agent is suitably any one of a number of oxazolidinone compounds having therapeutically and/or prophylactically useful antibiotic activity. Among such compounds are those disclosed in the following patents, each of which is incorporated by reference herein: U.S. Patent No. 5,164,510 (Brickner); U.S. Patent No. 5,231,188 (Brickner); U.S. Patent No. 5,565,571 (Barbachyn et al.)\ U.S. Patent No. 5,627,181 (Riedl et al.); U.S. Patent No. 5,652,238 (Barbachyn et al); U.S. Patent No. 5,688,792 (Barbachyn et al); U.S. Patent No. 5,698,574 (Riedl et al); and U.S. Patent No. 6,069,145 (Betts).

[0016] Oxazolidinone antibacterial agents exhibit antibacterial activity against gram-positive organisms. The oxazolidinone antibacterial agent included in the formulations and used in the methods of the present invention preferably exhibit antibacterial activity against gram-positive organisms of at least one of the following ^•genera:— Staphylococcus— (e_^g.-, - Staphylococcus aureus, Staphylococcus epidermidis), Streptococcus (e.g., Streptococcus viridans, Streptococcus pneumoniae), Enterococcus (e.g., Enterococcus fecalis, Enterococcus faecium), Bacillus, Corynebacterium, Chlamydia and Neisseria. Many such gram-positive organisms have developed significant levels of resistance to other antibiotics. Oxazolidinone antibacterial agents are also generally effective against anaerobic organisms such as those of the genera Bacteroides and Clostridia, and against acid-fast organisms such as those of the genus Mycobacterium. [0017] In one embodiment of the formulation and method of the present invention, the oxazolidinone antibacterial agent is a compound of formula (I), below:

(I) [0018] wherein: [0019] R¹ is selected from (a) H, (b) C_1-8 alkyl optionally substituted with at least one

F, Cl, OH, Ci_-8 alkoxy, and Ci_-8 acyloxy or Ci_-8 benzoxy, including a C_3-6 cycloalkyl group, (c) amino, (d) mono- and di(C_1-8 alkyl)amino and (e) Ci_-8 alkoxy groups;

[0020] R² and R³ are each independently selected from H, F and Cl;

[0021] R⁴ is H or CH₃;

[0022] R⁵ is selected from H, CH₃, CN, CO₂R¹ and (CH₂)_mR⁶, where R¹ is as defined above, R⁶ is selected from H, OH, OR¹, OCOR¹, NHCOR¹, amino, mono- and di(C_1-8 alkyl)amino groups, and m is 1 or 2;

[0023] R⁶ is O or S;

[0024] n is 0, 1 or 2; and

[0025] X is O, S, SO, SO₂, a p-toluenesulfonyl group, SNR⁷ or S(O)NR⁷ where R⁷ is selected from H, Q_-4 alkyl, Ci_-4 alkyl substituted with one or more F, Cl, OH, Ci_-8 alkoxy, amino, C_1-8 mono- or di(Q_-8 alkyl)amino group;

[0026] or a pharmaceutically acceptable salt thereof.

[0027] The oxazolidinone antibacterial drug of Formula I is preferably (5)-N-[[3-[3- fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, referred to herein as "linezolid." Linezolid has the structure shown in formula (I):

[0028] and is in commercial use as a medicament under the trademark Zyvox® of Pharmacia Corporation. Linezolid exhibits strong antibacterial activity against gram- positive organisms of all of the genera of such organisms listed above. [0029] In the formulation of the present invention, the oxazolidinone antibacterial agent is dissolved in a solution comprising water and a monohydric non-aromatic alcohol, wherein the monohydric non-aromatic alcohol is a hydrocarbon comprising one to seven carbon atoms. The seven carbon atoms are suitably linear or branched, and the bonds between carbon atoms can be saturated or unsaturated. The monohydric non-aromatic alcohol is preferably two to four carbons in length. Suitable monohydric non-aromatic alcohols include ethanol, isopropanol, butanol, and n-propanol. The monohydric non- aromatic alcohol is preferably ethanol or isopropanol, more preferably isopropanol. [0030] In one embodiment, the concentration of the oxazolidinone antibacterial agent in the formulation of the present invention is greater than the equilibrium solubility of the drug in water. The oxazolidinone antibacterial agent is preferably present at a concentration of at least 1.5 times, more preferably at least 2 times, more preferably at least 5 times, more preferably at least 10 times, more preferably at least 15 times, or more preferably at least 20 times the equilibrium solubility of the oxazolidinone antibacterial agent in water.

[0031] In another embodiment, the concentration of the oxazolidinone antibacterial agent in the formulation of the present invention is greater than the equilibrium solubility of the drug in alcohol. The concentration of oxazolidinone antibacterial agent is preferably at least 1.5 times, more preferably at least 2 times, even more preferably at least 5 times the equilibrium solubility of the oxazolidinone antibacterial agent in alcohol. [0032] The solubility of linezolid in water is about 2.7 mg/ml. In an embodiment of the formulation of the present invention, when the oxazolidinone antibacterial agent is linezolid, the concentration of linezolid in the formulation is preferably at least 4 mg/ml, more preferably at least 5 mg/ml, more preferably at least 14 mg/ml, more preferably at least 27 mg/ml, even more preferably at least 40 mg/ml.

[0033] The maximum concentration of any oxazolidinone antibacterial agent in a formulation of the present invention depends upon the solubility of the drug in the formulation. Which monohydric non-aromatic alcohol is included in the formulation can affect the solubility of the oxazolidinone in the formulation. For example, linezolid is significantly more soluble in isopropanol than it is in ethanol. When the oxazolidinone antibacterial agent in a formulation of the invention is linezolid and the only monohydric non-aromatic alcohol present in the formulation is ethanol, and no excipients are included which enhance or inhibit the solubility of linezolid in the formulation, the concentration of linezolid can be as high as about 60 mg/ml. When the monohydric non-aromatic alcohol in such a formulation is isopropanol, the concentration of linezolid can be as high as about 75 mg/ml.

[0034] The formulation can, optionally, include excipients which enhance, or even adversely affect the solubility of the oxazolidinone antibacterial agent in the formulation. [0035] In one embodiment, the only solvents in the hydro-alcoholic formulation of the present invention are the monohydric non-aromatic alcohol and water. The concentration of the monohydric non-aromatic alcohol in the formulation is preferably 20% to 90%, more preferably 30% to 90%, more preferably 40% to 90%, even more preferably 50% to 80%, most preferably 60% to 70% by weight.

[0036] In another embodiment, the formulation of the present invention further comprises a cosmetic oil. In this embodiment, the formulation is preferably a sebum- targeted formulation. The cosmetic oil included in this embodiment of the formulation of the present invention is preferably selected from the group consisting of fatty acid triglycerides (e.g. a caprylic/capric triglyceride, such as M3GLYOL^® 812 (Sasol North America, Westwood, NJ), MYRITOL^® 318 (Cognis-Care Chemicals, Cincinnati, OH), and NEOBEE^® M-5 (Stepan Company, Northfield, IL), and caprylic/capric linoleic triglyceride, such as MIGLYOL^® 818 (Sasol North America, Westwood, NJ); mono and diglycerides, such as MWITOR^® 308 and 312 (Sasol North America, Westwood, NJ); hydrogenated coco glycercides such as SOFTISAN^® 100 (Sasol North America, Westwood, NJ); volatile silicones (e.g., cyclomethicone such as Dow Corning Fluids 244, 245, 344, or 345; Union Carbide Volatile Silicone 7158, 7207, or 7349); fatty acid esters (e.g., octyl isononanoate, isononyl isononanoate, propylene glycol ricinoleate, glyceryl triacetyl hydroxystearate, octyl palmitate); propylene glycol caprylate (e.g. IMWITOR^® 408, Sasol North America, Westwood, NJ); propylene glycol dicaprylate/dicaprate (e.g., — MIGLYOL^® 840, Sasol North America,-Westwood, NJ840); propylene glycol dioctanoate or isostearyl neopentanoate; liquid fatty alcohols (e.g., oleyl alcohol); and natural oils (e.g., olive oil or palm oil). Particularly preferred cosmetic oils include fatty acid triglycerides, mono/diglycerides, and propylene glycol caprylate. The cosmetic oil is more preferably propylene glycol caprylate, or a fatty acid triglyceride. When the cosmetic oil is a fatty acid triglyceride, it is preferably a caprylic/capric triglyceride, such as MIGLYOL^® 812. The formulation of the present invention suitably contains a mixture of two or more cosmetic oils. The cosmetic oil preferably facilitates enhanced wicking of the oxazolidinone antibacterial agent into the sebaceous glands, when the formulation is applied to the skin.

[0037] The sebum-targeted formulation of the present invention preferably comprises at least about 0.2%, more preferably at least about 0.5% oxazolidinone antibacterial agent; at least about 40% of the monohydric non-aromatic alcohol; about 1.5% to about 10%, preferably about 1.5% to about 7%, and even more preferably about 2% to about 5% water; and about 20% to about 60% of a cosmetic oil. [0038] In another embodiment, the hydro-alcoholic formulation of the present invention further comprises an additional alcohol in the form of an aromatic alcohol or a multihydric alcohol, wherein the additional alcohol is liquid at room temperature, and suitable for topical application to the skin of a mammal.

[0039] When the additional alcohol is an aromatic alcohol, it is preferably benzyl _. alcohol or phenoxyethanol.

[0040] When the additional alcohol is a multihydric alcohol, it is suitably a non- aromatic diol, triol, or polyol. When the multihydric alcohol is a diol, it is preferably a glycol or a non-aromatic glycol derivative. Suitable glycol derivatives include butylene glycol, polyethylene glycol, propylene glycol, hexylene glycol, dipropylene glycol, hexanediol, or polybutylene glycol. When the multihydric alcohol is a triol, it is suitably 1, 2, 6 hexanetriol. When the multihydric alcohol is a polyol, at least one carbon atom does not have a hydroxyl group bound thereto. Examples of polyols wherein a hydroxyl group is bound to every carbon atom include glycerol and sugars, such as sorbitol. Some ethoxylates of such polyols are, however, suitable for use in the formulations of the present invention, provided they are liquid at room temperature, for example, sorbeth 6, sorbeth 20, sorbeth 30, and sorbeth 40. The multihydric alcohol is preferably propylene glycol, butylene glycol, or polyethylene glycol. The additional alcohol is preferably butylene glycol or propylene glycol, more preferably propylene glycol. [0041] Formulations and methods of the present invention are suitable for use in the treatment of skin infections. Specific types of skin infections that are suitably treated with formulations and methods of the present invention include acne and soft-tissue infections, such as infections caused by staphylococci or streptococci. Soft-tissue infections of the foot are particularly prevalent in individuals with diabetes. Diabetic foot infections are typically treated by oral administration of antibiotics. However, individuals with late stage forms of diabetes tend to have very poor circulation, making delivery of orally administered drugs to infected extremities, such as feet, difficult. Topical delivery of oxazolidinone antibacterial agents through administration of formulations of the present invention to affected areas, such as to a diabetic foot, better ensures treatment of an underlying infection than oral delivery. For a discussion of the advantages of topical delivery of oxazolidinone antibacterial agents in the treatment of acne and diabetic foot, see WO 03/030906.

[0042] The method of the present invention comprises topically administering the formulation of the present invention to a subject. The formulation is administered to the subject in order to treat or prevent a gram-positive bacteria infection. The infection can be due to any gram-positive bacteria; but, is preferably due to an infection by one or more bacteria of a genus selected from the group consisting of: Staphylococcus, Streptococcus, Enterococcus, Bacillus, Corynebacterium, Chlamydia and Neisseria. When the genus is Staphylococcus, the species of bacteria is preferably Staphylococcus aureus or Staphylococcus epidermidis. When the genus is Streptococcus, the species of bacteria is preferably Streptococcus viridans or Streptococcus pneumoniae. When the genus is Enterroruccus, the species is preferably Enterococcus fecalis or Enterococcus faecium. [0043] Treatment of the infection according to the method of the present invention preferably comprises administering a sufficient amount of the oxazolidinone antibacterial drug to the affected area to either kill the gram-positive bacteria present therein and/ or to stop them from growing to a point where the subject's natural defense mechanism can reduce or eradicate the bacteria. Prevention according to the method of the present invention preferably comprises preventing an infection by gram-positive bacteria, or preventing a minor infection of such bacteria from growing into a larger infection. Prevention of infection is a particularly important step in preparing a subject for surgery. [0044] In the method of the present invention, the oxazolidinone antibacterial agent can be used either individually or in combination with another oxazolidinone antibacterial agent, whether both agents are included in the same formulation or administered separately. Further, the oxazolidinone antibacterial agent can be used in combination with other antibacterial agents, whether administered separately or whether both are included in the formulation of the present invention. In addition, the formulation of the present invention can be used with non-antibacterial agents in treating infections, whether the non- antibacterial agents are administered separately or included in the formulation. [0045] The exact dosage and frequency of administration of formulations of the present invention depends upon the particular oxazolidinone antibiotic agent used, the particular condition being treated, the severity of the condition being treated; the age, weight, and general physical condition of the particular patient; and other medication the particular patient may be taking. Such factors are well known to those skilled in the art and can be more accurately determined by the patient's response to the particular treatment administered.

[0046] Formulations of the present invention are preferably formulated for direct application to the skin in the form of a liquid, ointment, foam, or spray. [0047] The present invention is further illustrated by the following examples. These examples are intended to be illustrative of the invention and should not be used to limit or restrict its scope.

EXAMPLES

[0048] The following examples illustrate one or more of the embodiments of the invention described above.

[0049] EXAMPLE 1 - Solubility of Linezolid in Ethanol/Water Mixtures [0050] The equilibrium solubility of linezolid in various co-solvent systems of ethanol and water was determined. The results are shown in Table 1, below. % ethanol and % water amounts in the table are expressed as weight/weight. [0051]

TABLE l

[0052] Linezolid was at least twice as soluble in co-solvent systems with 20 to 90% ' ethanol than in water alone. Linezolid was more soluble in the 70% ethanol/30% water and 60% ethanol/40% water co-solvent systems than in any other system tested. [0053] EXAMPLE 2 - Solubility in Water/Isopropanol Co-Solvent Systems [0054] Linezolid and two other oxazolidinone compounds, N-[[(5S)-3-[-fluoro-4- (tetrahydro- 1 , 1 -dioxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]acedamide ("PNU-141659") and N-[[(5S)-3-[3-fluoro-4-(l-oxido-4- thiomorpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]ethanethioamide ("PNU-177553") were tested to determine their equilibrium solubility in various water/isopropanol co- solvent systems. Results obtained are shown in Table 2, below. %water and %isopropanol in each co-solvent system is expressed in terms of weight/weight. [0055]

TABLE 2

[0056] All three oxazolidinones tested were at least 1.8 times as soluble in co-solvent systems containing 10 to 90% isopropanol than in either isopropanol or water alone. AU three oxazolidinones were more soluble in the 60% isopropanol/40% water co-solvent system than in any other system tested.

[0057] EXAMPLE 3 - Non-Aqueous Sebum-Targeted Linezolid Solutions

[0058] Several attempts were made, with varying success, to prepare a non-aqueous sebum-targeted solution of linezolid, with the following composition: 1% linezolid, 40%

MIGLYOL^® 812 (SASOL North America, Inc., USA), 5% propylene glycol, and 54% isopropanol. The linezolid was completely solubilized in lOOg and 125 g preparations of the solution. However, when an attempt was made to prepare 500 g and two 1.5 Kg batches of the same formulation, linezolid never went into solution after over an hour of mixing. The 500 g preparation was mixed for 14 hours; but, there was still linezolid present in the formulation that had not gone into solution by the end of that period.

[0059] EXAMPLE 4 - Addition of Water to Sebum Targeted Solutions

[0060] An attempt was made to prepare sebum targeted solutions in the same way as described in Example 3, above, but with 1%, 1.5%, or 2% water, as shown in Table 3, below:

[0061]

TABLE 3

[0062] The linezolid did not go into solution in Formula 1 (1% water). The linezolid did not go into solution in Formula 2 (1.5% water) after mixing for about an hour; however, it went into solution after sitting over a weekend at room temperature. Linezolid went into solution in Formula 3 (2% water) within 20 minutes after addition of the final component to the formulation.

[0063] EXAMPLE 5 - In Vivo Testing of Aqueous Sebum Targeted Solutions

[0064] Aqueous Sebum Targeted Solutions were prepared with 2% water and 0%

("placebo" solution), 0.5%, or 1% linezolid, with formulations shown in Table 4, below, and tested in vivo, as described below:

[0065] TABLE 4

[0066] The linezolid solutions and placebo solutions prepared as described in Table 3, above, were applied twice daily to the dorsal skin of hair-deficient female fz/fz "fuzzy" rats. This particular type of rat was selected for use in the study because of the high sensitivity of the skin of such animals to irritation, and because the skin condition is easier to observe than the skin of rats with more hair. The skin of each rat was inspected daily for irritancy (i.e., erythema and edema), and transepidermal water loss ("TEWL"), a measure of water efflux through the skin, which was measured before and after the 4 day treatment regimens. Blood samples were also taken 3 hours after doses 5 and 7 for plasma drug analyses, and terminal skin biopsies were taken for histological examination. [0067] The placebo and linezolid solutions appeared to be well tolerated, without irritation or histological changes, and with slight decreases in TEWL; although, some of the rats administered the 0.5 and 1.0% linezolid solutions had minimal histological changes involving intracellular edema, increased neutrophils, and focal folliculitis. TEWL increased moderately with respect to basal levels for each sebum-targeted solution and was inversely proportional to drug concentration. Plasma concentrations showed low systemic absorption, averaging 0.09 μg/ml for the 0.5% linezolid solution, and 0.12 μg/ml for the 1.0% linezolid solution. Thus, it was found that the two sebum-targeted linezolid solutions tested were well tolerated, with minimal systemic uptake during the four day twice-daily topical application described above, onto the back skin of hair-deficient female fuzzy rats, indicating that such solutions are likely to be suitable for cutaneous administration to humans.

Claims

CLAIMS We claim:

1. A formulation suitable for topical administration comprising: an oxazolidinone antibacterial agent dissolved in a solution comprising water and a monohydric non- aromatic alcohol of one to seven carbon atoms, wherein the oxazolidinone antibacterial agent is present at a concentration at least 1.5 times the equilibrium solubility of the oxazolidinone antibacterial agent in water.

2. The formulation of claim 1, wherein the formulation is effective for treatment or prophylaxis of a gram-positive bacterial infection when topically administered to a subject.

3. The formulation of claim 1 wherein the oxazolidinone antibacterial agent is a compound of formula (I)

(D wherein:

R¹ is selected from (a) H, (b) C_1-8 alkyl optionally substituted with at least one F,

Cl, OH, C_1-8 alkoxy, and C_1-8 acyloxy or C_1-8 benzoxy, including a C_3-6 cycloalkyl group, (c) amino, (d) mono- and di(Ci_-8 alkyl)amino and (e) C_1-8 alkoxy groups;

R² and R³ are each independently selected from H, F and Cl; R⁴ is H or CH₃; R⁵ is selected from H, CH₃, CN, CO₂R¹ and (CH₂)_mR⁶, where R¹ is as defined above, R⁶ is selected from H, OH, OR¹, OCOR¹, NHCOR¹, amino, mono- and di(Ci_-8 alkyl)amino groups, and m is 1 or 2; R⁶ is O or S; n is O, 1 or 2; and X is O, S, SO, SO₂, a p-toluenesulfonyl group, SNR⁷ or S(O)NR⁷ where R⁷ is selected from H, Ci_-4 alkyl, C_1-4 alkyl substituted with one or more F, Cl, OH, C_1-8 alkoxy, amino, C_1-8 mono- or di(C_1-8 alkyl)amino group; or a pharmaceutically acceptable salt thereof.

4. The formulation of claim 3 wherein, R is CH₃; R and R are independently selected from H and F but at least one of R² and R³ is F; R⁴ and R⁵ are each H; n is 1; and X is selected from O, S and SO₂.

5. The formulation of claim 1 wherein the oxazolidinone antibacterial agent is selected from the group consisting of: linezolid;

N-((5S)-3-(3-fluoro-4-(4-(2-fluoroethyl)-3-oxopiperazin-l-yl)phenyl)-2- oxooxazolidin-5-ylmethyl)acetamide;

(5)-N-[[3-[5-(3-pyridyl)thiophen-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide;

(S)-N-[[3-[5-(4-pyridyl)pyrid-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride;

N-[[(55)-3-[4-(l,l-dioxido-4-thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-5- oxazolidinyl]methyl] acetamide;

N-[[(5S)-3-[3-fluoro-4-tetrahydro-l,l-dioxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5- oxazolidinyl]methyl]methyl]acetamide; and

N-[[(5S)-3-[3-fluoro-4-thiomorpholinyl)phenyl]-2oxo-5- oxazolidinyl]methyl]ethanethioamide.

6. The formulation of claim 1 wherein the oxazolidinone antibacterial agent is linezolid, and the concentration of linezolid in the formulation is about 5 mg/ml to about 100 mg/ml.

7. The formulation of claim 1, wherein the monohydric non-aromatic alcohol is selected from the group consisting of ethanol, isopropanol, butanol, and n-propanol.

8. The formulation of claim 1, wherein the formulation comprises at least 40% of the monohydric non-aromatic alcohol and at least 1% water, by weight.

9. The formulation of claim 1, further comprising a cosmetic oil, wherein the cosmetic oil is preferably selected from the group consisting of fatty acid triglycerides, mono/diglycerides, and propylene glycol caprylate. 11.

10. The formulation of claim 9, wherein the formulation contains at least 30% alcohol and about 1.5 % to about 20% water.

11. The formulation of claim 1, further comprising an aromatic alcohol wherein the aromatic alcohol is preferably selected from the group consisting of benzyl alcohol and phenoxyethanol.

12. The formulation of claim 1, further comprising a multihydric alcohol, wherein the multihydric alcohol is preferably selected from the group consisting of propylene glycol, butylene glycol, polyethylene glycol, hexylene glycol, dipropylene glycol, hexanediol, 1,2,6 hexanetriol, polybutylene glycol, and ethoxydiglycol.

13. A method of treatment or prevention of infection by gram-positive bacteria comprising topically administering the formulation of claim 1 to a subject.

14. The method of claim 16, wherein the subject is a mammal, preferably a human being.