JP2002525326A - Antibiotic composition for treatment of eyes, ears and nose - Google Patents

Abstract

  (57) [Summary] The present invention provides eye, ear and nasal compositions containing a new class of antibiotics, such as moxifloxacin. The composition also preferably contains one or more anti-inflammatory agents. The composition can be used for the treatment of eye, ear and nasal disorders by topically applying the composition to the affected tissue.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION The present invention is directed to topical antibiotic pharmaceutical compositions for treating eye, ear or nasal infections, especially bacterial infections, and by applying these compositions to diseased tissues. It provides a method of treating an eye, ear or nasal infection. The compositions and methods according to the invention are based on the use of a new class of antibiotics. The composition according to the invention can also contain one or more anti-inflammatory drugs. The use of quinolone antibiotics in the treatment of infections represents the current state of the art in the field of ophthalmic pharmaceutical compositions and methods of treatment. As an example, an ophthalmic topical composition containing quinolone ciprofloxacin can be obtained from Alcon Laboratories, Inc.
ILOXAN) (registered trade name) (ciprofloxacin 0.3%) is commercially available under the trade name of Ophthalmic Solution ((Ophthalmic Solution) (ophthalmic solution)). The following quinolones have also been used in ophthalmic antibiotic compositions:

[0002] The quinolone products manufacturer ofloxacin Ok Phlox (registered trade name) Allergan (Ofloxacin) (OCUFLOX) (Allergan ) norfloxacin Chiburokishin (registered trade name) Merck (Norfloxacin) (CHIBROXIN) (Merck ) lomefloxacin Lome Phlox (registered trade name) Sengju (Lomefloxacin) (LOMEFLOX) (Senju)

[0003] The above quinolone antibiotic compositions are generally effective in treating ocular infections, and conventional ophthalmic antibiotic compositions, particularly those having a relatively limited spectrum of antimicrobial activity, such as primarily gram-negative pathogens Neomycin useful against
, Polymyxin B, gentamicin and tobramycin, and bacitracin, gramicidin and erythromycin (e), which are primarily active against gram-positive pathogens.
rythromycin) has particular advantages. However, despite the general effectiveness of currently available ophthalmic quinolone treatments, they are more effective than existing antibiotics against key ocular pathogens and tend to develop less resistance by these pathogens. There is a need for improved compositions and methods of treatment based on the use of certain antibiotics.

[0004] There is a greater need for topical compositions and methods that are effective in treating eye, ear or nasal infections, particularly bacterial infections. The use of oral antibiotics to treat ear infections in children has limited efficacy and creates a significant risk of pathogen resistance to orally administered antibiotics. Eye, ear, or nose infections are often accompanied by inflammation of the infected eye, ear, or nose tissue and possibly surrounding tissue. Similarly, surgical procedures for the eye, ear, or nose also often pose a risk for microbial infection, causing inflammation of the affected tissue. Therefore,
Ophthalmic, otic or nasal pharmaceutical compositions wherein one or more antibiotics are combined in a single composition with one or more steroidal or non-steroidal anti-inflammatory active agents Is required.

SUMMARY OF THE INVENTION [0005] The present invention relates to the use of a powerful new class of antibiotics to treat eye, ear or nasal infections, and the use of surgical or other trauma to eye, ear or nasal tissue. It is later based on the prophylactic use of these antibiotics. The composition according to the present invention can also be administered to the affected tissue during surgical treatment of eye, ear or nasal tissue, thereby preventing or reducing post-operative infection. The composition also preferably contains one or more anti-inflammatory drugs to treat inflammation associated with infection of the eye, ear or nasal tissue. The anti-inflammatory component of the present compositions is also useful in treating inflammation associated with physical trauma to eye, ear or nasal tissue, including inflammation resulting from surgical procedures. Accordingly, the compositions according to the present invention are particularly useful for the treatment of inflammation associated with a trauma to the eye, ear or nasal tissue, which is infected or may be infected by this trauma.

[0006] Examples of ophthalmic conditions that can be treated by the compositions according to the present invention include conjunctivitis, keratitis, blepharitis, lacrimal inflammation, stye and corneal ulcer. The compositions according to the invention can also be used prophylactically in connection with various ophthalmic surgical procedures where the risk of infection occurs. Examples of otic conditions that can be treated by the composition according to the present invention include otitis externa and otitis media. In connection with the treatment of otitis media, the compositions according to the invention are mainly useful if the eardrum has ruptured or if a tympanic puncture tube has been implanted. The compositions can also be used to treat infections associated with otic surgery, such as myringotomy, or to prevent such infections. The compositions according to the invention are specially formulated for topical application to the eye, ear and nasal tissues. The composition is preferably sterile and includes a weakened tissue in the eye,
Physical properties particularly suitable for application to ear and nasal tissues (eg, osmotic pressure and p
H).

DETAILED DESCRIPTION OF THE INVENTION The antibiotics used in the compositions and methods of the present invention are compounds having the formula: or pharmaceutically useful salts thereof.

Wherein R 1 is 1 selected from the group consisting of C 1 -C 6 alkyl and halogen atoms
Cyclopropyl optionally substituted by 1 to 3 substituents; phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of C1 to C6 alkoxy, halogen atom and hydroxy; halogen atom, C2 C1-C6 alkyl optionally substituted by -C6 alkanoyloxy or hydroxy;
R2 is a C1-C6 alkyl group, a C1-C6 alkanoyl group, a phenyl (C1
-C6) having 1 to 3 substituents selected from the group consisting of an alkyl group, and a 2-oxo-1,3-dioxolenmethyl group optionally substituted by a phenyl group or a C1 to C6 alkyl group; Optionally a 1-piperazinyl group; C1 to C
An amino group optionally having 1 to 2 substituents selected from the group consisting of a 6 alkyl group and a (C1 to C6) alkoxy-carbonyl group;
An amino (C1-C6) alkyl group and a C1-C6 alkyl group which may have 1-2 substituent (s) selected from the group consisting of a C1-C6 alkyl group and a (C1-C6) alkoxy-carbonyl group; A monophorino group optionally having 1 to 3 substituents selected from the group consisting of: a C1 to C6 alkyl group, a hydroxy, a halogen atom and an oxo group; A 1-piperidinyl group which may be possessed; and a member selected from a 1,4-diazobicyclo [4.3.0] nonan-4-yl group; R3 is a C1-C6 alkyl; X is a hydrogen atom or C1-C6 alkyl, and X is a halogen atom.

[0009] The compound Grepafloxacin is most preferred. Grepafloxacin has the following structure:

A more detailed description of the structure, preparation and physical properties of grepafloxacin and other compounds of formula (I) can be found in US Pat. No. 5,563,138.
No. has been provided. The concentration of the antibiotic of formula (I) in the composition of the invention will depend on the intended use of the composition (eg, to treat pre-existing inflammation or prevent post-surgical infection) and choice. It depends on the relevant antimicrobial activity of the particular antibiotic given. Antimicrobial activity of antibiotics is generally expressed as the minimum concentration required to inhibit the growth of a particular pathogen. This concentration is also referred to as "minimum inhibitory concentration" or "MIC". The term "MIC90" refers to ninety percent (9
0%) represents the minimum concentration of antibiotic required to inhibit growth. The concentration of antibiotic required to kill a particular bacterium globally is called the "minimum bactericidal concentration" or "
MBC ". The following table shows the minimum inhibitory concentrations of grepafloxacin against several bacteria commonly associated with eye, ear and nasal infections:

Microbial MIC ₉₀ S. aureus / methicillin sensitivity 0.13 S. aureus / methicillin resistance 0.13 S. aureus / quinolone resistance 0.13 S. epidermidis / methicillin 13 Susceptibility S. epidermidis / methicillin resistance 0.13 S. pneumoniae / penicillin 0.25 Susceptibility S. pneumoniae / penicillin resistance 0.25 P. aeruginosa 8.0 H. influenzae H. influenzae) / 0.008 β-lactamase positive H. influenzae / β-lactamase 0.008 negative

The concentrations are all expressed in micrograms / milliliter (“mcg / ml”). Suitable antibiotic concentrations for ophthalmic compositions are generally selected antibiotic (s) against Gram-negative and Gram-positive organisms usually associated with ocular infections
Concentration of one or more antibiotics of formula (I) in an amount sufficient to impart a concentration equal to or greater than the MIC90 level of the eye to aqueous humor and tears of the eye. It is. Suitable concentrations for otic and nasal compositions are generally equal to the MIC90 level of the selected antibiotic (s) for Gram-negative and Gram-positive organisms usually associated with otic or nasal infections. Or an amount of one or two sufficient to impart a concentration above this level to the infected tissue.
The concentration of one or more antibiotics of the formula (I). In the present specification, such an amount is represented by the term “antimicrobial effective amount”. Compositions of the invention typically comprise 1
One or more compounds of formula (I) are used in an amount of from about 0.1 to about 1.
It is contained at a concentration of 0 weight percent ("wt%").

[0013] The compositions of the present invention may also contain one or more anti-inflammatory agents. The anti-inflammatory drugs used in the present invention are broadly classified as steroids or non-steroids. Preferred steroidal anti-inflammatory drugs are glucocorticoids (glucocorticoids).
oids). Glucocorticoids suitable for the eye and ear include dexamethasone (dexamethaso
ne), lotepredonol, rimexolone, prednisolone, fluorometholone and hydrocortisone. Glucocorticoids suitable for the nose include mometasone (mometasone), fluticasone (fluticasone), beclomethasone (b
eclomethasone), flunisolide (flunisolide), triamcinolone (triamcinolo)
ne) and budesonide.

The dexamethasone derivatives described in US Pat. No. 5,223,493 (Boltralik) are also suitable steroidal anti-inflammatory drugs, especially for compositions for the treatment of ocular inflammation. The following compounds are particularly preferred:

In the present specification, these compounds are represented by the term “21-ether derivative of dexamethasone”. 21-benzyl ether derivative (ie, compound AL
-2512) is particularly preferred. Suitable non-steroidal anti-inflammatory drugs include prostaglandine H synthase inhibitors (CoxI or CoxII) referred to as cyclooxygenase type I and type II inhibitors [eg, diclofenac,
Flurbiprofen, ketorolac, suprofen
(suprofen), nepafenac (nepafenac), amfenac (amfenac), indomethacin (indomethacin), naproxen (naproxen), ibuprofen (ibuprofen)
), Bromfenac, ketoprofen, meclofenamate, piroxicam, salindac
c), mefanamic acid, diflusinal, oxaprozin, tolmetin, fenoprofen (fenoprofen), benoxaprofen (benoxaprofen), nabumetome, etodolac (eto
dolac), phenylbutazone, phenylbutazone, aspirin, oxyphenbutazone, NCX-4016, HCT-1026, NCX-284, NCX-456,
Tenoxicam and caprofen];

[0016] Cyclooxygenase type II selective inhibitors [eg, NS-398, bios (vioxx
), Celecoxib, P54, etodolac, L-804600, and S-3351]; PAF antagonists [eg, SR-27417, A-137491, ABT-299, apafant, bepafant] , Minopafant, E-61
23, BN-50727, nupafant and modipafant];
PDE IV inhibitors [eg ariflo, torbafyllin
e), rolipram, filaminast, picramilast (pic
lamilast), cipamfylline, CG-1088, V-11294A, CT-2820,
PD-168787, CP-293121, DWP-205297, CP-220629, SH-636, BAY-19-8004 and roflumilast]; an inhibitor of cytokin production [for example, NFk]
B transcription factor inhibitors]; or other anti-inflammatory agents known to those skilled in the art.

[0017] The concentration of the anti-inflammatory agent contained in the composition of the present invention will vary based on the agent or agents selected and the type of inflammation being treated. This concentration is sufficient to reduce inflammation in the target eye, ear or nasal tissues after topical application of the composition to those tissues. Such an amount is referred to herein as an "anti-inflammatory effective amount."
Compositions according to the present invention typically comprise one or more anti-inflammatory agents at about 0.01
To about 1.0 wt%. The compositions are typically prepared by topical application of 1 to 4 drops of a sterile solution or suspension, or an equivalent amount of an ointment, gel or other solid or semi-solid formulation, 1 to 4 times a day. Administered to the affected eye, ear or nasal tissue. However, the composition may also be formulated as a wash solution applied to the affected eye, ear or nasal tissue during the surgical procedure.

The ophthalmic, otic or nasal composition according to the invention comprises one or more compounds of the formula (I) and preferably one or more anti-inflammatory drugs, which are pharmaceutically acceptable. To be contained in the vehicle. The composition typically has a pH in the range of 4.5-8.0. Ophthalmic compositions must also be formulated to have an osmotic pressure value corresponding to the aqueous humor and ocular tissue of the eye. Such osmotic pressure values are generally about 200
To about 400 mOsm / kg ("mOsm / kg"), but preferably about 300 mOsm / kg. Ophthalmic, otic or nasal pharmaceutical formulations are typically packaged in multi-dose form. Therefore, a preservative is required to prevent microbial contamination during use. Suitable preservatives include polyquaternium-1 and benzalkonium chloride (b
enzalkonium chloride), thimerosal, chlorobutanol
obutanol), methyl paraben, propyl parben
aben), phenylethyl alcohol, edetate disodium
) Or other preservatives known to those skilled in the art. It is preferred to use polyquatermium-1 as an antimicrobial preservative. Typically, such preservatives are used at a level of from 0.001% to 1.0% by weight.

The solubility of the components of the composition according to the invention can be enhanced by a surfactant or other suitable co-solvent in the composition. Such co-solvents include polysorbate-20, 60 and 80, polyoxyethylene / polyoxypropylene surfactants [eg, Pluronic F-68, F-84 and P-103], cycloalkyl Dextrins or other surfactants known to those skilled in the art are included. Typically, such co-solvents are used at levels of 0.01% to 2% by weight. To obtain a composition according to the invention having a viscosity greater than that of a simple aqueous solution, a viscosity enhancer is used to increase the ocular absorption of the active compound by the target tissue or to increase the retention time in the eye, ear or nose. It is desirable to increase. Such viscosity enhancers include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, or other auxiliaries known to those skilled in the art. Such auxiliaries are typically used at a level of from 0.01% to 2% by weight.

The following examples are provided to further illustrate eye, ear, or nasal compositions according to the present invention. Example 1 Eye / ear / nose solution component amount (wt%) grepafoxacin 0.35 sodium acetate 0.03 acetic acid 0.04 mannitol 4.60 EDTA 0.05 benzalkonium chloride 0.006 water Suitable amount to

Example 2 Eye / Ear / Nasal Suspension Ingredients (wt%) Grepafloxacin 0.3 Dexamethasone, finely ground USP 0.10 Benzalkonium chloride 0.01 Edetate disodium, USP 0.01 Sodium chloride, USP 0.3 Sodium sulfate, USP 1.2 Tyloxapol, USP 0.05 (Tyloxapol) hydroxyethylcellulose 0.25 Sulfuric acid and / or sodium hydroxide, NF Adjusting pH to 5.5 Purified water, USP Suitable amount to make the total amount 100

Example 3 Ophthalmic ointment component (wt%) Grepafloxacin 0.35 Mineral oil, USP 2.0 White petrolatum, USP Suitable amount to make the total amount 100 (White petrolatium)

Example 4 Ophthalmic ointment component (wt%) Grepafloxacin 0.3 Fluorometholone acetate, USP 0.1 (Fluorometholone) chlorobutanol, anhydrous, NF 0.5 Mineral oil, USP 5 White petrolatum, USP Suitable amount to make the total amount 100

The present invention has been described herein with reference to certain preferred embodiments. However, since these obvious modifications will be apparent to those skilled in the art, the present invention should not be deemed to be limited thereto.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) // C07D 401/04 C07D 401/04 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), AU, BR, CA, JP, MX, US (72) Inventor Stroman, David, AW United States Texas, Irving, Waterford 2603 (72) Inventor Yannni, John, M United States Texas, Burleson, Donnybrook Drive 2821 F-term (reference) 4C063 AA01 BB06 CC34 DD14 EE01 4C086 AA01 AA02 BC29 BC50 DA06 DA10 DA50 GA07 GA12 MA01 MA02 MA04 MA17 MA21 MA28 MA34 MA58 MA59 NA05 ZA33 ZA34 ZB11 ZB 35

Claims (10)

[Claims] 1. An eye, ear and nose containing an antimicrobial effective amount of one or more compounds of formula I, their pharmaceutically effective salts, and a pharmaceutically acceptable vehicle. Topical pharmaceutical composition for: Wherein R1 is 1 selected from the group consisting of C1-C6 alkyl and halogen atoms.
Cyclopropyl optionally substituted by 1 to 3 substituents; phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of C1 to C6 alkoxy, halogen atom and hydroxy; halogen atom, C2 C1-C6 alkyl optionally substituted by -C6 alkanoyloxy or hydroxy;
R2 is a C1-C6 alkyl group, a C1-C6 alkanoyl group, a phenyl (C1
To C6) an alkyl group and 1 to 3 substituents selected from the group consisting of a 2-oxo-1,3-dioxolenmethyl group which may be substituted by a phenyl group or a C1 to C6 alkyl group. 1-piperazinyl group which may be substituted;
An amino group optionally having 1 to 2 substituents selected from the group consisting of a 6 alkyl group and a (C1-C6) alkoxy-carbonyl group;
An amino (C1-C6) alkyl group optionally having 1-2 substituents selected from the group consisting of a C1-C6 alkyl group and a (C1-C6) alkoxy-carbonyl group; and a C1-C6 alkyl group. 1-pyrrolidinyl group optionally having 1 to 3 substituents selected from the group consisting of: a morpholino group optionally having 1 to 3 substituents of a C1 to C6 alkyl group; C1 to C6 alkyl A 1-piperidinyl group optionally having 1 to 3 substituents selected from the group consisting of a group, hydroxy, a halogen atom and an oxo group; and 1,4-diazobicyclo [4.3.0] nonane- A member selected from the group consisting of a 4-yl group, R3 is C1-C6 alkyl, R is a hydrogen atom or C1-C6 alkyl, and X is a halogen atom. 2. The topical composition according to claim 1, wherein the composition further comprises an anti-inflammatory effective amount of a steroidal or non-steroidal anti-inflammatory drug. 3. The topical composition according to claim 2, wherein the anti-inflammatory drug comprises a glucocorticoid. 4. Glucocorticoid is dexamethasone, dexamethasone,
Rimexolone, prednisolone, fluorometholone
(fluorometholone), hydrocortisone (hydrocortisone), mometasone (momet
asone), fluticasone (fluticasone), beclomethasone (beclomethasone), flunisolide (flunisolide), triamcinolone (triamcinolone) and budesonide
4. The topical composition according to claim 3, wherein the composition is selected from the group consisting of (budesonide). 5. The method of claim 2, wherein the anti-inflammatory drug comprises a non-steroidal drug selected from the group consisting of prostaglandin H, synthase inhibitors, PAF antagonists and PDE IV inhibitors. A topical composition as described. 6. The compound of formula I is grepafloxacin.
2. The topical composition according to claim 1, comprising cin). 7. The topical composition according to claim 6, wherein the composition further comprises an anti-inflammatory effective amount of a steroidal or non-steroidal anti-inflammatory drug. 8. A method for treating or preventing an ocular, ear or nasal infection, comprising topically applying a therapeutically effective amount of the composition of claim 1 to the affected eye, ear or nasal tissue. The above method, comprising: 9. A method for treating or preventing eye, ear or nasal infections and predicted infections, comprising administering a therapeutically effective amount of the composition of claim 2 to an eye, ear or nasal tissue affected. A method as described above comprising topical application to a subject. 10. A method for treating or preventing ocular, ear or nasal infections and anticipated infections, comprising administering a therapeutically effective amount of the composition of claim 7 to an affected eye, ear or nasal tissue. A method as described above comprising topical application to a subject.